Sample records for cell signaling systems

  1. Altered B cell receptor signaling in human systemic lupus erythematosus (United States)

    Jenks, Scott A.; Sanz, Iñaki


    Regulation of B cell receptor signaling is essential for the development of specific immunity while retaining tolerance to self. Systemic lupus erythematosus (SLE) is characterized by a loss of B cell tolerance and the production of anti-self antibodies. Accompanying this break down in tolerance are alterations in B cell receptor signal transduction including elevated induced calcium responses and increased protein phosphorylation. Specific pathways that negatively regulate B cell signaling have been shown to be impaired in some SLE patients. These patients have reduced levels of the kinase Lyn in lipid raft microdomains and this reduction is inversely correlated with increased CD45 in lipid rafts. Function and expression of the inhibitory immunoglobulin receptor FcγRIIB is also reduced in Lupus IgM- CD27+ memory cells. Because the relative contribution of different memory and transitional B cell subsets can be abnormal in SLE patients, we believe studies targeted to well defined B cell subsets will be necessary to further our understanding of signaling abnormalities in SLE. Intracellular flow cytometric analysis of signaling is a useful approach to accomplish this goal. PMID:18723129

  2. Signal transduction in cells of the immune system in microgravity

    Directory of Open Access Journals (Sweden)

    Huber Kathrin


    Full Text Available Abstract Life on Earth developed in the presence and under the constant influence of gravity. Gravity has been present during the entire evolution, from the first organic molecule to mammals and humans. Modern research revealed clearly that gravity is important, probably indispensable for the function of living systems, from unicellular organisms to men. Thus, gravity research is no more or less a fundamental question about the conditions of life on Earth. Since the first space missions and supported thereafter by a multitude of space and ground-based experiments, it is well known that immune cell function is severely suppressed in microgravity, which renders the cells of the immune system an ideal model organism to investigate the influence of gravity on the cellular and molecular level. Here we review the current knowledge about the question, if and how cellular signal transduction depends on the existence of gravity, with special focus on cells of the immune system. Since immune cell function is fundamental to keep the organism under imnological surveillance during the defence against pathogens, to investigate the effects and possible molecular mechanisms of altered gravity is indispensable for long-term space flights to Earth Moon or Mars. Thus, understanding the impact of gravity on cellular functions on Earth will provide not only important informations about the development of life on Earth, but also for therapeutic and preventive strategies to cope successfully with medical problems during space exploration.

  3. Tip cell-derived RTK signaling initiates cell movements in the Drosophila stomatogastric nervous system anlage. (United States)

    González-Gaitán, M; Jäckle, H


    The stomatogastric nervous system (SNS) of Drosophila is a simply organized neural circuitry that innervates the anterior enteric system. Unlike the central and the peripheral nervous systems, the SNS derives from a compact epithelial anlage in which three invagination centers, each giving rise to an invagination fold headed by a tip cell, are generated. Tip cell selection involves lateral inhibition, a process in which Wingless (Wg) activity adjusts the range of Notch signaling. Here we show that RTK signaling mediated by the Drosophila homolog of the epidermal growth factor receptor, DER, plays a key role in two consecutive steps during early SNS development. Like Wg, DER signaling participates in adjusting the range of Notch-dependent lateral inhibition during tip cell selection. Subsequently, tip cells secrete the DER ligand Spitz and trigger local RTK signaling, which initiates morphogenetic movements resulting in the tip cell-directed invaginations within the SNS anlage.

  4. Systems biology. Conditional density-based analysis of T cell signaling in single-cell data. (United States)

    Krishnaswamy, Smita; Spitzer, Matthew H; Mingueneau, Michael; Bendall, Sean C; Litvin, Oren; Stone, Erica; Pe'er, Dana; Nolan, Garry P


    Cellular circuits sense the environment, process signals, and compute decisions using networks of interacting proteins. To model such a system, the abundance of each activated protein species can be described as a stochastic function of the abundance of other proteins. High-dimensional single-cell technologies, such as mass cytometry, offer an opportunity to characterize signaling circuit-wide. However, the challenge of developing and applying computational approaches to interpret such complex data remains. Here, we developed computational methods, based on established statistical concepts, to characterize signaling network relationships by quantifying the strengths of network edges and deriving signaling response functions. In comparing signaling between naïve and antigen-exposed CD4(+) T lymphocytes, we find that although these two cell subtypes had similarly wired networks, naïve cells transmitted more information along a key signaling cascade than did antigen-exposed cells. We validated our characterization on mice lacking the extracellular-regulated mitogen-activated protein kinase (MAPK) ERK2, which showed stronger influence of pERK on pS6 (phosphorylated-ribosomal protein S6), in naïve cells as compared with antigen-exposed cells, as predicted. We demonstrate that by using cell-to-cell variation inherent in single-cell data, we can derive response functions underlying molecular circuits and drive the understanding of how cells process signals.

  5. Engineering cell-cell signaling. (United States)

    Blagovic, Katarina; Gong, Emily S; Milano, Daniel F; Natividad, Robert J; Asthagiri, Anand R


    Juxtacrine cell-cell signaling mediated by the direct interaction of adjoining mammalian cells is arguably the mode of cell communication that is most recalcitrant to engineering. Overcoming this challenge is crucial for progress in biomedical applications, such as tissue engineering, regenerative medicine, immune system engineering and therapeutic design. Here, we describe the significant advances that have been made in developing synthetic platforms (materials and devices) and synthetic cells (cell surface engineering and synthetic gene circuits) to modulate juxtacrine cell-cell signaling. In addition, significant progress has been made in elucidating design rules and strategies to modulate juxtacrine signaling on the basis of quantitative, engineering analysis of the mechanical and regulatory role of juxtacrine signals in the context of other cues and physical constraints in the microenvironment. These advances in engineering juxtacrine signaling lay a strong foundation for an integrative approach to utilize synthetic cells, advanced 'chassis' and predictive modeling to engineer the form and function of living tissues.

  6. Engineering Cell-Cell Signaling


    Blagovic, Katarina; Gong, Emily S.; Milano, Daniel F.; Natividad, Robert J.; Asthagiri, Anand R


    Juxtacrine cell-cell signaling mediated by the direct interaction of adjoining mammalian cells is arguably the mode of cell communication that is most recalcitrant to engineering. Overcoming this challenge is crucial for progress in biomedical applications, such as tissue engineering, regenerative medicine, immune system engineering and therapeutic design. Here, we describe the significant advances that have been made in developing synthetic platforms (materials and devices) and synthetic cel...

  7. Pavement cells: a model system for non-transcriptional auxin signalling and crosstalks. (United States)

    Chen, Jisheng; Wang, Fei; Zheng, Shiqin; Xu, Tongda; Yang, Zhenbiao


    Auxin (indole acetic acid) is a multifunctional phytohormone controlling various developmental patterns, morphogenetic processes, and growth behaviours in plants. The transcription-based pathway activated by the nuclear TRANSPORT INHIBITOR RESISTANT 1/auxin-related F-box auxin receptors is well established, but the long-sought molecular mechanisms of non-transcriptional auxin signalling remained enigmatic until very recently. Along with the establishment of the Arabidopsis leaf epidermal pavement cell (PC) as an exciting and amenable model system in the past decade, we began to gain insight into non-transcriptional auxin signalling. The puzzle-piece shape of PCs forms from intercalated or interdigitated cell growth, requiring local intra- and inter-cellular coordination of lobe and indent formation. Precise coordination of this interdigitated pattern requires auxin and an extracellular auxin sensing system that activates plasma membrane-associated Rho GTPases from plants and subsequent downstream events regulating cytoskeletal reorganization and PIN polarization. Apart from auxin, mechanical stress and cytokinin have been shown to affect PC interdigitation, possibly by interacting with auxin signals. This review focuses upon signalling mechanisms for cell polarity formation in PCs, with an emphasis on non-transcriptional auxin signalling in polarized cell expansion and pattern formation and how different auxin pathways interplay with each other and with other signals.

  8. Mapping membrane protein interactions in cell signaling systems.

    Energy Technology Data Exchange (ETDEWEB)

    Light, Yooli Kim; Hadi, Masood Z.; Lane, Pamela; Jacobsen, Richard B.; Hong, Joohee; Ayson, Marites J.; Wood, Nichole L.; Schoeniger, Joseph S.; Young, Malin M.


    We proposed to apply a chemical cross-linking, mass spectrometry and modeling method called MS3D to the structure determination of the rhodopsin-transducin membrane protein complex (RTC). Herein we describe experimental progress made to adapt the MS3D approach for characterizing membrane protein systems, and computational progress in experimental design, data analysis and protein structure modeling. Over the past three years, we have developed tailored experimental methods for all steps in the MS3D method for rhodopsin, including protein purification, a functional assay, cross-linking, proteolysis and mass spectrometry. In support of the experimental effort. we have out a data analysis pipeline in place that automatically selects the monoisotopic peaks in a mass spectrometric spectrum, assigns them and stores the results in a database. Theoretical calculations using 24 experimentally-derived distance constraints have resulted in a backbone-level model of the activated form of rhodopsin, which is a critical first step towards building a model of the RTC. Cross-linked rhodopsin-transducin complexes have been isolated via gel electrophoresis and further mass spectrometric characterization of the cross-links is underway.

  9. Cell signaling review series

    Institute of Scientific and Technical Information of China (English)

    Aiming Lin; Zhenggang Liu


    @@ Signal transduction is pivotal for many, if not all, fundamental cellular functions including proliferation, differentiation, transformation and programmed cell death. Deregulation of cell signaling may result in certain types of cancers and other human diseases.

  10. Microgravity-induced alterations in signal transduction in cells of the immune system (United States)

    Paulsen, Katrin; Thiel, Cora; Timm, Johanna; Schmidt, Peter M.; Huber, Kathrin; Tauber, Svantje; Hemmersbach, Ruth; Seibt, Dieter; Kroll, Hartmut; Grote, Karl-Heinrich; Zipp, Frauke; Schneider-Stock, Regine; Cogoli, Augusto; Hilliger, Andre; Engelmann, Frank; Ullrich, Oliver


    Since decades it is known that the activity of cells of the immune system is severely dysregulated in microgravity, however, the underlying molecular aspects have not been elucidated yet. The identification of gravity-sensitive molecular mechanisms in cells of the immune system is an important and indispensable prerequisite for the development of counteractive measures to prevent or treat disturbed immune cell function of astronauts during long-term space missions. Moreover, their sensitivity to altered gravity renders immune cells an ideal model system to understand if and how gravity on Earth is required for normal mammalian cell function and signal transduction. We investigated the effect of simulated weightlessness (2D clinostat) and of real microgravity (parabolic flights) on key signal pathways in a human monocytic and a T lymphocyte cell line. We found that cellular responses to microgravity strongly depend on the cell-type and the conditions in which the cells are subjected to microgravity. In Jurkat T cells, enhanced phosphorylation of the MAP kinases ERK-1/2, MEK and p38 and inhibition of nuclear translocation of NF-kB were the predominant responses to simulated weightlessness, in either stimulated or non-stimulated cells. In contrast, non-stimulated monocytic U937 cells responded to simulated weightlessness with enhanced overall tyrosine-phosphorylation and activation of c-jun, whereas PMA-stimulated U937 cells responded the opposite way with reduced tyrosine-phosphorylation and reduced activation of c-jun, compared with PMA-stimulated 1 g controls. P53 protein was phosphorylated rapidly in microgravity. The identification of gravi-sensitive mechanisms in cells of the immune system will not only enable us to understand and prevent the negative effects of long time exposure to microgravity on Astronauts, but could also lead to novel therapeutic targets in general.

  11. IL-9 signaling affects central nervous system resident cells during inflammatory stimuli. (United States)

    Ding, Xiaoli; Cao, Fang; Cui, Langjun; Ciric, Bogoljub; Zhang, Guang-Xian; Rostami, Abdolmohamad


    Interleukin (IL) 9, a dominant cytokine in Th9 cells, has been proven to play a pathogenic role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by augmenting T cell activation and differentiation; however, whether IL-9 signaling affects central nervous system (CNS)-resident cells during CNS autoimmunity remains unknown. In the present study, we found that the IL-9 receptor (IL-9R) was highly expressed in astrocytes, oligodendrocyte progenitor cells (OPCs), oligodendrocytes and microglia cells, and that its expression was significantly upregulated in brain and spinal cord during EAE. In addition, IL-9 increased chemokine expression, including CXCL9, CCL20 and MMP3, in primary astrocytes. Although IL-9 had no effect on the proliferation of microglia cells, it decreased OPC proliferation and differentiation when in combination with other pro-inflammatory cytokines, but not with IFN-γ. IL-9 plus IFN-γ promoted OPC proliferation and differentiation. These findings indicate that CNS-restricted IL-9 signaling may be involved in the pathogenesis of MS/EAE, thus providing a potential therapeutic target for future MS/EAE treatment through disruption of CNS cell-specific IL-9 signaling.

  12. Enzyme- and affinity biomolecule-mediated polymerization systems for biological signal amplification and cell screening. (United States)

    Malinowska, Klara H; Nash, Michael A


    Enzyme-mediated polymerization and polymerization-based signal amplification have emerged as two closely related techniques that are broadly applicable in the nanobio sciences. We review recent progress on polymerization systems mediated by biological molecules (e.g., affinity molecules and enzymes), and highlight newly developed formats and configurations of these systems to perform such tasks as non-instrumented biodetection, synthesis of core-shell nanomaterials, isolation of rare cells, and high-throughput screening. We discuss useful features of biologically mediated polymerization systems, such as multiple mechanisms of amplification (e.g., enzymatic, radical chain propagation), and the ability to localize structures at interfaces and at cell surfaces with microscopic spatial confinement. We close with a perspective on desirable improvements that need to be addressed to adapt these molecular systems to future applications.

  13. BioSig: A bioinformatic system for studying the mechanism of intra-cell signaling

    Energy Technology Data Exchange (ETDEWEB)

    Parvin, B.; Cong, G.; Fontenay, G.; Taylor, J.; Henshall, R.; Barcellos-Hoff, M.H.


    Mapping inter-cell signaling pathways requires an integrated view of experimental and informatic protocols. BioSig provides the foundation of cataloging inter-cell responses as a function of particular conditioning, treatment, staining, etc. for either in vivo or in vitro experiments. This paper outlines the system architecture, a functional data model for representing experimental protocols, algorithms for image analysis, and the required statistical analysis. The architecture provides remote shared operation of an inverted optical microscope, and couples instrument operation with images acquisition and annotation. The information is stored in an object-oriented database. The algorithms extract structural information such as morphology and organization, and map it to functional information such as inter-cellular responses. An example of usage of this system is included.

  14. Interference of cranberry constituents in cell-cell signaling system of Vibrio harveyi. (United States)

    Feldman, Mark; Weiss, Ervin I; Ofek, Itzhak; Steinberg, Doron


    Cranberry juice has long been recognized in folk medicine as a therapeutic agent, mainly in urinary track infections. It acts as an antibiofilm agent against various pathogens. Quorum sensing is process where bacteria communicate with each other via signal molecules known as autoinducers. This process is strongly involved in various bacterial pathological and physiological pathways. Various strains of Vibrio harveyi bacteria were incubated with different concentrations of nondialyzable material of cranberry (NDM) with or without addition of exogenous autoinducer. Bioluminescence regulated by the autoinducers was measured in GENios reader. Effect of NDM alone or NDM supplemented with autoinducer on quorum sensing was determined as change in bioluminescence in each treated sample compared to appropriate control in every strain. Using model of V. harveyi, we found an inhibitory effect of cranberry constituents on bacterial signaling system. This effect was reversible, since exogenous autoinducer was able to recover bioluminescence which was decreased by NDM. We hypothesized that cranberry NDM interacts with V. harveyi quorum sensing by competition with autoinducer for binding to autoinducer sensor.

  15. Electromagnetic field effects on cells of the immune system: The role of calcium signaling

    Energy Technology Data Exchange (ETDEWEB)

    Walleczek, J. (Lawrence Berkeley Lab., CA (United States))


    During the past decade considerable evidence has accumulated demonstrating that nonthermal exposures of cells of the immune system to extremely low-frequency (ELF) electromagnetic fields (< 300 Hz) can elicit cellular changes that might be relevant to in vivo immune activity. A similar responsiveness to nonionizing electromagnetic energy in this frequency range has also been documented for tissues of the neuroendocrine and musculoskeletal system. However, knowledge about the underlying biological mechanisms by which such fields can induce cellular changes is still very limited. It is generally believed that the cell membrane and Ca[sup 2+]-regulated activity is involved in bioactive ELF field coupling to living systems. This article begins with a short review of the current state of knowledge concerning the effects of nonthermal levels of ELF electromagnetic fields on the biochemistry and activity of immune cells and then closely examines new results that suggest a role for Ca[sup 2+] in the induction of these cellular field effects. Based on these findings it is proposed that membrane-mediated Ca[sup 2+] in the induction of these cellular field effects. Based on these findings it is proposed that membrane-mediated Ca[sup 2+] signaling processes are involved in the mediation of field effects on the immune system. 69 refs., 2 tabs.

  16. Cell Polarity Signaling in Arabidopsis


    Yang, Zhenbiao


    Cell polarization is intimately linked to plant development, growth, and responses to the environment. Major advances have been made in our understanding of the signaling pathways and networks that regulate cell polarity in plants owing to recent studies on several model systems, e.g., tip growth in pollen tubes, cell morphogenesis in the leaf epidermis, and polar localization of PINs. From these studies we have learned that plant cells use conserved mechanisms such as Rho family GTPases to i...

  17. Electromagnetic field effects on cells of the immune system: The role of calcium signalling

    Energy Technology Data Exchange (ETDEWEB)

    Walleczek, J.


    During the past decade considerable evidence has accumulated demonstrating the exposures of cells of the immune system to relatively weak extremely-low-frequency (ELF) electromagnetic fields (< 300 Hz) can elicit cellular changes which might be relevant to in-vivo immune activity. However, knowledge about the underlying biological mechanisms by which weak fields induce cellular changes is still very limited. It is generally believed that the cell membrane and Ca{sup 2+} regulated activity is involved in bioactive ELF field-coupling to living systems. This article begins with a short review of the current state of knowledge concerning the effects of nonthermal levels of ELF electromagnetic fields on the biochemistry and activity of immune cells, and then closely examines new results which suggest a role for Ca{sup 2+} in the induction of these cellular field effects. Based on these findings it is proposed that membrane-mediated Ca{sup 2+} signalling processes are involved in the mediation of field effects on the immune system. 64 refs., 2 tabs.

  18. Biomedical signals and systems

    CERN Document Server

    Tranquillo, Joseph V


    Biomedical Signals and Systems is meant to accompany a one-semester undergraduate signals and systems course. It may also serve as a quick-start for graduate students or faculty interested in how signals and systems techniques can be applied to living systems. The biological nature of the examples allows for systems thinking to be applied to electrical, mechanical, fluid, chemical, thermal and even optical systems. Each chapter focuses on a topic from classic signals and systems theory: System block diagrams, mathematical models, transforms, stability, feedback, system response, control, time

  19. A system of recurrent neural networks for modularising, parameterising and dynamic analysis of cell signalling networks. (United States)

    Samarasinghe, S; Ling, H


    In this paper, we show how to extend our previously proposed novel continuous time Recurrent Neural Networks (RNN) approach that retains the advantage of continuous dynamics offered by Ordinary Differential Equations (ODE) while enabling parameter estimation through adaptation, to larger signalling networks using a modular approach. Specifically, the signalling network is decomposed into several sub-models based on important temporal events in the network. Each sub-model is represented by the proposed RNN and trained using data generated from the corresponding ODE model. Trained sub-models are assembled into a whole system RNN which is then subjected to systems dynamics and sensitivity analyses. The concept is illustrated by application to G1/S transition in cell cycle using Iwamoto et al. (2008) ODE model. We decomposed the G1/S network into 3 sub-models: (i) E2F transcription factor release; (ii) E2F and CycE positive feedback loop for elevating cyclin levels; and (iii) E2F and CycA negative feedback to degrade E2F. The trained sub-models accurately represented system dynamics and parameters were in good agreement with the ODE model. The whole system RNN however revealed couple of parameters contributing to compounding errors due to feedback and required refinement to sub-model 2. These related to the reversible reaction between CycE/CDK2 and p27, its inhibitor. The revised whole system RNN model very accurately matched dynamics of the ODE system. Local sensitivity analysis of the whole system model further revealed the most dominant influence of the above two parameters in perturbing G1/S transition, giving support to a recent hypothesis that the release of inhibitor p27 from Cyc/CDK complex triggers cell cycle stage transition. To make the model useful in a practical setting, we modified each RNN sub-model with a time relay switch to facilitate larger interval input data (≈20min) (original model used data for 30s or less) and retrained them that produced

  20. Two-component signal transduction pathways regulating growth and cell cycle progression in a bacterium: a system-level analysis.

    Directory of Open Access Journals (Sweden)

    Jeffrey M Skerker


    Full Text Available Two-component signal transduction systems, comprised of histidine kinases and their response regulator substrates, are the predominant means by which bacteria sense and respond to extracellular signals. These systems allow cells to adapt to prevailing conditions by modifying cellular physiology, including initiating programs of gene expression, catalyzing reactions, or modifying protein-protein interactions. These signaling pathways have also been demonstrated to play a role in coordinating bacterial cell cycle progression and development. Here we report a system-level investigation of two-component pathways in the model organism Caulobacter crescentus. First, by a comprehensive deletion analysis we show that at least 39 of the 106 two-component genes are required for cell cycle progression, growth, or morphogenesis. These include nine genes essential for growth or viability of the organism. We then use a systematic biochemical approach, called phosphotransfer profiling, to map the connectivity of histidine kinases and response regulators. Combining these genetic and biochemical approaches, we identify a new, highly conserved essential signaling pathway from the histidine kinase CenK to the response regulator CenR, which plays a critical role in controlling cell envelope biogenesis and structure. Depletion of either cenK or cenR leads to an unusual, severe blebbing of cell envelope material, whereas constitutive activation of the pathway compromises cell envelope integrity, resulting in cell lysis and death. We propose that the CenK-CenR pathway may be a suitable target for new antibiotic development, given previous successes in targeting the bacterial cell wall. Finally, the ability of our in vitro phosphotransfer profiling method to identify signaling pathways that operate in vivo takes advantage of an observation that histidine kinases are endowed with a global kinetic preference for their cognate response regulators. We propose that this

  1. Macula densa cell signaling. (United States)

    Bell, P Darwin; Lapointe, Jean Yves; Peti-Peterdi, János


    Macula densa cells are renal sensor elements that detect changes in distal tubular fluid composition and transmit signals to the glomerular vascular elements. This tubuloglomerular feedback mechanism plays an important role in regulating glomerular filtration rate and blood flow. Macula densa cells detect changes in luminal sodium chloride concentration through a complex series of ion transport-related intracellular events. NaCl entry via a Na:K:2Cl cotransporter and Cl exit through a basolateral channel lead to cell depolarization and increases in cytosolic calcium. Na/H exchange (NHE2) results in cell alkalization, whereas intracellular [Na] is regulated by an apically located H(Na)-K ATPase and not by the traditional basolateral Na:K ATPase. Communication from macula densa cells to the glomerular vascular elements involves ATP release across the macula densa basolateral membrane through a maxi-anion channel. The adaptation of multi-photon microscopy is providing new insights into macula densa-glomerular signaling.

  2. DC-ATLAS : a systems biology resource to dissect receptor specific signal transduction in dendritic cells

    NARCIS (Netherlands)

    Cavalieri, D.; Rivero, D.; Beltrame, L.; Buschow, S.I.; Calura, E.; Rizzetto, L.; Gessani, S.; Gauzzi, M.C.; Reith, W.; Baur, A.; Bonaiuti, R.; Brandizi, M.; Filippo, C. De; D'Oro, U.; Draghici, S.; Dunand-Sauthier, I.; Gatti, E.; Granucci, F.; Gundel, M.; Kramer, M.; Kuka, M.; Lanyi, A.; Melief, C.J.; Montfoort, N. van; Ostuni, R.; Pierre, P.; Popovici, R.; Rajnavolgyi, E.; Schierer, S.; Schuler, G.; Soumelis, V.; Splendiani, A.; Stefanini, I.; Torcia, M.G.; Zanoni, I.; Zollinger, R.; Figdor, C.G.; Austyn, J.M.


    BACKGROUND: The advent of Systems Biology has been accompanied by the blooming of pathway databases. Currently pathways are defined generically with respect to the organ or cell type where a reaction takes place. The cell type specificity of the reactions is the foundation of immunological research,

  3. Systemic defense signaling in tomato

    Institute of Scientific and Technical Information of China (English)

    LI Changbao; SUN Jiaqiang; JIANG Hongling; WU Xiaoyan; LI Chuanyou


    The wound-inducible expression of proteinase inhibitors (PIs) genes in tomato provides a powerful model system to elucidate the signal transduction pathway of sys- temic defense response. An increasing body of evidence indi- cates that systemin and jasmonic acid (JA) work in the same signaling pathway to activate the expression of PIs and other defense-related genes. However, little is known about how systemin and JA interact to regulate cell to cell communica- tion over long distances. Genetic analysis of the systemin/JA signaling pathway in tomato plants provides a unique opportunity to dissect the mechanism by which peptide and oxylipin signals interact to coordinate systemic expression of defense-related genes. Previously, it has been proposed that systemin is the long-distance mobile signal for systemic expression of defense related genes. However, recent genetic approach provided new evidence that jasmonic acid, rather than systemin, functions as the systemic wound signal, and that the peptide systemin works to regulate the biosynthesis of JA.

  4. Quantitative phosphoproteomic analysis reveals system-wide signaling pathways downstream of SDF-1/CXCR4 in breast cancer stem cells. (United States)

    Yi, Tingfang; Zhai, Bo; Yu, Yonghao; Kiyotsugu, Yoshikawa; Raschle, Thomas; Etzkorn, Manuel; Seo, Hee-Chan; Nagiec, Michal; Luna, Rafael E; Reinherz, Ellis L; Blenis, John; Gygi, Steven P; Wagner, Gerhard


    Breast cancer is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.7 million new cases and 522,000 deaths around the world in 2012 alone. Cancer stem cells (CSCs) are essential for tumor reoccurrence and metastasis which is the major source of cancer lethality. G protein-coupled receptor chemokine (C-X-C motif) receptor 4 (CXCR4) is critical for tumor metastasis. However, stromal cell-derived factor 1 (SDF-1)/CXCR4-mediated signaling pathways in breast CSCs are largely unknown. Using isotope reductive dimethylation and large-scale MS-based quantitative phosphoproteome analysis, we examined protein phosphorylation induced by SDF-1/CXCR4 signaling in breast CSCs. We quantified more than 11,000 phosphorylation sites in 2,500 phosphoproteins. Of these phosphosites, 87% were statistically unchanged in abundance in response to SDF-1/CXCR4 stimulation. In contrast, 545 phosphosites in 266 phosphoproteins were significantly increased, whereas 113 phosphosites in 74 phosphoproteins were significantly decreased. SDF-1/CXCR4 increases phosphorylation in 60 cell migration- and invasion-related proteins, of them 43 (>70%) phosphoproteins are unrecognized. In addition, SDF-1/CXCR4 upregulates the phosphorylation of 44 previously uncharacterized kinases, 8 phosphatases, and 1 endogenous phosphatase inhibitor. Using computational approaches, we performed system-based analyses examining SDF-1/CXCR4-mediated phosphoproteome, including construction of kinase-substrate network and feedback regulation loops downstream of SDF-1/CXCR4 signaling in breast CSCs. We identified a previously unidentified SDF-1/CXCR4-PKA-MAP2K2-ERK signaling pathway and demonstrated the feedback regulation on MEK, ERK1/2, δ-catenin, and PPP1Cα in SDF-1/CXCR4 signaling in breast CSCs. This study gives a system-wide view of phosphorylation events downstream of SDF-1/CXCR4 signaling in breast CSCs, providing a resource for the study of CSC-targeted cancer therapy.

  5. Signaling at the cell surface in the circulatory and ventilatory systems

    CERN Document Server

    Thiriet, Marc


    The volumes in this authoritative series present a multidisciplinary approach to modeling and simulation of flows in the cardiovascular and ventilatory systems, especially multiscale modeling and coupled simulations. The cardiovascular and respiratory systems are tightly coupled, as their primary function is to supply oxygen to and remove carbon dioxide from the body's cells. Because physiological conduits have deformable and reactive walls, macroscopic flow behavior and prediction must be coupled to nano- and microscopic events in a corrector scheme of regulated mechanisms when the vessel lumen caliber varies markedly. Therefore, investigation of flows of blood and air in physiological conduits requires an understanding of the biology, chemistry, and physics of these systems together with the mathematical tools to describe their functioning. Volume 3 is devoted to the set of mediators of the cell surface, especially ion and molecular carriers and catalytic receptors that, once liganded and activated, initiat...

  6. A c-di-GMP effector system controls cell adhesion by inside-out signaling and surface protein cleavage.

    Directory of Open Access Journals (Sweden)

    Peter D Newell

    Full Text Available In Pseudomonas fluorescens Pf0-1 the availability of inorganic phosphate (Pi is an environmental signal that controls biofilm formation through a cyclic dimeric GMP (c-di-GMP signaling pathway. In low Pi conditions, a c-di-GMP phosphodiesterase (PDE RapA is expressed, depleting cellular c-di-GMP and causing the loss of a critical outer-membrane adhesin LapA from the cell surface. This response involves an inner membrane protein LapD, which binds c-di-GMP in the cytoplasm and exerts a periplasmic output promoting LapA maintenance on the cell surface. Here we report how LapD differentially controls maintenance and release of LapA: c-di-GMP binding to LapD promotes interaction with and inhibition of the periplasmic protease LapG, which targets the N-terminus of LapA. We identify conserved amino acids in LapA required for cleavage by LapG. Mutating these residues in chromosomal lapA inhibits LapG activity in vivo, leading to retention of the adhesin on the cell surface. Mutations with defined effects on LapD's ability to control LapA localization in vivo show concomitant effects on c-di-GMP-dependent LapG inhibition in vitro. To establish the physiological importance of the LapD-LapG effector system, we track cell attachment and LapA protein localization during Pi starvation. Under this condition, the LapA adhesin is released from the surface of cells and biofilms detach from the substratum. This response requires c-di-GMP depletion by RapA, signaling through LapD, and proteolytic cleavage of LapA by LapG. These data, in combination with the companion study by Navarro et al. presenting a structural analysis of LapD's signaling mechanism, give a detailed description of a complete c-di-GMP control circuit--from environmental signal to molecular output. They describe a novel paradigm in bacterial signal transduction: regulation of a periplasmic enzyme by an inner membrane signaling protein that binds a cytoplasmic second messenger.

  7. Pam2 lipopeptides systemically increase myeloid-derived suppressor cells through TLR2 signaling

    Energy Technology Data Exchange (ETDEWEB)

    Maruyama, Akira; Shime, Hiroaki, E-mail:; Takeda, Yohei; Azuma, Masahiro; Matsumoto, Misako; Seya, Tsukasa, E-mail:


    Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that exhibit potent immunosuppressive activity. They are increased in tumor-bearing hosts and contribute to tumor development. Toll-like receptors (TLRs) on MDSCs may modulate the tumor-supporting properties of MDSCs through pattern-recognition. Pam2 lipopeptides represented by Pam2CSK4 serve as a TLR2 agonist to exert anti-tumor function by dendritic cell (DC)-priming that leads to NK cell activation and cytotoxic T cell proliferation. On the other hand, TLR2 enhances tumor cell progression/invasion by activating tumor-infiltrating macrophages. How MDSCs respond to TLR2 agonists has not yet been determined. In this study, we found intravenous administration of Pam2CSK4 systemically up-regulated the frequency of MDSCs in EG7 tumor-bearing mice. The frequency of tumor-infiltrating MDSCs was accordingly increased in response to Pam2CSK4. MDSCs were not increased by Pam2CSK4 stimuli in TLR2 knockout (KO) mice. Adoptive transfer experiments using CFSE-labeled MDSCs revealed that the TLR2-positive MDSCs survived long in tumor-bearing mice in response to Pam2CSK4 treatment. Since the increased MDSC population sustained immune-suppressive properties, our study suggests that Pam2CSK4-triggered TLR2 activation enhances the MDSC potential and suppress antitumor immune response in tumor microenvironment. - Highlights: • Pam2CSK4 administration induces systemic accumulation of CD11b{sup +}Gr1{sup +} MDSCs. • TLR2 is essential for Pam2CSK4-induced accumulation of CD11b{sup +}Gr1{sup +} MDSCs. • Pam2CSK4 supports survival of CD11b{sup +}Gr1{sup +} MDSCs in vivo.

  8. Gene Expression Profile Reveals Abnormalities of Multiple Signaling Pathways in Mesenchymal Stem Cell Derived from Patients with Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Yu Tang


    Full Text Available We aimed to compare bone-marrow-derived mesenchymal stem cells (BMMSCs between systemic lupus erythematosus (SLE and normal controls by means of cDNA microarray, immunohistochemistry, immunofluorescence, and immunoblotting. Our results showed there were a total of 1, 905 genes which were differentially expressed by BMMSCs derived from SLE patients, of which, 652 genes were upregulated and 1, 253 were downregulated. Gene ontology (GO analysis showed that the majority of these genes were related to cell cycle and protein binding. Pathway analysis exhibited that differentially regulated signal pathways involved actin cytoskeleton, focal adhesion, tight junction, and TGF-β pathway. The high protein level of BMP-5 and low expression of Id-1 indicated that there might be dysregulation in BMP/TGF-β signaling pathway. The expression of Id-1 in SLE BMMSCs was reversely correlated with serum TNF-α levels. The protein level of cyclin E decreased in the cell cycling regulation pathway. Moreover, the MAPK signaling pathway was activated in BMMSCs from SLE patients via phosphorylation of ERK1/2 and SAPK/JNK. The actin distribution pattern of BMMSCs from SLE patients was also found disordered. Our results suggested that there were distinguished differences of BMMSCs between SLE patients and normal controls.

  9. Computation of Low Frequency Electric Field Generation System for Analysis of Induced Signals in In-Vitro Cultured Cells

    Directory of Open Access Journals (Sweden)

    Jenniffer Zapata-Giraldo


    Full Text Available Various modeling and simulation studies about cellular systems reactions and human exposure to external electric fields, have established exposure thresholds, therapeutic application ranges, and different levels of experimental variables in order to use in different pathologies and characterization of physio-electric mechanisms. In this work, we developed a 3D computational model that consists of an electric field source and cell content deposited in a Falcom plate. The model considered the geometries, properties, meshing, simulation conditions, and type of results analysis. The development was performed in the ANSYS® software and it allowed estimate the behavior of the induced current density in cell cultures from various stimulation conditions. The developed model and the results are supportive of the estimation and prediction of the electrical signal induced in cells with which to associate a biological response.

  10. Rhomboids, signalling and cell biology. (United States)

    Freeman, Matthew


    Here, I take a somewhat personal perspective on signalling control, focusing on the rhomboid-like superfamily of proteins that my group has worked on for almost 20 years. As well as describing some of the key and recent advances, I attempt to draw out signalling themes that emerge. One important message is that the genetic and biochemical perspective on signalling has tended to underplay the importance of cell biology. There is clear evidence that signalling pathways exploit the control of intracellular trafficking, protein quality control and degradation and other cell biological phenomena, as important regulatory opportunities.

  11. Wnt signalling pathway parameters for mammalian cells.

    Directory of Open Access Journals (Sweden)

    Chin Wee Tan

    Full Text Available Wnt/β-catenin signalling regulates cell fate, survival, proliferation and differentiation at many stages of mammalian development and pathology. Mutations of two key proteins in the pathway, APC and β-catenin, have been implicated in a range of cancers, including colorectal cancer. Activation of Wnt signalling has been associated with the stabilization and nuclear accumulation of β-catenin and consequential up-regulation of β-catenin/TCF gene transcription. In 2003, Lee et al. constructed a computational model of Wnt signalling supported by experimental data from analysis of time-dependent concentration of Wnt signalling proteins in Xenopus egg extracts. Subsequent studies have used the Xenopus quantitative data to infer Wnt pathway dynamics in other systems. As a basis for understanding Wnt signalling in mammalian cells, a confocal live cell imaging measurement technique is developed to measure the cell and nuclear volumes of MDCK, HEK293T cells and 3 human colorectal cancer cell lines and the concentrations of Wnt signalling proteins β-catenin, Axin, APC, GSK3β and E-cadherin. These parameters provide the basis for formulating Wnt signalling models for kidney/intestinal epithelial mammalian cells. There are significant differences in concentrations of key proteins between Xenopus extracts and mammalian whole cell lysates. Higher concentrations of Axin and lower concentrations of APC are present in mammalian cells. Axin concentrations are greater than APC in kidney epithelial cells, whereas in intestinal epithelial cells the APC concentration is higher than Axin. Computational simulations based on Lee's model, with this new data, suggest a need for a recalibration of the model.A quantitative understanding of Wnt signalling in mammalian cells, in particular human colorectal cancers requires a detailed understanding of the concentrations of key protein complexes over time. Simulations of Wnt signalling in mammalian cells can be initiated

  12. TACI-dependent APRIL signaling maintains autoreactive B cells in a mouse model of systemic lupus erythematosus. (United States)

    Tran, Ngoc Lan; Schneider, Pascal; Santiago-Raber, Marie-Laure


    Autoantibodies contribute to the development of Systemic Lupus Erythematosus (SLE). APRIL (a proliferation-inducing ligand), a member of the TNF superfamily, regulates plasma-cell survival and binds to TACI (transmembrane activator CAML interactor) and BCMA (B cell maturation antigen). We previously showed that APRIL blockade delayed disease onset in lupus-prone mice. In order to evaluate the role of APRIL receptors in the development of SLE, APRIL, TACI, BCMA or double TACI.BCMA null mutations were introduced into the Nba2.Yaa spontaneous lupus mouse model. Mortality as a consequence of Glomerulonephritis (GN) was reduced in Nba2.APRIL(-/-) .Yaa, Nba2.TACI(-/-) .Yaa and double-KO mice compared with Nba2.Yaa mice and correlated with lower levels of circulating antibodies, while splenic populations remained unchanged. In contrast, the appearance of symptoms was accelerated in BCMA-deficient mice, in which TACI signaling was increased. Finally, lupus-prone mice deficient for the APRIL-TACI axis produced less pathogenic antibodies and developed less GN. Disease reduction was attributed to impaired T-independent type 2 responses when the APRIL-TACI signaling axis was disrupted. Collectively, our results have identified and confirmed APRIL as a new target involved in B-cell activation, in the maintenance of plasma cell survival and subsequent increased autoantibody production that sustains lupus development in mice. This article is protected by copyright. All rights reserved.

  13. Development of the enteric nervous system: bringing together cells, signals and genes. (United States)

    Burns, A J; Pachnis, V


    The enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract that controls essential functions such as motility, secretion and blood flow, comprises a vast number of neurons and glial cells that are organized into complex networks of interconnected ganglia distributed throughout the entire length of the gut wall. Enteric neurons and glia are derived from neural crest cells that undergo extensive migration, proliferation, differentiation and survival in order to form a functional ENS. Investigations of the developmental processes that underlie ENS formation in animal models, and of the common human congenital ENS abnormality Hirschsprung's disease, have been intimately related and recently led to major advances in the field. This review touches on some of these advances and introduces two topics that are elaborated upon in this journal issue: (i) genome wide approaches for profiling gene expression in wild type and mutant ENS that have been used to identify novel molecules with important roles in enteric neurogenesis, and (ii) the use of multilineage ENS progenitors isolated from embryonic or postnatal gut as novel cell replacement therapies for Hirschsprung's disease. Such studies will not only unravel the mechanisms underlying ENS development, but will also shed light on the pathogenesis of ENS developmental disorders and help to establish novel therapeutic strategies for restoring or repairing malfunctioning enteric neural circuits prevalent in numerous gastrointestinal diseases.

  14. Signal transducer and activator of transcription 3 and 5 regulate system Xc- and redox balance in human breast cancer cells. (United States)

    Linher-Melville, Katja; Haftchenary, Sina; Gunning, Patrick; Singh, Gurmit


    System Xc- is a cystine/glutamate antiporter that contributes to the maintenance of cellular redox balance. The human xCT (SLC7A11) gene encodes the functional subunit of system Xc-. Transcription factors regulating antioxidant defense mechanisms including system Xc- are of therapeutic interest, especially given that aggressive breast cancer cells exhibit increased system Xc- function. This investigation provides evidence that xCT expression is regulated by STAT3 and/or STAT5A, functionally affecting the antiporter in human breast cancer cells. Computationally analyzing two kilobase pairs of the xCT promoter/5' flanking region identified a distal gamma-activated site (GAS) motif, with truncations significantly increasing luciferase reporter activity. Similar transcriptional increases were obtained after treating cells transiently transfected with the full-length xCT promoter construct with STAT3/5 pharmacological inhibitors. Knock-down of STAT3 or STAT5A with siRNAs produced similar results. However, GAS site mutation significantly reduced xCT transcriptional activity, suggesting that STATs may interact with other transcription factors at more proximal promoter sites. STAT3 and STAT5A were bound to the xCT promoter in MDA-MB-231 cells, and binding was disrupted by pre-treatment with STAT inhibitors. Pharmacologically suppressing STAT3/5 activation significantly increased xCT mRNA and protein levels, as well as cystine uptake, glutamate release, and total levels of intracellular glutathione. Our data suggest that STAT proteins negatively regulate basal xCT expression. Blocking STAT3/5-mediated signaling induces an adaptive, compensatory mechanism to protect breast cancer cells from stress, including reactive oxygen species, by up-regulating xCT expression and the function of system Xc-. We propose that targeting system Xc- together with STAT3/5 inhibitors may heighten therapeutic anti-cancer effects.

  15. Cell cycle and cell signal transduction in marine phytoplankton

    Institute of Scientific and Technical Information of China (English)

    LIU Jingwen; JIAO Nianzhi; CAI Huinong


    As unicellular phytoplankton, the growth of a marine phytoplankton population results directly from the completion of a cell cycle, therefore, cell-environment communication is an important way which involves signal transduction pathways to regulate cell cycle progression and contribute to growth, metabolism and primary production and respond to their surrounding environment in marine phytoplankton. Cyclin-CDK and CaM/Ca2+ are essentially key regulators in control of cell cycle and signal transduction pathway, which has important values on both basic research and applied biotechnology. This paper reviews progress made in this research field, which involves the identification and characterization of cyclins and cell signal transduction system, cell cycle control mechanisms in marine phytoplankton cells, cell cycle proteins as a marker of a terminal event to estimate the growth rate of phytoplankton at the species level, cell cycle-dependent toxin production of toxic algae and cell cycle progression regulated by environmental factors.

  16. Calcium signaling in taste cells. (United States)

    Medler, Kathryn F


    The sense of taste is a common ability shared by all organisms and is used to detect nutrients as well as potentially harmful compounds. Thus taste is critical to survival. Despite its importance, surprisingly little is known about the mechanisms generating and regulating responses to taste stimuli. All taste responses depend on calcium signals to generate appropriate responses which are relayed to the brain. Some taste cells have conventional synapses and rely on calcium influx through voltage-gated calcium channels. Other taste cells lack these synapses and depend on calcium release to formulate an output signal through a hemichannel. Beyond establishing these characteristics, few studies have focused on understanding how these calcium signals are formed. We identified multiple calcium clearance mechanisms that regulate calcium levels in taste cells as well as a calcium influx that contributes to maintaining appropriate calcium homeostasis in these cells. Multiple factors regulate the evoked taste signals with varying roles in different cell populations. Clearly, calcium signaling is a dynamic process in taste cells and is more complex than has previously been appreciated. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

  17. Sonic hedgehog signaling during nervous system development

    Institute of Scientific and Technical Information of China (English)

    Qin Yang; Peng Xie


    The Hedgehog signaling pathway plays a key role in embryonic development and organ formation.Sonic hedgehog signaling participates in nervous system development,regulates proliferation and differentiation of neural stem cells,controls growth and targeting of axons,and contributes to specialization of oligodendrocytes.For further studies of the Sonic hedgehog signaling pathway and for the development of new drugs in the treatment of nervous system diseases,it is beneficial to understand these mechanisms.

  18. Cell signalling and phospholipid metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Boss, W.F.


    These studies explored whether phosphoinositide (PI) has a role in plants analogous to its role in animal cells. Although no parallel activity of PI in signal transduction was found in plant cells, activity of inositol phospholipid kinase was found to be modulated by light and by cell wall degrading enzymes. These studies indicate a major role for inositol phospholipids in plant growth and development as membrane effectors but not as a source of second messengers.

  19. Acoustic Signals and Systems

    DEFF Research Database (Denmark)


    The Handbook of Signal Processing in Acoustics will compile the techniques and applications of signal processing as they are used in the many varied areas of Acoustics. The Handbook will emphasize the interdisciplinary nature of signal processing in acoustics. Each Section of the Handbook...... will present topics on signal processing which are important in a specific area of acoustics. These will be of interest to specialists in these areas because they will be presented from their technical perspective, rather than a generic engineering approach to signal processing. Non-specialists, or specialists...

  20. A systems biology approach to identify the signalling network regulated by Rho-GDI-γ during neural stem cell differentiation. (United States)

    Wang, Jiao; Hu, Fuyan; Cheng, Hua; Zhao, Xing-Ming; Wen, Tieqiao


    Understanding the molecular mechanism that underlies the differentiation of neural stem cells (NSCs) is vital to develop regenerative medicines for neurological disorders. In our previous work, Rho-GDI-γ was found to be able to prompt neuronal differentiation when it was down regulated. However, it is unclear how Rho-GDI-γ regulates this differentiation process. Therefore, a novel systems biology approach is presented here to identify putative signalling pathways regulated by Rho-GDI-γ during NSC differentiation, and these pathways can provide insights into the NSC differentiation mechanisms. In particular, our proposed approach combines the predictive power of computational biology and molecular experiments. With different biological experiments, the genes in the computationally identified signalling network were validated to be indeed regulated by Rho-GDI-γ during the differentiation of NSCs. In particular, one randomly selected pathway involving Vcp, Mapk8, Ywhae and Ywhah was experimentally verified to be regulated by Rho-GDI-γ. These promising results demonstrate the effectiveness of our proposed systems biology approach, indicating the potential predictive power of integrating computational and experimental approaches.

  1. Signals and systems for dummies

    CERN Document Server

    Wickert, Mark


    Getting mixed signals in your signals and systems course? The concepts covered in a typical signals and systems course are often considered by engineering students to be some of the most difficult to master. Thankfully, Signals & Systems For Dummies is your intuitive guide to this tricky course, walking you step-by-step through some of the more complex theories and mathematical formulas in a way that is easy to understand. From Laplace Transforms to Fourier Analyses, Signals & Systems For Dummies explains in plain English the difficult concepts that can trip you up

  2. Embedded fiber-optic sensing for accurate internal monitoring of cell state in advanced battery management systems part 2: Internal cell signals and utility for state estimation (United States)

    Ganguli, Anurag; Saha, Bhaskar; Raghavan, Ajay; Kiesel, Peter; Arakaki, Kyle; Schuh, Andreas; Schwartz, Julian; Hegyi, Alex; Sommer, Lars Wilko; Lochbaum, Alexander; Sahu, Saroj; Alamgir, Mohamed


    A key challenge hindering the mass adoption of Lithium-ion and other next-gen chemistries in advanced battery applications such as hybrid/electric vehicles (xEVs) has been management of their functional performance for more effective battery utilization and control over their life. Contemporary battery management systems (BMS) reliant on monitoring external parameters such as voltage and current to ensure safe battery operation with the required performance usually result in overdesign and inefficient use of capacity. More informative embedded sensors are desirable for internal cell state monitoring, which could provide accurate state-of-charge (SOC) and state-of-health (SOH) estimates and early failure indicators. Here we present a promising new embedded sensing option developed by our team for cell monitoring, fiber-optic (FO) sensors. High-performance large-format pouch cells with embedded FO sensors were fabricated. This second part of the paper focuses on the internal signals obtained from these FO sensors. The details of the method to isolate intercalation strain and temperature signals are discussed. Data collected under various xEV operational conditions are presented. An algorithm employing dynamic time warping and Kalman filtering was used to estimate state-of-charge with high accuracy from these internal FO signals. Their utility for high-accuracy, predictive state-of-health estimation is also explored.

  3. From genomes to metabolomes: Understanding mechanisms of symbiosis and cell-cell signaling using the archaeal system Ignicoccus-Nanoarchaeum

    Energy Technology Data Exchange (ETDEWEB)

    Podar, Mircea [Univ. of Tennessee, Knoxville, TN (United States). Biosciences Division; Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Hettich, Robert [Univ. of Tennessee, Knoxville, TN (United States). Biosciences Division; Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Copie, Valerie [Montana State Univ., Bozeman, MT (United States). Dept. of Chemistry and Biochemistry; Bothner, Brian [Montana State Univ., Bozeman, MT (United States). Dept. of Chemistry and Biochemistry


    (manuscript in preparation) and by characterizing other similar Nanoarchaeota systems. Using a single cell genomics approach we characterized the first terrestrial geothermal Nanoarchaeota system, from Yellowstone National Park. That nanoarchaeon uses a different host, a species of Sulfolobales, and comparative genomics with N. equitans-Ignicoccus allowed us to come up with an evolutionary model for the evolution of this group of organisms across marine and terrestrial ecosystems. Based on metabolic inferences we were also able to isolate in culture the first such terrestrial nanoarchaeal system, also from Yellowstone, which involves a species of Acidilobus. The novel nanoarchaeal system was characterized using proteomics and it helped us better understand the metabolic capabilities of these organisms as well as how co-evolution shapes the genomes of interacting species. It was also one of the very few cases in which prior genomic data was used to successfully design an approach to culture an organism, which remains the gold standard in microbiology research. As a better understanding of interspecies interaction requires multiple model systems, we have pursued identification and genomic characterization or isolation of additional nanoarchaeal systems from geographically and geochemically distinct environments. Two additional nanoarchaeal systems are presently being characterized from hot springs in Yellowstone and Iceland and will be the subject to future publications.

  4. B Cell Autonomous TLR Signaling and Autoimmunity (United States)

    Meyer-Bahlburg, Almut; Rawlings, David J


    B cells play a central role in the pathogenesis of multiple autoimmune diseases and the recognition of importance of B cells in these disorders has grown dramatically in association with the remarkable success of B-cell depletion as a treatment for autoimmunity. The precise mechanisms that promote alterations in B cell tolerance remain incompletely defined. There is increasing evidence, however, that TLRs play a major role in these events. Stimulation of B cells via the TLR pathway not only leads to an increase in antibody production but also promotes additional changes including cytokine production and upregulation of activation markers increasing the effectiveness of B cells as APCs. Understanding the role of TLRs in systemic autoimmunity will not only provide insight into the disease pathogenesis but may also lead to the development of novel therapies. This article gives an overview of TLR signaling in B cells and the possible involvement of such signals in autoimmune diseases. PMID:18295736

  5. Fidelity in planar cell polarity signalling. (United States)

    Ma, Dali; Yang, Chung-hui; McNeill, Helen; Simon, Michael A; Axelrod, Jeffrey D


    The polarity of Drosophila wing hairs displays remarkable fidelity. Each of the approximately 30,000 wing epithelial cells constructs an actin-rich prehair that protrudes from its distal vertex and points distally. The distal location and orientation of the hairs is virtually error free, thus forming a nearly perfect parallel array. This process is controlled by the planar cell polarity signalling pathway. Here we show that interaction between two tiers of the planar cell polarity signalling mechanism results in the observed high fidelity. The first tier, mediated by the cadherin Fat, dictates global orientation by transducing a directional signal to individual cells. The second tier, orchestrated by the 7-pass transmembrane receptor Frizzled, aligns each cell's polarity with that of its neighbours through the action of an intercellular feedback loop, enabling polarity to propagate from cell to cell. We show that all cells need not respond correctly to the presumably subtle signal transmitted by Fat. Subsequent action of the Frizzled feedback loop is sufficient to align all the cells cooperatively. This economical system is therefore highly robust, and produces virtually error-free arrays.

  6. A special issue on cell signaling, disease, and stem cells

    Institute of Scientific and Technical Information of China (English)

    Dangsheng Li


    As the basic unit of life,cells utilize signaling pathways to receive inputs from the environment and translate such information into appropriate cellular behaviors and responses.Cell signaling is also pivotal for multicellular organisms such as mammals,as cells need to communicate extensively among each other and with the environment in order to orchestrate appropriate actions,which are in turn integrated at the system level for the proper functioning and well-being of the organism.Thus,understanding the molecular mechanisms of cell signaling constitutes a fundamental quest of today's life science research.Not surprisingly,dysregulation of cell signaling causes many diseases such as cancer,and in such cases,a thorough understanding of the nature of cell signaling under disease states would provide an important basis to the efforts of developing novel therapeutic strategies.In this context,we are pleased to present this 2012 Cell Research Special Issue focusing on "Cell signaling,disease,and stem cells".

  7. Planar cell polarity signaling in vertebrates. (United States)

    Jones, Chonnettia; Chen, Ping


    Planar cell polarity (PCP) refers to the polarization of a field of cells within the plane of a cell sheet. This form of polarization is required for diverse cellular processes in vertebrates, including convergent extension (CE), the establishment of PCP in epithelial tissues and ciliogenesis. Perhaps the most distinct example of vertebrate PCP is the uniform orientation of stereociliary bundles at the apices of sensory hair cells in the mammalian auditory sensory organ. The establishment of PCP in the mammalian cochlea occurs concurrently with CE in this ciliated epithelium, therefore linking three cellular processes regulated by the vertebrate PCP pathway in the same tissue and emerging as a model system for dissecting PCP signaling. This review summarizes the morphogenesis of this model system to assist the interpretation of the emerging data and proposes molecular mechanisms underlying PCP signaling in vertebrates.

  8. Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system (United States)

    Cordiglieri, Chiara; Odoardi, Francesca; Zhang, Bo; Nebel, Merle; Kawakami, Naoto; Klinkert, Wolfgang E. F.; Lodygin, Dimtri; Lühder, Fred; Breunig, Esther; Schild, Detlev; Ulaganathan, Vijay Kumar; Dornmair, Klaus; Dammermann, Werner; Potter, Barry V. L.; Guse, Andreas H.


    Nicotinic acid adenine dinucleotide phosphate represents a newly identified second messenger in T cells involved in antigen receptor-mediated calcium signalling. Its function in vivo is, however, unknown due to the lack of biocompatible inhibitors. Using a recently developed inhibitor, we explored the role of nicotinic acid adenine dinucleotide phosphate in autoreactive effector T cells during experimental autoimmune encephalomyelitis, the animal model for multiple sclerosis. We provide in vitro and in vivo evidence that calcium signalling controlled by nicotinic acid adenine dinucleotide phosphate is relevant for the pathogenic potential of autoimmune effector T cells. Live two photon imaging and molecular analyses revealed that nicotinic acid adenine dinucleotide phosphate signalling regulates T cell motility and re-activation upon arrival in the nervous tissues. Treatment with the nicotinic acid adenine dinucleotide phosphate inhibitor significantly reduced both the number of stable arrests of effector T cells and their invasive capacity. The levels of pro-inflammatory cytokines interferon-gamma and interleukin-17 were strongly diminished. Consecutively, the clinical symptoms of experimental autoimmune encephalomyelitis were ameliorated. In vitro, antigen-triggered T cell proliferation and cytokine production were evenly suppressed. These inhibitory effects were reversible: after wash-out of the nicotinic acid adenine dinucleotide phosphate antagonist, the effector T cells fully regained their functions. The nicotinic acid derivative BZ194 induced this transient state of non-responsiveness specifically in post-activated effector T cells. Naïve and long-lived memory T cells, which express lower levels of the putative nicotinic acid adenine dinucleotide phosphate receptor, type 1 ryanodine receptor, were not targeted. T cell priming and recall responses in vivo were not reduced. These data indicate that the nicotinic acid adenine dinucleotide phosphate

  9. Bright fluorescence monitoring system utilizing Zoanthus sp. green fluorescent protein (ZsGreen for human G-protein-coupled receptor signaling in microbial yeast cells.

    Directory of Open Access Journals (Sweden)

    Yasuyuki Nakamura

    Full Text Available G-protein-coupled receptors (GPCRs are currently the most important pharmaceutical targets for drug discovery because they regulate a wide variety of physiological processes. Consequently, simple and convenient detection systems for ligands that regulate the function of GPCR have attracted attention as powerful tools for new drug development. We previously developed a yeast-based fluorescence reporter ligand detection system using flow cytometry. However, using this conventional detection system, fluorescence from a cell expressing GFP and responding to a ligand is weak, making detection of these cells by fluorescence microscopy difficult. We here report improvements to the conventional yeast fluorescence reporter assay system resulting in the development of a new highly-sensitive fluorescence reporter assay system with extremely bright fluorescence and high signal-to-noise (S/N ratio. This new system allowed the easy detection of GPCR signaling in yeast using fluorescence microscopy. Somatostatin receptor and neurotensin receptor (implicated in Alzheimer's disease and Parkinson's disease, respectively were chosen as human GPCR(s. The facile detection of binding to these receptors by cognate peptide ligands was demonstrated. In addition, we established a highly sensitive ligand detection system using yeast cell surface display technology that is applicable to peptide screening, and demonstrate that the display of various peptide analogs of neurotensin can activate signaling through the neurotensin receptor in yeast cells. Our system could be useful for identifying lead peptides with agonistic activity towards targeted human GPCR(s.

  10. Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production. (United States)

    Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin; Terhorst, Cox; Kyttaris, Vasileios C; Tsokos, George C


    T cells from patients with systemic lupus erythematosus (SLE) display a number of abnormalities, including increased early signaling events following engagement of the TCR. Signaling lymphocytic activation molecule family cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating the immune response. We present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and three men with SLE, independent of disease activity. In SLE T cells, SAP protein is also subject to increased degradation by caspase-3. Forced expression of SAP in SLE T cells normalized IL-2 production, calcium (Ca(2+)) responses, and tyrosine phosphorylation of a number of proteins. Exposure of normal T cells to SLE serum IgG, known to contain anti-CD3/TCR Abs, resulted in SAP downregulation. We conclude that SLE T cells display reduced levels of the adaptor protein SAP, probably as a result of continuous T cell activation and degradation by caspase-3. Restoration of SAP levels in SLE T cells corrects the overexcitable lupus T cell phenotype.

  11. Regulation of amphiregulin gene expression by β-catenin signaling in human hepatocellular carcinoma cells: a novel crosstalk between FGF19 and the EGFR system. (United States)

    Latasa, Maria U; Salis, Fabiana; Urtasun, Raquel; Garcia-Irigoyen, Oihane; Elizalde, Maria; Uriarte, Iker; Santamaria, Monica; Feo, Francesco; Pascale, Rosa M; Prieto, Jesús; Berasain, Carmen; Avila, Matías A


    Hepatocellular carcinoma (HCC) is the most prevalent liver tumor and a deadly disease with limited therapeutic options. Dysregulation of cell signaling pathways is a common denominator in tumorigenesis, including hepatocarcinogenesis. The epidermal growth factor receptor (EGFR) signaling system is commonly activated in HCC, and is currently being evaluated as a therapeutic target in combination therapies. We and others have identified a central role for the EGFR ligand amphiregulin (AR) in the proliferation, survival and drug resistance of HCC cells. AR expression is frequently up-regulated in HCC tissues and cells through mechanisms not completely known. Here we identify the β-catenin signaling pathway as a novel mechanism leading to transcriptional activation of the AR gene in human HCC cells. Activation of β-catenin signaling, or expression of the T41A β-catenin active mutant, led to the induction of AR expression involving three specific β-catenin-Tcf responsive elements in its proximal promoter. We demonstrate that HCC cells expressing the T41A β-catenin active mutant show enhanced proliferation that is dependent in part on AR expression and EGFR signaling. We also demonstrate here a novel cross-talk of the EGFR system with fibroblast growth factor 19 (FGF19). FGF19 is a recently identified driver gene in hepatocarcinogenesis and an activator of β-catenin signaling in HCC and colon cancer cells. We show that FGF19 induced AR gene expression through the β-catenin pathway in human HCC cells. Importantly, AR up-regulation and EGFR signaling participated in the induction of cyclin D1 and cell proliferation elicited by FGF19. Finally, we demonstrate a positive correlation between FGF19 and AR expression in human HCC tissues, therefore supporting in clinical samples our experimental observations. These findings identify the AR/EGFR system as a key mediator of FGF19 responses in HCC cells involving β-catenin signaling, and suggest that combined targeting of

  12. Regulation of amphiregulin gene expression by β-catenin signaling in human hepatocellular carcinoma cells: a novel crosstalk between FGF19 and the EGFR system.

    Directory of Open Access Journals (Sweden)

    Maria U Latasa

    Full Text Available Hepatocellular carcinoma (HCC is the most prevalent liver tumor and a deadly disease with limited therapeutic options. Dysregulation of cell signaling pathways is a common denominator in tumorigenesis, including hepatocarcinogenesis. The epidermal growth factor receptor (EGFR signaling system is commonly activated in HCC, and is currently being evaluated as a therapeutic target in combination therapies. We and others have identified a central role for the EGFR ligand amphiregulin (AR in the proliferation, survival and drug resistance of HCC cells. AR expression is frequently up-regulated in HCC tissues and cells through mechanisms not completely known. Here we identify the β-catenin signaling pathway as a novel mechanism leading to transcriptional activation of the AR gene in human HCC cells. Activation of β-catenin signaling, or expression of the T41A β-catenin active mutant, led to the induction of AR expression involving three specific β-catenin-Tcf responsive elements in its proximal promoter. We demonstrate that HCC cells expressing the T41A β-catenin active mutant show enhanced proliferation that is dependent in part on AR expression and EGFR signaling. We also demonstrate here a novel cross-talk of the EGFR system with fibroblast growth factor 19 (FGF19. FGF19 is a recently identified driver gene in hepatocarcinogenesis and an activator of β-catenin signaling in HCC and colon cancer cells. We show that FGF19 induced AR gene expression through the β-catenin pathway in human HCC cells. Importantly, AR up-regulation and EGFR signaling participated in the induction of cyclin D1 and cell proliferation elicited by FGF19. Finally, we demonstrate a positive correlation between FGF19 and AR expression in human HCC tissues, therefore supporting in clinical samples our experimental observations. These findings identify the AR/EGFR system as a key mediator of FGF19 responses in HCC cells involving β-catenin signaling, and suggest that

  13. A systems toxicology approach identifies Lyn as a key signaling phosphoprotein modulated by mercury in a B lymphocyte cell model

    Energy Technology Data Exchange (ETDEWEB)

    Caruso, Joseph A.; Stemmer, Paul M. [Institute of Environmental Health Sciences, Wayne State University, Detroit, MI (United States); Dombkowski, Alan [Department of Pediatrics, Wayne State University, Detroit, MI (United States); Caruthers, Nicholas J. [Institute of Environmental Health Sciences, Wayne State University, Detroit, MI (United States); Gill, Randall [Department of Immunology and Microbiology, Wayne State University, Detroit, MI (United States); Rosenspire, Allen J., E-mail: [Department of Immunology and Microbiology, Wayne State University, Detroit, MI (United States)


    Network and protein–protein interaction analyses of proteins undergoing Hg{sup 2+}-induced phosphorylation and dephosphorylation in Hg{sup 2+}-intoxicated mouse WEHI-231 B cells identified Lyn as the most interconnected node. Lyn is a Src family protein tyrosine kinase known to be intimately involved in the B cell receptor (BCR) signaling pathway. Under normal signaling conditions the tyrosine kinase activity of Lyn is controlled by phosphorylation, primarily of two well known canonical regulatory tyrosine sites, Y-397 and Y-508. However, Lyn has several tyrosine residues that have not yet been determined to play a major role under normal signaling conditions, but are potentially important sites for phosphorylation following mercury exposure. In order to determine how Hg{sup 2+} exposure modulates the phosphorylation of additional residues in Lyn, a targeted MS assay was developed. Initial mass spectrometric surveys of purified Lyn identified 7 phosphorylated tyrosine residues. A quantitative assay was developed from these results using the multiple reaction monitoring (MRM) strategy. WEHI-231 cells were treated with Hg{sup 2+}, pervanadate (a phosphatase inhibitor), or anti-Ig antibody (to stimulate the BCR). Results from these studies showed that the phosphoproteomic profile of Lyn after exposure of the WEHI-231 cells to a low concentration of Hg{sup 2+} closely resembled that of anti-Ig antibody stimulation, whereas exposure to higher concentrations of Hg{sup 2+} led to increases in the phosphorylation of Y-193/Y-194, Y-501 and Y-508 residues. These data indicate that mercury can disrupt a key regulatory signal transduction pathway in B cells and point to phospho-Lyn as a potential biomarker for mercury exposure. - Highlights: • Inorganic mercury (Hg{sup 2+}) induces changes in the WEHI-231 B cell phosphoproteome. • The B cell receptor (BCR) signaling pathway was the pathway most affected by Hg{sup 2+}. • The Src family phosphoprotein kinase Lyn was the

  14. Disturbed T Cell Signaling and Altered Th17 and Regulatory T Cell Subsets in the Pathogenesis of Systemic Lupus Erythematosus

    NARCIS (Netherlands)

    Rother, N; Vlag, J. van der


    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nuclear components. Circulating immune complexes of chromatin and autoantibodies deposit in various tissues leading to inflammation and tissue damage. It has been well documented that

  15. Signals and systems with MATLAB

    CERN Document Server

    Yang, Won Young; Song, Ik H; Cho, Yong S


    Covers some of the theoretical foundations and mathematical derivations that can be used in higher-level related subjects such as signal processing, communication, and control, minimizing the mathematical difficulty and computational burden. This book illustrates the usage of MATLAB and Simulink for signal and system analysis and design.

  16. Cell and Tissue Organization in the Circulatory and Ventilatory Systems Volume 1 Signaling in Cell Organization, Fate, and Activity, Part A Cell Structure and Environment

    CERN Document Server

    Thiriet, Marc


    The volumes in this authoritative series present a multidisciplinary approach to modeling and simulation of flows in the cardiovascular and ventilatory systems, especially multiscale modeling and coupled simulations. The cardiovascular and respiratory systems are tightly coupled, as their primary function is to supply oxygen to and remove carbon dioxide from the body's cells. Because physiological conduits have deformable and reactive walls, macroscopic flow behavior and prediction must be coupled to nano- and microscopic events in a corrector scheme of regulated mechanisms. Therefore, investigation of flows of blood and air in physiological conduits requires an understanding of the biology, chemistry, and physics of these systems together with the mathematical tools to describe their functioning.  The present volume is devoted to cellular events that allow adaptation to environmental conditions, particularly mechanotransduction. It begins with cell organization and a survey of cell types in the vasculatur...

  17. Signal processing by the endosomal system. (United States)

    Villaseñor, Roberto; Kalaidzidis, Yannis; Zerial, Marino


    Cells need to decode chemical or physical signals from their environment in order to make decisions on their fate. In the case of signalling receptors, ligand binding triggers a cascade of chemical reactions but also the internalization of the activated receptors in the endocytic pathway. Here, we highlight recent studies revealing a new role of the endosomal network in signal processing. The diversity of entry pathways and endosomal compartments is exploited to regulate the kinetics of receptor trafficking, and interactions with specific signalling adaptors and effectors. By governing the spatio-temporal distribution of signalling molecules, the endosomal system functions analogously to a digital-analogue computer that regulates the specificity and robustness of the signalling response.

  18. Notch Signaling in Vascular Smooth Muscle Cells. (United States)

    Baeten, J T; Lilly, B


    The Notch signaling pathway is a highly conserved pathway involved in cell fate determination in embryonic development and also functions in the regulation of physiological processes in several systems. It plays an especially important role in vascular development and physiology by influencing angiogenesis, vessel patterning, arterial/venous specification, and vascular smooth muscle biology. Aberrant or dysregulated Notch signaling is the cause of or a contributing factor to many vascular disorders, including inherited vascular diseases, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, associated with degeneration of the smooth muscle layer in cerebral arteries. Like most signaling pathways, the Notch signaling axis is influenced by complex interactions with mediators of other signaling pathways. This complexity is also compounded by different members of the Notch family having both overlapping and unique functions. Thus, it is vital to fully understand the roles and interactions of each Notch family member in order to effectively and specifically target their exact contributions to vascular disease. In this chapter, we will review the Notch signaling pathway in vascular smooth muscle cells as it relates to vascular development and human disease.

  19. Designer cell signal processing circuits for biotechnology. (United States)

    Bradley, Robert W; Wang, Baojun


    Microorganisms are able to respond effectively to diverse signals from their environment and internal metabolism owing to their inherent sophisticated information processing capacity. A central aim of synthetic biology is to control and reprogramme the signal processing pathways within living cells so as to realise repurposed, beneficial applications ranging from disease diagnosis and environmental sensing to chemical bioproduction. To date most examples of synthetic biological signal processing have been built based on digital information flow, though analogue computing is being developed to cope with more complex operations and larger sets of variables. Great progress has been made in expanding the categories of characterised biological components that can be used for cellular signal manipulation, thereby allowing synthetic biologists to more rationally programme increasingly complex behaviours into living cells. Here we present a current overview of the components and strategies that exist for designer cell signal processing and decision making, discuss how these have been implemented in prototype systems for therapeutic, environmental, and industrial biotechnological applications, and examine emerging challenges in this promising field.

  20. Handbook of signal processing systems

    CERN Document Server

    Deprettere, Ed; Leupers, Rainer; Takala, Jarmo


    Handbook of Signal Processing Systems is organized in three parts. The first part motivates representative applications that drive and apply state-of-the art methods for design and implementation of signal processing systems; the second part discusses architectures for implementing these applications; the third part focuses on compilers and simulation tools, describes models of computation and their associated design tools and methodologies. This handbook is an essential tool for professionals in many fields and researchers of all levels.

  1. Small signal gain in DPAL systems (United States)

    Galbally-Kinney, Kristin L.; Maser, Daniel L.; Kessler, William J.; Rawlins, Wilson T.; Davis, Steven J.


    In this paper we describe a platform for small signal gain measurements for alkali atom laser systems based on the DPAL excitation method. We present initial results that clearly show the transition from absorption on the alkali atom D1 lines in Cs and Rb to optical transparency and positive gain. The achievement of optical gain is critically dependent upon alkali cell conditions and collision partners. We also present the first spatially resolved gain measurements in a DPAL system. The small signal gain methods described will be valuable tools for power scaling of these laser systems.

  2. A novel piggyBac transposon inducible expression system identifies a role for AKT signalling in primordial germ cell migration.

    Directory of Open Access Journals (Sweden)

    James D Glover

    Full Text Available In this work, we describe a single piggyBac transposon system containing both a tet-activator and a doxycycline-inducible expression cassette. We demonstrate that a gene product can be conditionally expressed from the integrated transposon and a second gene can be simultaneously targeted by a short hairpin RNA contained within the transposon, both in vivo and in mammalian and avian cell lines. We applied this system to stably modify chicken primordial germ cell (PGC lines in vitro and induce a reporter gene at specific developmental stages after injection of the transposon-modified germ cells into chicken embryos. We used this vector to express a constitutively-active AKT molecule during PGC migration to the forming gonad. We found that PGC migration was retarded and cells could not colonise the forming gonad. Correct levels of AKT activation are thus essential for germ cell migration during early embryonic development.

  3. Tanshinone IIA attenuates interleukin-17A-induced systemic sclerosis patient-derived dermal vascular smooth muscle cell activation via inhibition of the extracellular signal-regulated kinase signaling pathway

    Directory of Open Access Journals (Sweden)

    Mengguo Liu


    Full Text Available OBJECTIVE: Salvia miltiorrhiza has long been used to treat systemic sclerosis. Tanshinone IIA, one of the phytochemicals derived from the roots of Salvia miltiorrhiza, exhibits multiple biological activities. The present study aimed to investigate whether tanshinone IIA has an effect on the interleukin-17A-induced functional activation of systemic sclerosis patient-derived dermal vascular smooth muscle cells. METHODS: Systemic sclerosis patient-derived dermal vascular smooth muscle cells were incubated with various dosages of tanshinone IIA in the presence of interleukin-17A or the serum of systemic sclerosis patients. Cell proliferation was assessed using Cell Counting Kit-8. The expression of collagen 1 and 3 in cells was evaluated by immunofluorescence. Cell migration was measured using a transwell assay. The expression of phospho-extracellular signal-regulated kinase was detected by Western blotting. RESULTS: Our data demonstrate that tanshinone IIA exerts an inhibitory effect on interleukin-17A-induced systemic sclerosis patient-derived dermal vascular smooth muscle cell proliferation, collagen synthesis and migration. CONCLUSION: These findings suggest that tanshinone IIA might serve as a promising therapeutic agent for the treatment of systemic sclerosis.

  4. Hedgehog signaling pathway and gastrointestinal stem cell signaling network (review). (United States)

    Katoh, Yuriko; Katoh, Masaru


    Hedgehog, BMP/TGFbeta, FGF, WNT and Notch signaling pathways constitute the stem cell signaling network, which plays a key role in a variety of processes, such as embryogenesis, maintenance of adult tissue homeostasis, tissue repair during chronic persistent inflammation, and carcinogenesis. Sonic hedgehog (SHH), Indian hedgehog (IHH) and Desert hedgehog (DHH) bind to PTCH1/PTCH or PTCH2 receptor to release Smoothened (SMO) signal transducer from Patched-dependent suppression. SMO then activates STK36 serine/threonine kinase to stabilize GLI family members and to phosphorylate SUFU for nuclear accumulation of GLI. Hedgehog signaling activation leads to GLI-dependent transcriptional activation of target genes, such as GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1. GLI1-dependent positive feedback loop combined with PTCH1-dependent negative feedback loop gives rise to transient proliferation of Hedgehog target cells. Iguana homologs (DZIP1 and DZIP1L) and Costal-2 homologs (KIF7 and KIF27) are identified by comparative integromics. SHH-dependent parietal cell proliferation is implicated in gastric mucosal repair during chronic Helicobacter pylori infection. BMP-RUNX3 signaling induces IHH expression in surface differentiated epithelial cells of stomach and intestine. Hedgehog signals from epithelial cells then induces FOXL1-mediated BMP4 upregulation in mesenchymal cells. Hedgehog signaling is frequently activated in esophageal cancer, gastric cancer and pancreatic cancer due to transcriptional upregulation of Hedgehog ligands and epigenetic silencing of HHIP1/HHIP gene, encoding the Hedgehog inhibitor. However, Hedgehog signaling is rarely activated in colorectal cancer due to negative regulation by the canonical WNT signaling pathway. Hedgehog signaling molecules or targets, such as SHH, IHH, HHIP1, PTCH1 and GLI1, are applied as biomarkers for cancer diagnostics, prognostics and therapeutics. Small-molecule inhibitors for SMO or STK36 are suitable to be used for

  5. Coupling planar cell polarity signaling to morphogenesis. (United States)

    Axelrod, Jeffrey D; McNeill, Helen


    Epithelial cells and other groups of cells acquire a polarity orthogonal to their apical-basal axes, referred to as Planar Cell Polarity (PCP). The process by which these cells become polarized requires a signaling pathway using Frizzled as a receptor. Responding cells sense cues from their environment that provide directional information, and they translate this information into cellular asymmetry. Most of what is known about PCP derives from studies in the fruit fly, Drosophila. We review what is known about how cells translate an unknown signal into asymmetric cytoskeletal reorganization. We then discuss how the vertebrate processes of convergent extension and cochlear hair-cell development may relate to Drosophila PCP signaling.

  6. Regulation of cell fate by lymphotoxin (LT) receptor signalling: Functional differences and similarities of the LT system to other TNF superfamily (TNFSF) members. (United States)

    Albarbar, Balid; Dunnill, Christopher; Georgopoulos, Nikolaos T


    The role of TNFR family members in regulating cell fate both in the immune system and in non-lymphoid tissues has been under extensive research for decades. Moreover, the ability of several family members (death receptors) to induce death (mainly via apoptosis) represents a promising target for cancer therapy. Many studies have focused mostly on death receptors such as TNFRI, Fas and TRAIL-R due to their strong pro-apoptotic potential. Yet, cell death can be triggered via non-classical death receptors, and the lymphotoxin (LT) system represents a very good example of such a TNFR subfamily. Here we provide a comprehensive review of intracellular signalling pathways and cellular responses to LT-specific signalling, and compare for the first time the LT system to other TNFRs, such as CD40. Our aim is to highlight that non-classical TNFR-TNFL dyads such as the LT system demonstrate more complex, cell-type and context-specific capabilities. Understanding these complexities will permit a better understanding of the biological mechanisms via which non-death domain-containing TNFRs induce cell death, but may also allow the design of better therapeutic strategies.

  7. The IRS-1 signaling system. (United States)

    Myers, M G; Sun, X J; White, M F


    Insulin-receptor substrate 1 (IRS-1) is a principal substrate of the receptor tyrosine kinase for insulin and insulin-like growth factor 1, and a substrate for a tyrosine kinase activated by interleukin 4. IRS-1 undergoes multisite tyrosine phosphorylation and mediates downstream signals by 'docking' various proteins that contain Src homology 2 domains. IRS-1 appears to be a unique molecule; however, 4PS, a protein found mainly in hemopoietic cells, may represent another member of this family.

  8. Handbook of signal processing systems

    CERN Document Server

    Bhattacharyya, Shuvra S; Leupers, Rainer; Takala, Jarmo


    The Handbook is organized in four parts. The first part motivates representative applications that drive and apply state-of-the art methods for design and implementation of signal processing systems; the second part discusses architectures for implementing these applications; the third part focuses on compilers and simulation tools; and the fourth part describes models of computation and their associated design tools and methodologies.

  9. VLSI mixed signal processing system (United States)

    Alvarez, A.; Premkumar, A. B.


    An economical and efficient VLSI implementation of a mixed signal processing system (MSP) is presented in this paper. The MSP concept is investigated and the functional blocks of the proposed MSP are described. The requirements of each of the blocks are discussed in detail. A sample application using active acoustic cancellation technique is described to demonstrate the power of the MSP approach.

  10. Cerebellar endocannabinoids: retrograde signaling from purkinje cells. (United States)

    Marcaggi, Païkan


    The cerebellar cortex exhibits a strikingly high expression of type 1 cannabinoid receptor (CB1), the cannabinoid binding protein responsible for the psychoactive effects of marijuana. CB1 is primarily found in presynaptic elements in the molecular layer. While the functional importance of cerebellar CB1 is supported by the effect of gene deletion or exogenous cannabinoids on animal behavior, evidence for a role of endocannabinoids in synaptic signaling is provided by in vitro experiments on superfused acute rodent cerebellar slices. These studies have demonstrated that endocannabinoids can be transiently released by Purkinje cells and signal at synapses in a direction opposite to information transfer (retrograde). Here, following a description of the reported expression pattern of the endocannabinoid system in the cerebellum, I review the accumulated in vitro data, which have addressed the mechanism of retrograde endocannabinoid signaling and identified 2-arachidonoylglycerol as the mediator of this signaling. The mechanisms leading to endocannabinoid release, the effects of CB1 activation, and the associated synaptic plasticity mechanisms are discussed and the remaining unknowns are pointed. Notably, it is argued that the spatial specificity of this signaling and the physiological conditions required for its induction need to be determined in order to understand endocannabinoid function in the cerebellar cortex.

  11. Purinergic signaling pathways in endocrine system. (United States)

    Bjelobaba, Ivana; Janjic, Marija M; Stojilkovic, Stanko S


    Adenosine-5'-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5'-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5'-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5'-triphosphate hydrolysis to adenosine-5'-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling.

  12. Cell signaling in the interaction between pathogenic bacteria and immune cells. (United States)

    Yang, Hui; Liu, Yaxiong; Tang, Ruihua; Shao, Dongyan; Li, Jing; Li, Ji; Ye, Linjie; Jin, Mingliang; Huang, Qingsheng; Shi, Junling


    Cell signaling is an essential part in the complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is essential for cell survival and basic biological function. In the defense from pathogenic bacteria, the immune cells exert their function through various signaling pathways. In this review, we will summarize recent findings on the role of cell signaling in the interaction between pathogenic bacteria and immune cells, focusing on neutrophils and macrophages, which are part of the innate immunity, and also T cells, which are components of the adaptive immune system.

  13. A novel orally available inhibitor of focal adhesion signaling increases survival in a xenograft model of diffuse large B-cell lymphoma with central nervous system involvement. (United States)

    Bosch, Rosa; Moreno, María José; Dieguez-Gonzalez, Rebeca; Céspedes, María Virtudes; Gallardo, Alberto; Trias, Manuel; Grañena, Albert; Sierra, Jorge; Casanova, Isolda; Mangues, Ramon


    Central nervous system dissemination is a relatively uncommon but almost always fatal complication in diffuse large B-cell lymphoma patients. Optimal therapy for central nervous involvement in this malignancy has not been established. In this paper, we aimed to evaluate the therapeutic effect of E7123, a celecoxib derivative that inhibits focal adhesion signaling, in a novel xenograft model of diffuse large B-cell lymphoma with central nervous system involvement. Cells obtained after disaggregation of HT subcutaneous tumors (HT-SC cells) were intravenously injected in NOD/SCID mice. These mice received oral vehicle or 75 mg/kg of E7123 daily until they were euthanized for weight loss or signs of sickness. The antitumor effect of E7123 was validated in an independent experiment using a bioluminescent mouse model. Intravenously injected HT-SC cells showed higher take rate and higher central nervous system tropism (associated with increased expression of β1-integrin and p130Cas proteins) than HT cells. The oral administration of E7123 significantly increased survival time in 2 independent experiments using mice injected with unmodified or bioluminescent HT-SC cells. We have developed a new xenograft model of diffuse large B-cell lymphoma with central nervous system involvement that can be used in the pre-clinical evaluation of new drugs for this malignancy. E7123 is a new, well-tolerated and orally available therapeutic agent that merits further investigation since it may improve current management of diffuse large B-cell lymphoma patients with central nervous system involvement.

  14. Neuronal apoptosis: signal and cell diversity

    Directory of Open Access Journals (Sweden)

    Lina Vanessa Becerra


    Full Text Available Programmed cell death occurs as a physiological process during development. In the brain and spinal cord this event determines the number and location of the different cell types. In adulthood, programmed cell death or apoptosis is more restricted but it may play a major role in different acute and chronic pathological entities. However, in contrast to other tissues where apoptosis has been widely documented from a morphological point of view, in the central nervous system complete anatomical evidence of apoptosis is scanty. In spite of this there is consensus about the activation of different signal systems associated to programmed cell death. In the present article we attempt to summarize the main apoptotic pathways so far identified in nervous tissue. Considering that apoptotic pathways are multiple, the neuronal cell types are highly diverse and specialized and that neuronal response to injury and survival depends upon tissue context, (i.e., preservation of connectivity, glial integrity and cell matrix, blood supply and trophic factors availability what is relevant for the apoptotic process in a sector of the brain may not be important in another.

  15. Calcium signaling in pluripotent stem cells. (United States)

    Apáti, Ágota; Pászty, Katalin; Erdei, Zsuzsa; Szebényi, Kornélia; Homolya, László; Sarkadi, Balázs


    Pluripotent stem cells represent a new source of biological material allowing the exploration of signaling phenomena during normal cell development and differentiation. Still, the calcium signaling pathways and intracellular calcium responses to various ligands or stress conditions have not been sufficiently explored as yet in embryonic or induced pluripotent stem cells and in their differentiated offspring. This is partly due to the special culturing conditions of these cell types, the rapid morphological and functional changes in heterogeneous cell populations during early differentiation, and methodological problems in cellular calcium measurements. In this paper, we review the currently available data in the literature on calcium signaling in pluripotent stem cells and discuss the potential shortcomings of these studies. Various assay methods are surveyed for obtaining reliable data both in undifferentiated embryonic stem cells and in specific, stem cell-derived human tissues. In this paper, we present the modulation of calcium signaling in human embryonic stem cells (hESC) and in their derivates; mesenchymal stem cell like (MSCl) cells and cardiac tissues using the fluorescent calcium indicator Fluo-4 and confocal microscopy. LPA, trypsin and angiotensin II were effective in inducing calcium signals both in HUES9 and MSCl cells. Histamine and thrombin induced calcium signal exclusively in the MSCl cells, while ATP was effective only in HUES9 cells. There was no calcium signal evoked by GABA, even at relatively high concentrations. In stem cell-derived cardiomyocytes a rapid increase in the beating rate and an increase of the calcium signal peaks could be observed after the addition of adrenaline, while verapamil led to a strong decrease in cellular calcium and stopped spontaneous contractions in a relaxed state.

  16. Wnt/β-catenin signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients through the p53/p21 pathway. (United States)

    Gu, Zhifeng; Tan, Wei; Feng, Guijuan; Meng, Yan; Shen, Biyu; Liu, Hong; Cheng, Chun


    Recent studies have shown that allogeneic bone marrow (BM)-mesenchymal stem cell transplantation (MSCT) appears to be effective in systemic lupus erythematosus (SLE) patients and lupus-prone mice, contrary to studies in syngeneic BM-MSCT. These studies indicated that the abnormalities of BM-MSCs may be involved in the pathogenesis of SLE. Our studies and other previous studies have revealed that BM-MSCs from SLE patients exhibited early signs of senescence, such as flattened morphology, slow proliferation, increased senescence-associated β-galactosidase (SA-β-gal) activity, and so on. However, the mechanisms by which these cells senescences were still unclear. Previous studies have demonstrated that Wnt/β-catenin signaling plays an important role in stem cell senescence. In the current study, we investigated whether Wnt/β-catenin signaling mediates the senescence of BM-MSCs from SLE patients. We have found that Wnt/β-catenin signaling and the p53/p21 pathway were significantly hyperactivated in senescent SLE BM-MSCs. Treatment with 100 ng/mL Dickkopf-1 (DKK1), a Wnt/β-catenin signaling inhibitor or β-catenin siRNA for 48 h could reverse the senescent features of SLE BM-MSCs. Additionally, the expression levels of p53 and p21 were reduced in treated-SLE BM-MSCs compared with the untreated group. In summary, our study indicated that Wnt/β-catenin signaling may play a critical role in the senescence of SLE BM-MSCs through the p53/p21 pathway.

  17. Wnt Signaling in Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Qi Xu


    Full Text Available Renal cell carcinoma (RCC accounts for 90% of all kidney cancers. Due to poor diagnosis, high resistance to the systemic therapies and the fact that most RCC cases occur sporadically, current research switched its focus on studying the molecular mechanisms underlying RCC. The aim is the discovery of new effective and less toxic anti-cancer drugs and novel diagnostic markers. Besides the PI3K/Akt/mTOR, HGF/Met and VHL/hypoxia cellular signaling pathways, the involvement of the Wnt/β-catenin pathway in RCC is commonly studied. Wnt signaling and its targeted genes are known to actively participate in different biological processes during embryonic development and renal cancer. Recently, studies have shown that targeting this pathway by alternating/inhibiting its intracellular signal transduction can reduce cancer cells viability and inhibit their growth. The targets and drugs identified show promising potential to serve as novel RCC therapeutics and prognostic markers. This review aims to summarize the current status quo regarding recent research on RCC focusing on the involvement of the Wnt/β-catenin pathway and how its understanding could facilitate the identification of potential therapeutic targets, new drugs and diagnostic biomarkers.

  18. TNF-α stimulates System A amino acid transport in primary human trophoblast cells mediated by p38 MAPK signaling. (United States)

    Aye, Irving L M H; Jansson, Thomas; Powell, Theresa L


    Maternal obesity and gestational diabetes mellitus (GDM) increase the risk of delivering infants that are large for gestational age with greater adiposity, who are prone to the development of metabolic disease in childhood and beyond. These maternal conditions are also associated with increased levels of the proinflammatory cytokine TNF-α in maternal tissues and the placenta. Recent evidence suggests that changes in placental amino acid transport contribute to altered fetal growth. TNF-α was previously shown to stimulate System A amino acid transport in primary human trophoblasts (PHTs), however the molecular mechanisms remain unknown. In this study, we tested the hypothesis that TNF-α regulates amino acid uptake in cultured PHTs by a mitogen-activated protein kinase (MAPK)-dependent mechanism. Treatment of PHTs with TNF-α significantly increased System A amino acid transport, as well as Erk and p38 MAPK signaling. Pharmacological antagonism of p38, but not Erk MAPK activity, inhibited TNF-α stimulated System A activity. Silencing of p38 MAPK using siRNA transfections prevented TNF-α stimulated System A transport in PHTs. TNF-α significantly increased the protein expression of System A transporters SNAT1 and SNAT2, but did not affect their mRNA expression. The effects of TNF-α on SNAT1 and SNAT2 protein expression were reversed by p38 MAPK siRNA silencing. In conclusion, TNF-α regulates System A activity through increased SNAT1 and SNAT2 transporter protein expression in PHTs. These findings suggest that p38 MAPK may represent a critical mechanistic link between elevated proinflammatory cytokines and increased placental amino acid transport in obese and GDM pregnancies associated with fetal overgrowth.

  19. A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection

    Directory of Open Access Journals (Sweden)

    Mukta Dutta


    Full Text Available The unprecedented 2013–2016 outbreak of Ebola virus (EBOV resulted in over 11,300 human deaths. Host resistance to RNA viruses requires RIG-I-like receptor (RLR signaling through the adaptor protein, mitochondrial antiviral signaling protein (MAVS, but the role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here we apply a systems approach to MAVS−/− mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through the expression of IFNα, regulation of inflammatory responses in the spleen, and prevention of cell death in the liver, with macrophages implicated as a major cell type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional MAVS deletion in LysM+ myeloid cells. These findings reveal tissue-specific MAVS-dependent transcriptional pathways associated with resistance to EBOV, and they demonstrate that EBOV adaptation to cause disease in mice involves changes in two distinct events, RLR-MAVS antagonism and suppression of RLR-independent IFN-I responses.

  20. Spectrin-based skeleton as an actor in cell signaling. (United States)

    Machnicka, B; Grochowalska, R; Bogusławska, D M; Sikorski, A F; Lecomte, M C


    This review focuses on the recent advances in functions of spectrins in non-erythroid cells. We discuss new data concerning the commonly known role of the spectrin-based skeleton in control of membrane organization, stability and shape, and tethering protein mosaics to the cellular motors and to all major filament systems. Particular effort has been undertaken to highlight recent advances linking spectrin to cell signaling phenomena and its participation in signal transduction pathways in many cell types.

  1. Wnt Signaling in Cancer Stem Cell Biology. (United States)

    de Sousa E Melo, Felipe; Vermeulen, Louis


    Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like tumor cells that are responsible for fueling tumor growth. As therapeutic targeting of these tumor stem cells is an intense area of investigation, a concise understanding on how Wnt activity relates to cancer stem cell traits is needed. This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer.

  2. 49 CFR 236.514 - Interconnection of cab signal system with roadway signal system. (United States)


    ... 49 Transportation 4 2010-10-01 2010-10-01 false Interconnection of cab signal system with roadway signal system. 236.514 Section 236.514 Transportation Other Regulations Relating to Transportation... Interconnection of cab signal system with roadway signal system. The automatic cab signal system shall...

  3. Applied signal processing concepts, circuits, and systems

    CERN Document Server

    Hamdy, Nadder


    Introduction What are Signals? Signal parameters Why Signal processing? Analog vs. Digital Signal processing Practical Signal processing Systems Analog Signal Processing Amplitude Shaping Frequency Spectrum Shaping Phase Errors Correction Waveform Generation Analog Filter Design Describing Equations Design Procedures Filter Specifications Approximations to the Ideal Response Realization Practical RC-Filters Design Switched Capacitor Filter Realization Design examples Data Converters Introduction A typical DSP System Specifications of Data Converters Sampling Samp

  4. A model of cell biological signaling predicts a phase transition of signaling and provides mathematical formulae. (United States)

    Tsuruyama, Tatsuaki


    A biological signal is transmitted by interactions between signaling molecules in the cell. To date, there have been extensive studies regarding signaling pathways using numerical simulation of kinetic equations that are based on equations of continuity and Fick's law. To obtain a mathematical formulation of cell signaling, we propose a stability kinetic model of cell biological signaling of a simple two-parameter model based on the kinetics of the diffusion-limiting step. In the present model, the signaling is regulated by the binding of a cofactor, such as ATP. Non-linearity of the kinetics is given by the diffusion fluctuation in the interaction between signaling molecules, which is different from previous works that hypothesized autocatalytic reactions. Numerical simulations showed the presence of a critical concentration of the cofactor beyond which the cell signaling molecule concentration is altered in a chaos-like oscillation with frequency, which is similar to a discontinuous phase transition in physics. Notably, we found that the frequency is given by the logarithm function of the difference of the outside cofactor concentration from the critical concentration. This implies that the outside alteration of the cofactor concentration is transformed into the oscillatory alteration of cell inner signaling. Further, mathematical stability kinetic analysis predicted a discontinuous dynamic phase transition in the critical state at which the cofactor concentration is equivalent to the critical concentration. In conclusion, the present model illustrates a unique feature of cell signaling, and the stability analysis may provide an analytical framework of the cell signaling system and a novel formulation of biological signaling.

  5. Coupling Planar Cell Polarity Signaling to Morphogenesis

    Directory of Open Access Journals (Sweden)

    Jeffrey D. Axelrod


    Full Text Available Epithelial cells and other groups of cells acquire a polarity orthogonal to their apical–basal axes, referred to as Planar Cell Polarity (PCP. The process by which these cells become polarized requires a signaling pathway using Frizzled as a receptor. Responding cells sense cues from their environment that provide directional information, and they translate this information into cellular asymmetry. Most of what is known about PCP derives from studies in the fruit fly, Drosophila. We review what is known about how cells translate an unknown signal into asymmetric cytoskeletal reorganization. We then discuss how the vertebrate processes of convergent extension and cochlear hair-cell development may relate to Drosophila PCP signaling.

  6. Neuropeptide signalling systems in flatworms. (United States)

    McVeigh, P; Kimber, M J; Novozhilova, E; Day, T A


    Two distinct families of neuropeptides are known to endow platyhelminth nervous systems - the FMRFamide-like peptides (FLPs) and the neuropeptide Fs (NPFs). Flatworm FLPs are structurally simple, each 4-6 amino acids in length with a carboxy terminal aromatic-hydrophobic-Arg-Phe-amide motif. Thus far, four distinct flatworm FLPs have been characterized, with only one of these from a parasite. They have a widespread distribution within the central and peripheral nervous system of every flatworm examined, including neurones serving the attachment organs, the somatic musculature and the reproductive system. The only physiological role that has been identified for flatworm FLPs is myoexcitation. Flatworm NPFs are believed to be invertebrate homologues of the vertebrate neuropeptide Y (NPY) family of peptides. Flatworm NPFs are 36-39 amino acids in length and are characterized by a caboxy terminal GRPRFamide signature and conserved tyrosine residues at positions 10 and 17 from the carboxy terminal. Like FLPs, NPF occurs throughout flatworm nervous systems, although less is known about its biological role. While there is some evidence for a myoexcitatory action in cestodes and flukes, more compelling physiological data indicate that flatworm NPF inhibits cAMP levels in a manner that is characteristic of NPY action in vertebrates. The widespread expression of these neuropeptides in flatworm parasites highlights the potential of these signalling systems to yield new targets for novel anthelmintics. Although platyhelminth FLP and NPF receptors await identification, other molecules that play pivotal roles in neuropeptide signalling have been uncovered. These enzymes, involved in the biosynthesis and processing of flatworm neuropeptides, have recently been described and offer other distinct and attractive targets for therapeutic interference.

  7. Wnt signaling and stem cell control

    Institute of Scientific and Technical Information of China (English)

    Roel Nusse


    Wnt signaling has been implicated in the control over various types of stem cells and may act as a niche factor to maintain stem cells in a self-renewing state.As currently understood,Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface.Through several cytoplasmic relay components,the signal is transduced to B-catenin,which then enters the nucleus and forms a complex with TCF to activate transcription of Wnt target genes.Wnts can also signal through tyrosine kinase receptors,in particular the ROR and RYK receptors,leading to alternative modes of Wnt signaling.During the growth of tissues,these ligands and receptors are dynamically expressed,often transcriptionally controlled by Wnt signals themselves,to ensure the right balance between proliferation and differentiation.Isolated Wnt proteins are active on a variety of stem cells,including neural,mammary and embryonic stem cells.In general,Wnt proteins act to maintain the undifferentiated state of stem cells,while other growth factors instruct the cells to proliferate.These other factors include FGF and EGF,signaling through tyrosine kinase pathways.

  8. Cell signaling underlying epileptic behavior

    Directory of Open Access Journals (Sweden)

    Yuri eBozzi


    Full Text Available Epilepsy is a complex disease, characterized by the repeated occurrence of bursts of electrical activity (seizures in specific brain areas. The behavioral outcome of seizure events strongly depends on the brain regions that are affected by overactivity. Here we review the intracellular signaling pathways involved in the generation of seizures in epileptogenic areas. Pathways activated by modulatory neurotransmitters (dopamine, norepinephrine and serotonin, involving the activation of extracellular-regulated kinases (ERKs and the induction of immediate early genes (IEGs will be first discussed in relation to the occurrence of acute seizure events. Activation of immediate early genes has been proposed to lead to long-term molecular and behavioral responses induced by acute seizures. We also review deleterious consequences of seizure activity, focusing on the contribution of apoptosis-associated signaling pathways to the progression of the disease. A deep understanding of signaling pathways involved in both acute and long-term responses to seizures continues to be crucial to unravel the origins of epileptic behaviors and ultimately identify novel therapeutic targets for the cure of epilepsy.

  9. N-Acetylglucosamine Functions in Cell Signaling

    Directory of Open Access Journals (Sweden)

    James B. Konopka


    Full Text Available The amino sugar N-acetylglucosamine (GlcNAc is well known for the important structural roles that it plays at the cell surface. It is a key component of bacterial cell wall peptidoglycan, fungal cell wall chitin, and the extracellular matrix of animal cells. Interestingly, recent studies have also identified new roles for GlcNAc in cell signaling. For example, GlcNAc stimulates the human fungal pathogen Candida albicans to undergo changes in morphogenesis and expression of virulence genes. Pathogenic E. coli responds to GlcNAc by altering the expression of fimbriae and CURLI fibers that promote biofilm formation and GlcNAc stimulates soil bacteria to undergo changes in morphogenesis and production of antibiotics. Studies with animal cells have revealed that GlcNAc influences cell signaling through the posttranslational modification of proteins by glycosylation. O-linked attachment of GlcNAc to Ser and Thr residues regulates a variety of intracellular proteins, including transcription factors such as NFκB, c-myc, and p53. In addition, the specificity of Notch family receptors for different ligands is altered by GlcNAc attachment to fucose residues in the extracellular domain. GlcNAc also impacts signal transduction by altering the degree of branching of N-linked glycans, which influences cell surface signaling proteins. These emerging roles of GlcNAc as an activator and mediator of cellular signaling in fungi, animals, and bacteria will be the focus of this paper.

  10. Activated PTHLH Coupling Feedback Phosphoinositide to G-Protein Receptor Signal-Induced Cell Adhesion Network in Human Hepatocellular Carcinoma by Systems-Theoretic Analysis

    Directory of Open Access Journals (Sweden)

    Lin Wang


    Full Text Available Studies were done on analysis of biological processes in the same high expression (fold change ≥2 activated PTHLH feedback-mediated cell adhesion gene ontology (GO network of human hepatocellular carcinoma (HCC compared with the corresponding low expression activated GO network of no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection. Activated PTHLH feedback-mediated cell adhesion network consisted of anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolism, cell adhesion, cell differentiation, cell-cell signaling, G-protein-coupled receptor protein signaling pathway, intracellular transport, metabolism, phosphoinositide-mediated signaling, positive regulation of transcription, regulation of cyclin-dependent protein kinase activity, regulation of transcription, signal transduction, transcription, and transport in HCC. We proposed activated PTHLH coupling feedback phosphoinositide to G-protein receptor signal-induced cell adhesion network. Our hypothesis was verified by the different activated PTHLH feedback-mediated cell adhesion GO network of HCC compared with the corresponding inhibited GO network of no-tumor hepatitis/cirrhotic tissues, or the same compared with the corresponding inhibited GO network of HCC. Activated PTHLH coupling feedback phosphoinositide to G-protein receptor signal-induced cell adhesion network included BUB1B, GNG10, PTHR2, GNAZ, RFC4, UBE2C, NRXN3, BAP1, PVRL2, TROAP, and VCAN in HCC from GEO dataset using gene regulatory network inference method and our programming.

  11. Spectrin-based skeleton as an actor in cell signaling


    Machnicka, B.; Grochowalska, R.; Bogusławska, D. M.; Sikorski, A F; Lecomte, M C


    This review focuses on the recent advances in functions of spectrins in non-erythroid cells. We discuss new data concerning the commonly known role of the spectrin-based skeleton in control of membrane organization, stability and shape, and tethering protein mosaics to the cellular motors and to all major filament systems. Particular effort has been undertaken to highlight recent advances linking spectrin to cell signaling phenomena and its participation in signal transduction pathways in man...

  12. Syndecans, signaling, and cell adhesion

    DEFF Research Database (Denmark)

    Couchman, J R; Woods, A


    Syndecans are transmembrane proteoglycans which can participate in diverse cell surface interactions, involving extracellular matrix macromolecules, growth factors, protease inhibitors, and even viral entry. Currently, all extracellular interactions are believed to be mediated by distinct...... structures within the heparan sulfate chains, leaving the roles of chondroitin sulfate chains and extracellular portion of the core proteins to be elucidated. Evidence that syndecans are a class of receptor involved in cell adhesion is mounting, and their small cytoplasmic domains may link...

  13. Tracking Hypoxic Signaling in Encapsulated Stem Cells (United States)

    Sahai, Suchit; McFarland, Rachel; Skiles, Mathew L.; Sullivan, Denise; Williams, Amanda


    Oxygen is not only a nutrient but also an important signaling molecule whose concentration can influence the fate of stem cells. This study details the development of a marker of hypoxic signaling for use with encapsulated cells. Testing of the marker was performed with adipose-derived stem cells (ADSCs) in two-dimensional (2D) and 3D culture conditions in varied oxygen environments. The cells were genetically modified with our hypoxia marker, which produces a red fluorescent protein (DsRed-DR), under the control of a hypoxia-responsive element (HRE) trimer. For 3D culture, ADSCs were encapsulated in poly(ethylene glycol)–based hydrogels. The hypoxia marker (termed HRE DsRed-DR) is built on a recombinant adenovirus and ADSCs infected with the marker will display red fluorescence when hypoxic signaling is active. This marker was not designed to measure local oxygen concentration but rather to show how a cell perceives its local oxygen concentration. ADSCs cultured in both 2D and 3D were exposed to 20% or 1% oxygen environments for 96 h. In 2D at 20% O2, the marker signal was not observed during the study period. In 1% O2, the fluorescent signal was first observed at 24 h, with maximum prevalence observed at 96 h as 59%±3% cells expressed the marker. In 3D, the signal was observed in both 1% and 20% O2. The onset of signal in 1% O2 was observed at 4 h, reaching maximum prevalence at 96 h with 76%±4% cells expressing the marker. Interestingly, hypoxic signal was also observed in 20% O2, with 13%±3% cells showing positive marker signal after 96 h. The transcription factor subunit hypoxia inducible factor-1α was tracked in these cells over the same time period by immunostaining and western blot analysis. Immunostaining results in 2D correlated well with our marker at 72 h and 96 h, but 3D results did not correlate well. The western blotting results in 2D and 3D correlated well with the fluorescent marker. The HRE DsRed-DR virus can be used to track

  14. Altered calcium signaling in cancer cells. (United States)

    Stewart, Teneale A; Yapa, Kunsala T D S; Monteith, Gregory R


    It is the nature of the calcium signal, as determined by the coordinated activity of a suite of calcium channels, pumps, exchangers and binding proteins that ultimately guides a cell's fate. Deregulation of the calcium signal is often deleterious and has been linked to each of the 'cancer hallmarks'. Despite this, we do not yet have a full understanding of the remodeling of the calcium signal associated with cancer. Such an understanding could aid in guiding the development of therapies specifically targeting altered calcium signaling in cancer cells during tumorigenic progression. Findings from some of the studies that have assessed the remodeling of the calcium signal associated with tumorigenesis and/or processes important in invasion and metastasis are presented in this review. The potential of new methodologies is also discussed. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

  15. Novel, unifying mechanism for mescaline in the central nervous system: electrochemistry, catechol redox metabolite, receptor, cell signaling and structure activity relationships. (United States)

    Kovacic, Peter; Somanathan, Ratnasamy


    A unifying mechanism for abused drugs has been proposed previously from the standpoint of electron transfer. Mescaline can be accommodated within the theoretical framework based on redox cycling by the catechol metabolite with its quinone counterpart. Electron transfer may play a role in electrical effects involving the nervous system in the brain. This approach is in accord with structure activity relationships involving mescaline, abused drugs, catecholamines, and etoposide. Inefficient demethylation is in keeping with the various drug properties, such as requirement for high dosage and slow acting. There is a discussion of receptor binding, electrical effects, cell signaling and other modes of action. Mescaline is a nonselective, seretonin receptor agonist. 5-HTP receptors are involved in the stimulus properties. Research addresses the aspect of stereochemical requirements. Receptor binding may involve the proposed quinone metabolite and/or the amino sidechain via protonation. Electroencephalographic studies were performed on the effects of mescaline on men. Spikes are elicited by stimulation of a cortical area. The potentials likely originate in nonsynaptic dendritic membranes. Receptor-mediated signaling pathways were examined which affect mescaline behavior. The hallucinogen belongs to the class of 2AR agonists which regulate pathways in cortical neurons. The research identifies neural and signaling mechanisms responsible for the biological effects. Recently, another hallucinogen, psilocybin, has been included within the unifying mechanistic framework. This mushroom constituent is hydrolyzed to the phenol psilocin, also active, which is subsequently oxidized to an ET o-quinone or iminoquinone.

  16. Notch signaling in cancer stem cells. (United States)

    Wang, Jialiang; Sullenger, Bruce A; Rich, Jeremy N


    Subpopulations of cancer cells with stem cell-like characteristics, termed cancer stem cells, have been identified in a wide range of human cancers. Cancer stem cells are defined by their ability to self-renew as well as recapitulate the original heterogeneity of cancer cells in culture and in serial xenotransplants. Not only are cancer stem cells highly tumorigenic, but these cells are implicated in tumor resistance to conventional chemotherapy and radiotherapy, thus highlighting their significance as therapeutic targets. Considerable similarities have been found between cancer stem cells and normal stem cells on their dependence on certain signaling pathways. More specifically, the core stem cell signaling pathways, such as the Wnt, Notch and Hedgehog pathways, also critically regulate the self-renewal and survival of cancer stem cells. While the oncogenic functions of Notch pathway have been well documented, its role in cancer stem cells is just emerging. In this chapter, we will discuss recent advances in cancer stem cell research and highlight the therapeutic potential of targeting Notch in cancer stem cells.

  17. Cell signalling and phospholipid metabolism. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Boss, W.F.


    These studies explored whether phosphoinositide (PI) has a role in plants analogous to its role in animal cells. Although no parallel activity of PI in signal transduction was found in plant cells, activity of inositol phospholipid kinase was found to be modulated by light and by cell wall degrading enzymes. These studies indicate a major role for inositol phospholipids in plant growth and development as membrane effectors but not as a source of second messengers.

  18. Minocycline suppresses interleukine-6, its receptor system and signaling pathways and impairs migration, invasion and adhesion capacity of ovarian cancer cells: in vitro and in vivo studies.

    Directory of Open Access Journals (Sweden)

    Parvin Ataie-Kachoie

    Full Text Available Interleukin (IL-6 has been shown to be a major contributing factor in growth and progression of ovarian cancer. The cytokine exerts pro-tumorigenic activity through activation of several signaling pathways in particular signal transducer and activator of transcription (STAT3 and extracellular signal-regulated kinase (ERK1/2. Hence, targeting IL-6 is becoming increasingly attractive as a treatment option in ovarian cancer. Here, we investigated the effects of minocycline on IL-6 and its signaling pathways in ovarian cancer. In vitro, minocycline was found to significantly suppress both constitutive and IL-1β or 4-hydroxyestradiol (4-OH-E2-stimulated IL-6 expression in human ovarian cancer cells; OVCAR-3, SKOV-3 and CAOV-3. Moreover, minocycline down-regulated two major components of IL-6 receptor system (IL-6Rα and gp130 and blocked the activation of STAT3 and ERK1/2 pathways leading to suppression of the downstream product MCL-1. In female nude mice bearing intraperitoneal OVCAR-3 tumors, acute administration (4 and 24 h of minocycline (30 mg/kg led to suppression of IL-6. Even single dose of minocycline was effective at significantly lowering plasma and tumor IL-6 levels. In line with this, tumoral expression of p-STAT3, p-ERK1/2 and MCL-1 were decreased in minocycline-treated mice. Evaluation of the functional implication of minocycline on metastatic activity revealed the capacity of minocycline to inhibit cellular migration, invasion and adhesion associated with down-regulation of matrix metalloproteinases (MMP-2 and 9. Thus, the data suggest a potential role for minocycline in suppressing IL-6 expression and activity. These effects may prove to be an important attribute to the upcoming clinical trials of minocycline in ovarian cancer.

  19. Novel aspects concerning the functional cross-talk between the insulin/IGF-I system and estrogen signaling in cancer cells

    Directory of Open Access Journals (Sweden)

    Marcello eMaggiolini


    Full Text Available The insulin/IGF system plays an important role in cancer progression. Accordingly, elevated levels of circulating insulin have been associated with an increased cancer risk as well as with aggressive and metastatic cancer phenotypes. Numerous studies have documented that estrogens cooperate with the insulin/IGF system in multiple pathophysiological conditions. The biological responses to estrogens are mainly mediated by the estrogen receptors (ERα and ERβ, which act as transcription factors, however, several studies have recently demonstrated that a member of the G protein-coupled receptors, named GPR30/GPER, is also involved in the estrogen signaling in normal and malignant cells as well as in cancer-associated fibroblasts (CAFs. In this regard, novel mechanisms linking the action of estrogens through GPER with the insulin/IGF system have been recently demonstrated. This review recapitulates the relevant aspects of this functional cross-talk between the insulin/IGF and the estrogenic GPER transduction pathways, which occurs in various cell types and may account for cancer progression.

  20. Development and validation of a high-throughput cell-based screen to identify activators of a bacterial two-component signal transduction system. (United States)

    van Rensburg, Julia J; Fortney, Kate R; Chen, Lan; Krieger, Andrew J; Lima, Bruno P; Wolfe, Alan J; Katz, Barry P; Zhang, Zhong-Yin; Spinola, Stanley M


    CpxRA is a two-component signal transduction system (2CSTS) found in many drug-resistant Gram-negative bacteria. In response to periplasmic stress, CpxA autophosphorylates and donates a phosphoryl group to its cognate response regulator, CpxR. Phosphorylated CpxR (CpxR-P) upregulates genes involved in membrane repair and downregulates multiple genes that encode virulence factors, which are trafficked across the cell membrane. Mutants that constitutively activate CpxRA in Salmonella enterica serovar Typhimurium and Haemophilus ducreyi are avirulent in mice and humans, respectively. Thus, the activation of CpxRA has high potential as a novel antimicrobial/antivirulence strategy. Using a series of Escherichia coli strains containing a CpxR-P-responsive lacZ reporter and deletions in genes encoding CpxRA system components, we developed and validated a novel cell-based high-throughput screen (HTS) for CpxRA activators. A screen of 36,000 compounds yielded one hit compound that increased reporter activity in wild-type cells. This is the first report of a compound that activates, rather than inhibits, a 2CSTS. The activity profile of the compound against CpxRA pathway mutants in the presence of glucose suggested that the compound inhibits CpxA phosphatase activity. We confirmed that the compound induced the accumulation of CpxR-P in treated cells. Although the hit compound contained a nitro group, a derivative lacking this group retained activity in serum and had lower cytotoxicity than that of the initial hit. This HTS is amenable for the screening of larger libraries to find compounds that activate CpxRA by other mechanisms, and it could be adapted to find activators of other two-component systems.

  1. Etk/Bmx mediates expression of stress-induced adaptive genes VEGF, PAI-1, and iNOS via multiple signaling cascades in different cell systems. (United States)

    Chau, Cindy H; Clavijo, Carlos A; Deng, Hong-Tao; Zhang, Qunzhou; Kim, Kwang-Jin; Qiu, Yun; Le, Anh D; Ann, David K


    We recently showed that Etk/Bmx, a member of the Tec family of nonreceptor protein tyrosine kinases, promotes tight junction formation during chronic hypoxic exposure and augments normoxic VEGF expression via a feedforward mechanism. Here we further characterized Etk's role in potentiating hypoxia-induced gene expression in salivary epithelial Pa-4 cells. Using transient transfection in conditionally activated Etk (DeltaEtk:ER) cells, we demonstrated that Etk enhances hypoxia-response element-dependent reporter activation in normoxia and hypoxia. This Etk-driven reporter activation is ameliorated by treatment with wortmannin or LFM-A13. Using lentivirus-mediated gene delivery and small interfering RNA, we provided direct evidence that hypoxia leads to transient Etk and Akt activation and hypoxia-mediated Akt activation is Etk dependent. Northern blot analyses confirmed that Etk activation led to induction of steady-state mRNA levels of endogenous VEGF and plasminogen activator inhibitor (PAI)-1, a hallmark of hypoxia-mediated gene regulation. We also demonstrated that Etk utilizes a phosphatidylinositol 3-kinase/Akt pathway to promote reporter activation driven by NF-kappaB, another oxygen-sensitive transcription factor, and to augment cytokine-induced inducible nitric oxide synthase expression in endothelial cells. To establish the clinical relevance of Etk-induced, hypoxia-mediated gene regulation, we examined Etk expression in keloid, which has elevated VEGF and PAI-1. We found that Etk is overexpressed in keloid (but not normal skin) tissues. The differential steady-state Etk protein levels were further confirmed in primary fibroblast cultures derived from these tissues, suggesting an Etk role in tissue fibrosis. Our results provide further understanding of Etk function within multiple signaling cascades to govern adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial cells, brain endothelial cells, and dermal

  2. Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. (United States)

    Axelrod, J D; Miller, J R; Shulman, J M; Moon, R T; Perrimon, N


    In Drosophila, planar cell polarity (PCP) signaling is mediated by the receptor Frizzled (Fz) and transduced by Dishevelled (Dsh). Wingless (Wg) signaling also requires Dsh and may utilize DFz2 as a receptor. Using a heterologous system, we show that Dsh is recruited selectively to the membrane by Fz but not DFz2, and this recruitment depends on the DEP domain but not the PDZ domain in Dsh. A mutation in the DEP domain impairs both membrane localization and the function of Dsh in PCP signaling, indicating that translocation is important for function. Further genetic and molecular analyses suggest that conserved domains in Dsh function differently during PCP and Wg signaling, and that divergent intracellular pathways are activated. We propose that Dsh has distinct roles in PCP and Wg signaling. The PCP signal may selectively result in focal Fz activation and asymmetric relocalization of Dsh to the membrane, where Dsh effects cytoskeletal reorganization to orient prehair initiation.

  3. Cytokine signalling in embryonic stem cells

    DEFF Research Database (Denmark)

    Kristensen, David Møbjerg; Kalisz, Mark; Nielsen, Jens Høiriis


    Cytokines play a central role in maintaining self-renewal in mouse embryonic stem (ES) cells through a member of the interleukin-6 type cytokine family termed leukemia inhibitory factor (LIF). LIF activates the JAK-STAT3 pathway through the class I cytokine receptor gp130, which forms a trimeric...... pathways seem to converge on c-myc as a common target to promote self-renewal. Whereas LIF does not seem to stimulate self-renewal in human embryonic stem cells it cannot be excluded that other cytokines are involved. The pleiotropic actions of the increasing number of cytokines and receptors signalling...... via JAKs, STATs and SOCS exhibit considerable redundancy, compensation and plasticity in stem cells in accordance with the view that stem cells are governed by quantitative variations in strength and duration of signalling events known from other cell types rather than qualitatively different stem...

  4. Primary Cilia, Signaling Networks and Cell Migration

    DEFF Research Database (Denmark)

    Veland, Iben Rønn

    Primary cilia are microtubule-based, sensory organelles that emerge from the centrosomal mother centriole to project from the surface of most quiescent cells in the human body. Ciliary entry is a tightly controlled process, involving diffusion barriers and gating complexes that maintain a unique...... this controls directional cell migration as a physiological response. The ciliary pocket is a membrane invagination with elevated activity of clathrin-dependent endocytosis (CDE). In paper I, we show that the primary cilium regulates TGF-β signaling and the ciliary pocket is a compartment for CDE...... on formation of the primary cilium and CDE at the pocket region. The ciliary protein Inversin functions as a molecular switch between canonical and non-canonical Wnt signaling. In paper II, we show that Inversin and the primary cilium control Wnt signaling and are required for polarization and cell migration...

  5. IAP family of cell death and signaling regulators. (United States)

    Silke, John; Vucic, Domagoj


    Inhibitor of apoptosis (IAP) proteins interface with, and regulate a large number of, cell signaling pathways. If there is a common theme to these pathways, it is that they are involved in the development of the immune system, immune responses, and unsurprisingly, given their name, cell death. Beyond that it is difficult to discover an underlying logic because sometimes IAPs are required to inhibit or prevent signaling, whereas in other cases they are required for signaling to take place. In whatever role they play, they are recruited into signaling complexes and function as ubiquitin E3 ligases, via their RING domains. This review discusses IAP regulation of signaling pathways and focuses on the mammalian IAPs, XIAP, c-IAP1, and c-IAP2, with a particular emphasis on techniques and methods that were used to uncover their roles. We also provide a perspective on targeting IAP proteins for therapeutic intervention and methods used to define the clinical relevance of IAP proteins.

  6. The application of information theory to biochemical signaling systems. (United States)

    Rhee, Alex; Cheong, Raymond; Levchenko, Andre


    Cell signaling can be thought of fundamentally as an information transmission problem in which chemical messengers relay information about the external environment to the decision centers within a cell. Due to the biochemical nature of cellular signal transduction networks, molecular noise will inevitably limit the fidelity of any messages received and processed by a cell's signal transduction networks, leaving it with an imperfect impression of its environment. Fortunately, Shannon's information theory provides a mathematical framework independent of network complexity that can quantify the amount of information that can be transmitted despite biochemical noise. In particular, the channel capacity can be used to measure the maximum number of stimuli a cell can distinguish based upon the noisy responses of its signaling systems. Here, we provide a primer for quantitative biologists that covers fundamental concepts of information theory, highlights several key considerations when experimentally measuring channel capacity, and describes successful examples of the application of information theoretic analysis to biological signaling.

  7. Syndecans in tumor cell adhesion and signaling

    Directory of Open Access Journals (Sweden)

    Rapraeger Alan C


    Full Text Available Abstract Anchorage of cells to "heparin" – binding domains that are prevalent in extracellular matrix (ECM components is thought to occur primarily through the syndecans, a four-member family of transmembrane heparan sulfate proteoglycans that communicate environmental cues from the ECM to the cytoskeleton and the signaling apparatus of the cell. Known activities of the syndecans trace to their highly conserved cytoplasmic domains and to their heparan sulfate chains, which can serve to regulate the signaling of growth factors and morphogens. However, several emerging studies point to critical roles for the syndecans' extracellular protein domains in tumor cell behavior to include cell adhesion and invasion. Although the mechanisms of these activities remain largely unknown, one possibility involves "co-receptor" interactions with integrins that may regulate integrin function and the cell adhesion-signaling phenotype. Thus, alterations in syndecan expression, leading to either overexpression or loss of expression, both of which take place in tumor cells, may have dramatic effects on tumor cell invasion.

  8. The IRS-1 signaling system. (United States)

    White, M F


    IRS-1 is a principal substrate of the insulin receptor tyrosine kinase. It undergoes multi-site tyrosine phosphorylation and mediates the insulin signal by associating with various signaling molecules containing Src homology 2 domains. Interleukin-4 also stimulates IRS-1 phosphorylation, and it is suspected that a few more growth factors or cytokines will be added to form a select group of receptors that utilize the IRS-1 signaling pathway. More IRS-1-like adapter molecules, such as 4PS (IRS-2), may remain to be found.

  9. Signals and systems primer with Matlab

    CERN Document Server

    Poularikas, Alexander D


    Signals and Systems Primer with MATLAB® equally emphasizes the fundamentals of both analog and digital signals and systems. To ensure insight into the basic concepts and methods, the text presents a variety of examples that illustrate a wide range of applications, from microelectromechanical to worldwide communication systems. It also provides MATLAB functions and procedures for practice and verification of these concepts.Taking a pedagogical approach, the author builds a solid foundation in signal processing as well as analog and digital systems. The book first introduces orthogonal signals,

  10. LIF signaling in stem cells and development. (United States)

    Onishi, Kento; Zandstra, Peter W


    Leukemia inhibitory factor (LIF) is a member of the interleukin-6 (IL-6) cytokine family. All members of this family activate signal transducer and activator of transcription 3 (STAT3), a transcription factor that influences stem and progenitor cell identity, proliferation and cytoprotection. The role of LIF in development was first identified when LIF was demonstrated to support the propagation of mouse embryonic stem cells. Subsequent studies of mice deficient for components of the LIF pathway have revealed important roles for LIF signaling during development and homeostasis. Here and in the accompanying poster, we provide a broad overview of JAK-STAT signaling during development, with a specific focus on LIF-mediated JAK-STAT3 activation.

  11. MAPK Cascades in Guard Cell Signal Transduction (United States)

    Lee, Yuree; Kim, Yun Ju; Kim, Myung-Hee; Kwak, June M.


    Guard cells form stomata on the epidermis and continuously respond to endogenous and environmental stimuli to fine-tune the gas exchange and transpirational water loss, processes which involve mitogen-activated protein kinase (MAPK) cascades. MAPKs form three-tiered kinase cascades with MAPK kinases and MAPK kinase kinases, by which signals are transduced to the target proteins. MAPK cascade genes are highly conserved in all eukaryotes, and they play crucial roles in myriad developmental and physiological processes. MAPK cascades function during biotic and abiotic stress responses by linking extracellular signals received by receptors to cytosolic events and gene expression. In this review, we highlight recent findings and insights into MAPK-mediated guard cell signaling, including the specificity of MAPK cascades and the remaining questions. PMID:26904052

  12. MAPK cascades in guard cell signal transduction

    Directory of Open Access Journals (Sweden)

    Yuree eLee


    Full Text Available Guard cells form stomata on the epidermis and continuously respond to endogenous and environmental stimuli to fine-tune the gas exchange and transpirational water loss, processes which involve mitogen-activated protein kinase (MAPK cascades. MAPKs form three-tiered kinase cascades with MAPK kinases and MAPK kinase kinases, by which signals are transduced to the target proteins. MAPK cascade genes are highly conserved in all eukaryotes, and they play crucial roles in myriad developmental and physiological processes. MAPK cascades function during biotic and abiotic stress responses by linking extracellular signals received by receptors to cytosolic events and gene expression. In this review, we highlight recent findings and insights into MAPK-mediated guard cell signaling, including the specificity of MAPK cascades and the remaining questions.

  13. Signaling involved in stem cell reprogramming and differentiation

    Institute of Scientific and Technical Information of China (English)

    Shihori; Tanabe


    Stem cell differentiation is regulated by multiple signaling events. Recent technical advances have reve-aled that differentiated cells can be reprogrammed into stem cells. The signals involved in stem cell pro-gramming are of major interest in stem cell research. The signaling mechanisms involved in regulating stem cell reprogramming and differentiation are the subject of intense study in the field of life sciences. In this review,the molecular interactions and signaling pathways related to stem cell differentiation are discussed.

  14. Chloroplast signaling within, between and beyond cells.

    Directory of Open Access Journals (Sweden)

    Krzysztof eBobik


    Full Text Available The most conspicuous function of the plastid is oxygenic photosynthesis of chloroplasts, yet plastids are super-factories that produce a plethora of compounds that are indispensable for proper plant physiology and development. Given their origins as free-living prokaryotes, it is not surprising that the plastid possesses its own genome whose expression is essential to plastid function. This semi-autonomous character of plastids requires the existence of sophisticated regulatory mechanisms that provide reliable communication between them and other cellular compartments. Such intracellular signaling is necessary for coordinating whole-cell responses to constantly varying environmental cues and cellular metabolic needs. This is achieved by plastids acting as receivers and transmitters of specific signals that coordinate expression of the nuclear and plastid genomes according to particular needs. In this review we will consider the so-called retrograde signaling occurring between plastids and nucleus, and between plastids and other organelles. Another important role of the plastid we will discuss is the involvement of plastid signaling in biotic and abiotic stress that, in addition to influencing retrograde signaling has direct effects on several cellular compartments including the cell wall. We will also review recent evidence pointing to an intriguing function of chloroplasts in regulating intercellular symplasmic transport. Finally, we consider an intriguing yet neglected aspect of plant biology, chloroplast signaling from the perspective of the entire plant. Thus, accumulating evidence highlights that chloroplasts, with their complex signaling pathways, provide a mechanism for exquisite regulation of plant development, metabolism and responses to the environment. As chloroplast processes are targeted for engineering for improved productivity the effect of such modifications on chloroplast signaling will have to be carefully considered in order

  15. Probing Signal Design for Power System Identification

    Energy Technology Data Exchange (ETDEWEB)

    Pierre, John W.; Zhou, Ning; Tuffner, Francis K.; Hauer, John F.; Trudnowski, Daniel J.; Mittelstadt, William


    This paper investigates the design of effective input signals for low-level probing of power systems. In 2005, 2006, and 2008 the Western Electricity Coordinating Council (WECC) conducted four large-scale system wide tests of the western interconnected power system where probing signals were injected by modulating the control signal at the Celilo end of the Pacific DC intertie. A major objective of these tests is the accurate estimation of the inter-area electromechanical modes. A key aspect of any such test is the design of an effective probing signal that leads to measured outputs rich in information about the modes. This paper specifically studies low-level probing signal design for power-system identification. The paper describes the design methodology and the advantages of this new probing signal which was successfully applied during these tests. This probing input is a multi-sine signal with its frequency content focused in the range of the inter-area modes. The period of the signal is over two minutes providing high-frequency resolution. Up to 15 cycles of the signal are injected resulting in a processing gain of 15. The resulting system response is studied in the time and frequency domains. Because of the new probing signal characteristics, these results show significant improvement in the output SNR compared to previous tests.

  16. Neurotrophin signaling in cancer stem cells. (United States)

    Chopin, Valérie; Lagadec, Chann; Toillon, Robert-Alain; Le Bourhis, Xuefen


    Cancer stem cells (CSCs), are thought to be at the origin of tumor development and resistance to therapies. Thus, a better understanding of the molecular mechanisms involved in the control of CSC stemness is essential to the design of more effective therapies for cancer patients. Cancer cell stemness and the subsequent expansion of CSCs are regulated by micro-environmental signals including neurotrophins. Over the years, the roles of neurotrophins in tumor development have been well established and regularly reviewed. Especially, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are reported to stimulate tumor cell proliferation, survival, migration and/or invasion, and favors tumor angiogenesis. More recently, neurotrophins have been reported to regulate CSCs. This review briefly presents neurotrophins and their receptors, summarizes their roles in different cancers, and discusses the emerging evidence of neurotrophins-induced enrichment of CSCs as well as the involved signaling pathways.

  17. Intracellular Signals of T Cell Costimulation

    Institute of Scientific and Technical Information of China (English)

    Jianxun Song; Fengyang Tylan Lei; Xiaofang Xiong; Rizwanul Haque


    Ligation of T cell receptor (TCR) alone is insufficient to induce full activation of T lymphocytes. Additional ligand-receptor interactions (costimulation) on antigen presenting cells (APCs) and T cells are required. T cell costimulation has been shown to be essential for eliciting efficient T cell responses, involving all phases during T cell development. However, the mechanisms by which costimulation affects the function of T cells still need to be elucidated. In recent years, advances have been made in studies of costimulation as potential therapies in cancer, infectious disease as well as autoimmune disease. In this review, we discussed intracellular costimulation signals that regulate T cell proliferation, cell cycle progression, cytokine production, survival, and memory development. In general, the pathway of phosphoinositide-3 kinase (PBK)/protein kinase B (PKB, also known as Akt)/nuclear factor κB (NF-κB) might be central to many costimulatory effects. Through these pathways, costimulation controls T-cell expansion and proliferation by maintenance of survivin and aurora B expression, and sustains long-term T-cell survival and memory development by regulating the expression of bci-2 family members. Cellular & Molecular Immunology.2008;5(4):239-247.

  18. Tracking Hypoxic Signaling within Encapsulated Cell Aggregates (United States)

    Skiles, Matthew L.; Sahai, Suchit; Blanchette, James O.


    In Diabetes mellitus type 1, autoimmune destruction of the pancreatic β-cells results in loss of insulin production and potentially lethal hyperglycemia. As an alternative treatment option to exogenous insulin injection, transplantation of functional pancreatic tissue has been explored1,2. This approach offers the promise of a more natural, long-term restoration of normoglycemia. Protection of the donor tissue from the host's immune system is required to prevent rejection and encapsulation is a method used to help achieve this aim. Biologically-derived materials, such as alginate3 and agarose4, have been the traditional choice for capsule construction but may induce inflammation or fibrotic overgrowth5 which can impede nutrient and oxygen transport. Alternatively, synthetic poly(ethylene glycol) (PEG)-based hydrogels are non-degrading, easily functionalized, available at high purity, have controllable pore size, and are extremely biocompatible,6,7,8. As an additional benefit, PEG hydrogels may be formed rapidly in a simple photo-crosslinking reaction that does not require application of non-physiological temperatures6,7. Such a procedure is described here. In the crosslinking reaction, UV degradation of the photoinitiator, 1-[4-(2-Hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propane-1-one (Irgacure 2959), produces free radicals which attack the vinyl carbon-carbon double bonds of dimethacrylated PEG (PEGDM) inducing crosslinking at the chain ends. Crosslinking can be achieved within 10 minutes. PEG hydrogels constructed in such a manner have been shown to favorably support cells7,9, and the low photoinitiator concentration and brief exposure to UV irradiation is not detrimental to viability and function of the encapsulated tissue10. While we methacrylate our PEG with the method described below, PEGDM can also be directly purchased from vendors such as Sigma. An inherent consequence of encapsulation is isolation of the cells from a vascular network. Supply of

  19. Tracking hypoxic signaling within encapsulated cell aggregates. (United States)

    Skiles, Matthew L; Sahai, Suchit; Blanchette, James O


    In Diabetes mellitus type 1, autoimmune destruction of the pancreatic β-cells results in loss of insulin production and potentially lethal hyperglycemia. As an alternative treatment option to exogenous insulin injection, transplantation of functional pancreatic tissue has been explored. This approach offers the promise of a more natural, long-term restoration of normoglycemia. Protection of the donor tissue from the host's immune system is required to prevent rejection and encapsulation is a method used to help achieve this aim. Biologically-derived materials, such as alginate and agarose, have been the traditional choice for capsule construction but may induce inflammation or fibrotic overgrowth which can impede nutrient and oxygen transport. Alternatively, synthetic poly(ethylene glycol) (PEG)-based hydrogels are non-degrading, easily functionalized, available at high purity, have controllable pore size, and are extremely biocompatible. As an additional benefit, PEG hydrogels may be formed rapidly in a simple photo-crosslinking reaction that does not require application of non-physiological temperatures. Such a procedure is described here. In the crosslinking reaction, UV degradation of the photoinitiator, 1-[4-(2-Hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propane-1-one (Irgacure 2959), produces free radicals which attack the vinyl carbon-carbon double bonds of dimethacrylated PEG (PEGDM) inducing crosslinking at the chain ends. Crosslinking can be achieved within 10 minutes. PEG hydrogels constructed in such a manner have been shown to favorably support cells, and the low photoinitiator concentration and brief exposure to UV irradiation is not detrimental to viability and function of the encapsulated tissue. While we methacrylate our PEG with the method described below, PEGDM can also be directly purchased from vendors such as Sigma. An inherent consequence of encapsulation is isolation of the cells from a vascular network. Supply of nutrients, notably oxygen

  20. Intelligent Multimodal Signal Adaptation System Project (United States)

    National Aeronautics and Space Administration — Micro Analysis and Design (MA&D) is pleased to submit this proposal to design an Intelligent Multimodal Signal Adaptation System. This system will dynamically...

  1. Cytokinin signaling regulates pavement cell morphogenesis in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    Hongjiang Li; Tongda Xu; Deshu Lin; Mingzhang Wen; Mingtang Xie; Jér(o)me Duclercq; Agnieszka Bielach


    The puzzle piece-shaped Arabidopsis leaf pavement cells (PCs) with interdigitated lobes and indents is a good model system to investigate the mechanisms that coordinate cell polarity and shape formation within a tissue.Auxin has been shown to coordinate the interdigitation by activating ROP GTPase-dependent signaling pathways.To identify additional components or mechanisms,we screened for mutants with abnormal PC morphogenesis and found that cytokinin signaling regulates the PC interdigitation pattern.Reduction in cytokinin accumulation and defects in cytokinin signaling (such as in ARR7-over-expressing lines,the ahk3cre1 cytokinin receptor mutant,and the ahp12345 cytokinin signaling mutant) enhanced PC interdigitation,whereas over-production of cytokinin and over-activation of cytokinin signaling in an ARR20 over-expression line delayed or abolished PC interdigitation throughout the cotyledon.Genetic and biochemical analyses suggest that cytokinin signaling acts upstream of ROPs to suppress the formation of interdigitated pattern.Our results provide novel mechanistic understanding of the pathways controlling PC shape and uncover a new role for cytokinin signaling in cell morphogenesis.

  2. From cell signaling to cancer therapy

    Institute of Scientific and Technical Information of China (English)

    Jin DING; Yun FENG; Hong-yang WANG


    Cancer has been seriously threatening the health and life of humans for a long period. Despite the intensive effort put into revealing the underlying mechanisms of cancer, the detailled machinery of carcinogenesis is still far from fully understood.Numerous studies have illustrated that cell signaling is extensively involved in tumor initiation, promotion and progression. Therefore, targeting the key mol-ecules in the oncogenic signaling pathway might be one of the most promising ways to conquer cancer. Some targeted drugs, such as imatinib mesylate (Gleevec),herceptin, gefitinib (Iressa), sorafenib (Nexavar) and sunitinib (Sutent), which evolve from monotarget drug into multitarget ones, have been developed with encouraging effects.

  3. Melatonin signaling in T cells: Functions and applications. (United States)

    Ren, Wenkai; Liu, Gang; Chen, Shuai; Yin, Jie; Wang, Jing; Tan, Bie; Wu, Guoyao; Bazer, Fuller W; Peng, Yuanyi; Li, Tiejun; Reiter, Russel J; Yin, Yulong


    Melatonin affects a variety of physiological processes including circadian rhythms, cellular redox status, and immune function. Importantly, melatonin significantly influences T-cell-mediated immune responses, which are crucial to protect mammals against cancers and infections, but are associated with pathogenesis of many autoimmune diseases. This review focuses on our current understanding of the significance of melatonin in T-cell biology and the beneficial effects of melatonin in T-cell response-based diseases. In addition to expressing both membrane and nuclear receptors for melatonin, T cells have the four enzymes required for the synthesis of melatonin and produce high levels of melatonin. Meanwhile, melatonin is highly effective in modulating T-cell activation and differentiation, especially for Th17 and Treg cells, and also memory T cells. Mechanistically, the influence of melatonin in T-cell biology is associated with membrane and nuclear receptors as well as receptor-independent pathways, for example, via calcineurin. Several cell signaling pathways, including ERK1/2-C/EBPα, are involved in the regulatory roles of melatonin in T-cell biology. Through modulation in T-cell responses, melatonin exerts beneficial effects in various inflammatory diseases, such as type 1 diabetes, systemic lupus erythematosus, and multiple sclerosis. These findings highlight the importance of melatonin signaling in T-cell fate determination, and T cell-based immune pathologies.

  4. A role for Wnt/planar cell polarity signaling during lens fiber cell differentiation? (United States)

    Chen, Y; Stump, R J W; Lovicu, F J; McAvoy, J W


    Wnt signaling through frizzled (Fz) receptors plays key roles in just about every developmental system that has been studied. Several Wnt-Fz signaling pathways have been identified including the Wnt/planar cell polarity (PCP) pathway. PCP signaling is crucial for many developmental processes that require major cytoskeletal rearrangements. Downstream of Fz, PCP signaling is thought to involve the GTPases, Rho, Rac and Cdc42 and regulation of the JNK cascade. Here we report on the localization of these GTPases and JNK in the lens and assess their involvement in the cytoskeletal reorganisation that is a key element of FGF-induced lens fiber cell differentiation.

  5. Cell to cell signalling during vertebrate limb bud development

    NARCIS (Netherlands)

    Panman, Lia


    Communication between cells is essential during embryonic development. The vertebrate limb bud provides us a model to study signalling interactions between cells during patterning of embryonic tissues and organogenesis. In chapter 1 I give an introduction about limb bud development that is focussed

  6. Modulation of host-cell MAPkinase signaling during fungal infection

    Directory of Open Access Journals (Sweden)

    Nir Osherov


    Full Text Available Fungal infections contribute substantially to human suffering and mortality. The interaction between fungal pathogens and their host involves the invasion and penetration of the surface epithelium, activation of cells of the innate immune system and the generation of an effective response to block infection. Numerous host-cell signaling pathways are activated during fungal infection. This review will focus on the main fungal pathogens Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans and their ability to activate the host MAP-kinase signaling pathways leading to cytokine secretion, increased cell motility and killing of the pathogen. Both epithelial and innate immune cells specifically recognize fungal antigens and in particular cell surface polysaccharides such as β-glucans and react to them by activating multiple signaling pathways, including those containing MAP-kinase modules. Recent findings suggest that the host response to fungal infection utilizes the MAP-kinase pathway to differentiate between commensal and pathogenic fungi to selectively react only to the pathogenic forms. However, the paucity of relevant publications strongly emphasize that our understanding of host MAP-kinase signaling in response to fungal infection is still at a very early stage. It is clear, based on studies of host MAP-kinase signaling during viral and bacterial infections, that in fungi as well, a wealth of exciting findings await us.

  7. Modulation of host-cell MAPkinase signaling during fungal infection



    Fungal infections contribute substantially to human suffering and mortality. The interaction between fungal pathogens and their host involves the invasion and penetration of the surface epithelium, activation of cells of the innate immune system and the generation of an effective response to block infection. Numerous host-cell signaling pathways are activated during fungal infection. This review will focus on the main fungal pathogens Aspergillus fumigatus, Candida albicans and Cryptococcus n...

  8. AlliedSignal solid oxide fuel cell technology

    Energy Technology Data Exchange (ETDEWEB)

    Minh, N.; Barr, K.; Kelly, P.; Montgomery, K. [AlliedSignal Aerospace Equipment Systems, Torrance, CA (United States)


    AlliedSignal has been developing high-performance, lightweight solid oxide fuel cell (SOFC) technology for a broad spectrum of electric power generation applications. This technology is well suited for use in a variety of power systems, ranging from commercial cogeneration to military mobile power sources. The AlliedSignal SOFC is based on stacking high-performance thin-electrolyte cells with lightweight metallic interconnect assemblies to form a compact structure. The fuel cell can be operated at reduced temperatures (600{degrees} to 800{degrees}C). SOFC stacks based on this design has the potential of producing 1 kW/kg and 1 ML. This paper summarizes the technical status of the design, manufacture, and operation of AlliedSignal SOFCs.

  9. P2 receptor-mediated signaling in mast cell biology. (United States)

    Bulanova, Elena; Bulfone-Paus, Silvia


    Mast cells are widely recognized as effector cells of allergic inflammatory reactions. They contribute to the pathogenesis of different chronic inflammatory diseases, wound healing, fibrosis, thrombosis/fibrinolysis, and anti-tumor immune responses. In this paper, we summarized the role of P2X and P2Y receptors in mast cell activation and effector functions. Mast cells are an abundant source of ATP which is stored in their granules and secreted upon activation. We discuss the contribution of mast cells to the extracellular ATP release and to the maintenance of extracellular nucleotides pool. Recent publications highlight the importance of purinergic signaling for the pathogenesis of chronic airway inflammation. Therefore, the role of ATP and P2 receptors in allergic inflammation with focus on mast cells was analyzed. Finally, ATP functions as mast cell autocrine/paracrine factor and as messenger in intercellular communication between mast cells, nerves, and glia in the central nervous system.

  10. The Interconnectedness of Cancer Cell Signaling

    Directory of Open Access Journals (Sweden)

    Alnawaz Rehemtulla


    Full Text Available The elegance of fundamental and applied research activities have begun to reveal a myriad of spatial and temporal alterations in downstream signaling networks affected by cell surface receptor stimulation including G protein– coupled receptors and receptor tyrosine kinases. Interconnected biochemical pathways serve to integrate and distribute the signaling information throughout the cell by orchestration of complex biochemical circuits consisting of protein interactions and covalent modification processes. It is clear that scientific literature summarizing results from both fundamental and applied scientific research activities has served to provide a broad foundational biologic data-base that has been instrumental in advancing our continued understanding of underlying cancer biology. This article reflects on historical advances and the role of innovation in the competitive world of grant-sponsored research.

  11. System for surveillance of spectral signals (United States)

    Gross, Kenneth C.; Wegerich, Stephan W.; Criss-Puszkiewicz, Cynthia; Wilks, Alan D.


    A method and system for monitoring at least one of a system, a process and a data source. A method and system have been developed for carrying out surveillance, testing and modification of an ongoing process or other source of data, such as a spectroscopic examination. A signal from the system under surveillance is collected and compared with a reference signal, a frequency domain transformation carried out for the system signal and reference signal, a frequency domain difference function established. The process is then repeated until a full range of data is accumulated over the time domain and a SPRT sequential probability ratio test methodology applied to determine a three-dimensional surface plot characteristic of the operating state of the system under surveillance.

  12. Zebrafish gastrulation: cell movements, signals, and mechanisms. (United States)

    Rohde, Laurel A; Heisenberg, Carl-Philipp


    Gastrulation is a morphogenetic process that results in the formation of the embryonic germ layers. Here we detail the major cell movements that occur during zebrafish gastrulation: epiboly, internalization, and convergent extension. Although gastrulation is known to be regulated by signaling pathways such as the Wnt/planar cell polarity pathway, many questions remain about the underlying molecular and cellular mechanisms. Key factors that may play a role in gastrulation cell movements are cell adhesion and cytoskeletal rearrangement. In addition, some of the driving force for gastrulation may derive from tissue interactions such as those described between the enveloping layer and the yolk syncytial layer. Future exploration of gastrulation mechanisms relies on the development of sensitive and quantitative techniques to characterize embryonic germ-layer properties.

  13. Molecular signal transduction in vascular cell apoptosis

    Institute of Scientific and Technical Information of China (English)


    Apoptosis is a form of genetically programmed cell death, which plays a key role in regulation of cellularity in a variety of tissue and cell types including the cardiovascular tissues. Under both physiological and pathophysiological conditions, various biophysiological and biochemical factors, including mechanical forces, reactive oxygen and nitrogen species, cytokines, growth factors, oxidized lipoproteins, etc., may influence apoptosis of vascular cells. The Fas/Fas ligand/caspase death-signaling pathway, Bcl-2 protein family/mitochondria, the tumor suppressive gene p53, and the proto-oncogene c-myc may be activated in atherosclerotic lesions, and mediates vascular apoptosis during the development of atherosclerosis. Abnormal expression and dysfunction of these apoptosis-regulating genes may attenuate or accelerate vascular cell apoptosis and affect the integrity and stability of atherosclerotic plaques. Clarification of the molecular mechanism that regulates apoptosis may help design a new strategy for treatment of atherosclerosis and its major complication, the acute vascular syndromes.

  14. Cell death signaling and anticancer therapy

    Directory of Open Access Journals (Sweden)

    Lorenzo eGalluzzi


    Full Text Available For a long time, it was commonly believed that efficient anticancer regimens would either trigger the apoptotic demise of tumor cells or induce a permanent arrest in the G1 phase of the cell cycle, i.e., senescence. The recent discovery that necrosis can occur in a regulated fashion and the increasingly more precise characterization of the underlying molecular mechanisms have raised great interest, as non-apoptotic pathways might be instrumental to circumvent the resistance of cancer cells to conventional, pro-apoptotic therapeutic regimens. Moreover, it has been shown that some anticancer regimens engage lethal signaling cascades that can ignite multiple oncosuppressive mechanisms, including apoptosis, necrosis and senescence. Among these signaling pathways is mitotic catastrophe, whose role as a bona fide cell death mechanism has recently been reconsidered. Thus, anticancer regimens get ever more sophisticated, and often distinct strategies are combined to maximize efficacy and minimize side effects. In this review, we will discuss the importance of apoptosis, necrosis and mitotic catastrophe in the response of tumor cells to the most common clinically employed and experimental anticancer agents.

  15. Research on Portable Fatigue Signal Detection System

    Directory of Open Access Journals (Sweden)

    Bowen Li


    Full Text Available According to the characteristics of human pulse wave signals, the acquisition system acquisition system with excellent performance is designed, 16 bit MCU MSP430 with ultralow power is used to record, process and transmit the collected pulse wave signals. In order to make the hardware part satisfy acquisition requirements of pulse wave, the paper focuses on discussing composition, operating principle, analysis method and performance parameter of analog circuit. The software part makes use of the design tools of Matlab graphical user interface (GUI for designing pulse wave signal measurement system. The trial on intelligent fatigue test signal adopts relatively unique methods no matter in hardware circuit design or software algorithm process, which provides important and meaningful reference for objective and quantitative research on fatigue signal.

  16. An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration. (United States)

    Ye, Lihua; Robertson, Morgan A; Mastracci, Teresa L; Anderson, Ryan M


    As one of the key nutrient sensors, insulin signaling plays an important role in integrating environmental energy cues with organism growth. In adult organisms, relative insufficiency of insulin signaling induces compensatory expansion of insulin-secreting pancreatic beta (β) cells. However, little is known about how insulin signaling feedback might influence neogenesis of β cells during embryonic development. Using genetic approaches and a unique cell transplantation system in developing zebrafish, we have uncovered a novel role for insulin signaling in the negative regulation of pancreatic progenitor cell differentiation. Blocking insulin signaling in the pancreatic progenitors hastened the expression of the essential β cell genes insulin and pdx1, and promoted β cell fate at the expense of alpha cell fate. In addition, loss of insulin signaling promoted β cell regeneration and destabilization of alpha cell character. These data indicate that insulin signaling constitutes a tunable mechanism for β cell compensatory plasticity during early development. Moreover, using a novel blastomere-to-larva transplantation strategy, we found that loss of insulin signaling in endoderm-committed blastomeres drove their differentiation into β cells. Furthermore, the extent of this differentiation was dependent on the function of the β cell mass in the host. Altogether, our results indicate that modulation of insulin signaling will be crucial for the development of β cell restoration therapies for diabetics; further clarification of the mechanisms of insulin signaling in β cell progenitors will reveal therapeutic targets for both in vivo and in vitro β cell generation.

  17. Rescue effects in radiobiology: Unirradiated bystander cells assist irradiated cells through intercellular signal feedback

    Energy Technology Data Exchange (ETDEWEB)

    Chen, S. [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong); Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China); Zhao, Y. [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China); Han, W. [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong); Chiu, S.K. [Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong); Zhu, L. [Office of Admission and Careers Advisory Service, Shenzhen University, Shenzhen 518060 (China); Wu, L. [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China); Yu, K.N., E-mail: [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong)


    Mammalian cells respond to ionization radiation by sending out extracellular signals to affect non-irradiated neighboring cells, which is referred to as radiation induced bystander effect. In the present paper, we described a phenomenon entitled the 'rescue effects', where the bystander cells rescued the irradiated cells through intercellular signal feedback. The effect was observed in both human primary fibroblast (NHLF) and cancer cells (HeLa) using two-cell co-culture systems. After co-culturing irradiated cells with unirradiated bystander cells for 24 h, the numbers of 53BP1 foci, corresponding to the number of DNA double-strand breaks in the irradiated cells were less than those in the irradiated cells that were not co-cultured with the bystander cells (0.78 {+-} 0.04 foci/cell vs. 0.90 {+-} 0.04 foci/cell) at a statistically significant level. Similarly, both micronucleus formation and extent of apoptosis in the irradiated cells were different at statistically significant levels if they were co-cultured with the bystander cells. Furthermore, it was found that unirradiated normal cells would also reduce the micronucleus formation in irradiated cancer cells. These results suggested that the rescue effects could participate in repairing the radiation-induced DNA damages through a media-mediated signaling feedback, thereby mitigating the cytotoxicity and genotoxicity of ionizing radiation.

  18. GTPases in bacterial cell polarity and signalling. (United States)

    Bulyha, Iryna; Hot, Edina; Huntley, Stuart; Søgaard-Andersen, Lotte


    In bacteria, large G domain GTPases have well-established functions in translation, protein translocation, tRNA modification and ribosome assembly. In addition, bacteria also contain small Ras-like GTPases consisting of stand-alone G domains. Recent data have revealed that small Ras-like GTPases as well as large G domain GTPases in bacteria function in the regulation of cell polarity, signal transduction and possibly also in cell division. The small Ras-like GTPase MglA together with its cognate GAP MglB regulates cell polarity in Myxococcus xanthus, and the small Ras-like GTPase CvnD9 in Streptomyces coelicolor is involved in signal transduction. Similarly, the large GTPase FlhF together with the ATPase FlhG regulates the localization and number of flagella in polarly flagellated bacteria. Moreover, large dynamin-like GTPases in bacteria may function in cell division. Thus, the function of GTPases in bacteria may be as pervasive as in eukaryotes.

  19. Regulation of interferon gamma signaling by suppressors of cytokine signaling and regulatory T cells

    Directory of Open Access Journals (Sweden)

    Joseph eLarkin


    Full Text Available Regulatory T cells (Tregs play an indispensable role in the prevention of autoimmune disease, as interferon gamma (IFN mediated, lethal autoimmunity occurs (in both mice and humans in their absence. In addition, regulatory T cells have been implicated in preventing the onset of autoimmune and auto-inflammatory conditions associated with aberrant IFN signaling such as type 1 diabetes, lupus, and LPS mediated endotoxemia. Notably, suppressor of cytokine signaling 1 deficient (SOCS1-/- mice also succumb to a lethal auto-inflammatory disease, dominated by excessive IFN signaling and bearing similar disease course kinetics to Treg deficient mice. Moreover SOCS1 deficiency has been implicated in lupus progression, and increased susceptibility to LPS mediated endotoxemia. Although it has been established that Tregs and SOCS1 play a critical role in the regulation of IFN signaling, and the prevention of lethal auto-inflammatory disease, the role of Treg/SOCS1 cross-talk in the regulation of IFN signaling has been essentially unexplored. This is especially pertinent as recent publications have implicated a role of SOCS1 in the stability of peripheral Tregs. This review will examine the emerging research findings implicating a critical role of the intersection of the SOCS1 and Treg regulatory pathways in the control of IFN gamma signaling and immune system function.

  20. The yeast three-hybrid system as an experimental platform to identify proteins interacting with small signaling molecules in plant cells: Potential and limitations

    Directory of Open Access Journals (Sweden)

    Stéphanie eCottier


    Full Text Available Chemical genetics is a powerful scientific strategy that utilizes small bioactive molecules as experimental tools to unravel biological processes. Bioactive compounds occurring in nature represent an enormous diversity of structures that can be used to dissect functions of biological systems. Once the bioactivity of a natural or synthetic compound has been critically evaluated the challenge remains to identify its molecular target and mode of action, which usually is a time consuming and labor-intensive process. To facilitate this task, we decided to implement the yeast three-hybrid (Y3H technology as a general experimental platform to scan the whole Arabidopsis proteome for targets of small signaling molecules. The Y3H technology is based on the yeast two-hybrid system and allows direct cloning of proteins that interact in vivo with a synthetic hybrid ligand, which comprises the biologically active molecule of interest covalently linked to methotrexate (Mtx. In yeast nucleus the hybrid ligand connects two fusion proteins: the Mtx part binding to dihydrofolate reductase fused to a DNA binding domain (encoded in the yeast strain, and the bioactive molecule part binding to its potential protein target fused to a DNA activating domain (encoded on a cDNA expression vector. During cDNA library screening, the formation of this ternary, transcriptional activator complex leads to reporter gene activation in yeast cells, and thereby allows selection of the putative targets of small bioactive molecules of interest. Here we present the strategy and experimental details for construction and application of a Y3H platform, including chemical synthesis of different hybrid ligands, construction of suitable cDNA libraries, the choice of yeast strains, and appropriate screening conditions. Based on the results obtained and the current literature we discussed the perspectives and limitations of the Y3H approach for identifying targets of small bioactive molecules.

  1. Signals and transforms in linear systems analysis

    CERN Document Server

    Wasylkiwskyj, Wasyl


    Signals and Transforms in Linear Systems Analysis covers the subject of signals and transforms, particularly in the context of linear systems theory. Chapter 2 provides the theoretical background for the remainder of the text. Chapter 3 treats Fourier series and integrals. Particular attention is paid to convergence properties at step discontinuities. This includes the Gibbs phenomenon and its amelioration via the Fejer summation techniques. Special topics include modulation and analytic signal representation, Fourier transforms and analytic function theory, time-frequency analysis and frequency dispersion. Fundamentals of linear system theory for LTI analogue systems, with a brief account of time-varying systems, are covered in Chapter 4 . Discrete systems are covered in Chapters 6 and 7.  The Laplace transform treatment in Chapter 5 relies heavily on analytic function theory as does Chapter 8 on Z -transforms. The necessary background on complex variables is provided in Appendix A. This book is intended to...

  2. Role of inositol phospholipid signaling in natural killer cell biology

    Directory of Open Access Journals (Sweden)

    Matthew eGumbleton


    Full Text Available Natural Killer (NK cells are important in the host defense against malignancy and infection. At a cellular level NK cells are activated when signals from activating receptors exceed signaling from inhibitory receptors. At a molecular level NK cells undergo an education process to prevent autoimmunity. Mouse models have shown important roles for inositol phospholipid signaling in lymphocytes. NK cells from mice with deletion in different members of the PI3K signaling pathway have defective development, natural killer cell repertoire expression (NKRR and effector function. Here we review the role of inositol phospholipid signaling in NK cell biology.

  3. Linear Frequency Modulated Signals VS Orthogonal Frequency Division Multiplexing Signals for Synthetic Aperture Radar Systems (United States)



  4. Robust Signal Processing in Living Cells (United States)

    Steuer, Ralf; Waldherr, Steffen; Sourjik, Victor; Kollmann, Markus


    Cellular signaling networks have evolved an astonishing ability to function reliably and with high fidelity in uncertain environments. A crucial prerequisite for the high precision exhibited by many signaling circuits is their ability to keep the concentrations of active signaling compounds within tightly defined bounds, despite strong stochastic fluctuations in copy numbers and other detrimental influences. Based on a simple mathematical formalism, we identify topological organizing principles that facilitate such robust control of intracellular concentrations in the face of multifarious perturbations. Our framework allows us to judge whether a multiple-input-multiple-output reaction network is robust against large perturbations of network parameters and enables the predictive design of perfectly robust synthetic network architectures. Utilizing the Escherichia coli chemotaxis pathway as a hallmark example, we provide experimental evidence that our framework indeed allows us to unravel the topological organization of robust signaling. We demonstrate that the specific organization of the pathway allows the system to maintain global concentration robustness of the diffusible response regulator CheY with respect to several dominant perturbations. Our framework provides a counterpoint to the hypothesis that cellular function relies on an extensive machinery to fine-tune or control intracellular parameters. Rather, we suggest that for a large class of perturbations, there exists an appropriate topology that renders the network output invariant to the respective perturbations. PMID:22215991

  5. Phosphorylation site dynamics of early T-cell receptor signaling

    DEFF Research Database (Denmark)

    Chylek, Lily A; Akimov, Vyacheslav; Dengjel, Jörn;


    a systems-level understanding of how these components cooperate to control signaling dynamics, especially during the crucial first seconds of stimulation. Here, we used quantitative proteomics to characterize reshaping of the T-cell phosphoproteome in response to TCR/CD28 co-stimulation, and found...... that diverse dynamic patterns emerge within seconds. We detected phosphorylation dynamics as early as 5 s and observed widespread regulation of key TCR signaling proteins by 30 s. Development of a computational model pointed to the presence of novel regulatory mechanisms controlling phosphorylation of sites...

  6. Evidence for involvement of Wnt signalling in body polarities, cell proliferation, and the neuro-sensory system in an adult ctenophore.

    Directory of Open Access Journals (Sweden)

    Muriel Jager

    Full Text Available Signalling through the Wnt family of secreted proteins originated in a common metazoan ancestor and greatly influenced the evolution of animal body plans. In bilaterians, Wnt signalling plays multiple fundamental roles during embryonic development and in adult tissues, notably in axial patterning, neural development and stem cell regulation. Studies in various cnidarian species have particularly highlighted the evolutionarily conserved role of the Wnt/β-catenin pathway in specification and patterning of the primary embryonic axis. However in another key non-bilaterian phylum, Ctenophora, Wnts are not involved in early establishment of the body axis during embryogenesis. We analysed the expression in the adult of the ctenophore Pleurobrachia pileus of 11 orthologues of Wnt signalling genes including all ctenophore Wnt ligands and Fz receptors and several members of the intracellular β-catenin pathway machinery. All genes are strongly expressed around the mouth margin at the oral pole, evoking the Wnt oral centre of cnidarians. This observation is consistent with primary axis polarisation by the Wnts being a universal metazoan feature, secondarily lost in ctenophores during early development but retained in the adult. In addition, local expression of Wnt signalling genes was seen in various anatomical structures of the body including in the locomotory comb rows, where their complex deployment suggests control by the Wnts of local comb polarity. Other important contexts of Wnt involvement which probably evolved before the ctenophore/cnidarian/bilaterian split include proliferating stem cells and progenitors irrespective of cell types, and developing as well as differentiated neuro-sensory structures.

  7. Gpr125 modulates Dishevelled distribution and planar cell polarity signaling. (United States)

    Li, Xin; Roszko, Isabelle; Sepich, Diane S; Ni, Mingwei; Hamm, Heidi E; Marlow, Florence L; Solnica-Krezel, Lilianna


    During vertebrate gastrulation, Wnt/planar cell polarity (PCP) signaling orchestrates polarized cell behaviors underlying convergence and extension (C&E) movements to narrow embryonic tissues mediolaterally and lengthen them anteroposteriorly. Here, we have identified Gpr125, an adhesion G protein-coupled receptor, as a novel modulator of the Wnt/PCP signaling system. Excess Gpr125 impaired C&E movements and the underlying cell and molecular polarities. Reduced Gpr125 function exacerbated the C&E and facial branchiomotor neuron (FBMN) migration defects of embryos with reduced Wnt/PCP signaling. At the molecular level, Gpr125 recruited Dishevelled to the cell membrane, a prerequisite for Wnt/PCP activation. Moreover, Gpr125 and Dvl mutually clustered one another to form discrete membrane subdomains, and the Gpr125 intracellular domain directly interacted with Dvl in pull-down assays. Intriguingly, Dvl and Gpr125 were able to recruit a subset of PCP components into membrane subdomains, suggesting that Gpr125 may modulate the composition of Wnt/PCP membrane complexes. Our study reveals a role for Gpr125 in PCP-mediated processes and provides mechanistic insight into Wnt/PCP signaling.

  8. Video signals integrator (VSI) system architecture (United States)

    Kasprowicz, Grzegorz; Pastuszak, Grzegorz; Poźniak, Krzysztof; Trochimiuk, Maciej; Abramowski, Andrzej; Gaska, Michal; Bukowiecka, Danuta; Tyburska, Agata; Struniawski, Jarosław; Jastrzebski, Pawel; Jewartowski, Blazej; Frasunek, Przemysław; Nalbach-Moszynska, Małgorzata; Brawata, Sebastian; Bubak, Iwona; Gloza, Małgorzata


    The purpose of the project is development of a platform which integrates video signals from many sources. The signals can be sourced by existing analogue CCTV surveillance installations, recent internet-protocol (IP) cameras or single cameras of any type. The system will consist of portable devices that provide conversion, encoding, transmission and archiving. The sharing subsystem will use distributed file system and also user console which provides simultaneous access to any of video streams in real time. The system is fully modular so its extension is possible, both from hardware and software side. Due to standard modular technology used, partial technology modernization is also possible during a long exploitation period.

  9. Molecular cell biology of androgen receptor signalling. (United States)

    Bennett, Nigel C; Gardiner, Robert A; Hooper, John D; Johnson, David W; Gobe, Glenda C


    The classical action of androgen receptor (AR) is to regulate gene transcriptional processes via AR nuclear translocation, response element binding and recruitment of, or crosstalk with, transcription factors. AR also utilises non-classical, non-genomic mechanisms of signal transduction. These precede gene transcription or protein synthesis, and involve steroid-induced modulation of cytoplasmic or cell membrane-bound regulatory proteins. Despite many decades of investigation, the role of AR in gene regulation of cells and tissues remains only partially characterised. AR exerts most of its effects in sex hormone-dependent tissues of the body, but the receptor is also expressed in many tissues not previously thought to be androgen sensitive. Thus it is likely that a complex, more over-arching, role for AR exists. Each AR domain co-ordinates a multitude of individual and vital roles via a diverse array of interacting partner molecules that are necessary for cellular and tissue development and maintenance. Aberrant AR activity, promoted by mutations or binding partner misregulation, can present as many clinical manifestations including androgen insensitivity syndrome and prostate cancer. In the case of malignant prostate cancer, treatment generally revolves around androgen deprivation therapies designed to interfere with AR action and the androgen signalling axis. Androgen therapies for prostate cancer often fail, highlighting a real need for increased research into AR function.

  10. A Network Map of FGF-1/FGFR Signaling System

    Directory of Open Access Journals (Sweden)

    Rajesh Raju


    Full Text Available Fibroblast growth factor-1 (FGF-1 is a well characterized growth factor among the 22 members of the FGF superfamily in humans. It binds to all the four known FGF receptors and regulates a plethora of functions including cell growth, proliferation, migration, differentiation, and survival in different cell types. FGF-1 is involved in the regulation of diverse physiological processes such as development, angiogenesis, wound healing, adipogenesis, and neurogenesis. Deregulation of FGF-1 signaling is not only implicated in tumorigenesis but also is associated with tumor invasion and metastasis. Given the biomedical significance of FGFs and the fact that individual FGFs have different roles in diverse physiological processes, the analysis of signaling pathways induced by the binding of specific FGFs to their cognate receptors demands more focused efforts. Currently, there are no resources in the public domain that facilitate the analysis of signaling pathways induced by individual FGFs in the FGF/FGFR signaling system. Towards this, we have developed a resource of signaling reactions triggered by FGF-1/FGFR system in various cell types/tissues. The pathway data and the reaction map are made available for download in different community standard data exchange formats through NetPath and NetSlim signaling pathway resources.

  11. Robustness of MEK-ERK Dynamics and Origins of Cell-to-Cell Variability in MAPK Signaling

    Directory of Open Access Journals (Sweden)

    Sarah Filippi


    Full Text Available Cellular signaling processes can exhibit pronounced cell-to-cell variability in genetically identical cells. This affects how individual cells respond differentially to the same environmental stimulus. However, the origins of cell-to-cell variability in cellular signaling systems remain poorly understood. Here, we measure the dynamics of phosphorylated MEK and ERK across cell populations and quantify the levels of population heterogeneity over time using high-throughput image cytometry. We use a statistical modeling framework to show that extrinsic noise, particularly that from upstream MEK, is the dominant factor causing cell-to-cell variability in ERK phosphorylation, rather than stochasticity in the phosphorylation/dephosphorylation of ERK. We furthermore show that without extrinsic noise in the core module, variable (including noisy signals would be faithfully reproduced downstream, but the within-module extrinsic variability distorts these signals and leads to a drastic reduction in the mutual information between incoming signal and ERK activity.

  12. Cell signalling pathways underlying induced pluripotent stem cell reprogramming

    Institute of Scientific and Technical Information of China (English)

    Kate; Hawkins; Shona; Joy; Tristan; Mc; Kay


    Induced pluripotent stem(i PS) cells, somatic cells reprogrammed to the pluripotent state by forced expression of defined factors, represent a uniquely valuable resource for research and regenerative medicine. However, this methodology remains inefficient due to incomplete mechanistic understanding of the reprogramming process. In recent years, various groups have endeavoured to interrogate the cell signalling that governs the reprogramming process, including LIF/STAT3, BMP, PI3 K, FGF2, Wnt, TGFβ and MAPK pathways, with the aim of increasing our understanding and identifying new mechanisms of improving safety, reproducibility and efficiency. This has led to a unified model of reprogramming that consists of 3 stages: initiation, maturation and stabilisation. Initiation of reprogramming occurs in almost all cells that receive the reprogramming transgenes; most commonly Oct4, Sox2, Klf4 and c Myc, and involves a phenotypic mesenchymal-to-epithelial transition. The initiation stage is also characterised by increased proliferation and a metabolic switch from oxidative phosphorylation to glycolysis. The maturation stage is considered the major bottleneck within the process, resulting in very few "stabilisation competent" cells progressing to the final stabilisation phase. To reach this stage in both mouse and human cells, pre-i PS cells must activate endogenous expression of the core circuitry of pluripotency, comprising Oct4, Sox2, and Nanog, and thus reach a state of transgene independence. By the stabilisation stage, i PS cells generally use the same signalling networks that govern pluripotency in embryonic stem cells. These pathways differ between mouse and human cells although recent work has demonstrated that this is context dependent. As i PS cell generation technologies move forward, tools are being developed to interrogate the process in more detail, thus allowing a greater understanding of this intriguing biological phenomenon.

  13. Disruption of Cell-to-Cell Signaling Does Not Abolish the Antagonism of Phaeobacter gallaeciensis toward the Fish Pathogen Vibrio anguillarum in Algal Systems

    DEFF Research Database (Denmark)

    Prol García, María Jesús; D'Alvise, Paul; Gram, Lone


    Quorum sensing (QS) regulates Phaeobacter gallaeciensis antagonism in broth systems; however, we demonstrate here that QS is not important for antagonism in algal cultures. QS mutants reduced Vibrio anguillarum to the same extent as the wild type. Consequently, a combination of probiotic Phaeobac......Quorum sensing (QS) regulates Phaeobacter gallaeciensis antagonism in broth systems; however, we demonstrate here that QS is not important for antagonism in algal cultures. QS mutants reduced Vibrio anguillarum to the same extent as the wild type. Consequently, a combination of probiotic...

  14. Dose-response aligned circuits in signaling systems. (United States)

    Yan, Long; Ouyang, Qi; Wang, Hongli


    Cells use biological signal transduction pathways to respond to environmental stimuli and the behavior of many cell types depends on precise sensing and transmission of external information. A notable property of signal transduction that was characterized in the Saccharomyces cerevisiae yeast cell and many mammalian cells is the alignment of dose-response curves. It was found that the dose response of the receptor matches closely the dose responses of the downstream. This dose-response alignment (DoRA) renders equal sensitivities and concordant responses in different parts of signaling system and guarantees a faithful information transmission. The experimental observations raise interesting questions about the nature of the information transmission through DoRA signaling networks and design principles of signaling systems with this function. Here, we performed an exhaustive computational analysis on network architectures that underlie the DoRA function in simple regulatory networks composed of two and three enzymes. The minimal circuits capable of DoRA were examined with Michaelis-Menten kinetics. Several motifs that are essential for the dynamical function of DoRA were identified. Systematic analysis of the topology space of robust DoRA circuits revealed that, rather than fine-tuning the network's parameters, the function is primarily realized by enzymatic regulations on the controlled node that are constrained in limiting regions of saturation or linearity.

  15. The cAMP signaling system inhibits the repair of {gamma}-ray-induced DNA damage by promoting Epac1-mediated proteasomal degradation of XRCC1 protein in human lung cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Eun-Ah [Department of Biochemistry and Molecular Biology, Cancer Research Center, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Juhnn, Yong-Sung, E-mail: [Department of Biochemistry and Molecular Biology, Cancer Research Center, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of)


    Highlights: Black-Right-Pointing-Pointer cAMP signaling system inhibits repair of {gamma}-ray-induced DNA damage. Black-Right-Pointing-Pointer cAMP signaling system inhibits DNA damage repair by decreasing XRCC1 expression. Black-Right-Pointing-Pointer cAMP signaling system decreases XRCC1 expression by promoting its proteasomal degradation. Black-Right-Pointing-Pointer The promotion of XRCC1 degradation by cAMP signaling system is mediated by Epac1. -- Abstract: Cyclic AMP is involved in the regulation of metabolism, gene expression, cellular growth and proliferation. Recently, the cAMP signaling system was found to modulate DNA-damaging agent-induced apoptosis by regulating the expression of Bcl-2 family proteins and inhibitors of apoptosis. Thus, we hypothesized that the cAMP signaling may modulate DNA repair activity, and we investigated the effects of the cAMP signaling system on {gamma}-ray-induced DNA damage repair in lung cancer cells. Transient expression of a constitutively active mutant of stimulatory G protein (G{alpha}sQL) or treatment with forskolin, an adenylyl cyclase activator, augmented radiation-induced DNA damage and inhibited repair of the damage in H1299 lung cancer cells. Expression of G{alpha}sQL or treatment with forskolin or isoproterenol inhibited the radiation-induced expression of the XRCC1 protein, and exogenous expression of XRCC1 abolished the DNA repair-inhibiting effect of forskolin. Forskolin treatment promoted the ubiquitin and proteasome-dependent degradation of the XRCC1 protein, resulting in a significant decrease in the half-life of the protein after {gamma}-ray irradiation. The effect of forskolin on XRCC1 expression was not inhibited by PKA inhibitor, but 8-pCPT-2 Prime -O-Me-cAMP, an Epac-selective cAMP analog, increased ubiquitination of XRCC1 protein and decreased XRCC1 expression. Knockdown of Epac1 abolished the effect of 8-pCPT-2 Prime -O-Me-cAMP and restored XRCC1 protein level following {gamma}-ray irradiation. From

  16. Estrogen receptors regulate innate immune cells and signaling pathways. (United States)

    Kovats, Susan


    Humans show strong sex differences in immunity to infection and autoimmunity, suggesting sex hormones modulate immune responses. Indeed, receptors for estrogens (ERs) regulate cells and pathways in the innate and adaptive immune system, as well as immune cell development. ERs are ligand-dependent transcription factors that mediate long-range chromatin interactions and form complexes at gene regulatory elements, thus promoting epigenetic changes and transcription. ERs also participate in membrane-initiated steroid signaling to generate rapid responses. Estradiol and ER activity show profound dose- and context-dependent effects on innate immune signaling pathways and myeloid cell development. While estradiol most often promotes the production of type I interferon, innate pathways leading to pro-inflammatory cytokine production may be enhanced or dampened by ER activity. Regulation of innate immune cells and signaling by ERs may contribute to the reported sex differences in innate immune pathways. Here we review the recent literature and highlight several molecular mechanisms by which ERs regulate the development or functional responses of innate immune cells.

  17. Notch signaling and development of the hematopoietic system. (United States)

    Sandy, Ashley R; Jones, Morgan; Maillard, Ivan


    Notch signaling exerts multiple important functions in the hematopoietic system. Notch1-mediated signals are essential to induce the onset of definitive hematopoiesis within specialized domains of hemogenic endothelium in the fetal dorsal aorta. In contrast, Notch is dispensable for the subsequent maintenance of hematopoietic stem cells in the adult bone marrow. Notch is a key regulator of early T-cell development in the thymus. An expanding number of hematopoietic and lymphoid cell types have been reported to receive context-dependent inputs from the Notch pathway that regulate their differentiation and function. Progress in the field will continue to bring fundamental information about hematopoiesis and practical insights into the potential to modulate Notch signaling for therapeutic purposes.

  18. Traffic Signal Using Smart Agent System

    Directory of Open Access Journals (Sweden)

    Cheonshik Kim


    Full Text Available In this research, we propose an electro-sensitive traffic light using the smart agent algorithm to reduce traffic congestion and traffic accidents. The multi-agent system approach can provide a new and preferable solution. The proposed method adaptively controls the cycle of traffic signals even though the traffic volume varies. Consequently, we reduce the car waiting time and start-up delay time using fuzzy control of feedback data. In particular, we have designed and implemented a system to create optimum traffic signals in congested conditions. The effectiveness of this method was shown through simulation of multiple intersections.

  19. Cell polarity signaling in the plasticity of cancer cell invasiveness. (United States)

    Gandalovičová, Aneta; Vomastek, Tomáš; Rosel, Daniel; Brábek, Jan


    Apico-basal polarity is typical of cells present in differentiated epithelium while front-rear polarity develops in motile cells. In cancer development, the transition from epithelial to migratory polarity may be seen as the hallmark of cancer progression to an invasive and metastatic disease. Despite the morphological and functional dissimilarity, both epithelial and migratory polarity are controlled by a common set of polarity complexes Par, Scribble and Crumbs, phosphoinositides, and small Rho GTPases Rac, Rho and Cdc42. In epithelial tissues, their mutual interplay ensures apico-basal and planar cell polarity. Accordingly, altered functions of these polarity determinants lead to disrupted cell-cell adhesions, cytoskeleton rearrangements and overall loss of epithelial homeostasis. Polarity proteins are further engaged in diverse interactions that promote the establishment of front-rear polarity, and they help cancer cells to adopt different invasion modes. Invading cancer cells can employ either the collective, mesenchymal or amoeboid invasion modes or actively switch between them and gain intermediate phenotypes. Elucidation of the role of polarity proteins during these invasion modes and the associated transitions is a necessary step towards understanding the complex problem of metastasis. In this review we summarize the current knowledge of the role of cell polarity signaling in the plasticity of cancer cell invasiveness.

  20. Wnt signaling inhibits adrenal steroidogenesis by cell-autonomous and non-cell-autonomous mechanisms. (United States)

    Walczak, Elisabeth M; Kuick, Rork; Finco, Isabella; Bohin, Natacha; Hrycaj, Steven M; Wellik, Deneen M; Hammer, Gary D


    Wnt/β-catenin (βcat) signaling is critical for adrenal homeostasis. To elucidate how Wnt/βcat signaling elicits homeostatic maintenance of the adrenal cortex, we characterized the identity of the adrenocortical Wnt-responsive population. We find that Wnt-responsive cells consist of sonic hedgehog (Shh)-producing adrenocortical progenitors and differentiated, steroidogenic cells of the zona glomerulosa, but not the zona fasciculata and rarely cells that are actively proliferating. To determine potential direct inhibitory effects of βcat signaling on zona fasciculata-associated steroidogenesis, we used the mouse ATCL7 adrenocortical cell line that serves as a model system of glucocorticoid-producing fasciculata cells. Stimulation of βcat signaling caused decreased corticosterone release consistent with the observed reduced transcription of steroidogenic genes Cyp11a1, Cyp11b1, Star, and Mc2r. Decreased steroidogenic gene expression was correlated with diminished steroidogenic factor 1 (Sf1; Nr5a1) expression and occupancy on steroidogenic promoters. Additionally, βcat signaling suppressed the ability of Sf1 to transactivate steroidogenic promoters independent of changes in Sf1 expression level. To investigate Sf1-independent effects of βcat on steroidogenesis, we used Affymetrix gene expression profiling of Wnt-responsive cells in vivo and in vitro. One candidate gene identified, Ccdc80, encodes a secreted protein with unknown signaling mechanisms. We report that Ccdc80 is a novel βcat-regulated gene in adrenocortical cells. Treatment of adrenocortical cells with media containing secreted Ccdc80 partially phenocopies βcat-induced suppression of steroidogenesis, albeit through an Sf1-independent mechanism. This study reveals multiple mechanisms of βcat-mediated suppression of steroidogenesis and suggests that Wnt/βcat signaling may regulate adrenal homeostasis by inhibiting fasciculata differentiation and promoting the undifferentiated state of progenitor

  1. Three cyanobacteriochromes work together to form a light color-sensitive input system for c-di-GMP signaling of cell aggregation. (United States)

    Enomoto, Gen; Ni-Ni-Win; Narikawa, Rei; Ikeuchi, Masahiko


    Cyanobacteriochromes (CBCRs) are cyanobacterial photoreceptors that have diverse spectral properties and domain compositions. Although large numbers of CBCR genes exist in cyanobacterial genomes, no studies have assessed whether multiple CBCRs work together. We recently showed that the diguanylate cyclase (DGC) activity of the CBCR SesA from Thermosynechococcus elongatus is activated by blue-light irradiation and that, when irradiated, SesA, via its product cyclic dimeric GMP (c-di-GMP), induces aggregation of Thermosynechococcus vulcanus cells at a temperature that is suboptimum for single-cell viability. For this report, we first characterize the photobiochemical properties of two additional CBCRs, SesB and SesC. Blue/teal light-responsive SesB has only c-di-GMP phosphodiesterase (PDE) activity, which is up-regulated by teal light and GTP. Blue/green light-responsive SesC has DGC and PDE activities. Its DGC activity is enhanced by blue light, whereas its PDE activity is enhanced by green light. A ΔsesB mutant cannot suppress cell aggregation under teal-green light. A ΔsesC mutant shows a less sensitive cell-aggregation response to ambient light. ΔsesA/ΔsesB/ΔsesC shows partial cell aggregation, which is accompanied by the loss of color dependency, implying that a nonphotoresponsive DGC(s) producing c-di-GMP can also induce the aggregation. The results suggest that SesB enhances the light color dependency of cell aggregation by degrading c-di-GMP, is particularly effective under teal light, and, therefore, seems to counteract the induction of cell aggregation by SesA. In addition, SesC seems to improve signaling specificity as an auxiliary backup to SesA/SesB activities. The coordinated action of these three CBCRs highlights why so many different CBCRs exist.

  2. Power systems signal processing for smart grids

    CERN Document Server

    Ribeiro, Paulo Fernando; Ribeiro, Paulo Márcio; Cerqueira, Augusto Santiago


    With special relation to smart grids, this book provides clear and comprehensive explanation of how Digital Signal Processing (DSP) and Computational Intelligence (CI) techniques can be applied to solve problems in the power system. Its unique coverage bridges the gap between DSP, electrical power and energy engineering systems, showing many different techniques applied to typical and expected system conditions with practical power system examples. Surveying all recent advances on DSP for power systems, this book enables engineers and researchers to understand the current state of the art a

  3. Signal conditioning circuitry design for instrumentation systems.

    Energy Technology Data Exchange (ETDEWEB)

    Larsen, Cory A.


    This report details the current progress in the design, implementation, and validation of the signal conditioning circuitry used in a measurement instrumentation system. The purpose of this text is to document the current progress of a particular design in signal conditioning circuitry in an instrumentation system. The input of the signal conditioning circuitry comes from a piezoresistive transducer and the output will be fed to a 250 ksps, 12-bit analog-to-digital converter (ADC) with an input range of 0-5 V. It is assumed that the maximum differential voltage amplitude input from the sensor is 20 mV with an unknown, but presumably high, sensor bandwidth. This text focuses on a specific design; however, the theory is presented in such a way that this text can be used as a basis for future designs.

  4. Notch signalling inhibits CD4 expression during initiation and differentiation of human T cell lineage.

    Directory of Open Access Journals (Sweden)

    Stephen M Carlin

    Full Text Available The Delta/Notch signal transduction pathway is central to T cell differentiation from haemopoietic stem cells (HSCs. Although T cell development is well characterized using expression of cell surface markers, the detailed mechanisms driving differentiation have not been established. This issue becomes central with observations that adult HSCs exhibit poor differentiation towards the T cell lineage relative to neonatal or embryonic precursors. This study investigates the contribution of Notch signalling and stromal support cells to differentiation of adult and Cord Blood (CB human HSCs, using the Notch signalling OP9Delta co-culture system. Co-cultured cells were assayed at weekly intervals during development for phenotype markers using flow cytometry. Cells were also assayed for mRNA expression at critical developmental stages. Expression of the central thymocyte marker CD4 was initiated independently of Notch signalling, while cells grown with Notch signalling had reduced expression of CD4 mRNA and protein. Interruption of Notch signalling in partially differentiated cells increased CD4 mRNA and protein expression, and promoted differentiation to CD4(+ CD8(+ T cells. We identified a set of genes related to T cell development that were initiated by Notch signalling, and also a set of genes subsequently altered by Notch signal interruption. These results demonstrate that while Notch signalling is essential for establishment of the T cell lineage, at later stages of differentiation, its removal late in differentiation promotes more efficient DP cell generation. Notch signalling adds to signals provided by stromal cells to allow HSCs to differentiate to T cells via initiation of transcription factors such as HES1, GATA3 and TCF7. We also identify gene expression profile differences that may account for low generation of T cells from adult HSCs.

  5. Epigenetic disruption of cell signaling in nasopharyngeal carcinoma

    Institute of Scientific and Technical Information of China (English)

    Li-Li Li; Xing-Sheng Shu; Zhao-Hui Wang; Ya Cao; Qian Tao


    Nasopharyngeal carcinoma (NPC) is a malignancy with remarkable ethnic and geographic distribution in southern China and Southeast Asia. Alternative to genetic changes, aberrant epigenetic events disrupt multiple genes involved in cell signaling pathways through DNA methylation of promoter CpG islands and/ or histone modifications. These epigenetic alterations grant cell growth advantage and contribute to the initiation and progression of NPC. In this review, we summariye the epigenetic deregulation of cell signaling in NPC tumorigenesis and highlight the importance of identifying epigenetic cell signaling regulators in NPC research. Developing pharmacologic strategies to reverse the epigenetic-silencing of cell signaling regulators might thus be useful to NPC prevention and therapy.

  6. Signal Separation and Reconstruction Method for Simultaneously Received Multi-System Signals in Flexible Wireless System (United States)

    Yamada, Takayuki; Lee, Doohwan; Shiba, Hiroyuki; Yamaguchi, Yo; Akabane, Kazunori; Uehara, Kazuhiro

    We previously proposed a unified wireless system called “Flexible Wireless System”. Comprising of flexible access points and a flexible signal processing unit, it collectively receives a wideband spectrum that includes multiple signals from various wireless systems. In cases of simultaneous multiple signal reception, however, reception performance degrades due to the interference among multiple signals. To address this problem, we propose a new signal separation and reconstruction method for spectrally overlapped signals. The method analyzes spectral information obtained by the short-time Fourier transform to extract amplitude and phase values at each center frequency of overlapped signals at a flexible signal processing unit. Using these values enables signals from received radio wave data to be separated and reconstructed for simultaneous multi-system reception. In this paper, the BER performance of the proposed method is evaluated using computer simulations. Also, the performance of the interference suppression is evaluated by analyzing the probability density distribution of the amplitude of the overlapped interference on a symbol of the received signal. Simulation results confirmed the effectiveness of the proposed method.

  7. Interrogating a cell signalling network sensitively monitors cell fate transition during early differentiation of mouse embryonic stem cells

    Institute of Scientific and Technical Information of China (English)

    LIU; Yi-Hsin; HO; Chih-ming


    The different cell types in an animal are often considered to be specified by combinations of transcription factors,and defined by marker gene expression.This paradigm is challenged,however,in stem cell research and application.Using a mouse embryonic stem cell(mESC) culture system,here we show that the expression level of many key stem cell marker genes/transcription factors such as Oct4,Sox2 and Nanog failed to monitor cell status transition during mESC differentiation.On the other hand,the response patterns of cell signalling network to external stimuli,as monitored by the dynamics of protein phosphorylation,changed dramatically.Our results also suggest that an irreversible alternation in the cell signalling network precedes the adjustment of transcription factor levels.This is consistent with the notion that signal transduction events regulate cell fate specification.We propose that interrogating a cell signalling network can assess the cell property more precisely,and provide a sensitive measurement for the early events in cell fate transition.We wish to bring attention to the potential problem of cell identification using a few marker genes,and suggest a novel methodology to address this issue.

  8. Haptic teleoperation systems signal processing perspective

    CERN Document Server

    Lee, Jae-young


    This book examines the signal processing perspective in haptic teleoperation systems. This text covers the topics of prediction, estimation, architecture, data compression, and error correction that can be applied to haptic teleoperation systems. The authors begin with an overview of haptic teleoperation systems, then look at a Bayesian approach to haptic teleoperation systems. They move onto a discussion of haptic data compression, haptic data digitization and forward error correction.   ·         Presents haptic data prediction/estimation methods that compensate for unreliable networks   ·         Discusses haptic data compression that reduces haptic data size over limited network bandwidth and haptic data error correction that compensate for packet loss problem   ·         Provides signal processing techniques used with existing control architectures.

  9. Cell signaling pathways and HIV-1 therapeutics. (United States)

    He, Johnny J


    Host-virus interactions permeate every aspect of both virus life cycle and host response and involve host cell macromolecular machinery and viral elements. It is these intimate interactions that mandate the outcomes of the infection and pathogenesis. It is also these intimate interactions that lay the foundation for the development of pharmaceutical interventions. HIV-1 is no exception in these regards. In the first two decades, HIV/AIDS research has led to the successful development of a number of antiviral inhibitors and the landmark formulation of the suppressive therapy. It has become apparent that this therapy does not offer a complete solution to cure and eradicate the virus. Meanwhile, this therapy has changed the overall landscape of HIV-associated neurological disorders to a more common and prevalent form so-called minor cognitive motor disorder. Thus, there is an important and continued need for new anti-HIV therapeutics. We believe that this is an excellent opportunity to compile and present the latest works being done during the last few years in this exciting field of HIV-host interactions, particularly cell signaling pathways. We hope that this special issue composed of one brief report, eight thematic reviews, and two original articles will serve to foster the exchange of new scientific ideas on HIV-host interactions and anti-HIV therapy and eventually contribute to HIV/AIDS eradication.

  10. Calcium Signalling Triggered by NAADP in T Cells Determines Cell Shape and Motility During Immune Synapse Formation (United States)

    Nebel, Merle; Zhang, Bo; Odoardi, Francesca; Flügel, Alexander; Potter, Barry V. L.; Guse, Andreas H.


    Nicotinic acid adenine dinucleotide phosphate (NAADP) has been implicated as an initial Ca2+ trigger in T cell Ca2+ signalling, but its role in formation of the immune synapse in CD4+ effector T cells has not been analysed. CD4+ T cells are activated by the interaction with peptide-MHCII complexes on the surface of antigen-presenting cells. Establishing a two-cell system including primary rat CD4+ T cells specific for myelin basic protein and rat astrocytes enabled us to mirror this activation process in vitro and to analyse Ca2+ signalling, cell shape changes and motility in T cells during formation and maintenance of the immune synapse. After immune synapse formation, T cells showed strong, antigen-dependent increases in free cytosolic calcium concentration ([Ca2+]i). Analysis of cell shape and motility revealed rounding and immobilization of T cells depending on the amplitude of the Ca2+ signal. NAADP-antagonist BZ194 effectively blocked Ca2+ signals in T cells evoked by the interaction with antigen-presenting astrocytes. BZ194 reduced the percentage of T cells showing high Ca2+ signals thereby supporting the proposed trigger function of NAADP for global Ca2+ signalling. Taken together, the NAADP signalling pathway is further confirmed as a promising target for specific pharmacological intervention to modulate T cell activation. PMID:27747143

  11. Tracking Hypoxic Signaling within Encapsulated Cell Aggregates


    Skiles, Matthew L.; Sahai, Suchit; Blanchette, James O.


    In Diabetes mellitus type 1, autoimmune destruction of the pancreatic β-cells results in loss of insulin production and potentially lethal hyperglycemia. As an alternative treatment option to exogenous insulin injection, transplantation of functional pancreatic tissue has been explored1,2. This approach offers the promise of a more natural, long-term restoration of normoglycemia. Protection of the donor tissue from the host's immune system is required to prevent rejection and encapsulation is...

  12. Continuous signals and systems with Matlab

    CERN Document Server

    ElAli, Taan


    Designed for a one-semester undergraduate course in continuous linear systems, Continuous Signals and Systems with MATLAB®, Second Edition presents the tools required to design, analyze, and simulate dynamic systems. It thoroughly describes the process of the linearization of nonlinear systems, using MATLAB® to solve most examples and problems. With updates and revisions throughout, this edition focuses more on state-space methods, block diagrams, and complete analog filter design. New to the Second Edition           A chapter on block diagrams that covers various classical and state-space

  13. Probing Embryonic Stem Cell Autocrine and Paracrine Signaling Using Microfluidics (United States)

    Przybyla, Laralynne; Voldman, Joel


    Although stem cell fate is traditionally manipulated by exogenously altering the cells' extracellular signaling environment, the endogenous autocrine and paracrine signals produced by the cells also contribute to their two essential processes: self-renewal and differentiation. Autocrine and/or paracrine signals are fundamental to both embryonic stem cell self-renewal and early embryonic development, but the nature and contributions of these signals are often difficult to fully define using conventional methods. Microfluidic techniques have been used to explore the effects of cell-secreted signals by controlling cell organization or by providing precise control over the spatial and temporal cellular microenvironment. Here we review how such techniques have begun to be adapted for use with embryonic stem cells, and we illustrate how many remaining questions in embryonic stem cell biology could be addressed using microfluidic technologies.

  14. Cross-membrane signal transduction of receptor tyrosine kinases (RTKs): from systems biology to systems pharmacology. (United States)

    Benson, Neil; van der Graaf, Piet H; Peletier, Lambertus A


    Receptor tyrosine kinases are high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. They straddle the cell wall and play an important role in cross-membrane signalling. We present a two-component systems pharmacology model based on the local physiology and identify characteristic features of its dynamics. We thus present a transparent tool for studying the effects of drug intervention and ways of administration on cross-membrane signalling through these receptors.

  15. The merged basins of signal transduction pathways in spatiotemporal cell biology. (United States)

    Hou, Yingchun; Hou, Yang; He, Siyu; Ma, Caixia; Sun, Mengyao; He, Huimin; Gao, Ning


    Numerous evidences have indicated that a signal system is composed by signal pathways, each pathway is composed by sub-pathways, and the sub-pathway is composed by the original signal terminals initiated with a protein/gene. We infer the terminal signals merged signal transduction system as "signal basin". In this article, we discussed the composition and regulation of signal basins, and the relationship between the signal basin control and triple W of spatiotemporal cell biology. Finally, we evaluated the importance of the systemic regulation to gene expression by signal basins under triple W. We hope our discussion will be the beginning to cause the attention for this area from the scientists of life science.

  16. Distinguishing autocrine and paracrine signals in hematopoietic stem cell culture using a biofunctional microcavity platform (United States)

    Müller, Eike; Wang, Weijia; Qiao, Wenlian; Bornhäuser, Martin; Zandstra, Peter W.; Werner, Carsten; Pompe, Tilo


    Homeostasis of hematopoietic stem cells (HSC) in the mammalian bone marrow stem cell niche is regulated by signals of the local microenvironment. Besides juxtacrine, endocrine and metabolic cues, paracrine and autocrine signals are involved in controlling quiescence, proliferation and differentiation of HSC with strong implications on expansion and differentiation ex vivo as well as in vivo transplantation. Towards this aim, a cell culture analysis on a polymer microcavity carrier platform was combined with a partial least square analysis of a mechanistic model of cell proliferation. We could demonstrate the discrimination of specific autocrine and paracrine signals from soluble factors as stimulating and inhibitory effectors in hematopoietic stem and progenitor cell culture. From that we hypothesize autocrine signals to be predominantly involved in maintaining the quiescent state of HSC in single-cell niches and advocate our analysis platform as an unprecedented option for untangling convoluted signaling mechanisms in complex cell systems being it of juxtacrine, paracrine or autocrine origin.

  17. Signal molecule-mediated hepatic cell communication during liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Zhen-Yu Zheng; Shun-Yan Weng; Yan Yu


    Liver regeneration is a complex and well-orchestrated process, during which hepatic cells are activated to produce large signal molecules in response to liver injury or mass reduction. These signal molecules, in turn, set up the connections and cross-talk among liver cells to promote hepatic recovery. In this review, we endeavor to summarize the network of signal molecules that mediates hepatic cell communication in the regulation of liver regeneration.

  18. Integrin Signaling in Mammary Epithelial Cells and Breast Cancer


    Lambert, Arthur W.; Sait Ozturk; Sam Thiagalingam


    Cells sense and respond to the extracellular matrix (ECM) by way of integrin receptors, which facilitate cell adhesion and intracellular signaling. Advances in understanding the mammary epithelial cell hierarchy are converging with new developments that reveal how integrins regulate the normal mammary gland. But in breast cancer, integrin signaling contributes to the development and progression of tumors. This paper highlights recent studies which examine the role of integrin signaling in mam...

  19. SLIT/ROBO2 Signaling Promotes Mammary Stem Cell Senescence by Inhibiting Wnt Signaling

    Directory of Open Access Journals (Sweden)

    Gwyndolen Harburg


    Full Text Available WNT signaling stimulates the self-renewal of many types of adult stem cells, including mammary stem cells (MaSCs, but mechanisms that limit this activity are poorly understood. Here, we demonstrate that SLIT2 restricts stem cell renewal by signaling through ROBO2 in a subset of basal cells to negatively regulate WNT signaling. The absence of SLIT/ROBO2 signaling leads to increased levels of nuclear β-catenin. Robo2 loss does not increase the number of stem cells; instead, stem cell renewal is enhanced in the absence of SLIT/ROBO2 signaling. This is due to repressed expression of p16 INK4a, which, in turn, delays MaSC senescence. Together, our studies support a model in which SLITs restrict the expansion of MaSCs by countering the activity of WNTs and limiting self-renewal.

  20. Determinants of cell-to-cell variability in protein kinase signaling.

    Directory of Open Access Journals (Sweden)

    Matthias Jeschke

    Full Text Available Cells reliably sense environmental changes despite internal and external fluctuations, but the mechanisms underlying robustness remain unclear. We analyzed how fluctuations in signaling protein concentrations give rise to cell-to-cell variability in protein kinase signaling using analytical theory and numerical simulations. We characterized the dose-response behavior of signaling cascades by calculating the stimulus level at which a pathway responds ('pathway sensitivity' and the maximal activation level upon strong stimulation. Minimal kinase cascades with gradual dose-response behavior show strong variability, because the pathway sensitivity and the maximal activation level cannot be simultaneously invariant. Negative feedback regulation resolves this trade-off and coordinately reduces fluctuations in the pathway sensitivity and maximal activation. Feedbacks acting at different levels in the cascade control different aspects of the dose-response curve, thereby synergistically reducing the variability. We also investigated more complex, ultrasensitive signaling cascades capable of switch-like decision making, and found that these can be inherently robust to protein concentration fluctuations. We describe how the cell-to-cell variability of ultrasensitive signaling systems can be actively regulated, e.g., by altering the expression of phosphatase(s or by feedback/feedforward loops. Our calculations reveal that slow transcriptional negative feedback loops allow for variability suppression while maintaining switch-like decision making. Taken together, we describe design principles of signaling cascades that promote robustness. Our results may explain why certain signaling cascades like the yeast pheromone pathway show switch-like decision making with little cell-to-cell variability.

  1. A sharp T-cell antigen receptor signaling threshold for T-cell proliferation


    Au-Yeung, Byron B.; Zikherman, Julie; James L. Mueller; Ashouri, Judith F.; Matloubian, Mehrdad; Cheng, Debra A.; Chen, Yiling; Shokat, Kevan M; Weiss, Arthur


    Biochemical signals triggered by the T-cell receptor (TCR) are required for stimulating T cells and can be initiated within seconds. However, a hallmark of T-cell activation, cell division, occurs hours after TCR signaling has begun, implying that T cells require a minimum duration and/or accumulate TCR signaling events to drive proliferation. To visualize the accumulated signaling experienced by T cells, we used a fluorescent reporter gene that is activated by TCR stimulation. This technique...

  2. Calcium signaling in plant cells in altered gravity (United States)

    Kordyum, E. L.


    tension → alterations in the physicochemical properties of the membrane → changes in membrane permeability, ion transport, membrane-bound enzyme activity, etc. → metabolism rearrangements → physiological responses. An analysis of data available on biological effects of altered gravity at the cellular level allows one to conclude that microgravity environment appears to affect cytoskeleton, carbohydrate and lipid metabolism, cell wall biogenesis via changes in enzyme activity and protein expression, with involvement of regulatory Ca 2+ messenger system. Changes in Ca 2+ influx/efflux and possible pathways of Ca 2+ signaling in plant cell biochemical regulation in altered gravity are discussed.

  3. Marine bromophenol bis(2,3-dibromo-4,5-dihydroxybenzyl) ether, represses angiogenesis in HUVEC cells and in zebrafish embryos via inhibiting the VEGF signal systems. (United States)

    Qi, Xin; Liu, Ge; Qiu, Lin; Lin, Xiukun; Liu, Ming


    Bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE) is a bromophenol compound derived from marine algae. Our previous reports have shown that BDDE possessed anticancer activity in vitro. However, its antiangiogenesis activity and possible mechanisms remain unclear. The present study demonstrated that BDDE displayed in vitro antiangiogenesis capabilities by significantly inhibiting HUVEC cells proliferation, migration, and tube formation, without any effect on the preformed vascular tube. Western blot analysis revealed that BDDE decreased the protein level of VEGF and VEGFR but not that of EGFR, FGFR, and IGFR. In addition, BDDE inactivated the VEGF downstream signaling molecules including mTOR and Src, whereas activated Akt and ERK. Moreover, BDDE blocked subintestinal vessel formation in zebrafish embryos in vivo and showed toxicity under high concentrations of BDDE. The results of this present study indicated that BDDE, which has unique chemical structure different from current antiangiogenesis agents, could be used as a potential drug candidate for cancer prevention and therapy.

  4. The application of information theory to biochemical signaling systems (United States)

    Rhee, Alex; Cheong, Raymond; Levchenko, Andre


    Cell signaling can be thought of fundamentally as an information transmission problem in which chemical messengers relay information about the external environment to the decision centers within a cell. Due to the biochemical nature of cellular signal transduction networks, molecular noise will inevitably limit the fidelity of any messages received and processed by a cell’s signal transduction networks, leaving it with an imperfect impression of its environment. Fortunately, Shannon’s information theory provides a mathematical framework independent of network complexity that can quantify the amount of information that can be transmitted despite biochemical noise. In particular, the channel capacity can be used to measure the maximum number of stimuli a cell can distinguish based upon the noisy responses of its signaling systems. Here, we provide a primer for quantitative biologists that covers fundamental concepts of information theory, highlights several key considerations when experimentally measuring channel capacity, and describes successful examples of the application of information theoretic analysis to biological signaling. PMID:22872091

  5. Ephrin signalling in the developing nervous system. (United States)

    Klein, Rüdiger; Kania, Artur


    Ephrin ligands and their Eph receptors hold our attention since their link to axon guidance almost twenty years ago. Since then, they have been shown to be critical for short distance cell-cell interactions in the nervous system. The interest in their function has not abated, leading to ever-more sophisticated studies generating as many surprising answers about their function as new questions. We discuss recent insights into their functions in the developing nervous system, including neuronal progenitor sorting, stochastic cell migration, guidance of neuronal growth cones, topographic map formation, as well as synaptic plasticity.

  6. Encoding olfactory signals via multiple chemosensory systems. (United States)

    Ma, Minghong


    Most animals have evolved multiple olfactory systems to detect general odors as well as social cues. The sophistication and interaction of these systems permit precise detection of food, danger, and mates, all crucial elements for survival. In most mammals, the nose contains two well described chemosensory apparatuses (the main olfactory epithelium and the vomeronasal organ), each of which comprises several subtypes of sensory neurons expressing distinct receptors and signal transduction machineries. In many species (e.g., rodents), the nasal cavity also includes two spatially segregated clusters of neurons forming the septal organ of Masera and the Grueneberg ganglion. Results of recent studies suggest that these chemosensory systems perceive diverse but overlapping olfactory cues and that some neurons may even detect the pressure changes carried by the airflow. This review provides an update on how chemosensory neurons transduce chemical (and possibly mechanical) stimuli into electrical signals, and what information each system brings into the brain. Future investigation will focus on the specific ligands that each system detects with a behavioral context and the processing networks that each system involves in the brain. Such studies will lead to a better understanding of how the multiple olfactory systems, acting in concert, offer a complete representation of the chemical world.

  7. Dissecting Nck/Dock Signaling Pathways in Drosophila Visual System

    Directory of Open Access Journals (Sweden)


    Full Text Available The establishment of neuronal connections during embryonic development requires the precise guidance and targeting of the neuronal growth cone, an expanded cellular structure at the leading tip of a growing axon. The growth cone contains sophisticated signaling systems that allow the rapid communication between guidance receptors and the actin cytoskeleton in generating directed motility. Previous studies demonstrated a specific role for the Nck/Dock SH2/SH3 adapter protein in photoreceptor (R cell axon guidance and target recognition in the Drosophila visual system, suggesting strongly that Nck/Dock is one of the long-sought missing links between cell surface receptors and the actin cytoskeleton. In this review, I discuss the recent progress on dissecting the Nck/Dock signaling pathways in R-cell growth cones. These studies have identified additional key components of the Nck/Dock signaling pathways for linking the receptor signaling to the remodeling of the actin cytoskeleton in controlling growth-cone motility.

  8. Hydrogen Peroxide-Mediated Growth of the Root System Occurs via Auxin Signaling Modification and Variations in the Expression of Cell-Cycle Genes in Rice Seedlings Exposed to Cadmium Stress

    Institute of Scientific and Technical Information of China (English)

    Feng-Yun Zhao; Ming-Ming Han; Shi-Yong Zhang; Kai Wang; Cheng-Ren Zhang; Tao Liu; Wen Liu


    The link between root growth,H2O2,auxin signaling,and the cell cycle in cadmium (Cd)-stressed rice (Oryza sativa No.11) was analyzed in this study.Exposure to Cd induced a significant accumulation of Cd,but caused a decrease in zinc (Zn) content which resulted from the decreased expression of OsHMA9 and OsZIP.Analysis using a Cd-specific probe showed that Cd was mainly localized in the meristematic zone and vascular tissues.Formation and elongation of the root system were significantly promoted by 3-amino-1,2,4-triazole (AT),but were markedly inhibited by N,N'-dimethylthiourea (DMTU) under Cd stress.The effect of H2O2 on Cd-stressed root growth was further confirmed by examining a gain-of-function rice mutant (carrying catalase1 and glutathione-S-transferase) in the presence or absence of diphenylene iodonium.DR5-GUS staining revealed close associations between H2O2 and the concentration and distribution of auxin.H2O2 affected the expression of key genes,including OsYUCCA,OsPIN,OsARF,and OsIAA,in the auxin signaling pathway in Cd-treated plants.These results suggest that H2O2 functions upstream of the auxin signaling pathway.Furthermore,H2O2 modified the expression of cell-cycle genes in Cd-treated roots.The effects of H2O2 on root system growth are therefore linked to auxin signal modification and to variations in the expression of cell-cycle genes in Cd-stressed rice.A working model for the effects of H2O2 on Cd-stressed root system growth is thus proposed and discussed in this paper.

  9. Integration of light and metabolic signals for stem cell activation at the shoot apical meristem (United States)

    Pfeiffer, Anne; Janocha, Denis; Dong, Yihan; Medzihradszky, Anna; Schöne, Stefanie; Daum, Gabor; Suzaki, Takuya; Forner, Joachim; Langenecker, Tobias; Rempel, Eugen; Schmid, Markus; Wirtz, Markus; Hell, Rüdiger; Lohmann, Jan U


    A major feature of embryogenesis is the specification of stem cell systems, but in contrast to the situation in most animals, plant stem cells remain quiescent until the postembryonic phase of development. Here, we dissect how light and metabolic signals are integrated to overcome stem cell dormancy at the shoot apical meristem. We show on the one hand that light is able to activate expression of the stem cell inducer WUSCHEL independently of photosynthesis and that this likely involves inter-regional cytokinin signaling. Metabolic signals, on the other hand, are transduced to the meristem through activation of the TARGET OF RAPAMYCIN (TOR) kinase. Surprisingly, TOR is also required for light signal dependent stem cell activation. Thus, the TOR kinase acts as a central integrator of light and metabolic signals and a key regulator of stem cell activation at the shoot apex. DOI: PMID:27400267

  10. Competition in notch signaling with cis enriches cell fate decisions.

    Directory of Open Access Journals (Sweden)

    Pau Formosa-Jordan

    Full Text Available Notch signaling is involved in cell fate choices during the embryonic development of Metazoa. Commonly, Notch signaling arises from the binding of the Notch receptor to its ligands in adjacent cells driving cell-to-cell communication. Yet, cell-autonomous control of Notch signaling through both ligand-dependent and ligand-independent mechanisms is known to occur as well. Examples include Notch signaling arising in the absence of ligand binding, and cis-inhibition of Notch signaling by titration of the Notch receptor upon binding to its ligands within a single cell. Increasing experimental evidences support that the binding of the Notch receptor with its ligands within a cell (cis-interactions can also trigger a cell-autonomous Notch signal (cis-signaling, whose potential effects on cell fate decisions and patterning remain poorly understood. To address this question, herein we mathematically and computationally investigate the cell states arising from the combination of cis-signaling with additional Notch signaling sources, which are either cell-autonomous or involve cell-to-cell communication. Our study shows that cis-signaling can switch from driving cis-activation to effectively perform cis-inhibition and identifies under which conditions this switch occurs. This switch relies on the competition between Notch signaling sources, which share the same receptor but differ in their signaling efficiency. We propose that the role of cis-interactions and their signaling on fine-grained patterning and cell fate decisions is dependent on whether they drive cis-inhibition or cis-activation, which could be controlled during development. Specifically, cis-inhibition and not cis-activation facilitates patterning and enriches it by modulating the ratio of cells in the high-ligand expression state, by enabling additional periodic patterns like stripes and by allowing localized patterning highly sensitive to the precursor state and cell-autonomous bistability

  11. Moxonidine modulates cytokine signalling and effects on cardiac cell viability. (United States)

    Aceros, Henry; Farah, Georges; Noiseux, Nicolas; Mukaddam-Daher, Suhayla


    Regression of left ventricular hypertrophy and improved cardiac function in SHR by the centrally acting imidazoline I1-receptor agonist, moxonidine, are associated with differential actions on circulating and cardiac cytokines. Herein, we investigated cell-type specific I1-receptor (also known as nischarin) signalling and the mechanisms through which moxonidine may interfere with cytokines to affect cardiac cell viability. Studies were performed on neonatal rat cardiomyocytes and fibroblasts incubated with interleukin (IL)-1β (5 ng/ml), tumor necrosis factor (TNF)-α (10 ng/ml), and moxonidine (10(-7) and 10(-5) M), separately and in combination, for 15 min, and 24 and 48 h for the measurement of MAPKs (ERK1/2, JNK, and p38) and Akt activation and inducible NOS (iNOS) expression, by Western blotting, and cardiac cell viability/proliferation and apoptosis by flow cytometry, MTT assay, and Live/Dead assay. Participation of imidazoline I1-receptors and the signalling proteins in the detected effects was identified using imidazoline I1-receptor antagonist and signalling protein inhibitors. The results show that IL-1β, and to a lower extent, TNF-α, causes cell death and that moxonidine protects against starvation- as well as IL-1β -induced mortality, mainly by maintaining membrane integrity, and in part, by improving mitochondrial activity. The protection involves activation of Akt, ERK1/2, p38, JNK, and iNOS. In contrast, moxonidine stimulates basal and IL-1β-induced fibroblast mortality by mechanisms that include inhibition of JNK and iNOS. Thus, apart from their actions on the central nervous system, imidazoline I1-receptors are directly involved in cardiac cell growth and death, and may play an important role in cardiovascular diseases associated with inflammation.

  12. Aberrant signaling pathways in medulloblastomas: a stem cell connection

    Directory of Open Access Journals (Sweden)

    Carolina Oliveira Rodini


    Full Text Available Medulloblastoma is a highly malignant primary tumor of the central nervous system. It represents the most frequent type of solid tumor and the leading cause of death related to cancer in early childhood. Current treatment includes surgery, chemotherapy and radiotherapy which may lead to severe cognitive impairment and secondary brain tumors. New perspectives for therapeutic development have emerged with the identification of stem-like cells displaying high tumorigenic potential and increased radio- and chemo-resistance in gliomas. Under the cancer stem cell hypothesis, transformation of neural stem cells and/or granular neuron progenitors of the cerebellum are though to be involved in medulloblastoma development. Dissecting the genetic and molecular alterations associated with this process should significantly impact both basic and applied cancer research. Based on cumulative evidences in the fields of genetics and molecular biology of medulloblastomas, we discuss the possible involvement of developmental signaling pathways as critical biochemical switches determining normal neurogenesis or tumorigenesis. From the clinical viewpoint, modulation of signaling pathways such as TGFβ, regulating neural stem cell proliferation and tumor development, might be attempted as an alternative strategy for future drug development aiming at more efficient therapies and improved clinical outcome of patients with pediatric brain cancers.

  13. Phosphoproteomics-based systems analysis of signal transduction networks

    Directory of Open Access Journals (Sweden)

    Hiroko eKozuka-Hata


    Full Text Available Signal transduction systems coordinate complex cellular information to regulate biological events such as cell proliferation and differentiation. Although the accumulating evidence on widespread association of signaling molecules has revealed essential contribution of phosphorylation-dependent interaction networks to cellular regulation, their dynamic behavior is mostly yet to be analyzed. Recent technological advances regarding mass spectrometry-based quantitative proteomics have enabled us to describe the comprehensive status of phosphorylated molecules in a time-resolved manner. Computational analyses based on the phosphoproteome dynamics accelerate generation of novel methodologies for mathematical analysis of cellular signaling. Phosphoproteomics-based numerical modeling can be used to evaluate regulatory network elements from a statistical point of view. Integration with transcriptome dynamics also uncovers regulatory hubs at the transcriptional level. These omics-based computational methodologies, which have firstly been applied to representative signaling systems such as the epidermal growth factor receptor pathway, have now opened up a gate for systems analysis of signaling networks involved in immune response and cancer.

  14. Signals and Systems in Biomedical Engineering Signal Processing and Physiological Systems Modeling

    CERN Document Server

    Devasahayam, Suresh R


    The use of digital signal processing is ubiquitous in the field of physiology and biomedical engineering. The application of such mathematical and computational tools requires a formal or explicit understanding of physiology. Formal models and analytical techniques are interlinked in physiology as in any other field. This book takes a unitary approach to physiological systems, beginning with signal measurement and acquisition, followed by signal processing, linear systems modelling, and computer simulations. The signal processing techniques range across filtering, spectral analysis and wavelet analysis. Emphasis is placed on fundamental understanding of the concepts as well as solving numerical problems. Graphs and analogies are used extensively to supplement the mathematics. Detailed models of nerve and muscle at the cellular and systemic levels provide examples for the mathematical methods and computer simulations. Several of the models are sufficiently sophisticated to be of value in understanding real wor...

  15. Diffusion wave and signal transduction in biological live cells

    CERN Document Server

    Fan, Tian You


    Transduction of mechanical stimuli into biochemical signals is a fundamental subject for cell physics. In the experiments of FRET signal in cells a wave propagation in nanoscope was observed. We here develop a diffusion wave concept and try to give an explanation to the experimental observation. The theoretical prediction is in good agreement to result of the experiment.

  16. Constitutive activation of BMP signalling abrogates experimental metastasis of OVCA429 cells via reduced cell adhesion

    Directory of Open Access Journals (Sweden)

    Shepherd Trevor G


    reduced cell adhesion to the extracellular matrix substrates fibronectin and vitronectin that was observed. Conclusions We propose that the key steps of ovarian cancer metastasis, specifically cell cohesion of multicellular aggregates in ascites and cell adhesion for reattachment to secondary sites, may be inhibited by overactive BMP signalling, thereby decreasing the ultimate malignant potential of ovarian cancer in this model system.

  17. Retinoic acid signalling in thymocytes regulates T cell development

    DEFF Research Database (Denmark)

    Wendland, Kerstin; Sitnik, Katarzyna Maria; Kotarsky, Knut

    The Vitamin A derivative retinoic acid (RA) has emerged as an important regulator of peripheral T cell responses. However, whether there is endogenous retinoic acid receptor (RAR) signaling in developing thymocytes and the potential impact of such signals in thymocyte development remains unclear...... further enhanced in recently generated CD69+ CD4+ SP cells. To address the potential biological significance of RA signaling in developing thymocytes, we evaluated T cell development in CD4Cre-dnRAR mice, where RA signaling is blocked in thymocytes from the CD4+CD8+ double positive (DP) stage onwards due...... of this cell subset. Collectively, our data suggest a direct role for RA signaling in regulating thymocyte homeostasis and T cell development....

  18. Sphingosine 1-Phosphate Receptor 1 Signaling in Mammalian Cells

    Directory of Open Access Journals (Sweden)

    Nigel J. Pyne


    Full Text Available The bioactive lipid, sphingosine 1-phosphate (S1P binds to a family of G protein-coupled receptors, termed S1P1-S1P5. These receptors function in, for example, the cardiovascular system to regulate vascular barrier integrity and tone, the nervous system to regulate neuronal differentiation, myelination and oligodendrocyte/glial cell survival and the immune system to regulate T- and B-cell subsets and trafficking. S1P receptors also participate in the pathophysiology of autoimmunity, inflammatory disease, cancer, neurodegeneration and others. In this review, we describe how S1P1 can form a complex with G-protein and β-arrestin, which function together to regulate effector pathways. We also discuss the role of the S1P1-Platelet derived growth factor receptor β functional complex (which deploys G-protein/β-arrestin and receptor tyrosine kinase signaling in regulating cell migration. Possible mechanisms by which different S1P-chaperones, such as Apolipoprotein M-High-Density Lipoprotein induce biological programmes in cells are also described. Finally, the role of S1P1 in health and disease and as a target for clinical intervention is appraised.

  19. Analysis of Intracellular Calcium Signaling in Human Embryonic Stem Cells. (United States)

    Péntek, Adrienn; Pászty, Katalin; Apáti, Ágota


    Measurement of changes in intracellular calcium concentration is one of the most common and useful tools for studying signal transduction pathways or cellular responses in basic research and drug screening purposes as well. Increasing number of such applications using human pluripotent stem cells and their derivatives requires development of calcium signal measurements for this special cell type. Here we describe a modified protocol for analysis of calcium signaling events in human embryonic stem cells, which can be used for other pluripotent cell types (such as iPSC) or their differentiated offspring as well.

  20. Efficient audio signal processing for embedded systems (United States)

    Chiu, Leung Kin

    As mobile platforms continue to pack on more computational power, electronics manufacturers start to differentiate their products by enhancing the audio features. However, consumers also demand smaller devices that could operate for longer time, hence imposing design constraints. In this research, we investigate two design strategies that would allow us to efficiently process audio signals on embedded systems such as mobile phones and portable electronics. In the first strategy, we exploit properties of the human auditory system to process audio signals. We designed a sound enhancement algorithm to make piezoelectric loudspeakers sound ”richer" and "fuller." Piezoelectric speakers have a small form factor but exhibit poor response in the low-frequency region. In the algorithm, we combine psychoacoustic bass extension and dynamic range compression to improve the perceived bass coming out from the tiny speakers. We also developed an audio energy reduction algorithm for loudspeaker power management. The perceptually transparent algorithm extends the battery life of mobile devices and prevents thermal damage in speakers. This method is similar to audio compression algorithms, which encode audio signals in such a ways that the compression artifacts are not easily perceivable. Instead of reducing the storage space, however, we suppress the audio contents that are below the hearing threshold, therefore reducing the signal energy. In the second strategy, we use low-power analog circuits to process the signal before digitizing it. We designed an analog front-end for sound detection and implemented it on a field programmable analog array (FPAA). The system is an example of an analog-to-information converter. The sound classifier front-end can be used in a wide range of applications because programmable floating-gate transistors are employed to store classifier weights. Moreover, we incorporated a feature selection algorithm to simplify the analog front-end. A machine

  1. Signalling pathways that inhibit the capacity of precursor cells for myelin repair. (United States)

    Sabo, Jennifer K; Cate, Holly S


    In demyelinating disorders such as Multiple Sclerosis (MS), targets of injury are myelin and oligodendrocytes, leading to severe neurological dysfunction. Regenerative therapies aimed at promoting oligodendrocyte maturation and remyelination are promising strategies for treatment in demyelinating disorders. Endogenous precursor cells or exogenous transplanted cells are potential sources for remyelinating oligodendrocytes in the central nervous system (CNS). Several signalling pathways have been implicated in regulating the capacity of these cell populations for myelin repair. Here, we review neural precursor cells and oligodendrocyte progenitor cells as potential sources for remyelinating oligodendrocytes and evidence for the functional role of key signalling pathways in inhibiting regeneration from these precursor cell populations.

  2. Signalling Pathways that Inhibit the Capacity of Precursor Cells for Myelin Repair

    Directory of Open Access Journals (Sweden)

    Jennifer K. Sabo


    Full Text Available In demyelinating disorders such as Multiple Sclerosis (MS, targets of injury are myelin and oligodendrocytes, leading to severe neurological dysfunction. Regenerative therapies aimed at promoting oligodendrocyte maturation and remyelination are promising strategies for treatment in demyelinating disorders. Endogenous precursor cells or exogenous transplanted cells are potential sources for remyelinating oligodendrocytes in the central nervous system (CNS. Several signalling pathways have been implicated in regulating the capacity of these cell populations for myelin repair. Here, we review neural precursor cells and oligodendrocyte progenitor cells as potential sources for remyelinating oligodendrocytes and evidence for the functional role of key signalling pathways in inhibiting regeneration from these precursor cell populations.


    Institute of Scientific and Technical Information of China (English)

    LI Hong; ZHOU Zhiyuan; DAI Rongyang; LUO Bo; ZHENG Xiaoli; YANG Wenli; HE Tao; WU Minglu


    In cells, the interactions of distinct signaling transduction pathways originating from cross-talkings between signaling molecules give rise to the formation of signaling transduction networks, which contributes to the changes (emergency) of kinetic behaviors of signaling system compared with single molecule or pathway. Depending on the known experimental data, we have constructed a model for complex cellular signaling transduction system, which is derived from signaling transduction of epidermal growth factor receptor in neuron. By the computational simulating methods, the self-adaptive controls of this system have been investigated. We find that this model exhibits a relatively stable selfadaptive system, especially to over-stimulation of agonist, and the amplitude and duration of signaling intermediates in it could be controlled by multiple self-adaptive effects, such as "signal scattering", "positive feedback", "negative feedback" and "B-Raf shunt". Our results provide an approach to understanding the dynamic behaviors of complex biological systems.

  4. Deregulation of Interferon Signaling in Malignant Cells

    Directory of Open Access Journals (Sweden)

    Leonidas C. Platanias


    Full Text Available Interferons (IFNs are a family of cytokines with potent antiproliferative, antiviral, and immunomodulatory properties. Much has been learned about IFNs and IFN-activated signaling cascades over the last 50 years. Due to their potent antitumor effects in vitro and in vivo, recombinant IFNs have been used extensively over the years, alone or in combination with other drugs, for the treatment of various malignancies. This review summarizes the current knowledge on IFN signaling components and pathways that are deregulated in human malignancies. The relevance of deregulation of IFN signaling pathways in defective innate immune surveillance and tumorigenesis are discussed.

  5. TOR signaling regulates planarian stem cells and controls localized and organismal growth. (United States)

    Peiris, T Harshani; Weckerle, Frank; Ozamoto, Elyse; Ramirez, Daniel; Davidian, Devon; García-Ojeda, Marcos E; Oviedo, Néstor J


    Target of Rapamycin (TOR) controls an evolutionarily conserved signaling pathway that modulates cellular growth and division by sensing levels of nutrients, energy and stress. As such, TOR signaling is a crucial component of tissues and organs that translates systemic signals into cellular behavior. The ubiquitous nature of TOR signaling, together with the difficulty of analyzing tissue during cellular turnover and repair, have limited our understanding of how this kinase operates throughout the body. Here, we use the planarian model system to address TOR regulation at the organismal level. The planarian TOR homolog (Smed-TOR) is ubiquitously expressed, including stem cells (neoblasts) and differentiated tissues. Inhibition of TOR with RNA interference severely restricts cell proliferation, allowing the study of neoblasts with restricted proliferative capacity during regeneration and systemic cell turnover. Strikingly, TOR signaling is required for neoblast response to amputation and localized growth (blastema). However, in the absence of TOR signaling, regeneration takes place only within differentiated tissues. In addition, TOR is essential for maintaining the balance between cell division and cell death, and its dysfunction leads to tissue degeneration and lack of organismal growth in the presence of nutrients. Finally, TOR function is likely to be mediated through TOR Complex 1 as its disruption recapitulates signs of the TOR phenotype. Our data reveal novel roles for TOR signaling in controlling adult stem cells at a systemic level and suggest a new paradigm for studying TOR function during physiological turnover and regeneration.

  6. TGF-β Signaling in Neuronal Stem Cells

    Directory of Open Access Journals (Sweden)

    Chohee Yun


    Full Text Available Transforming growth factor beta (TGF-β signaling has diverse and complex roles in various biological phenomena such as cell growth, differentiation, embryogenesis and morphogenesis. ES cells provide an essential model for understanding the role of TGF-β signaling in lineage specification and differentiation. Recent studies have suggested significant role of TGF-β in stem/progenitor cell biology. Here in this review, we focus on the role of the TGF-β superfamily in neuronal development.

  7. Signal co-operation between integrins and other receptor systems. (United States)

    Streuli, Charles H; Akhtar, Nasreen


    The multicellular nature of metazoans means that all cellular processes need to be tuned by adhesive interactions between cells and their local microenvironment. The spatial organization of cells within tissues requires sophisticated networks of extracellular signals to control their survival and proliferation, movements and positioning, and differentiated function. These cellular characteristics are mediated by multiple inputs from adhesion systems in combination with soluble and developmental signals. In the present review we explore how one class of adhesion receptor, the integrins, co-operate with other types of receptor to control diverse aspects of cell fate. In particular we discuss: (i) how beta3 and beta1 integrins work together with growth factors to control angiogenesis; (ii) how alpha6beta4 integrin co-operates with receptor tyrosine kinases in normal epithelial function and cancer; (iii) the interplay between beta1 integrins and EGF (epidermal growth factor) receptor; (iv) signal integration connecting integrins and cytokine receptors for interleukins, prolactin and interferons; and (v) how integrins and syndecans co-operate in cell migration.

  8. Modeling Signal Transduction and Lipid Rafts in Immune Cells (United States)

    Prasad, Ashok


    Experimental evidence increasingly suggests that lipid rafts are nanometer sized cholesterol dependent dynamic assemblies enriched in sphingolipids and associated proteins. Lipid rafts are dynamic structures that break-up and reform on a relatively short time-scale, and are believed to facilitate the interactions of raft-associated proteins. The role of these rafts in signaling has been controversial, partly due to controversies regarding the existence and nature of the rafts themselves. Experimental evidence has indicated that in several cell types, especially T cells, rafts do influence signal transduction and T cell activation. Given the emerging consensus on the biophysical character of lipid rafts, the question can be asked as to what roles they possibly play in signal transduction. Here we carry out simulations of minimal models of the signal transduction network that regulates Src-family kinase dynamics in T cells and other cell types. By separately treating raft-based biochemical interactions, we find that rafts can indeed putatively play an important role in signal transduction, and in particular may affect the sensitivity of signal transduction. This illuminates possible functional consequences of membrane heterogeneities on signal transduction and points towards mechanisms for spatial control of signaling by cells.

  9. Adipocyte activation of cancer stem cell signaling in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Benjamin; Wolfson; Gabriel; Eades; Qun; Zhou


    Signaling within the tumor microenvironment has a critical role in cancer initiation and progression. Adipocytes, one of the major components of the breast microenvironment,have been shown to provide pro-tumorigenic signals that promote cancer cell proliferation and invasiveness in vitro and tumorigenicity in vivo. Adipocyte secreted factors such as leptin and interleukin-6(IL-6) have a paracrine effect on breast cancer cells. In adipocyte-adjacent breast cancer cells, the leptin and IL-6 signaling pathways activate janus kinase 2/signal transducer and activatorof transcription 5, promoting the epithelial-mesenchymal transition, and upregulating stemness regulators such as Notch, Wnt and the Sex determining region Y-box 2/octamer binding transcription factor 4/Nanog signaling axis. In this review we will summarize the major signaling pathways that regulate cancer stem cells in breast cancer and describe the effects that adipocyte secreted IL-6 and leptin have on breast cancer stem cell signaling. Finally we will introduce a new potential treatment paradigm of inhibiting the adipocyte-breast cancer cell signaling via targeting the IL-6 or leptin pathways.

  10. Type I interferon production during herpes simplex virus infection is controlled by cell-type-specific viral recognition through Toll-like receptor 9, the mitochondrial antiviral signaling protein pathway, and novel recognition systems

    DEFF Research Database (Denmark)

    Rasmussen, Simon Brandtoft; Sørensen, Louise Nørgaard; Malmgaard, Lene


    and fibroblasts, where the virus was able to replicate, HSV-induced IFN-alpha/beta production was dependent on both viral entry and replication, and ablated in cells unable to signal through the mitochondrial antiviral signaling protein pathway. Thus, during an HSV infection in vivo, multiple mechanisms......Recognition of viruses by germ line-encoded pattern recognition receptors of the innate immune system is essential for rapid production of type I interferon (IFN) and early antiviral defense. We investigated the mechanisms of viral recognition governing production of type I IFN during herpes....... In conventional DCs, the IFN response occurred independently of viral replication but was dependent on viral entry. Moreover, using a HSV-1 UL15 mutant, which fails to package viral DNA into the virion, we found that entry-dependent IFN induction also required the presence of viral genomic DNA. In macrophages...

  11. Endothelial-mural cell signaling in vascular development and angiogenesis. (United States)

    Gaengel, Konstantin; Genové, Guillem; Armulik, Annika; Betsholtz, Christer


    Mural cells are essential components of blood vessels and are necessary for normal development, homeostasis, and organ function. Alterations in mural cell density or the stable attachment of mural cells to the endothelium is associated with several human diseases such as diabetic retinopathy, venous malformation, and hereditary stroke. In addition mural cells are implicated in regulating tumor growth and have thus been suggested as potential antiangiogenic targets in tumor therapy. In recent years our knowledge of mural cell function and endothelial-mural cell signaling has increased dramatically, and we now begin to understand the mechanistic basis of the key signaling pathways involved. This is mainly thanks to sophisticated in vivo experiments using a broad repertoire of genetic technologies. In this review, we summarize the five currently best understood signaling pathways implicated in mural cell biology. We discuss PDGFB/PDGFRbeta- dependent pericyte recruitment, as well as the role of angiopoietins and Tie receptors in vascular maturation. In addition, we highlight the effects of sphingosine-1-phosphate signaling on adherens junction assembly and vascular stability, as well as the role of TGF-beta-signaling in mural cell differentiation. We further reflect recent data suggesting an important function for Notch3 signaling in mural cell maturation.

  12. Systemic low temperature signaling in Arabidopsis. (United States)

    Gorsuch, Peter A; Sargeant, Alexander W; Penfield, Steven D; Quick, W Paul; Atkin, Owen K


    When leaves are exposed to low temperature, sugars accumulate and transcription factors in the C-repeat binding factor (CBF) family are expressed, which, together with CBF-independent pathways, are known to contribute to the cold acclimation process and an increase in freezing tolerance. What is not known, however, is whether expression of these cold-regulated genes can be induced systemically in response to a localized cold treatment. To address this, pre-existing, mature leaves of warm-grown Arabidopsis thaliana were exposed to a localized cold treatment (near 10 °C) whilst conjoined newly developing leaves continued only to experience warmer temperatures. In initial experiments on wild-type A. thaliana (Col-0) using real-time reverse transcription--PCR (RT-PCR) we observed that some genes--including CBF genes, certain downstream cold-responsive (COR) targets and CBF-independent transcription factors--respond to a direct 9 °C treatment of whole plants. In subsequent experiments, we found that the treatment of expanded leaves with temperatures near 10 °C can induce cold-associated genes in conjoined warm-maintained tissues. CBF1 showed a particularly strong systemic response, although CBF-independent transcription factors also responded. Moreover, the localized cold treatment of A. thaliana (C24) plants with a luciferase reporter fused to the promoter region of KIN2 indicated that in warm-maintained leaves, KIN2 might respond to a systemic signal from remote, directly cold-treated leaves. Collectively, our study provides strong evidence that the processes involved in cold acclimation are partially mediated by a signal that acts systemically. This has the potential to act as an early-warning system to enable developing leaves to cope better with the cold environment in which they are growing.

  13. Calcium Signaling in Interstitial Cells: Focus on Telocytes. (United States)

    Radu, Beatrice Mihaela; Banciu, Adela; Banciu, Daniel Dumitru; Radu, Mihai; Cretoiu, Dragos; Cretoiu, Sanda Maria


    In this review, we describe the current knowledge on calcium signaling pathways in interstitial cells with a special focus on interstitial cells of Cajal (ICCs), interstitial Cajal-like cells (ICLCs), and telocytes. In detail, we present the generation of Ca(2+) oscillations, the inositol triphosphate (IP₃)/Ca(2+) signaling pathway and modulation exerted by cytokines and vasoactive agents on calcium signaling in interstitial cells. We discuss the physiology and alterations of calcium signaling in interstitial cells, and in particular in telocytes. We describe the physiological contribution of calcium signaling in interstitial cells to the pacemaking activity (e.g., intestinal, urinary, uterine or vascular pacemaking activity) and to the reproductive function. We also present the pathological contribution of calcium signaling in interstitial cells to the aortic valve calcification or intestinal inflammation. Moreover, we summarize the current knowledge of the role played by calcium signaling in telocytes in the uterine, cardiac and urinary physiology, and also in various pathologies, including immune response, uterine and cardiac pathologies.

  14. Apoptotic cell signaling in cancer progression and therapy. (United States)

    Plati, Jessica; Bucur, Octavian; Khosravi-Far, Roya


    Apoptosis is a tightly regulated cell suicide program that plays an essential role in the development and maintenance of tissue homeostasis by eliminating unnecessary or harmful cells. Impairment of this native defense mechanism promotes aberrant cellular proliferation and the accumulation of genetic defects, ultimately resulting in tumorigenesis, and frequently confers drug resistance to cancer cells. The regulation of apoptosis at several levels is essential to maintain the delicate balance between cellular survival and death signaling that is required to prevent disease. Complex networks of signaling pathways act to promote or inhibit apoptosis in response to various cues. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Various upstream signaling pathways can modulate apoptosis by converging on, and thereby altering the activity of, common central control points within the apoptotic signaling pathways, which involve the BCL-2 family proteins, inhibitor of apoptosis (IAP) proteins, and FLICE-inhibitory protein (c-FLIP). This review highlights the role of these fundamental regulators of apoptosis in the context of both normal apoptotic signaling mechanisms and dysregulated apoptotic pathways that can render cancer cells resistant to cell death. In addition, therapeutic strategies aimed at modulating the activity of BCL-2 family proteins, IAPs, and c-FLIP for the targeted induction of apoptosis are briefly discussed.

  15. Apoptotic cell signaling in cancer progression and therapy† (United States)

    Plati, Jessica; Bucur, Octavian; Khosravi-Far, Roya


    Apoptosis is a tightly regulated cell suicide program that plays an essential role in the development and maintenance of tissue homeostasis by eliminating unnecessary or harmful cells. Impairment of this native defense mechanism promotes aberrant cellular proliferation and the accumulation of genetic defects, ultimately resulting in tumorigenesis, and frequently confers drug resistance to cancer cells. The regulation of apoptosis at several levels is essential to maintain the delicate balance between cellular survival and death signaling that is required to prevent disease. Complex networks of signaling pathways act to promote or inhibit apoptosis in response to various cues. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Various upstream signaling pathways can modulate apoptosis by converging on, and thereby altering the activity of, common central control points within the apoptotic signaling pathways, which involve the BCL-2 family proteins, inhibitor of apoptosis (IAP) proteins, and FLICE-inhibitory protein (c-FLIP). This review highlights the role of these fundamental regulators of apoptosis in the context of both normal apoptotic signaling mechanisms and dysregulated apoptotic pathways that can render cancer cells resistant to cell death. In addition, therapeutic strategies aimed at modulating the activity of BCL-2 family proteins, IAPs, and c-FLIP for the targeted induction of apoptosis are briefly discussed. PMID:21340093

  16. Science Signaling Podcast for 29 November 2016: Pre-B cell receptor signaling in leukemia. (United States)

    Wilson, Bridget S; VanHook, Annalisa M


    This Podcast features an interview with Bridget Wilson, author of a Research Article that appears in the 29 November 2016 issue of Science Signaling, about pre-B cell receptor (pre-BCR) signaling in B cell precursor acute lymphoblastic leukemia (BCP-ALL). Signaling through the pre-BCR, an immature form of the BCR, promotes the survival of B cell progenitors and has been implicated in the pathology of BCP-ALL. Erasmus et al found that pre-BCRs formed transient homomeric complexes that correlated with pro-survival signaling. Preventing homotypic interactions between pre-BCRs sensitized B cells to chemotherapeutic agents, suggesting that interfering with such interactions may improve the efficacy of existing chemotherapies for BCP-ALL.Listen to Podcast.

  17. Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. (United States)

    Clevers, Hans; Loh, Kyle M; Nusse, Roel


    Stem cells fuel tissue development, renewal, and regeneration, and these activities are controlled by the local stem cell microenvironment, the "niche." Wnt signals emanating from the niche can act as self-renewal factors for stem cells in multiple mammalian tissues. Wnt proteins are lipid-modified, which constrains them to act as short-range cellular signals. The locality of Wnt signaling dictates that stem cells exiting the Wnt signaling domain differentiate, spatially delimiting the niche in certain tissues. In some instances, stem cells may act as or generate their own niche, enabling the self-organization of patterned tissues. In this Review, we discuss the various ways by which Wnt operates in stem cell control and, in doing so, identify an integral program for tissue renewal and regeneration.

  18. Ras and Rheb Signaling in Survival and Cell Death

    Energy Technology Data Exchange (ETDEWEB)

    Ehrkamp, Anja [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany); Herrmann, Christian [Department of Physical Chemistry1, Protein Interaction, Ruhr University of Bochum, 44780 Bochum (Germany); Stoll, Raphael [Biomolecular NMR, Ruhr University of Bochum, 44780 Bochum (Germany); Heumann, Rolf, E-mail: [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany)


    One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively.

  19. Synchronization of noisy systems by stochastic signals

    Energy Technology Data Exchange (ETDEWEB)

    Neiman, A.; Schimansky-Geier, L.; Moss, F. [Center for Neurodynamics, University of Missouri at St. Louis, St. Louis, Missouri 63121 (United States); Schimansky-Geier, L. [Institute of Physics, Humboldt University at Berlin, Invalidenstrasse 110, D-10115 Berlin (Germany); Shulgin, B.; Collins, J.J. [Center for BioDynamics and Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, Massachusetts 02215 (United States)


    We study, in terms of synchronization, the {ital nonlinear response} of noisy bistable systems to a stochastic external signal, represented by Markovian dichotomic noise. We propose a general kinetic model which allows us to conduct a full analytical study of the nonlinear response, including the calculation of cross-correlation measures, the mean switching frequency, and synchronization regions. Theoretical results are compared with numerical simulations of a noisy overdamped bistable oscillator. We show that dichotomic noise can instantaneously synchronize the switching process of the system. We also show that synchronization is most pronounced at an optimal noise level{emdash}this effect connects this phenomenon with aperiodic stochastic resonance. Similar synchronization effects are observed for a stochastic neuron model stimulated by a stochastic spike train. {copyright} {ital 1999} {ital The American Physical Society}

  20. An extracytoplasmic function sigma factor-mediated cell surface signaling system in Pseudomonas syringae pv. tomato DC3000 regulates gene expression in response to heterologous siderophores. (United States)

    Markel, Eric; Maciak, Charlene; Butcher, Bronwyn G; Myers, Christopher R; Stodghill, Paul; Bao, Zhongmeng; Cartinhour, Sam; Swingle, Bryan


    The diversity of regulatory systems encoded by bacteria provides an indication of the variety of stresses and interactions that these organisms encounter in nature. We have been investigating how the plant pathogen Pseudomonas syringae pv. tomato DC3000 responds to iron limitation and have focused on the iron starvation (IS) sigma factors to identify regulon members and to explore the mechanistic details of genetic control for this class of regulators. In the study described in this report, we used chromatin immunoprecipitation paired with high-throughput sequencing (ChIP-Seq) to screen the genome for locations associated with binding of the P. syringae IS sigma factor PSPTO_1203. We used multiple methods to demonstrate differential regulation of two genes identified in the ChIP-Seq screen and characterize the promoter elements that facilitate PSPTO_1203-dependent regulation. The genes regulated by PSPTO_1203 encode a TonB-dependent transducer (PSPTO_1206) and a cytoplasmic membrane protein (PSPTO_2145), which is located in the P. syringae pyoverdine cluster. Additionally, we identified siderophores that induce the activity of PSPTO_1203 and used this information to investigate the functional components of the signal transduction cascade.

  1. Activin Receptor Signaling Regulates Prostatic Epithelial Cell Adhesion and Viability

    Directory of Open Access Journals (Sweden)

    Derek P. Simon


    Full Text Available Mutational changes coupled with endocrine, paracrine, and/or autocrine signals regulate cell division during carcinogenesis. The hormone signals remain undefined, although the absolute requirement in vitro for fetal serum indicates the necessity for a fetal serum factor(s in cell proliferation. Using prostatic cancer cell (PCC lines as a model of cancer cell proliferation, we have identified the fetal serum component activin A and its signaling through the activin receptor type II (ActRII, as necessary, although not sufficient, for PCC proliferation. Activin A induced Smad2 phosphorylation and PCC proliferation, but only in the presence of fetal bovine serum (FBS. Conversely, activin A antibodies and inhibin A suppressed FBS-induced PCC proliferation confirming activin A as one of multiple serum components required for PCC proliferation. Basic fibroblast growth factor was subsequently shown to synergize activin A-induced PCC proliferation. Inhibition of ActRII signaling using a blocking antibody or antisense-P decreased mature ActRII expression, Smad2 phosphorylation, and the apparent viability of PCCs and neuroblastoma cells grown in FBS. Suppression of ActRII signaling in PCC and neuroblastoma cells did not induce apoptosis as indicated by the ratio of active/inactive caspase 3 but did correlate with increased cell detachment and ADAM-15 expression, a disintegrin whose expression is strongly correlated with prostatic metastasis. These findings indicate that ActRII signaling is required for PCC and neuroblastoma cell viability, with ActRII mediating cell fate via the regulation of cell adhesion. That ActRII signaling governs both cell viability and cell adhesion has important implications for developing therapeutic strategies to regulate cancer growth and metastasis.


    Institute of Scientific and Technical Information of China (English)


    After brief describing the principle of wavelet transform (WT) of signals, a new signals analysis system based on wavelet transform is introduced. The design and development of the instrument of wavelet transform are described. A number of practical uses of this system demonstrate that wavelet transform system is specially functional in identifying and processing impulse, singular and nonsmooth signals,so that it should be evaluated the most advanced signal analyzing system.

  3. Second International Conference on Communications, Signal Processing, and Systems

    CERN Document Server

    Mu, Jiasong; Wang, Wei; Liang, Qilian; Pi, Yiming


    The Proceedings of The Second International Conference on Communications, Signal Processing, and Systems provides the state-of-art developments of Communications, Signal Processing, and Systems. The conference covered such topics as wireless communications, networks, systems, signal processing for communications. This book is a collection of contributions coming out of The Second International Conference on Communications, Signal Processing, and Systems (CSPS) held September 2013 in Tianjin, China.

  4. Intracellular Signaling Mediators in the Circulatory and Ventilatory Systems

    CERN Document Server

    Thiriet, Marc


    The volumes in this authoritative series present a multidisciplinary approach to modeling and simulation of flows in the cardiovascular and ventilatory systems, especially multiscale modeling and coupled simulations. The cardiovascular and respiratory systems are tightly coupled, as their primary function is to supply oxygen to and remove carbon dioxide from the body's cells. Because physiological conduits have deformable and reactive walls, macroscopic flow behavior and prediction must be coupled to phenomenological models of nano- and microscopic events in a corrector scheme of regulated mechanisms when the vessel lumen caliber varies markedly. Therefore, investigation of flows of blood and air in physiological conduits requires an understanding of the biology, chemistry, and physics of these systems together with the mathematical tools to describe their functioning. Volume 4 is devoted to major sets of intracellular mediators that transmit signals upon stimulation of cell-surface receptors.  Activation of...

  5. Dissecting the interface between signaling and transcriptional regulation in human B cells

    DEFF Research Database (Denmark)

    Wang, Kai; Alvarez, Mariano J; Bisikirska, Brygida C


    . In this manuscript we extend the MINDy algorithm for the identification of posttranslational modulators of transcription factor activity, to produce a first genome-wide map of the interface between signaling and transcriptional regulatory programs in human B cells. We show that the serine-threonine kinase STK38......A key role of signal transduction pathways is to control transcriptional programs in the nucleus as a function of signals received by the cell via complex post-translational modification cascades. This determines cell-context specific responses to environmental stimuli. Given the difficulty...... of quantitating protein concentration and post-translational modifications, signaling pathway studies are still for the most part conducted one interaction at the time. Thus, genome-wide, cell-context specific dissection of signaling pathways is still an open challenge in molecular systems biology...

  6. System and method for traffic signal timing estimation

    KAUST Repository

    Dumazert, Julien


    A method and system for estimating traffic signals. The method and system can include constructing trajectories of probe vehicles from GPS data emitted by the probe vehicles, estimating traffic signal cycles, combining the estimates, and computing the traffic signal timing by maximizing a scoring function based on the estimates. Estimating traffic signal cycles can be based on transition times of the probe vehicles starting after a traffic signal turns green.

  7. Different activation signals induce distinct mast cell degranulation strategies (United States)

    Sibilano, Riccardo; Marichal, Thomas; Reber, Laurent L.; Cenac, Nicolas; McNeil, Benjamin D.; Dong, Xinzhong; Hernandez, Joseph D.; Sagi-Eisenberg, Ronit; Hammel, Ilan; Roers, Axel; Valitutti, Salvatore; Tsai, Mindy


    Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P–dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation. PMID:27643442

  8. Bone Morphogenetic Protein 4 Signalling in Neural Stem and Progenitor Cells during Development and after Injury

    Directory of Open Access Journals (Sweden)

    Alistair E. Cole


    Full Text Available Substantial progress has been made in identifying the extracellular signalling pathways that regulate neural stem and precursor cell biology in the central nervous system (CNS. The bone morphogenetic proteins (BMPs, in particular BMP4, are key players regulating neuronal and glial cell development from neural precursor cells in the embryonic, postnatal, and injured CNS. Here we review recent studies on BMP4 signalling in the generation of neurons, astrocytes, and oligodendroglial cells in the CNS. We also discuss putative mechanisms that BMP4 may utilise to influence glial cell development following CNS injury and highlight some questions for further research.

  9. IL-6/sIL-6R trans-signalling, but not TNF-alpha induced angiogenesis in a HUVEC and synovial cell co-culture system. (United States)

    Hashizume, Misato; Hayakawa, Naohiko; Suzuki, Miho; Mihara, Masahiko


    Angiogenesis in synovia is a characteristic of RA patients. We examined whether IL-6 or TNF-alpha induce tubule formation in a co-culture system of fibroblast-like synovial cells from RA patients (RA-FLS) and human umbilical vein endothelial cells (HUVEC). The effects of IL-6 and TNF-alpha on the expression of angiogenic factors in RA-FLS and HUVEC, and the proliferation of HUVEC were also studied. IL-6 + sIL-6R induced tubule formation, whereas IL-6 alone did not. IL-6/sIL-6R-induced tubule formation was completely suppressed by the addition of either anti-IL-6R or anti-VEGF antibody. TNF-alpha did not induce tubule formation. On the contrary, it decreased CD31-positive area compared with the control. IL-6 + sIL-6R augmented VEGF production in RA-FLS, whereas IL-6 alone did not. Anti-IL-6R antibody suppressed IL-6/sIL-6R-induced VEGF production, but not spontaneous VEGF production. In contrast, TNF-alpha did not induce VEGF production from RA-FLS and HUVEC. IL-6 + sIL-6R stimulation of RA-FLS strongly induced mRNA expression of VEGF, but not of other angiogenic factors, such as EGF, bFGF, TGF-beta, IL-1, TNF-alpha and IL-8. Neither IL-6 nor IL-6/sIL-6R promoted HUVEC proliferation, whereas TNF-alpha significantly inhibited VEGF-induced HUVEC proliferation. In conclusion, IL-6/sIL-6R complex showed angiogenic activity via the production of VEGF from RA-FLS, but TNF-alpha was anti-angiogenic in our experimental system.

  10. Homeostatic interplay between bacterial cell-cell signaling and iron in virulence.

    Directory of Open Access Journals (Sweden)

    Ronen Hazan


    Full Text Available Pathogenic bacteria use interconnected multi-layered regulatory networks, such as quorum sensing (QS networks to sense and respond to environmental cues and external and internal bacterial cell signals, and thereby adapt to and exploit target hosts. Despite the many advances that have been made in understanding QS regulation, little is known regarding how these inputs are integrated and processed in the context of multi-layered QS regulatory networks. Here we report the examination of the Pseudomonas aeruginosa QS 4-hydroxy-2-alkylquinolines (HAQs MvfR regulatory network and determination of its interaction with the QS acyl-homoserine-lactone (AHL RhlR network. The aim of this work was to elucidate paradigmatically the complex relationships between multi-layered regulatory QS circuitries, their signaling molecules, and the environmental cues to which they respond. Our findings revealed positive and negative homeostatic regulatory loops that fine-tune the MvfR regulon via a multi-layered dependent homeostatic regulation of the cell-cell signaling molecules PQS and HHQ, and interplay between these molecules and iron. We discovered that the MvfR regulon component PqsE is a key mediator in orchestrating this homeostatic regulation, and in establishing a connection to the QS rhlR system in cooperation with RhlR. Our results show that P. aeruginosa modulates the intensity of its virulence response, at least in part, through this multi-layered interplay. Our findings underscore the importance of the homeostatic interplay that balances competition within and between QS systems via cell-cell signaling molecules and environmental cues in the control of virulence gene expression. Elucidation of the fine-tuning of this complex relationship offers novel insights into the regulation of these systems and may inform strategies designed to limit infections caused by P. aeruginosa and related human pathogens.

  11. 3rd International Conference on Communications, Signal Processing, and Systems

    CERN Document Server

    Liang, Qilian; Wang, Wei; Zhang, Baoju; Pi, Yiming


    The Proceedings of The Third International Conference on Communications, Signal Processing, and Systems provides the state-of-art developments of communications, signal processing, and systems. This book is a collection of contributions from the conference and covers such topics as wireless communications, networks, systems, and signal processing for communications. The conference was held July 2014 in Hohhot, Inner Mongolia, China.

  12. Cell polarity determinants establish asymmetry in MEN signaling. (United States)

    Monje-Casas, Fernando; Amon, Angelika


    Components of the mitotic exit network (MEN), a signaling pathway that triggers exit from mitosis, localize to the spindle pole body (SPB) that migrates into the daughter cell during anaphase but are largely absent from the SPB that remains in the mother cell. Through the analysis of one of the determinants of this asymmetry, Bfa1, we find that the machinery responsible for establishing cell polarity and cytoplasmic microtubules collaborate to establish MEN asymmetry. In cells defective in the Cdc42 signaling pathway or the formin Bni1, Bfa1 localizes to both SPBs. The quantitative analysis of Bfa1 localization further shows that Bfa1 can associate with both SPBs in a transient and highly dynamic fashion, but the protein is stabilized on the SPB that migrates into the daughter cell during anaphase through microtubule-bud cortex interactions. Our results indicate that mother-daughter cell asymmetry determinants establish MEN signaling asymmetry through microtubule-bud cortex interactions.

  13. Power-Law Modeling of Cancer Cell Fates Driven by Signaling Data to Reveal Drug Effects (United States)

    Zhang, Fan; Wu, Min; Kwoh, Chee Keong; Zheng, Jie


    Extracellular signals are captured and transmitted by signaling proteins inside a cell. An important type of cellular responses to the signals is the cell fate decision, e.g., apoptosis. However, the underlying mechanisms of cell fate regulation are still unclear, thus comprehensive and detailed kinetic models are not yet available. Alternatively, data-driven models are promising to bridge signaling data with the phenotypic measurements of cell fates. The traditional linear model for data-driven modeling of signaling pathways has its limitations because it assumes that the a cell fate is proportional to the activities of signaling proteins, which is unlikely in the complex biological systems. Therefore, we propose a power-law model to relate the activities of all the measured signaling proteins to the probabilities of cell fates. In our experiments, we compared our nonlinear power-law model with the linear model on three cancer datasets with phosphoproteomics and cell fate measurements, which demonstrated that the nonlinear model has superior performance on cell fates prediction. By in silico simulation of virtual protein knock-down, the proposed model is able to reveal drug effects which can complement traditional approaches such as binding affinity analysis. Moreover, our model is able to capture cell line specific information to distinguish one cell line from another in cell fate prediction. Our results show that the power-law data-driven model is able to perform better in cell fate prediction and provide more insights into the signaling pathways for cancer cell fates than the linear model. PMID:27764199

  14. Signal Transduction Involved in Cell Volume Regulation

    NARCIS (Netherlands)

    Th. van der Wijk (Thea)


    textabstract1.fammalian cells are surrounded by a selective permeable plasma membrane that allmvs the interior of the cell to differ in composition from the surrounding solution. The plasma membrane is formed by a bilayer of (phospho-) lipids and contains many different proteins. Hydrophobic molecul

  15. Novel roles for GlcNAc in cell signaling. (United States)

    Naseem, Shamoon; Parrino, Salvatore M; Buenten, Dane M; Konopka, James B


    N-acetylglucosamine (GlcNAc) has long been known to play important roles in cell surface structure. Recent studies are now revealing new functions for GlcNAc in cell signaling. Exposure to GlcNAc regulates virulence functions in the human fungal pathogen Candida albicans and in pathogenic bacteria. These signaling pathways sense exogenous GlcNAc and are distinct from the O-GlcNAc signaling pathways in mammalian cells in which increased levels of intracellular GlcNAc synthesis leads to post-translational modification of proteins by attachment of O-GlcNAc. The novel roles of GlcNAc in cell signaling will be the subject of this mini-review.

  16. Crawling cells can close wounds without purse strings or signaling.

    Directory of Open Access Journals (Sweden)

    Pilhwa Lee


    Full Text Available When a gash or gouge is made in a confluent layer of epithelial cells, the cells move to fill in the "wound." In some cases, such as in wounded embryonic chick wing buds, the movement of the cells is driven by cortical actin contraction (i.e., a purse string mechanism. In adult tissue, though, cells apparently crawl to close wounds. At the single cell level, this crawling is driven by the dynamics of the cell's actin cytoskeleton, which is regulated by a complex biochemical network, and cell signaling has been proposed to play a significant role in directing cells to move into the denuded area. However, wounds made in monolayers of Madin-Darby canine kidney (MDCK cells still close even when a row of cells is deactivated at the periphery of the wound, and recent experiments show complex, highly-correlated cellular motions that extend tens of cell lengths away from the boundary. These experiments suggest a dominant role for mechanics in wound healing. Here we present a biophysical description of the collective migration of epithelial cells during wound healing based on the basic motility of single cells and cell-cell interactions. This model quantitatively captures the dynamics of wound closure and reproduces the complex cellular flows that are observed. These results suggest that wound healing is predominantly a mechanical process that is modified, but not produced, by cell-cell signaling.

  17. Stem cell signaling. An integral program for tissue renewal and regeneration : Wnt signaling and stem cell control

    NARCIS (Netherlands)

    Clevers, Hans; Loh, Kyle M; Nusse, Roel


    Stem cells fuel tissue development, renewal, and regeneration, and these activities are controlled by the local stem cell microenvironment, the "niche." Wnt signals emanating from the niche can act as self-renewal factors for stem cells in multiple mammalian tissues. Wnt proteins are lipid-modified,

  18. SAR processing using SHARC signal processing systems (United States)

    Huxtable, Barton D.; Jackson, Christopher R.; Skaron, Steve A.


    Synthetic aperture radar (SAR) is uniquely suited to help solve the Search and Rescue problem since it can be utilized either day or night and through both dense fog or thick cloud cover. Other papers in this session, and in this session in 1997, describe the various SAR image processing algorithms that are being developed and evaluated within the Search and Rescue Program. All of these approaches to using SAR data require substantial amounts of digital signal processing: for the SAR image formation, and possibly for the subsequent image processing. In recognition of the demanding processing that will be required for an operational Search and Rescue Data Processing System (SARDPS), NASA/Goddard Space Flight Center and NASA/Stennis Space Center are conducting a technology demonstration utilizing SHARC multi-chip modules from Boeing to perform SAR image formation processing.

  19. Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia. (United States)

    Vaughen, John; Igaki, Tatsushi


    Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers.

  20. Rho1-Wnd signaling regulates loss-of-cell polarity-induced cell invasion in Drosophila. (United States)

    Ma, X; Chen, Y; Zhang, S; Xu, W; Shao, Y; Yang, Y; Li, W; Li, M; Xue, L


    Both cell polarity and c-Jun N-terminal kinase (JNK) activity are essential to the maintenance of tissue homeostasis, and disruption of either is commonly seen in cancer progression. Despite the established connection between loss-of-cell polarity and JNK activation, much less is known about the molecular mechanism by which aberrant cell polarity induces JNK-mediated cell migration and tumor invasion. Here we show results from a genetic screen using an in vivo invasion model via knocking down cell polarity gene in Drosophila wing discs, and identify Rho1-Wnd signaling as an important molecular link that mediates loss-of-cell polarity-triggered JNK activation and cell invasion. We show that Wallenda (Wnd), a protein kinase of the mitogen-activated protein kinase kinase kinase family, by forming a complex with the GTPase Rho1, is both necessary and sufficient for Rho1-induced JNK-dependent cell invasion, MMP1 activation and epithelial-mesenchymal transition. Furthermore, Wnd promotes cell proliferation and tissue growth through wingless production when apoptosis is inhibited by p35. Finally, Wnd shows oncogenic cooperation with Ras(V12) to trigger tumor growth in eye discs and causes invasion into the ventral nerve cord. Together, our data not only provides a novel mechanistic insight on how cell polarity loss contributes to cell invasion, but also highlights the value of the Drosophila model system to explore human cancer biology.

  1. Lipocalin signaling controls unicellular tube development in the Caenorhabditis elegans excretory system. (United States)

    Stone, Craig E; Hall, David H; Sundaram, Meera V


    Unicellular tubes or capillaries composed of individual cells with a hollow lumen perform important physiological functions including fluid or gas transport and exchange. These tubes are thought to build intracellular lumina by polarized trafficking of apical membrane components, but the molecular signals that promote luminal growth and luminal connectivity between cells are poorly understood. Here we show that the lipocalin LPR-1 is required for luminal connectivity between two unicellular tubes in the Caenorhabditis elegans excretory (renal) system, the excretory duct cell and pore cell. Lipocalins are a large family of secreted proteins that transport lipophilic cargos and participate in intercellular signaling. lpr-1 is required at a time of rapid luminal growth, it is expressed by the duct, pore and surrounding cells, and it can function cell non-autonomously. These results reveal a novel signaling mechanism that controls unicellular tube formation, and provide a genetic model system for dissecting lipocalin signaling pathways.

  2. Data-driven quantification of the robustness and sensitivity of cell signaling networks (United States)

    Mukherjee, Sayak; Seok, Sang-Cheol; Vieland, Veronica J.; Das, Jayajit


    Robustness and sensitivity of responses generated by cell signaling networks has been associated with survival and evolvability of organisms. However, existing methods analyzing robustness and sensitivity of signaling networks ignore the experimentally observed cell-to-cell variations of protein abundances and cell functions or contain ad hoc assumptions. We propose and apply a data-driven maximum entropy based method to quantify robustness and sensitivity of Escherichia coli (E. coli) chemotaxis signaling network. Our analysis correctly rank orders different models of E. coli chemotaxis based on their robustness and suggests that parameters regulating cell signaling are evolutionary selected to vary in individual cells according to their abilities to perturb cell functions. Furthermore, predictions from our approach regarding distribution of protein abundances and properties of chemotactic responses in individual cells based on cell population averaged data are in excellent agreement with their experimental counterparts. Our approach is general and can be used to evaluate robustness as well as generate predictions of single cell properties based on population averaged experimental data in a wide range of cell signaling systems.

  3. Integrated Strategies to Gain a Systems-Level View of Dynamic Signaling Networks. (United States)

    Newman, Robert H; Zhang, Jin


    In order to survive and function properly in the face of an ever changing environment, cells must be able to sense changes in their surroundings and respond accordingly. Cells process information about their environment through complex signaling networks composed of many discrete signaling molecules. Individual pathways within these networks are often tightly integrated and highly dynamic, allowing cells to respond to a given stimulus (or, as is typically the case under physiological conditions, a combination of stimuli) in a specific and appropriate manner. However, due to the size and complexity of many cellular signaling networks, it is often difficult to predict how cellular signaling networks will respond under a particular set of conditions. Indeed, crosstalk between individual signaling pathways may lead to responses that are nonintuitive (or even counterintuitive) based on examination of the individual pathways in isolation. Therefore, to gain a more comprehensive view of cell signaling processes, it is important to understand how signaling networks behave at the systems level. This requires integrated strategies that combine quantitative experimental data with computational models. In this chapter, we first examine some of the progress that has recently been made toward understanding the systems-level regulation of cellular signaling networks, with a particular emphasis on phosphorylation-dependent signaling networks. We then discuss how genetically targetable fluorescent biosensors are being used together with computational models to gain unique insights into the spatiotemporal regulation of signaling networks within single, living cells.

  4. Cell Polarity Determinants Establish Asymmetry in MEN Signaling


    Monje-Casas, Fernando; Amon, Angelika


    Components of the Mitotic Exit Network (MEN), a signaling pathway that triggers exit from mitosis, localize to the spindle pole body (SPB) that migrates into the daughter cell during anaphase but are largely absent from the SPB that remains in the mother cell. Through the analysis of one of the determinants of this asymmetry, Bfa1, we find that the machinery responsible for establishing cell polarity and cytoplasmic microtubules collaborate to establish MEN asymmetry. In cells defective in th...

  5. Sensitivity of Dendritic Cells to Microenvironment Signals (United States)

    Motta, Juliana Maria; Rumjanek, Vivian Mary


    Dendritic cells are antigen-presenting cells capable of either activating the immune response or inducing and maintaining immune tolerance. They do this by integrating stimuli from the environment and changing their functional status as a result of plasticity. The modifications suffered by these cells have consequences in the way the organism may respond. In the present work two opposing situations known to affect dendritic cells are analyzed: tumor growth, leading to a microenvironment that favors the induction of a tolerogenic profile, and organ transplantation, which leads to a proinflammatory profile. Lessons learned from these situations may help to understand the mechanisms of modulation resulting not only from the above circumstances, but also from other pathologies. PMID:27088097

  6. Sensitivity of Dendritic Cells to Microenvironment Signals

    Directory of Open Access Journals (Sweden)

    Juliana Maria Motta


    Full Text Available Dendritic cells are antigen-presenting cells capable of either activating the immune response or inducing and maintaining immune tolerance. They do this by integrating stimuli from the environment and changing their functional status as a result of plasticity. The modifications suffered by these cells have consequences in the way the organism may respond. In the present work two opposing situations known to affect dendritic cells are analyzed: tumor growth, leading to a microenvironment that favors the induction of a tolerogenic profile, and organ transplantation, which leads to a proinflammatory profile. Lessons learned from these situations may help to understand the mechanisms of modulation resulting not only from the above circumstances, but also from other pathologies.

  7. Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc(-), the Na(+)-independent glutamate-cystine exchanger. (United States)

    Wang, Jing; Shanmugam, Arul; Markand, Shanu; Zorrilla, Eric; Ganapathy, Vadivel; Smith, Sylvia B


    Oxidative stress figures prominently in retinal diseases, including diabetic retinopathy, and glaucoma. Ligands for σ1R, a unique transmembrane protein localized to the endoplasmic reticulum, mitochondria, and nuclear and plasma membranes, have profound retinal neuroprotective properties in vitro and in vivo. Studies to determine the mechanism of σ1R-mediated retinal neuroprotection have focused mainly on neurons. Little is known about the effects of σ1R on Müller cell function, yet these radial glial cells are essential for homeostatic support of the retina. Here we investigated whether σ1R mediates the oxidative stress response of Müller cells using wild-type (WT) and σ1R-knockout (σ1RKO) mice. We observed increased endogenous reactive oxygen species (ROS) levels in σ1RKO Müller cells compared to WT, which was accompanied by decreased expression of Sod1, catalase, Nqo1, Hmox1, Gstm6, and Gpx1. The protein levels of SOD1, CAT, NQO1, and GPX1 were also significantly decreased. The genes encoding these antioxidants contain an antioxidant response element (ARE), which under stress is activated by NRF2, a transcription factor that typically resides in the cytoplasm bound by KEAP1. In the σ1RKO Müller cells Nrf2 expression was decreased significantly at the gene (and protein) level, whereas Keap1 gene (and protein) levels were markedly increased. NRF2-ARE binding affinity was decreased markedly in σ1RKO Müller cells. We investigated system xc(-), the cystine-glutamate exchanger important for synthesis of glutathione (GSH), and observed decreased function in σ1RKO Müller cells compared to WT as well as decreased GSH and GSH/GSSG ratios. This was accompanied by decreased gene and protein levels of xCT, the unique component of system xc(-). We conclude that Müller glial cells lacking σ1R manifest elevated ROS, perturbation of antioxidant balance, suppression of NRF2 signaling, and impaired function of system xc(-). The data suggest that the oxidative

  8. Isolation, characterisation and reconstitution of cell death signalling complexes. (United States)

    Hughes, Michelle A; Langlais, Claudia; Cain, Kelvin; MacFarlane, Marion


    Apoptosis and necroptosis are dependent on the formation/activation of distinct multi-protein complexes; these include the Death-Inducing Signalling Complex (DISC), apoptosome, piddosome, necrosome and ripoptosome. Despite intense research, the mechanisms that regulate assembly/function of several of these cell death signalling platforms remain to be elucidated. It is now increasingly evident that the composition and stoichiometry of components within these key signalling platforms not only determines the final signalling outcome but also the mode of cell death. Characterising these complexes can therefore provide new insights into how cell death is regulated and also how these cell death signalling platforms could potentially be targeted in the context of disease. Large multi-protein complexes can initially be separated according to their size by gel filtration or sucrose density gradient centrifugation followed by subsequent affinity-purification or immunoprecipitation. The advantage of combining these techniques is that you can assess the assembly of individual components into a complex and then assess the size and stoichiometric composition of the native functional signalling complex within a particular cell type. This, alongside reconstitution of a complex from its individual core components can therefore provide new insight into the mechanisms that regulate assembly/function of key multi-protein signalling complexes. Here, we describe the successful application of a range of methodologies that can be used to characterise the assembly of large multi-protein complexes such as the apoptosome, DISC and ripoptosome. Together with their subsequent purification and/or reconstitution, these approaches can provide novel insights into how cell death signalling platforms are regulated in both normal cell physiology and disease.

  9. Reconstruction and signal propagation analysis of the Syk signaling network in breast cancer cells (United States)

    Urbach, Serge; Montcourrier, Philippe; Roy, Christian; Solassol, Jérôme; Freiss, Gilles; Radulescu, Ovidiu


    The ability to build in-depth cell signaling networks from vast experimental data is a key objective of computational biology. The spleen tyrosine kinase (Syk) protein, a well-characterized key player in immune cell signaling, was surprisingly first shown by our group to exhibit an onco-suppressive function in mammary epithelial cells and corroborated by many other studies, but the molecular mechanisms of this function remain largely unsolved. Based on existing proteomic data, we report here the generation of an interaction-based network of signaling pathways controlled by Syk in breast cancer cells. Pathway enrichment of the Syk targets previously identified by quantitative phospho-proteomics indicated that Syk is engaged in cell adhesion, motility, growth and death. Using the components and interactions of these pathways, we bootstrapped the reconstruction of a comprehensive network covering Syk signaling in breast cancer cells. To generate in silico hypotheses on Syk signaling propagation, we developed a method allowing to rank paths between Syk and its targets. We first annotated the network according to experimental datasets. We then combined shortest path computation with random walk processes to estimate the importance of individual interactions and selected biologically relevant pathways in the network. Molecular and cell biology experiments allowed to distinguish candidate mechanisms that underlie the impact of Syk on the regulation of cortactin and ezrin, both involved in actin-mediated cell adhesion and motility. The Syk network was further completed with the results of our biological validation experiments. The resulting Syk signaling sub-networks can be explored via an online visualization platform. PMID:28306714

  10. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. (United States)

    Hovinga, Koos E; Shimizu, Fumiko; Wang, Rong; Panagiotakos, Georgia; Van Der Heijden, Maartje; Moayedpardazi, Hamideh; Correia, Ana Sofia; Soulet, Denis; Major, Tamara; Menon, Jayanthi; Tabar, Viviane


    Glioblastoma multiforme (GBM) is a highly heterogeneous malignant tumor. Recent data suggests the presence of a hierarchical organization within the GBM cell population that involves cancer cells with stem-like behavior, capable of repopulating the tumor and contributing to its resistance to therapy. Tumor stem cells are thought to reside within a vascular niche that provides structural and functional support. However, most GBM studies involve isolated tumor cells grown under various culture conditions. Here, we use a novel three-dimensional organotypic "explant" system of surgical GBM specimens that preserves cytoarchitecture and tumor stroma along with tumor cells. Notch inhibition in explants results in decreased proliferation and self-renewal of tumor cells but is also associated with a decrease in endothelial cells. When endothelial cells are selectively eliminated from the explants via a toxin conjugate, we also observed a decrease in self-renewal of tumor stem cells. These findings support a critical role for tumor endothelial cells in GBM stem cell maintenance, mediated at least in part by Notch signaling. The explant system further highlighted differences in the response to radiation between explants and isolated tumor neurospheres. Combination treatment with Notch blockade and radiation resulted in a substantial decrease in proliferation and in self-renewal in tumor explants while radiation alone was less effective. This data suggests that the Notch pathway plays a critical role in linking angiogenesis and cancer stem cell self-renewal and is thus a potential therapeutic target. Three-dimensional explant systems provide a novel approach for the study of tumor and microenvironment interactions.

  11. Shared signaling pathways in normal and breast cancer stem cells

    Directory of Open Access Journals (Sweden)

    Gautam K Malhotra


    Full Text Available Recent advances in our understanding of breast cancer biology have led to the identification of a subpopulation of cells within tumors that appear to be responsible for initiating and propagating the cancer. These tumor initiating cells are not only unique in their ability to generate tumors, but also share many similarities with elements of normal adult tissue stem cells, and have therefore been termed cancer stem cells (CSCs. These CSCs often inappropriately use many of the same signaling pathways utilized by their normal stem cell counterparts which may present a challenge to the development of CSC specific therapies. Here, we discuss three major stem cell signaling pathways (Notch, Wnt, and Hedgehog; with a focus on their function in normal mammary gland development and their misuse in breast cancer stem cell fate determination.

  12. The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis (United States)

    De Trez, Carl; Ware, Carl F.


    Dendritic cells (DC) constitute the most potent antigen presenting cells of the immune system, playing a key role bridging innate and adaptive immune responses. Specialized DC subsets differ depending on their origin, tissue location and the influence of trophic factors, the latter remain to be fully understood. Stromal cell and myeloid-associated Lymphotoxin-β receptor (LTβR) signaling is required for the local proliferation of lymphoid tissue DC. This review focuses the LTβR signaling cascade as a crucial positive trophic signal in the homeostasis of DC subsets. The noncanonical coreceptor pathway comprised of the Immunoglobulin (Ig) superfamily member, B and T lymphocyte attenuator (BTLA) and TNFR superfamily member, Herpesvirus entry mediator (HVEM) counter regulates the trophic signaling by LTβR. Together both pathways form an integrated signaling circuit achieving homeostasis of DC subsets. PMID:18511331

  13. The effect of suppressor of cytokine signaling 3 on GH signaling in beta-cells

    DEFF Research Database (Denmark)

    Rønn, Sif G; Hansen, Johnny A; Lindberg, Karen


    GH is an important regulator of cell growth and metabolism. In the pancreas, GH stimulates mitogenesis as well as insulin production in beta-cells. The cellular effects of GH are exerted mainly through activation of the Janus kinase-signal transducer and activator of transcription (STAT) pathway....... Furthermore, using Northern blot analysis it was shown that SOCS-3 can completely inhibit GH-induced insulin production in these cells. Finally, 5-bromodeoxyuridine incorporation followed by fluorescence-activated cell sorting analysis showed that SOCS-3 inhibits GH-induced proliferation of INS-1 cells...

  14. Wnt Signaling in Stem Cells and Cancer

    NARCIS (Netherlands)

    Y. Atlasi (Yaser)


    markdownabstract__Abstract__ Mammalian development starts from a fertilized egg that initially generates few pluripotent cells which eventually give rise to the embryo proper. Different ‘flavors’ of pluripotency have been captured in vitro which led to the establishment of different pluripotent cel

  15. Cell adhesion signalling in acute renal failure

    NARCIS (Netherlands)

    Qin, Yu


    Acute renal failure (ARF) remains a severe clinical problem with high mortality. Little progress has been made over the past two decades in preventing renal injury or reducing mortality. This thesis describes the research to investigate cell adhesion alterations during the pathopysiology of both isc

  16. Glucose Signaling-Mediated Coordination of Cell Growth and Cell Cycle in Saccharomyces Cerevisiae

    Directory of Open Access Journals (Sweden)

    Stefano Busti


    Full Text Available Besides being the favorite carbon and energy source for the budding yeast Sacchromyces cerevisiae, glucose can act as a signaling molecule to regulate multiple aspects of yeast physiology. Yeast cells have evolved several mechanisms for monitoring the level of glucose in their habitat and respond quickly to frequent changes in the sugar availability in the environment: the cAMP/PKA pathways (with its two branches comprising Ras and the Gpr1/Gpa2 module, the Rgt2/Snf3-Rgt1 pathway and the main repression pathway involving the kinase Snf1. The cAMP/PKA pathway plays the prominent role in responding to changes in glucose availability and initiating the signaling processes that promote cell growth and division. Snf1 (the yeast homologous to mammalian AMP-activated protein kinase is primarily required for the adaptation of yeast cell to glucose limitation and for growth on alternative carbon source, but it is also involved in the cellular response to various environmental stresses. The Rgt2/Snf3-Rgt1 pathway regulates the expression of genes required for glucose uptake. Many interconnections exist between the diverse glucose sensing systems, which enables yeast cells to fine tune cell growth, cell cycle and their coordination in response to nutritional changes.

  17. Hydrogen peroxide homeostasis and signaling in plant cells

    Institute of Scientific and Technical Information of China (English)


    The increases of H2O2 concentrations in plant cells often occur under biotic and abiotic stress conditions (e.g. light, environmental stresses and plant hormone abscisic acid).Atmospheric H2O2 as an ancient signal molecule not only plays the key role in inducing evolution of oxygenic photosynthesis, but also modulates many physiological events, such as stomatal movement, hypersensitive responses, programmed cell death and gene expressions. H2O2 levels in cells must sustain a fine equilibrium between production and scavenging. H2O2 enters cells from the apoplast or generated sources, and in turn is distributed in sub-cellular compartments.H2O2 can modulate the activities of many components in signaling, such as protein phosphatases,protein kinases, transcription factors (TFs), and calcium channels. Elevated cytosolic calcium concentrations will initiate further downstream responses, via the action of calcium-binding proteins. On the other hand, the research of H2O2 as a signal molecule is still in a comparatively juvenile stage, for example, little is known about how the cells sense H2O2, what the rate-limiting steps and most important cellular events are in cell signaling and what kind of genes is specific or necessary to H2O2 signaling. The answers to all the questions depend on the functional genomic and molecular genetics analysis.

  18. Systems cell biology. (United States)

    Mast, Fred D; Ratushny, Alexander V; Aitchison, John D


    Systems cell biology melds high-throughput experimentation with quantitative analysis and modeling to understand many critical processes that contribute to cellular organization and dynamics. Recently, there have been several advances in technology and in the application of modeling approaches that enable the exploration of the dynamic properties of cells. Merging technology and computation offers an opportunity to objectively address unsolved cellular mechanisms, and has revealed emergent properties and helped to gain a more comprehensive and fundamental understanding of cell biology.

  19. Regulation of Interferon Gamma Signaling by Suppressors of Cytokine Signaling and Regulatory T Cells



    Regulatory T cells (Tregs) play an indispensable role in the prevention of autoimmune disease, as interferon gamma (IFNγ) mediated, lethal auto-immunity occurs (in both mice and humans) in their absence. In addition, Tregs have been implicated in preventing the onset of autoimmune and auto-inflammatory conditions associated with aberrant IFNγ signaling such as type 1 diabetes, lupus, and lipopolysaccharide (LPS) mediated endotoxemia. Notably, suppressor of cytokine signaling-1 deficient (SOCS...

  20. Signal Transduction at the Single-Cell Level: Approaches to Study the Dynamic Nature of Signaling Networks. (United States)

    Handly, L Naomi; Yao, Jason; Wollman, Roy


    Signal transduction, or how cells interpret and react to external events, is a fundamental aspect of cellular function. Traditional study of signal transduction pathways involves mapping cellular signaling pathways at the population level. However, population-averaged readouts do not adequately illuminate the complex dynamics and heterogeneous responses found at the single-cell level. Recent technological advances that observe cellular response, computationally model signaling pathways, and experimentally manipulate cells now enable studying signal transduction at the single-cell level. These studies will enable deeper insights into the dynamic nature of signaling networks.

  1. Ubiquitin chain topology and its impact on plant cell signalling

    Directory of Open Access Journals (Sweden)

    Charlotte Kirsten Walsh


    Full Text Available Ubiquitin is a peptide modifier able to form polymers of varying length and linkage as part of a powerful signalling system. Perhaps the best-known aspect of this protein’s function is as the driver of targeted protein degradation through the Ubiquitin Proteasome System (UPS. Through the formation of lysine 48-linked polyubiquitin chains, it is able to direct the degradation of tagged proteins by the 26S proteasome, indirectly controlling many processes within the cell. However, recent research has indicated that ubiquitin performs a multitude of other roles within the cell beyond protein degradation. It is able to form 6 other ‘atypical’ linkages though lysine residues at positions 6, 11, 27, 29, 33 and 63. These atypical chains perform a range of diverse functions, including the regulation of iron uptake in response to perceived deficiency, repair of double stranded breaks in the DNA, and regulation of the auxin response through the non-proteasomal degradation of auxin efflux carrier protein PIN1. This review explores the role ubiquitin chain topology plays in plant cellular function. We aim to highlight the importance of these varying functions and the future challenges to be encountered within this field.

  2. Effect of signal modulating noise in bistable stochastic dynamical systems

    Institute of Scientific and Technical Information of China (English)

    肖方红; 闫桂荣; 张新武


    The effect of signal modulating noise in bistable stochastic dynamical systems is studied.The concept of instan taneous steady state is proposed for bistable dynamical systems.By making a dynamical analysis of bistable stochastic systems,we find that global and local effect of signal modulating noise as well as stochastic resonance can occur in bistable dynamical systems on which both a weak sinusoidal signal and noise are forced.The effect is demonstrated by numerical simulation.

  3. BMP2 Transfer to Neighboring Cells and Activation of Signaling. (United States)

    Alborzinia, Hamed; Shaikhkarami, Marjan; Hortschansky, Peter; Wölfl, Stefan


    Morphogen gradients and concentration are critical features during early embryonic development and cellular differentiation. Previously we reported the preparation of biologically active, fluorescently labeled BMP2 and quantitatively analyzed their binding to the cell surface and followed BMP2 endocytosis over time on the level of single endosomes. Here we show that this internalized BMP2 can be transferred to neighboring cells and, moreover, also activates downstream BMP signaling in adjacent cells, indicated by Smad1/5/8 phosphorylation and activation of the downstream target gene id1. Using a 3D matrix to modulate cell-cell contacts in culture we could show that direct cell-cell contact significantly increased BMP2 transfer. Using inhibitors of vesicular transport, transfer was strongly inhibited. Interestingly, cotreatment with the physiological BMP inhibitor Noggin increased BMP2 uptake and transfer, albeit activation of Smad signaling in neighboring cells was completely suppressed. Our findings present a novel and interesting mechanism by which morphogens such as BMP2 can be transferred between cells and how this is modulated by BMP antagonists such as Noggin, and how this influences activation of Smad signaling by BMP2 in neighboring cells.

  4. Resveratrol engages selective apoptotic signals in gastric adenocarcinoma cells

    Institute of Scientific and Technical Information of China (English)

    William L Riles; Jason Erickson; Sanjay Nayyar; Mary Jo Atten; Bashar M Attar; Oksana Holian


    AIM: To investigate the intracellular apoptotic signals engaged by resveratrol in three gastric adenocarcinoma cancer cell lines, two of which (AGS and SNU-1) express p53 and one (KATO-Ⅲ) with deleted p53.METHODS: Nuclear fragmentation was used to quantitate apoptotic cells; caspase activity was determined by photometric detection of cleaved substrates; formation of oxidized cytochrome C was used to measure cytochrome C activity, and Western blot analysis was used to determine protein expression.RESULTS: Gastric cancer cells, irrespective of their p53 status, responded to resveratrol with fragmentation of DNA and cleavage of nuclear lamins A and B and PARP, Resveratrol, however, has no effect on mitochondria-associated apoptotic proteins Bcl-2, Bclxl, Bax, Bid or Smac/Diablo, and did not promote subcellular redistribution of cytochrome C, indicating that resveratrol-induced apoptosis of gastric carcinoma cells does not require breakdown of mitochondrial membrane integrity. Resveratrol up-regulated p53 protein in SNU-1 and AGS cells but there was a difference in response of intracellular apoptotic signals between these cell lines.SNU-1 cells responded to resveratrol treatment with down-regulation of survivin, whereas in AGS and KATO-Ⅲ cells resveratrol stimulated caspase 3 and cytochrome C oxidase activities.CONCLUSION: These findings indicate that even within a specific cancer the intracellular apoptotic signals engaged by resveratrol are cell type dependent and suggest that such differences may be related to differentiation or lack of differentiation of these cells.

  5. The sulfiredoxin-peroxiredoxin (Srx-Prx) axis in cell signal transduction and cancer development. (United States)

    Mishra, Murli; Jiang, Hong; Wu, Lisha; Chawsheen, Hedy A; Wei, Qiou


    Redox signaling is a critical component of cell signaling pathways that are involved in the regulation of cell growth, metabolism, hormone signaling, immune regulation and variety of other physiological functions. Peroxiredoxin (Prx) is a family of thiol-based peroxidase that acts as a regulator of redox signaling. Members of Prx family can act as antioxidants and chaperones. Sulfiredoxin (Srx) is an antioxidant protein that exclusively reduces over-oxidized typical 2-Cys Prx. Srx has different affinities for individual Prx and it also catalyzes the deglutathionylation of variety of substrates. Individual component of the Srx-Prx system plays critical role in carcinogenesis by modulating cell signaling pathways involved in cell proliferation, migration and metastasis. Expression levels of individual component of the Srx-Prx axis have been correlated with patient survival outcome in multiple cancer types. This review will summarize the molecular basis of differences in the affinity of Srx for individual Prx and the role of individual component of the Srx-Prx system in tumor progression and metastasis. This enhanced understanding of molecular aspects of Srx-Prx interaction and its role in cell signal transduction will help define the Srx-Prx system as a future therapeutic target in human cancer.

  6. Copper as a key regulator of cell signalling pathways. (United States)

    Grubman, Alexandra; White, Anthony R


    Copper is an essential element in many biological processes. The critical functions associated with copper have resulted from evolutionary harnessing of its potent redox activity. This same property also places copper in a unique role as a key modulator of cell signal transduction pathways. These pathways are the complex sequence of molecular interactions that drive all cellular mechanisms and are often associated with the interplay of key enzymes including kinases and phosphatases but also including intracellular changes in pools of smaller molecules. A growing body of evidence is beginning to delineate the how, when and where of copper-mediated control over cell signal transduction. This has been driven by research demonstrating critical changes to copper homeostasis in many disorders including cancer and neurodegeneration and therapeutic potential through control of disease-associated cell signalling changes by modulation of copper-protein interactions. This timely review brings together for the first time the diverse actions of copper as a key regulator of cell signalling pathways and discusses the potential strategies for controlling disease-associated signalling processes using copper modulators. It is hoped that this review will provide a valuable insight into copper as a key signal regulator and stimulate further research to promote our understanding of copper in disease and therapy.

  7. Calcium signaling as a mediator of cell energy demand and a trigger to cell death. (United States)

    Bhosale, Gauri; Sharpe, Jenny A; Sundier, Stephanie Y; Duchen, Michael R


    Calcium signaling is pivotal to a host of physiological pathways. A rise in calcium concentration almost invariably signals an increased cellular energy demand. Consistent with this, calcium signals mediate a number of pathways that together serve to balance energy supply and demand. In pathological states, calcium signals can precipitate mitochondrial injury and cell death, especially when coupled to energy depletion and oxidative or nitrosative stress. This review explores the mechanisms that couple cell signaling pathways to metabolic regulation or to cell death. The significance of these pathways is exemplified by pathological case studies, such as those showing loss of mitochondrial calcium uptake 1 in patients and ischemia/reperfusion injury.

  8. Implementation of a Portable Personal EKG Signal Monitoring System (United States)

    Tan, Tan-Hsu; Chang, Ching-Su; Chen, Yung-Fu; Lee, Cheng

    This research develops a portable personal EKG signal monitoring system to help patients monitor their EKG signals instantly to avoid the occurrence of tragedies. This system is built with two main units: signal pro-cessing unit and monitoring and evaluation unit. The first unit consists of EKG signal sensor, signal amplifier, digitalization circuit, and related control circuits. The second unit is a software tool developed on an embedded Linux platform (called CSA). Experimental result indicates that the proposed system has the practical potential for users in health monitoring. It is demonstrated to be more convenient and with greater portability than the conventional PC-based EKG signal monitoring systems. Furthermore, all the application units embedded in the system are built with open source codes, no licensed fee is required for operating systems and authorized applications. Thus, the building cost is much lower than the traditional systems.

  9. A case study of proline isomerization in cell signaling. (United States)

    Min, Lie; Fulton, D Bruce; Andreotti, Amy H


    Protein-mediated interactions and enzymatic function provide the foundation upon which cellular signaling cascades control all of the activities of a cell. Post-translational modifications such as phosphorylation or ubiquitiation are well known means for modulating protein activity within the cell. These chemical modifications create new recognition motifs on proteins or shift conformational preferences such that protein catalytic and binding functions are altered in response to external stimuli. Moreover, detection of such modifications is often straightforward by conventional biochemical methods leading investigators toward mechanistic models of cell signaling involving post-translational modifications such as phosphorylation/dephosphorylation. While there is little doubt that such modifications play a significant role in transmission of information throughout the cell, there are certainly other mechanisms at work that are not as well understood at this time. Of particular interest in the context of this review is the intrinsic conformational switch afforded to a polypeptide by peptidyl prolyl cis/trans isomerization. Proline isomerization is emerging as a critical component of certain cell signaling cascades. In addition to serving as a conformational switch that enables a protein to adopt functionally distinct states, proline isomerization may serve as a recognition element for the ubiquitous peptidyl prolyl isomerases. This overview takes a close look at one particular signaling protein, the T cell specific tyrosine kinase Itk, and examines the role of proline isomerization and the peptidyl prolyl isomerase cyclophilin A in mediating Itk function following T cell receptor engagement.

  10. Key cancer cell signal transduction pathways as therapeutic targets. (United States)

    Bianco, Roberto; Melisi, Davide; Ciardiello, Fortunato; Tortora, Giampaolo


    Growth factor signals are propagated from the cell surface, through the action of transmembrane receptors, to intracellular effectors that control critical functions in human cancer cells, such as differentiation, growth, angiogenesis, and inhibition of cell death and apoptosis. Several kinases are involved in transduction pathways via sequential signalling activation. These kinases include transmembrane receptor kinases (e.g., epidermal growth factor receptor EGFR); or cytoplasmic kinases (e.g., PI3 kinase). In cancer cells, these signalling pathways are often altered and results in a phenotype characterized by uncontrolled growth and increased capability to invade surrounding tissue. Therefore, these crucial transduction molecules represent attractive targets for cancer therapy. This review will summarize current knowledge of key signal transduction pathways, that are altered in cancer cells, as therapeutic targets for novel selective inhibitors. The most advanced targeted agents currently under development interfere with function and expression of several signalling molecules, including the EGFR family; the vascular endothelial growth factor and its receptors; and cytoplasmic kinases such as Ras, PI3K and mTOR.

  11. Expression of the Wnt signaling system in central nervous system axon guidance and regeneration

    Directory of Open Access Journals (Sweden)

    Edmund eHollis


    Full Text Available Wnt signaling is essential for axon wiring throughout the development of the nervous system in vertebrates and invertebrates. In vertebrates, Wnts are expressed in gradients that span the entire anterior-posterior axis in the spinal cord and the medial-lateral axis in the superior colliculus. In the brainstem, Wnts are expressed in more complex gradients along the anterior-posterior axis. These gradients provide directional information for axon pathfinding and positional information for topographic mapping and are detected by cell polarity signaling pathways. The gradient expression of Wnts and the coordinated expression of Wnt signaling systems are regulated by mechanisms which are currently unknown. Injury to the adult spinal cord results in the re-induction of Wnts in multiple cell types around the lesion site and their signaling system in injured axons. Reinduced Wnts form gradients around the lesion site, with the lesion site being the peak. The reinduced Wnts may be responsible for the well-known retraction of descending motor axons through the atypical kinase receptor Ryk. Wnt signaling is an appealing therapeutic target for CNS repair. The mechanisms regulating the reinduction will be informative for therapeutic design.

  12. Signaling and Dynamic Actin Responses of B Cells on Topographical Substrates (United States)

    Ketchum, Christina; Sun, Xiaoyu; Fourkas, John; Song, Wenxia; Upadhyaya, Arpita

    B cells become activated upon physical contact with antigen on the surface of antigen presenting cells, such as dendritic cells. Binding of the B cell receptor with antigen initiates actin-mediated spreading of B cells, signaling cascades and eventually infection fighting antibodies. Lymphocytes, including B cells and T cells, have been shown to be responsive to the physical parameters of the contact surface, such as antigen mobility and substrate stiffness. However the roll of surface topography on lymphocyte function is unknown. Here we investigate the degree to which substrate topography controls actin-mediated spreading and B cell activation using nano-fabricated surfaces and live cell imaging. The model topographical system consists of 600 nanometer tall ridges with spacing varying between 800 nanometers and 5 micrometers. Using TIRF imaging we observe actin dynamics, B cell receptor motion and calcium signaling of B cells as they spread on the ridged substrates. We show that the spacing between ridges had a strong effect on the dynamics of actin and calcium influx on B cells. Our results indicate that B cells are highly sensitive to surface topography during cell spreading and signaling activation.

  13. Involvement of PACAP/ADNP signaling in the resistance to cell death in malignant peripheral nerve sheath tumor (MPNST) cells. (United States)

    Castorina, Alessandro; Giunta, Salvatore; Scuderi, Soraya; D'Agata, Velia


    Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas able to grow under conditions of metabolic stress caused by insufficient nutrients or oxygen. Both pituitary adenylate cyclase-activating polypeptide (PACAP) and activity-dependent neuroprotective protein (ADNP) have glioprotective potential. However, whether PACAP/ADNP signaling is involved in the resistance to cell death in MPNST cells remains to be clarified. Here, we investigated the involvement of this signaling system in the survival response of MPNST cells against hydrogen peroxide (H(2)O(2))-evoked death both in the presence of normal serum (NS) and in serum-starved (SS) cells. Results showed that ADNP levels increased time-dependently (6-48 h) in SS cells. Treatment with PACAP38 (10(-9) to 10(-5) M) dose-dependently increased ADNP levels in NS but not in SS cells. PAC(1)/VPAC receptor antagonists completely suppressed PACAP-stimulated ADNP increase and partially reduced ADNP expression in SS cells. NS-cultured cells exposed to H(2)O(2) showed significantly reduced cell viability (~50 %), increased p53 and caspase-3, and DNA fragmentation, without affecting ADNP expression. Serum starvation significantly reduced H(2)O(2)-induced detrimental effects in MPNST cells, which were not further ameliorated by PACAP38. Altogether, these finding provide evidence for the involvement of an endogenous PACAP-mediated ADNP signaling system that increases MPNST cell resistance to H(2)O(2)-induced death upon serum starvation.

  14. Information content in reflected global navigation satellite system signals

    DEFF Research Database (Denmark)

    Høeg, Per; Carlstrom, Anders


    The direct signals from satellites in global satellite navigation satellites systems (GNSS) as, GPS, GLONASS and GALILEO, constitute the primary source for positioning, navigation and timing from space. But also the reflected GNSS signals contain an important information content of signal travel...

  15. System proportions fluid-flow in response to demand signals (United States)


    Control system provides proportioned fluid flow rates in response to demand signals. It compares a digital signal, representing a flow demand, with a reference signal to yield a control voltage to one or more solenoid valves connected to orifices of a predetermined size.

  16. A regulatory framework for shoot stem cell control integrating metabolic, transcriptional, and phytohormone signals. (United States)

    Schuster, Christoph; Gaillochet, Christophe; Medzihradszky, Anna; Busch, Wolfgang; Daum, Gabor; Krebs, Melanie; Kehle, Andreas; Lohmann, Jan U


    Plants continuously maintain pluripotent stem cells embedded in specialized tissues called meristems, which drive long-term growth and organogenesis. Stem cell fate in the shoot apical meristem (SAM) is controlled by the homeodomain transcription factor WUSCHEL (WUS) expressed in the niche adjacent to the stem cells. Here, we demonstrate that the bHLH transcription factor HECATE1 (HEC1) is a target of WUS and that it contributes to SAM function by promoting stem cell proliferation, while antagonizing niche cell activity. HEC1 represses the stem cell regulators WUS and CLAVATA3 (CLV3) and, like WUS, controls genes with functions in metabolism and hormone signaling. Among the targets shared by HEC1 and WUS are phytohormone response regulators, which we show to act as mobile signals in a universal feedback system. Thus, our work sheds light on the mechanisms guiding meristem function and suggests that the underlying regulatory system is far more complex than previously anticipated.

  17. Cell-to-Cell stochastic fluctuations in apoptotic signaling can decide between life and death

    CERN Document Server

    Raychaudhuri, S; Nguyen, T; Khan, E M; Goldkorn, T


    Apoptosis, or genetically programmed cell death, is a crucial cellular process that maintains the balance between life and death in cells. The precise molecular mechanism of apoptosis signaling and how these two pathways are differentially activated under distinct apoptotic stimuli is poorly understood. We developed a Monte Carlo-based stochastic simulation model that can characterize distinct signaling behaviors in the two major pathways of apoptotic signaling using a novel probability distribution-based approach. Specifically, we show that for a weak death signal, such as low levels of death ligand Fas (CD95) binding or under stress conditions, the type 2 mitochondrial pathway dominates apoptotic signaling. Our results also show signaling in the type 2 pathway is stochastic, where the population average over many cells does not capture the cell-to-cell fluctuations in the time course (~1 - 10 hours) of downstream caspase-3 activation. On the contrary, the probability distribution of caspase-3 activation for...

  18. Sweet taste receptor expressed in pancreatic beta-cells activates the calcium and cyclic AMP signaling systems and stimulates insulin secretion.

    Directory of Open Access Journals (Sweden)

    Yuko Nakagawa

    Full Text Available BACKGROUND: Sweet taste receptor is expressed in the taste buds and enteroendocrine cells acting as a sugar sensor. We investigated the expression and function of the sweet taste receptor in MIN6 cells and mouse islets. METHODOLOGY/PRINCIPAL FINDINGS: The expression of the sweet taste receptor was determined by RT-PCR and immunohistochemistry. Changes in cytoplasmic Ca(2+ ([Ca(2+](c and cAMP ([cAMP](c were monitored in MIN6 cells using fura-2 and Epac1-camps. Activation of protein kinase C was monitored by measuring translocation of MARCKS-GFP. Insulin was measured by radioimmunoassay. mRNA for T1R2, T1R3, and gustducin was expressed in MIN6 cells. In these cells, artificial sweeteners such as sucralose, succharin, and acesulfame-K increased insulin secretion and augmented secretion induced by glucose. Sucralose increased biphasic increase in [Ca(2+](c. The second sustained phase was blocked by removal of extracellular calcium and addition of nifedipine. An inhibitor of inositol(1, 4, 5-trisphophate receptor, 2-aminoethoxydiphenyl borate, blocked both phases of [Ca(2+](c response. The effect of sucralose on [Ca(2+](c was inhibited by gurmarin, an inhibitor of the sweet taste receptor, but not affected by a G(q inhibitor. Sucralose also induced sustained elevation of [cAMP](c, which was only partially inhibited by removal of extracellular calcium and nifedipine. Finally, mouse islets expressed T1R2 and T1R3, and artificial sweeteners stimulated insulin secretion. CONCLUSIONS: Sweet taste receptor is expressed in beta-cells, and activation of this receptor induces insulin secretion by Ca(2+ and cAMP-dependent mechanisms.

  19. Illuminating the dynamics of signal integration in Natural Killer cells

    Directory of Open Access Journals (Sweden)

    Sophie Victoria Pageon


    Full Text Available Natural Killer (NK cell responses are shaped by the integration of signals transduced from multiple activating and inhibitory receptors at their surface. Biochemical and genetic approaches have identified most of the key proteins involved in signal integration but a major challenge remains in understanding how the spatial and temporal dynamics of their interactions lead to NK cells responding appropriately when encountering ligands on target cells. Well over a decade of research using fluorescence microscopy has revealed much about the architecture of the NK cell immune synapse – the structured interface between NK cells and target cells - and how it varies when inhibition or activation is the outcome of signal integration. However, key questions – such as the proximity of individual activating and inhibitory receptors – have remained unanswered because the resolution of optical microscopy has been insufficient, being limited by diffraction. Recent developments in fluorescence microscopy have broken this limit, seeding new opportunities for studying the nanometre-scale organisation of the NK cell immune synapse. Here, we discuss how these new imaging technologies, including super-resolution imaging and other novel light-based methods, can illuminate our understanding of NK cell biology.

  20. Optogenetic Control of Nodal Signaling Reveals a Temporal Pattern of Nodal Signaling Regulating Cell Fate Specification during Gastrulation. (United States)

    Sako, Keisuke; Pradhan, Saurabh J; Barone, Vanessa; Inglés-Prieto, Álvaro; Müller, Patrick; Ruprecht, Verena; Čapek, Daniel; Galande, Sanjeev; Janovjak, Harald; Heisenberg, Carl-Philipp


    During metazoan development, the temporal pattern of morphogen signaling is critical for organizing cell fates in space and time. Yet, tools for temporally controlling morphogen signaling within the embryo are still scarce. Here, we developed a photoactivatable Nodal receptor to determine how the temporal pattern of Nodal signaling affects cell fate specification during zebrafish gastrulation. By using this receptor to manipulate the duration of Nodal signaling in vivo by light, we show that extended Nodal signaling within the organizer promotes prechordal plate specification and suppresses endoderm differentiation. Endoderm differentiation is suppressed by extended Nodal signaling inducing expression of the transcriptional repressor goosecoid (gsc) in prechordal plate progenitors, which in turn restrains Nodal signaling from upregulating the endoderm differentiation gene sox17 within these cells. Thus, optogenetic manipulation of Nodal signaling identifies a critical role of Nodal signaling duration for organizer cell fate specification during gastrulation.

  1. Optogenetic Control of Nodal Signaling Reveals a Temporal Pattern of Nodal Signaling Regulating Cell Fate Specification during Gastrulation

    Directory of Open Access Journals (Sweden)

    Keisuke Sako


    Full Text Available During metazoan development, the temporal pattern of morphogen signaling is critical for organizing cell fates in space and time. Yet, tools for temporally controlling morphogen signaling within the embryo are still scarce. Here, we developed a photoactivatable Nodal receptor to determine how the temporal pattern of Nodal signaling affects cell fate specification during zebrafish gastrulation. By using this receptor to manipulate the duration of Nodal signaling in vivo by light, we show that extended Nodal signaling within the organizer promotes prechordal plate specification and suppresses endoderm differentiation. Endoderm differentiation is suppressed by extended Nodal signaling inducing expression of the transcriptional repressor goosecoid (gsc in prechordal plate progenitors, which in turn restrains Nodal signaling from upregulating the endoderm differentiation gene sox17 within these cells. Thus, optogenetic manipulation of Nodal signaling identifies a critical role of Nodal signaling duration for organizer cell fate specification during gastrulation.

  2. Sonic hedgehog signaling regulates mode of cell division of early cerebral cortex progenitors and increases astrogliogenesis

    Directory of Open Access Journals (Sweden)

    Geissy LL Araújo


    Full Text Available The morphogen Sonic Hedgehog (SHH plays a critical role in the development of different tissues. In the central nervous system, SHH is well known to contribute to the patterning of the spinal cord and separation of the brain hemispheres. In addition, it has recently been shown that SHH signaling also contributes to the patterning of the telencephalon and establishment of adult neurogenic niches. In this work, we investigated whether SHH signaling influences the behavior of neural progenitors isolated from the dorsal telencephalon, which generate excitatory neurons and macroglial cells in vitro. We observed that SHH increases proliferation of cortical progenitors and generation of astrocytes, whereas blocking SHH signaling with cyclopamine has opposite effects. In both cases, generation of neurons did not seem to be affected. However, cell survival was broadly affected by blockade of SHH signaling. SHH effects were related to three different cell phenomena: mode of cell division, cell cycle length and cell growth. Together, our data in vitro demonstrate that SHH signaling controls cell behaviors that are important for proliferation of cerebral cortex progenitors, as well as differentiation and survival of neurons and astroglial cells.

  3. Digital signal processing in communication systems

    CERN Document Server

    Frerking, Marvin E


    An engineer's introduction to concepts, algorithms, and advancements in Digital Signal Processing. This lucidly written resource makes extensive use of real-world examples as it covers all the important design and engineering references.


    Directory of Open Access Journals (Sweden)

    Valeriy Martynyuk


    Full Text Available In this article the periodic signal detection method on the base of Duffing system chaotic oscillations analysis is presented. This work is a development of the chaos-based signal detection technique. Generally, chaos-based signal detection is the detection of chaotic-to-periodic state transition under input periodic component influence. If the input periodic component reaches certain threshold value, the system transforms from chaotic state to periodic state. The Duffing-type chaotic systems are often used for such a signal detection purpose because of their ability to work in chaotic state for a long time and relatively simple realization. The main advantage of chaos-based signal detection methods is the utilization of chaotic system sensitivity to weak signals. But such methods are not used in practice because of the chaotic system state control problems. The method presented does not require an exact system state control. The Duffing system works continuously in chaotic state and the periodic signal detection process is based on the analysis of Duffing system Poincare map fractal structure. This structure does not depend on noise, and therefore the minimum input signal-to-noise ratio required for periodic signal detection is not limited by chaotic system state control tolerance.

  5. The Primary Cilium in Cell Signaling and Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Michaud III, Edward J [ORNL; Yoder, Bradley [University of Alabama, Birmingham


    The primary cilium is a microtubule-based antenna-like structure that emanates from the surface of virtually all cells in the mammalian body. It is anchored to the cell by the basal body, which develops from the mother centriole of the centrosome in a manner that is coordinately regulated with the cell cycle. The primary cilium is a sensory organelle that receives both mechanical and chemical signals from other cells and the environment, and transmits these signals to the nucleus to elicit a cellular response. Recent studies revealed that multiple components of the Sonic hedgehog and plateletderived growth factor receptor-A signal transduction pathways localize to the primary cilium, and that loss of the cilium blocks ligand-induced signaling by both pathways. In light of the major role that these pathways play in numerous types of cancer, we anticipate that the emerging discoveries being made about the function of the primary cilium in signaling pathways that are critical for embryonic development and tissue homeostasis in adults will also provide novel insights into the molecular mechanisms of carcinogenesis. (Cancer Res 2006; 66 13): 6463-7)

  6. Switching direction in electric-signal-induced cell migration by cyclic guanosine monophosphate and phosphatidylinositol signaling. (United States)

    Sato, Masayuki J; Kuwayama, Hidekazu; van Egmond, Wouter N; Takayama, Airi L K; Takagi, Hiroaki; van Haastert, Peter J M; Yanagida, Toshio; Ueda, Masahiro


    Switching between attractive and repulsive migration in cell movement in response to extracellular guidance cues has been found in various cell types and is an important cellular function for translocation during cellular and developmental processes. Here we show that the preferential direction of migration during electrotaxis in Dictyostelium cells can be reversed by genetically modulating both guanylyl cyclases (GCases) and the cyclic guanosine monophosphate (cGMP)-binding protein C (GbpC) in combination with the inhibition of phosphatidylinositol-3-OH kinases (PI3Ks). The PI3K-dependent pathway is involved in cathode-directed migration under a direct-current electric field. The catalytic domains of soluble GCase (sGC) and GbpC also mediate cathode-directed signaling via cGMP, whereas the N-terminal domain of sGC mediates anode-directed signaling in conjunction with both the inhibition of PI3Ks and cGMP production. These observations provide an identification of the genes required for directional switching in electrotaxis and suggest that a parallel processing of electric signals, in which multiple-signaling pathways act to bias cell movement toward the cathode or anode, is used to determine the direction of migration.

  7. Plant Cell and Signaling Biology Blooms in the Wuyi Mountain

    Institute of Scientific and Technical Information of China (English)

    Jianping Hu


    @@ INTRODUCTION The Eighth International Conference on Plant Biology Fron-tiers, organized by Zhenbiao Yang, Chentao Lin, and Xing-wang Deng, was convened in the Wuyi Mountain Yeohwa Resort in Fujian, China, 23-27 September 2010.The meeting's main theme was Cells and Signals, featuring four keynote speeches, 45 plenary talks, and over 40 poster presentations that covered a wide range of topics, from dynamic cellular structures to how developmental and environmental signals control various plant processes at the juncture of cells.

  8. Systems Biology and Stem Cell Pluripotency

    DEFF Research Database (Denmark)

    Mashayekhi, Kaveh; Hall, Vanessa; Freude, Kristine


    Recent breakthroughs in stem cell biology have accelerated research in the area of regenerative medicine. Over the past years, it has become possible to derive patient-specific stem cells which can be used to generate different cell populations for potential cell therapy. Systems biological...... modeling of stem cell pluripotency and differentiation have largely been based on prior knowledge of signaling pathways, gene regulatory networks, and epigenetic factors. However, there is a great need to extend the complexity of the modeling and to integrate different types of data, which would further...... improve systems biology and its uses in the field. In this chapter, we first give a general background on stem cell biology and regenerative medicine. Stem cell potency is introduced together with the hierarchy of stem cells ranging from pluripotent embryonic stem cells (ESCs) and induced pluripotent stem...

  9. Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells

    Institute of Scientific and Technical Information of China (English)

    Xiaosong Liu; Jinyan Huang; Taotao Chen; Ying Wang; Shunmei Xin; Jian Li; Gang Pei; Jiuhong Kang


    Yamanaka factors (Oct3/4,Sox2,KIf4,c-Myc) are highly expressed in embryonic stem (ES) cells,and their overexpression can induce pluripotency in both mouse and human somatic cells,indicating that these factors regulate the developmental signaling network necessary for ES cell pluripotency.However,systemic analysis of the signaling pathways regulated by Yamanaka factors has not yet been fully described.In this study,we identified the target promoters of endogenous Yamanaka factors on a whole genome scale using ChIP (chromatin immunoprecipitation)-on-chip in E14.1 mouse ES cells,and we found that these four factors co-occupied 58 promoters.Interestingly,when Oct4 and Sox2 were analyzed as core factors,Kif4 functioned to enhance the core factors for development regulation,whereas c-Myc seemed to play a distinct role in regulating metabolism.The pathway analysis revealed that Yamanaka factors collectively regulate a developmental signaling network composed of 16 developmental signaling pathways,nine of which represent earlier unknown pathways in ES cells,including apoptosis and cellcycle pathways.We further analyzed data from a recent study examining Yamanaka factors in mouse ES cells.Interestingly,this analysis also revealed 16 developmental signaling pathways,of which 14 pathways overlap with the ones revealed by this study,despite that the target genes and the signaling pathways regulated by each individual Yamanaka factor differ significantly between these two datasets.We suggest that Yamanaka factors critically regulate a developmental signaling network composed of approximately a dozen crucial developmental signaling pathways to maintain the pluripotency of ES cells and probably also to induce pluripotent stem cells.

  10. A pseudokinase couples signaling pathways to enable asymmetric cell division in a bacterium

    Directory of Open Access Journals (Sweden)

    W. Seth Childers


    Full Text Available Bacteria face complex decisions when initiating developmental events such as sporulation, nodulation, virulence, and asymmetric cell division. These developmental decisions require global changes in genomic readout, and bacteria typically employ intricate (yet poorly understood signaling networks that enable changes in cell function. The bacterium Caulobacter crescentus divides asymmetrically to yield two functionally distinct cells: a motile, chemotactic swarmer cell, and a sessile stalked cell with replication and division capabilities. Work from several Caulobacter labs has revealed that differentiation requires concerted regulation by several two-component system (TCS signaling pathways that are differentially positioned at the poles of the predivisional cell (Figure 1. The strict unidirectional flow from histidine kinase (HK to the response regulator (RR, observed in most studied TCS, is difficult to reconcile with the notion that information can be transmitted between two or more TCS signaling pathways. In this study, we uncovered a mechanism by which daughter cell fate, which is specified by the DivJ-DivK-PleC system and effectively encoded in the phosphorylation state of the single-domain RR DivK, is communicated to the CckA-ChpT-CtrA signaling pathway that regulates more than 100 genes for polar differentiation, replication initiation and cell division. Using structural biology and biochemical findings we proposed a mechanistic basis for TCS pathway coupling in which the DivL pseudokinase is repurposed as a sensor rather than participant in phosphotransduction.

  11. FGF signaling facilitates postinjury recovery of mouse hematopoietic system. (United States)

    Zhao, Meng; Ross, Jason T; Itkin, Tomer; Perry, John M; Venkatraman, Aparna; Haug, Jeffrey S; Hembree, Mark J; Deng, Chu-Xia; Lapidot, Tsvee; He, Xi C; Li, Linheng


    Previous studies have shown that fibroblast growth factor (FGF) signaling promotes hematopoietic stem and progenitor cell (HSPC) expansion in vitro. However, it is unknown whether FGF promotes HSPC expansion in vivo. Here we examined FGF receptor 1 (FGFR1) expression and investigated its in vivo function in HSPCs. Conditional knockout (CKO) of Fgfr1 did not affect phenotypical number of HSPCs and homeostatic hematopoiesis, but led to a reduced engraftment only in the secondary transplantation. When treated with 5-fluorouracil (5FU), the Fgfr1 CKO mice showed defects in both proliferation and subsequent mobilization of HSPCs. We identified megakaryocytes (Mks) as a major resource for FGF production, and further discovered a novel mechanism by which Mks underwent FGF-FGFR signaling dependent expansion to accelerate rapid FGF production under stress. Within HSPCs, we observed an up-regulation of nuclear factor κB and CXCR4, a receptor for the chemoattractant SDF-1, in response to bone marrow damage only in control but not in Fgfr1 CKO model, accounting for the corresponding defects in proliferation and migration of HSPCs. This study provides the first in vivo evidence that FGF signaling facilitates postinjury recovery of the mouse hematopoietic system by promoting proliferation and facilitating mobilization of HSPCs.

  12. Cell Radiation Experiment System (United States)

    Morrison, Dennis R.


    The cell radiation experiment system (CRES) is a perfused-cell culture apparatus, within which cells from humans or other animals can (1) be maintained in homeostasis while (2) being exposed to ionizing radiation during controlled intervals and (3) being monitored to determine the effects of radiation and the repair of radiation damage. The CRES can be used, for example, to determine effects of drug, radiation, and combined drug and radiation treatments on both normal and tumor cells. The CRES can also be used to analyze the effects of radiosensitive or radioprotectant drugs on cells subjected to radiation. The knowledge gained by use of the CRES is expected to contribute to the development of better cancer treatments and of better protection for astronauts, medical-equipment operators, and nuclear-power-plant workers, and others exposed frequently to ionizing radiation.

  13. Apoptosis and signalling in acid sphingomyelinase deficient cells

    Directory of Open Access Journals (Sweden)

    Sillence Dan J


    Full Text Available Abstract Background Recent evidence suggests that the activation of a non-specific lipid scramblase during apoptosis induces the flipping of sphingomyelin from the cell surface to the cytoplasmic leaftet of the plasma membrane. Inner leaflet sphingomyelin is then cleaved to ceramide by a neutral sphingomyelinase. The production of this non-membrane forming lipid induces blebbing of the plasma membrane to aid rapid engulfment by professional phagocytes. However contrary evidence suggests that cells which are deficient in acid sphingomyelinase are defective in apoptosis signalling. This data has been interpreted as support for the activation of acid sphingomyelinase as an early signal in apoptosis. Hypothesis An alternative explanation is put forward whereby the accumulation of intracellular sphingomyelin in sphingomyelinase deficient cells leads to the formation of intracellular rafts which lead to the sequestration of important signalling molecules that are normally present on the cell surface where they perform their function. Testing the hypothesis It is expected that the subcellular distribution of important signalling molecules is altered in acid sphingomyelinase deficient cells, leading to their sequestration in late endosomes / lysosomes. Other sphingolipid storage diseases such as Niemann-Pick type C which have normal acid sphingomyelinase activity would also be expected to show the same phenotype. Implications of the hypothesis If true the hypothesis would provide a mechanism for the pathology of the sphingolipid storage diseases at the cellular level and also have implications for the role of ceramide in apoptosis.

  14. Lipid body accumulation alters calcium signaling dynamics in immune cells. (United States)

    Greineisen, William E; Speck, Mark; Shimoda, Lori M N; Sung, Carl; Phan, Nolwenn; Maaetoft-Udsen, Kristina; Stokes, Alexander J; Turner, Helen


    There is well-established variability in the numbers of lipid bodies (LB) in macrophages, eosinophils, and neutrophils. Similarly to the steatosis observed in adipocytes and hepatocytes during hyperinsulinemia and nutrient overload, immune cell LB hyper-accumulate in response to bacterial and parasitic infection and inflammatory presentations. Recently we described that hyperinsulinemia, both in vitro and in vivo, drives steatosis and phenotypic changes in primary and transformed mast cells and basophils. LB reach high numbers in these steatotic cytosols, and here we propose that they could dramatically impact the transcytoplasmic signaling pathways. We compared calcium release and influx responses at the population and single cell level in normal and steatotic model mast cells. At the population level, all aspects of FcɛRI-dependent calcium mobilization, as well as activation of calcium-dependent downstream signaling targets such as NFATC1 phosphorylation are suppressed. At the single cell level, we demonstrate that LB are both sources and sinks of calcium following FcɛRI cross-linking. Unbiased analysis of the impact of the presence of LB on the rate of trans-cytoplasmic calcium signals suggest that LB enrichment accelerates calcium propagation, which may reflect a Bernoulli effect. LB abundance thus impacts this fundamental signaling pathway and its downstream targets.

  15. Jasmonic acid signaling modulates ozone-induced hypersensitive cell death. (United States)

    Rao, M V; Lee, H; Creelman, R A; Mullet, J E; Davis, K R


    Recent studies suggest that cross-talk between salicylic acid (SA)-, jasmonic acid (JA)-, and ethylene-dependent signaling pathways regulates plant responses to both abiotic and biotic stress factors. Earlier studies demonstrated that ozone (O(3)) exposure activates a hypersensitive response (HR)-like cell death pathway in the Arabidopsis ecotype Cvi-0. We now have confirmed the role of SA and JA signaling in influencing O(3)-induced cell death. Expression of salicylate hydroxylase (NahG) in Cvi-0 reduced O(3)-induced cell death. Methyl jasmonate (Me-JA) pretreatment of Cvi-0 decreased O(3)-induced H(2)O(2) content and SA concentrations and completely abolished O(3)-induced cell death. Cvi-0 synthesized as much JA as did Col-0 in response to O(3) exposure but exhibited much less sensitivity to exogenous Me-JA. Analyses of the responses to O(3) of the JA-signaling mutants jar1 and fad3/7/8 also demonstrated an antagonistic relationship between JA- and SA-signaling pathways in controlling the magnitude of O(3)-induced HR-like cell death.

  16. Intelligent Signal Processing for Detection System Optimization

    Energy Technology Data Exchange (ETDEWEB)

    Fu, C Y; Petrich, L I; Daley, P F; Burnham, A K


    A wavelet-neural network signal processing method has demonstrated approximately tenfold improvement in the detection limit of various nitrogen and phosphorus compounds over traditional signal-processing methods in analyzing the output of a thermionic detector attached to the output of a gas chromatograph. A blind test was conducted to validate the lower detection limit. All fourteen of the compound spikes were detected when above the estimated threshold, including all three within a factor of two above. In addition, two of six were detected at levels 1/2 the concentration of the nominal threshold. We would have had another two correct hits if we had allowed human intervention to examine the processed data. One apparent false positive in five nulls was traced to a solvent impurity, whose presence was identified by running a solvent aliquot evaporated to 1% residual volume, while the other four nulls were properly classified. We view this signal processing method as broadly applicable in analytical chemistry, and we advocate that advanced signal processing methods be applied as directly as possible to the raw detector output so that less discriminating preprocessing and post-processing does not throw away valuable signal.

  17. Intelligent Signal Processing for Detection System Optimization

    Energy Technology Data Exchange (ETDEWEB)

    Fu, C Y; Petrich, L I; Daley, P F; Burnham, A K


    A wavelet-neural network signal processing method has demonstrated approximately tenfold improvement over traditional signal-processing methods for the detection limit of various nitrogen and phosphorus compounds from the output of a thermionic detector attached to a gas chromatograph. A blind test was conducted to validate the lower detection limit. All fourteen of the compound spikes were detected when above the estimated threshold, including all three within a factor of two above the threshold. In addition, two of six spikes were detected at levels of 1/2 the concentration of the nominal threshold. Another two of the six would have been detected correctly if we had allowed human intervention to examine the processed data. One apparent false positive in five nulls was traced to a solvent impurity, whose presence was subsequently identified by analyzing a solvent aliquot evaporated to 1% residual volume, while the other four nulls were properly classified. We view this signal processing method as broadly applicable in analytical chemistry, and we advocate that advanced signal processing methods should be applied as directly as possible to the raw detector output so that less discriminating preprocessing and post-processing does not throw away valuable signal.

  18. TRPM5, a taste-signaling transient receptor potential ion-channel, is a ubiquitous signaling component in chemosensory cells

    Directory of Open Access Journals (Sweden)

    Hofmann Thomas


    Full Text Available Abstract Background A growing number of TRP channels have been identified as key players in the sensation of smell, temperature, mechanical forces and taste. TRPM5 is known to be abundantly expressed in taste receptor cells where it participates in sweet, amino acid and bitter perception. A role of TRPM5 in other sensory systems, however, has not been studied so far. Results Here, we systematically investigated the expression of TRPM5 in rat and mouse tissues. Apart from taste buds, where we found TRPM5 to be predominantly localized on the basolateral surface of taste receptor cells, TRPM5 immunoreactivity was seen in other chemosensory organs – the main olfactory epithelium and the vomeronasal organ. Most strikingly, we found solitary TRPM5-enriched epithelial cells in all parts of the respiratory and gastrointestinal tract. Based on their tissue distribution, the low cell density, morphological features and co-immunostaining with different epithelial markers, we identified these cells as brush cells (also known as tuft, fibrillovesicular, multivesicular or caveolated cells. In terms of morphological characteristics, brush cells resemble taste receptor cells, while their origin and biological role are still under intensive debate. Conclusion We consider TRPM5 to be an intrinsic signaling component of mammalian chemosensory organs, and provide evidence for brush cells being an important cellular correlate in the periphery.

  19. A sharp T-cell antigen receptor signaling threshold for T-cell proliferation (United States)

    Au-Yeung, Byron B.; Zikherman, Julie; Mueller, James L.; Ashouri, Judith F.; Matloubian, Mehrdad; Cheng, Debra A.; Chen, Yiling; Shokat, Kevan M.; Weiss, Arthur


    T-cell antigen receptor (TCR) signaling is essential for activation, proliferation, and effector function of T cells. Modulation of both intensity and duration of TCR signaling can regulate these events. However, it remains unclear how individual T cells integrate such signals over time to make critical cell-fate decisions. We have previously developed an engineered mutant allele of the critical T-cell kinase zeta-chain-associated protein kinase 70 kDa (Zap70) that is catalytically inhibited by a small molecule inhibitor, thereby blocking TCR signaling specifically and efficiently. We have also characterized a fluorescent reporter Nur77–eGFP transgenic mouse line in which T cells up-regulate GFP uniquely in response to TCR stimulation. The combination of these technologies unmasked a sharp TCR signaling threshold for commitment to cell division both in vitro and in vivo. Further, we demonstrate that this threshold is independent of both the magnitude of the TCR stimulus and Interleukin 2. Similarly, we identify a temporal threshold of TCR signaling that is required for commitment to proliferation, after which T cells are able to proliferate in a Zap70 kinase-independent manner. Taken together, our studies reveal a sharp threshold for the magnitude and duration of TCR signaling required for commitment of T cells to proliferation. These results have important implications for understanding T-cell responses to infection and optimizing strategies for immunomodulatory drug delivery. PMID:25136127

  20. Regulation of osteoprotegerin expression by Notch signaling in human oral squamous cell carcinoma cell line

    Institute of Scientific and Technical Information of China (English)

    Jeeranan Manokawinchoke; Thanaphum Osathanon; Prasit Pavasant


    Objective: To investigate the influence of Notch signaling on osteoprotegerin (OPG) expression in a human oral squamous cell carcinoma cell line. Methods: Activation of Notch signaling was performed by seeding cells on Jagged1 immobilized surfaces. In other experiments, a γ-secretase inhibitor was added to the culture medium to inhibit intracellular Notch signaling. OPG mRNA and protein were determined by real-time PCR and ELISA, respectively. Finally, publicly available microarray database analysis was performed using connection up- or down-regulation expression analysis of microarrays software. Results: Jagged1-treatment of HSC-4 cells enhanced HES1 and HEY1 mRNA expres-sion, confirming the intracellular activation of Notch signaling. OPG mRNA and protein levels were significantly suppressed upon Jagged1 treatment. Correspondingly, HSC-4 cells treated with a γ-secretase inhibitor resulted in a significant reduction of HES1 and HEY1 mRNA levels, and a marked increase in OPG protein expression was observed. These results implied that Notch signaling regulated OPG expression in HSC-4 cells. However, Jagged1 did not alter OPG expression in another human oral squamous cell carcinoma cell line (HSC-5) or a human head and neck squamous cell carcinoma cell line (HN22). Conclusions: Notch signaling regulated OPG expression in an HSC-4 cell line and this mechanism could be cell line specific.

  1. Regulation of osteoprotegerin expression by Notch signaling in human oral squamous cell carcinoma cell line

    Institute of Scientific and Technical Information of China (English)

    Jeeranan Manokawinchoke; Thanaphum Osathanon; Prasit Pavasant


    Objective: To investigate the influence of Notch signaling on osteoprotegerin(OPG)expression in a human oral squamous cell carcinoma cell line.Methods: Activation of Notch signaling was performed by seeding cells on Jagged1 immobilized surfaces. In other experiments, a g-secretase inhibitor was added to the culture medium to inhibit intracellular Notch signaling. OPG m RNA and protein were determined by real-time PCR and ELISA, respectively. Finally, publicly available microarray database analysis was performed using connection up- or down-regulation expression analysis of microarrays software.Results: Jagged1-treatment of HSC-4 cells enhanced HES1 and HEY1 m RNA expression, confirming the intracellular activation of Notch signaling. OPG m RNA and protein levels were significantly suppressed upon Jagged1 treatment. Correspondingly, HSC-4 cells treated with a g-secretase inhibitor resulted in a significant reduction of HES1 and HEY1 m RNA levels, and a marked increase in OPG protein expression was observed.These results implied that Notch signaling regulated OPG expression in HSC-4 cells.However, Jagged1 did not alter OPG expression in another human oral squamous cell carcinoma cell line(HSC-5) or a human head and neck squamous cell carcinoma cell line(HN22).Conclusions: Notch signaling regulated OPG expression in an HSC-4 cell line and this mechanism could be cell line specific.

  2. Differential ligand-signaling network of CCL19/CCL21-CCR7 system. (United States)

    Raju, Rajesh; Gadakh, Sachin; Gopal, Priyanka; George, Bijesh; Advani, Jayshree; Soman, Sowmya; Prasad, T S K; Girijadevi, Reshmi


    Chemokine (C-C motif) receptor 7 (CCR7), a class A subtype G-Protein Coupled Receptor (GPCR), is involved in the migration, activation and survival of multiple cell types including dendritic cells, T cells, eosinophils, B cells, endothelial cells and different cancer cells. Together, CCR7 signaling system has been implicated in diverse biological processes such as lymph node homeostasis, T cell activation, immune tolerance, inflammatory response and cancer metastasis. CCL19 and CCL21, the two well-characterized CCR7 ligands, have been established to be differential in their signaling through CCR7 in multiple cell types. Although the differential ligand signaling through single receptor have been suggested for many receptors including GPCRs, there exists no resource or platform to analyse them globally. Here, first of its kind, we present the cell-type-specific differential signaling network of CCL19/CCL21-CCR7 system for effective visualization and differential analysis of chemokine/GPCR signaling. Database URL: http:// www. netpath. org/ pathways? path_ id= NetPath_ 46.

  3. Curcumin blocks interleukin-1 signaling in chondrosarcoma cells.

    Directory of Open Access Journals (Sweden)

    Thomas Kalinski

    Full Text Available Interleukin (IL-1 signaling plays an important role in inflammatory processes, but also in malignant processes. The essential downstream event in IL-1 signaling is the activation of nuclear factor (NF-κB, which leads to the expression of several genes that are involved in cell proliferation, invasion, angiogenesis and metastasis, among them VEGF-A. As microenvironment-derived IL-1β is required for invasion and angiogenesis in malignant tumors, also in chondrosarcomas, we investigated IL-1β-induced signal transduction and VEGF-A expression in C3842 and SW1353 chondrosarcoma cells. We additionally performed in vitro angiogenesis assays and NF-κB-related gene expression analyses. Curcumin is a substance which inhibits IL-1 signaling very early by preventing the recruitment of IL-1 receptor associated kinase (IRAK to the IL-1 receptor. We demonstrate that IL-1 signaling and VEGF-A expression are blocked by Curcumin in chondrosarcoma cells. We further show that Curcumin blocks IL-1β-induced angiogenesis and NF-κB-related gene expression. We suppose that IL-1 blockade is an additional treatment option in chondrosarcoma, either by Curcumin, its derivatives or other IL-1 blocking agents.

  4. Regulation of behavioral plasticity by systemic temperature signaling in Caenorhabditis elegans. (United States)

    Sugi, Takuma; Nishida, Yukuo; Mori, Ikue


    Animals cope with environmental changes by altering behavioral strategy. Environmental information is generally received by sensory neurons in the neural circuit that generates behavior. However, although environmental temperature inevitably influences an animal's entire body, the mechanism of systemic temperature perception remains largely unknown. We show here that systemic temperature signaling induces a change in a memory-based behavior in C. elegans. During behavioral conditioning, non-neuronal cells as well as neuronal cells respond to cultivation temperature through a heat-shock transcription factor that drives newly identified gene expression dynamics. This systemic temperature signaling regulates thermosensory neurons non-cell-autonomously through the estrogen signaling pathway, producing thermotactic behavior. We provide a link between systemic environmental recognition and behavioral plasticity in the nervous system.

  5. A system for pulsed NQR spectrometer control and signal processing (United States)

    Gourdji, M.; Péneau, A.

    The system described was built at the IEF around a HP-21OOA computer and is presently used with a nitrogen-14 pulsed NQR spectrometer. Two main functions are provided: spectrometer control (radio-frequency, pulse sequence repetition rate, sample temperature settings) and signal processing (accumulation of the NQR signals, Fourier transform). Results are presented which show typical uses of the system for the observation of complex signals.

  6. Signaling pathways in failing human heart muscle cells. (United States)

    Drexler, H; Hasenfuss, G; Holubarsch, C


    Experimental studies have delineated important signaling pathways in cardiomyocytes and their alterations in heart failure; however, there is now evidence that these observations are not necessarily applicable to human cardiac muscle cells. For example, angiotensin II (A II) does not exert positive inotropic effects in human ventricular muscle cells, in contrast to observation in rats. Thus, it is important to elucidate cardiac signaling pathways in humans in order to appreciate the functional role of neurohumoral or mechanical stimulation in human myocardium in health and disease. In the present article, we review signal pathways in the failing human heart based on studies in human cardiac tissues and in vivo physiological studies related to A II, nitric oxide, and β-adrenergic stimulation. (Trends Cardiovasc Med 1997; 7:151-160). © 1997, Elsevier Science Inc.

  7. Phosphorelays Provide Tunable Signal Processing Capabilities for the Cell (United States)

    Kothamachu, Varun B.; Feliu, Elisenda; Wiuf, Carsten; Cardelli, Luca; Soyer, Orkun S.


    Achieving a complete understanding of cellular signal transduction requires deciphering the relation between structural and biochemical features of a signaling system and the shape of the signal-response relationship it embeds. Using explicit analytical expressions and numerical simulations, we present here this relation for four-layered phosphorelays, which are signaling systems that are ubiquitous in prokaryotes and also found in lower eukaryotes and plants. We derive an analytical expression that relates the shape of the signal-response relationship in a relay to the kinetic rates of forward, reverse phosphorylation and hydrolysis reactions. This reveals a set of mathematical conditions which, when satisfied, dictate the shape of the signal-response relationship. We find that a specific topology also observed in nature can satisfy these conditions in such a way to allow plasticity among hyperbolic and sigmoidal signal-response relationships. Particularly, the shape of the signal-response relationship of this relay topology can be tuned by altering kinetic rates and total protein levels at different parts of the relay. These findings provide an important step towards predicting response dynamics of phosphorelays, and the nature of subsequent physiological responses that they mediate, solely from topological features and few composite measurements; measuring the ratio of reverse and forward phosphorylation rate constants could be sufficient to determine the shape of the signal-response relationship the relay exhibits. Furthermore, they highlight the potential ways in which selective pressures on signal processing could have played a role in the evolution of the observed structural and biochemical characteristic in phosphorelays. PMID:24244132

  8. Lipid signalling dynamics at the β-cell plasma membrane. (United States)

    Wuttke, Anne


    Pancreatic β-cells are clustered in islets of Langerhans and secrete insulin in response to increased concentrations of circulating glucose. Insulin in turn acts on liver, muscle and fat tissue to store energy and normalize the blood glucose level. Inappropriate insulin release may lead to impaired glucose tolerance and diabetes. In addition to glucose, other nutrients, neural stimuli and hormonal stimuli control insulin secretion. Many of these signals are perceived at the plasma membrane, which is also the site where insulin granules undergo exocytosis. Therefore, it is not surprising that membrane lipids play an important role in the regulation of insulin secretion. β-cells release insulin in a pulsatile fashion. Signalling lipids integrate the nutrient and neurohormonal inputs to fine-tune, shape and co-ordinate the pulsatility. An important group of signalling lipids are phosphoinositides and their downstream messengers. This MiniReview will discuss new insights into lipid signalling dynamics in β-cells obtained from live-cell imaging experiments with fluorescent translocation biosensors. The plasma membrane concentration of several phosphoinositides and of their downstream messengers changes rapidly upon nutrient or neurohormonal stimulation. Glucose induces the most complex spatio-temporal patterns, typically involving oscillations of messenger concentrations, which sometimes are locally restricted. The tightly controlled levels of lipid messengers can mediate specific binding of downstream effectors to the plasma membrane, contributing to the appropriate regulation of insulin secretion.

  9. A signal processing analysis of Purkinje cells in vitro

    Directory of Open Access Journals (Sweden)

    Ze'ev R Abrams


    Full Text Available Cerebellar Purkinje cells in vitro fire recurrent sequences of Sodium and Calcium spikes. Here, we analyze the Purkinje cell using harmonic analysis, and our experiments reveal that its output signal is comprised of three distinct frequency bands, which are combined using Amplitude and Frequency Modulation (AM/FM. We find that the three characteristic frequencies - Sodium, Calcium and Switching – occur in various combinations in all waveforms observed using whole-cell current clamp recordings. We found that the Calcium frequency can display a frequency doubling of its frequency mode, and the Switching frequency can act as a possible generator of pauses that are typically seen in Purkinje output recordings. Using a reversibly photo-switchable kainate receptor agonist, we demonstrate the external modulation of the Calcium and Switching frequencies. These experiments and Fourier analysis suggest that the Purkinje cell can be understood as a harmonic signal oscillator, enabling a higher level of interpretation of Purkinje signaling based on modern signal processing techniques.

  10. Integrin signaling modes controlling cell migration and metastasis

    NARCIS (Netherlands)

    Truong, Hoa Hoang


    The aim of this thesis is to address how integrin-mediated signaling regulates cellular processes that have profound effects on cell morphology, motility, cancer metastasis, and FN fibrillogenesis, and how these findings can be utilized for relevant medical purposes or advancement of drug discovery.

  11. Mastoparan-Induced Cell Death Signalling in Chlamydomonas Reinhardtii

    NARCIS (Netherlands)

    Yordanova, Z.P.; Kapchina-Toteva, V.M.; Woltering, E.J.; Cristescu, S.M.; Harren, F.J.M.; Yakimova, E.T.


    The present study was focused on the elucidation of stress-induced cell death signaling events in the unicellular alga Chlamydomonas reinhardtii exposed to treatment with wasp venom mastoparan. By applying pharmacological approach with specific inhibitors, we have investigated the involvement of eth

  12. Intracellular signaling by diffusion: can waves of hydrogen peroxide transmit intracellular information in plant cells?

    DEFF Research Database (Denmark)

    Vestergaard, Christian L.; Flyvbjerg, Henrik; Møller, Ian Max


    Amplitude- and frequency-modulated waves of Ca(2+) ions transmit information inside cells. Reactive Oxygen Species (ROS), specifically hydrogen peroxide, have been proposed to have a similar role in plant cells. We consider the feasibility of such an intracellular communication system in view...... of the physical and biochemical conditions in plant cells. As model system, we use a H(2)O(2) signal originating at the plasma membrane (PM) and spreading through the cytosol. We consider two maximally simple types of signals, isolated pulses and harmonic oscillations. First we consider the basic limits...... which diffusion-mediated signaling is possible. We show that purely diffusive transmission of intracellular information by H(2)O(2) over a distance of 1 μm (typical distance between organelles, which may function as relay stations) is possible at frequencies well above 1 Hz, which is the highest...

  13. Intracellular signaling by diffusion: can waves of hydrogen peroxide transmit intracellular information in plant cells?

    DEFF Research Database (Denmark)

    Vestergaard, Christian Lyngby; Flyvbjerg, Henrik; Møller, Ian Max


    Amplitude- and frequency-modulated waves of Ca2+ ions transmit information inside cells. Reactive Oxygen Species (ROS), specifically hydrogen peroxide, have been proposed to have a similar role in plant cells. We consider the feasibility of such an intracellular communication system in view...... of the physical and biochemical conditions in plant cells. As model system, we use a H2O2 signal originating at the plasma membrane (PM) and spreading through the cytosol. We consider two maximally simple types of signals, isolated pulses and harmonic oscillations. First we consider the basic limits...... diffusion-mediated signaling is possible. We show that purely diffusive transmission of intracellular information by H2O2 over a distance of 1 μm (typical distance between organelles, which may function as relay stations) is possible at frequencies well above 1 Hz, which is the highest frequency observed...

  14. The Study of Full Light Speech Signal Collection System

    Institute of Scientific and Technical Information of China (English)

    JIA Bo; JIN Yaqiu; ZHANG Wei; HU Li; YE Kunzhen


    The demodulation character of 3×3 optic fiber couplers is analyzed, and the application in the coherent communication system and speech signal collection is pointed out in the paper. By the experiment, the feasibility of speech signal collection system by the way of the all light is verified.

  15. Utilization of excitation signal harmonics for control of nonlinear systems

    DEFF Research Database (Denmark)

    Vinther, Kasper; Rasmussen, Henrik; Izadi-Zamanabadi, Roozbeh;


    signal together with Fourier analysis to generate a feedback signal and simulations have shown that different system gains and time constants does not change the global equilibrium/operating point. An evaporator in a refrigeration system was used as example in the simulations, however, it is anticipated...


    Directory of Open Access Journals (Sweden)

    Roberta eMalaguarnera


    Full Text Available Cancer cells frequently exploit the IGF signaling, a fundamental pathway mediating development, cell growth and survival. As a consequence, several components of the IGF signaling are deregulated in cancer and sustain cancer progression. However, specific targeting of IGF-IR in humans has resulted efficacious only in small subsets of cancers, making researches wondering whether IGF system targeting is still worth pursuing in the clinical setting. Although no definite answer is yet available, it has become increasingly clear that other components of the IGF signaling pathway, such as IR-A, may substitute for the lack of IGF-IR, and induce cancer resistance and/or clonal selection. Moreover, accumulating evidence now indicates that IGF signaling is a central player in the induction/maintenance of epithelial mesenchymal transition (EMT and cell stemness, two strictly related programs, which play a key role in metastatic spread and resistance to cancer treatments. Here we review the evidences indicating that IGF signaling enhances the expression of transcription factors implicated in the EMT program and has extensive crosstalk with specific pathways involved in cell pluripotency and stemness maintenance. In turn, EMT and cell stemness activate positive feed-back mechanisms causing upregulation of various IGF signaling components. These findings may have novel translational implications.

  17. Signal transduction events in aluminum-induced cell death in tomato suspension cells

    NARCIS (Netherlands)

    Iakimova, E.T.; Kapchina-Toteva, V.M.; Woltering, E.J.


    In this study, some of the signal transduction events involved in AlCl3-induced cell death in tomato (Lycopersicon esculentum Mill.) suspension cells were elucidated. Cells treated with 100 ¿M AlCl3 showed typical features of programmed cell death (PCD) such as nuclear and cytoplasmic condensation.

  18. Biochemical signaling of PD-1 on T cells and its functional implications. (United States)

    Boussiotis, Vassiliki A; Chatterjee, Pranam; Li, Lequn


    Maintenance of peripheral tolerance is essential for homeostasis of the immune system. While central tolerance mechanisms result in deletion of the majority of self-reactive T cells, T lymphocytes specific for self-antigens also escape this process and circulate in the periphery. To control the development of autoimmunity, multiple mechanisms of peripheral tolerance have evolved, including T cell anergy, deletion, and suppression by regulatory T (Treg) cells. The pathway consisting of the programmed cell death 1 (PD-1) receptor (CD279) and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC; CD273) plays a vital role in the induction and maintenance of peripheral tolerance. This pathway also regulates the balance between stimulatory and inhibitory signals needed for effective immunity and maintenance of T cell homeostasis. In contrast to this important beneficial role in maintaining T cell homeostasis, PD-1 mediates potent inhibitory signals that prevent the expansion and function of T effector cells and have detrimental effects on antiviral and antitumor immunity. Despite the compelling studies on the significant functional role of PD-1 in mediating inhibition of activated T cells, little is known about how PD-1 blocks T cell activation. Here, we will provide a brief overview of the signaling events that are regulated by PD-1 triggering, and we will discuss their implications on cell intrinsic and extrinsic mechanisms that determine the fate and function of T effector cells.

  19. Dendritic planarity of Purkinje cells is independent of Reelin signaling. (United States)

    Kim, Jinkyung; Park, Tae-Ju; Kwon, Namseop; Lee, Dongmyeong; Kim, Seunghwan; Kohmura, Yoshiki; Ishikawa, Tetsuya; Kim, Kyong-Tai; Curran, Tom; Je, Jung Ho


    The dendritic planarity of Purkinje cells is critical for cerebellar circuit formation. In the absence of Crk and CrkL, the Reelin pathway does not function resulting in partial Purkinje cell migration and defective dendritogenesis. However, the relationships among Purkinje cell migration, dendritic development and Reelin signaling have not been clearly delineated. Here, we use synchrotron X-ray microscopy to obtain 3-D images of Golgi-stained Purkinje cell dendrites. Purkinje cells that failed to migrate completely exhibited conical dendrites with abnormal 3-D arborization and reduced dendritic complexity. Furthermore, their spines were fewer in number with a distorted morphology. In contrast, Purkinje cells that migrated successfully displayed planar dendritic and spine morphologies similar to normal cells, despite reduced dendritic complexity. These results indicate that, during cerebellar formation, Purkinje cells migrate into an environment that supports development of dendritic planarity and spine formation. While Reelin signaling is important for the migration process, it does not make a direct major contribution to dendrite formation.

  20. Novel aspects on pancreatic beta-cell signal-transduction. (United States)

    Leibiger, Ingo B; Brismar, Kerstin; Berggren, Per-Olof


    Pancreatic beta-cells release insulin in appropriate amounts in order to keep blood glucose levels within physiological limits. Failure to do so leads to the most common metabolic disorder in man, diabetes mellitus. The glucose-stimulus/insulin-secretion coupling represents a sophisticated interplay between glucose and a variety of modulatory factors. These factors are provided by the blood supply (such as nutrients, vitamins, incretins etc.), the nerval innervations, cell-cell contacts as well as by paracrine and autocrine feedback loops within the pancreatic islet of Langerhans. However, the underlying mechanisms of their action remain poorly understood. In the present mini-review we discuss novel aspects of selective insulin signaling in the beta-cell and novel insights into the role of higher inositol phosphates in insulin secretion. Finally we present a newly developed experimental platform that allows non-invasive and longitudinal in vivo imaging of pancreatic islet/beta-cell biology at single-cell resolution.

  1. Black Soybean Seed Coat Extract Prevents Hydrogen Peroxide-Mediated Cell Death via Extracellular Signal-Related Kinase Signalling in HepG2 Cells. (United States)

    Hashimoto, Naoto; Oki, Tomoyuki; Sasaki, Kazunori; Suda, Ikuo; Okuno, Shigenori


    Oxidative stress reduces cell viability and contributes to disease processes. Flavonoids including anthocyanins and proanthocyanidins reportedly induce intracellular antioxidant defence systems. Thus, in this study, we examined the antioxidant effects of a commercial extract from black soybean seed coats (BE), which are rich in anthocyanin and proanthocyanidin, and investigated the associated intracellular mechanisms in HepG2 cells. HepG2 cells treated with hydrogen peroxide (HPO) showed 60% viability, whereas pretreatment with BE-containing media for 2 h ameliorated HPO-mediated cell death by up to 90%. Pretreatment with BE for 2 h partially blocked HPO-mediated activation of ERK in HepG2 cells, and that for 1 h led to a 20% increase in intracellular total protein phosphatase (PP) activity, which is known to deactivate protein kinases. These results indicate that BE prevents HPO-mediated cell damage by inhibiting ERK signalling, potentially via PPs.

  2. Plant GSK3 proteins regulate xylem cell differentiation downstream of TDIF-TDR signalling (United States)

    Kondo, Yuki; Ito, Tasuku; Nakagami, Hirofumi; Hirakawa, Yuki; Saito, Masato; Tamaki, Takayuki; Shirasu, Ken; Fukuda, Hiroo


    During plant radial growth typically seen in trees, procambial and cambial cells act as meristematic cells in the vascular system to self-proliferate and differentiate into xylem cells. These two processes are regulated by a signalling pathway composed of a peptide ligand and its receptor; tracheary element differentiation inhibitory factor (TDIF) and TDIF RECEPTOR (TDR). Here we show that glycogen synthase kinase 3 proteins (GSK3s) are crucial downstream components of the TDIF signalling pathway suppressing xylem differentiation from procambial cells. TDR interacts with GSK3s at the plasma membrane and activates GSK3s in a TDIF-dependent fashion. Consistently, a specific inhibitor of plant GSK3s strongly induces xylem cell differentiation through BRI1-EMS SUPPRESSOR 1 (BES1), a well-known target transcription factor of GSK3s. Our findings provide insight into the regulation of cell fate determination in meristem maintenance.

  3. Effects of FGFR Signaling on Cell Proliferation and Differentiation of Apert Dental Cells. (United States)

    Lu, Changming; Huguley, Samuel; Cui, Chun; Cabaniss, Lauren B; Waite, Peter D; Sarver, David M; Mamaeva, Olga A; MacDougall, Mary


    The Apert syndrome is a rare congenital disorder most often arising from S252W or P253R mutations in fibroblast growth factor receptor (FGFR2). Numerous studies have focused on the regulatory role of Apert FGFR2 signaling in bone formation, whereas its functional role in tooth development is largely unknown. To investigate the role of FGFR signaling in cell proliferation and odontogenic differentiation of human dental cells in vitro, we isolated dental pulp and enamel organ epithelia (EOE) tissues from an Apert patient carrying the S252W FGFR2 mutation. Apert primary pulp and EOE cells were established and shown to exhibit normal morphology and express alkaline phosphatase under differentiation conditions. Similar to control cells, Apert dental pulp and EOE cells expressed all FGFRs, with highest levels of FGFR1 followed by FGFR2 and low levels of FGFR3 and FGFR4. However, Apert cells had increased cell growth compared with control cells. Distinct from previous findings in osteoblast cells, gain-of-function S252W FGFR2 mutation did not upregulate the expression of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFRα), but elevated extracellular signal-regulated kinase (ERK) signaling in cells after EGF stimulation. Unexpectedly, there was little effect of the S252W mutation on odontogenic gene expression in dental pulp and EOE cells. However, after inhibition of total FGFR signaling or ERK signaling, the expression of odontogenic genes was upregulated in both dental cell types, indicating the negative effect of whole FGFR signaling on odontogenic differentiation. This study provides novel insights on FGFR signaling and a common Apert FGFR2 mutation in the regulation of odontogenic differentiation of dental mesenchymal and epithelial cells.

  4. Novel, Unifying Mechanism for Mescaline in The Central Nervous System: Electrochemistry, Catechol Redox Metabolite, Receptor, Cell Signaling and Structure Activity Relationships

    Directory of Open Access Journals (Sweden)

    Peter Kovacic


    Full Text Available A unifying mechanism for abused drugs has been proposed previously from the standpoint of electron transfer. Mescaline can be accommodated within the theoretical framework based on redox cycling by the catechol metabolite with its quinone counterpart. Electron transfer may play a role in electrical effects involving the nervous system in the brain. This approach is in accord with structure activity relationships involving mescaline, abused drugs, catecholamines and etoposide. Inefficient demethylation is in keeping with the various drug properties, such as requirement for high dosage and slow acting.

  5. Inhibition of FGF signaling accelerates neural crest cell differentiation of human pluripotent stem cells. (United States)

    Jaroonwitchawan, Thiranut; Muangchan, Pattamon; Noisa, Parinya


    Neural crest (NC) is a transient population, arising during embryonic development and capable of differentiating into various somatic cells. The defects of neural crest development leads to neurocristopathy. Several signaling pathways were revealed their significance in NC cell specification. Fibroblast growth factor (FGF) is recognized as an important signaling during NC development, for instance Xenopus and avian; however, its contributions in human species are remained elusive. Here we used human pluripotent stem cells (hPSCs) to investigate the consequences of FGF inhibition during NC cell differentiation. The specific-FGF receptor inhibitor, SU5402, was used in this investigation. The inhibition of FGF did not found to affect the proliferation or death of hPSC-derived NC cells, but promoted hPSCs to commit NC cell fate. NC-specific genes, including PAX3, SLUG, and TWIST1, were highly upregulated, while hPSC genes, such as OCT4, and E-CAD, rapidly reduced upon FGF signaling blockage. Noteworthy, TFAP-2α, a marker of migratory NC cells, abundantly presented in SU5402-induced cells. This accelerated NC cell differentiation could be due to the activation of Notch signaling upon the blockage of ERK1/2 phosphorylation, since NICD was increased by SU5402. Altogether, this study proposed the contributions of FGF signaling in controlling human NC cell differentiation from hPSCs, the crosstalk between FGF and Notch, and might imply to the influences of FGF signaling in neurocristophatic diseases.

  6. Planar cell polarity signaling: a common mechanism for cellular polarization. (United States)

    Jenny, Andreas; Mlodzik, Marek


    Epithelial cells frequently display--in addition to the common apical-basolateral polarity--a polarization within the plane of the epithelium. This is commonly referred to as planar cell polarity (PCP) or tissue polarity. Examples of vertebrate PCP include epithelial patterning in the skin and inner ear, and also the morphogenetic movements of mesenchymal cells during convergent extension at gastrulation. In Drosophila, all adult epithelial structures of the cuticle are polarized within the plane. This review presents recent results and new insights into the molecular mechanisms underlying the establishment of PCP, and compares and contrasts the intriguing similarities between PCP signaling in Drosophila and vertebrates.

  7. Signaling and Gene Regulatory Networks Governing Definitive Endoderm Derivation From Pluripotent Stem Cells. (United States)

    Mohammadnia, Abdulshakour; Yaqubi, Moein; Pourasgari, Farzaneh; Neely, Eric; Fallahi, Hossein; Massumi, Mohammad


    The generation of definitive endoderm (DE) from pluripotent stem cells (PSCs) is a fundamental stage in the formation of highly organized visceral organs, such as the liver and pancreas. Currently, there is a need for a comprehensive study that illustrates the involvement of different signaling pathways and their interactions in the derivation of DE cells from PSCs. This study aimed to identify signaling pathways that have the greatest influence on DE formation using analyses of transcriptional profiles, protein-protein interactions, protein-DNA interactions, and protein localization data. Using this approach, signaling networks involved in DE formation were constructed using systems biology and data mining tools, and the validity of the predicted networks was confirmed experimentally by measuring the mRNA levels of hub genes in several PSCs-derived DE cell lines. Based on our analyses, seven signaling pathways, including the BMP, ERK1-ERK2, FGF, TGF-beta, MAPK, Wnt, and PIP signaling pathways and their interactions, were found to play a role in the derivation of DE cells from PSCs. Lastly, the core gene regulatory network governing this differentiation process was constructed. The results of this study could improve our understanding surrounding the efficient generation of DE cells for the regeneration of visceral organs. J. Cell. Physiol. 231: 1994-2006, 2016. © 2016 Wiley Periodicals, Inc.

  8. Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling. (United States)

    Chen, Su-Ren; Liu, Yi-Xun


    Spermatogenesis is a continuous and productive process supported by the self-renewal and differentiation of spermatogonial stem cells (SSCs), which arise from undifferentiated precursors known as gonocytes and are strictly controlled in a special 'niche' microenvironment in the seminiferous tubules. Sertoli cells, the only somatic cell type in the tubules, directly interact with SSCs to control their proliferation and differentiation through the secretion of specific factors. Spermatocyte meiosis is another key step of spermatogenesis, which is regulated by Sertoli cells on the luminal side of the blood-testis barrier through paracrine signaling. In this review, we mainly focus on the role of Sertoli cells in the regulation of SSC self-renewal and spermatocyte meiosis, with particular emphasis on paracrine and endocrine-mediated signaling pathways. Sertoli cell growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2), as well as Sertoli cell transcription factors, such as ETS variant 5 (ERM; also known as ETV5), nociceptin, neuregulin 1 (NRG1), and androgen receptor (AR), have been identified as the most important upstream factors that regulate SSC self-renewal and spermatocyte meiosis. Other transcription factors and signaling pathways (GDNF-RET-GFRA1 signaling, FGF2-MAP2K1 signaling, CXCL12-CXCR4 signaling, CCL9-CCR1 signaling, FSH-nociceptin/OPRL1, retinoic acid/FSH-NRG/ERBB4, and AR/RB-ARID4A/ARID4B) are also addressed.

  9. Ca2+ signaling in pancreatic acinar cells: physiology and pathophysiology

    Directory of Open Access Journals (Sweden)

    O.H. Petersen


    Full Text Available The pancreatic acinar cell is a classical model for studies of secretion and signal transduction mechanisms. Because of the extensive endoplasmic reticulum and the large granular compartment, it has been possible - by direct measurements - to obtain considerable insights into intracellular Ca2+ handling under both normal and pathological conditions. Recent studies have also revealed important characteristics of stimulus-secretion coupling mechanisms in isolated human pancreatic acinar cells. The acinar cells are potentially dangerous because of the high intra-granular concentration of proteases, which become inappropriately activated in the human disease acute pancreatitis. This disease is due to toxic Ca2+ signals generated by excessive liberation of Ca2+ from both the endoplasmic reticulum and the secretory granules.

  10. A New Indoor Positioning System Architecture Using GPS Signals (United States)

    Xu, Rui; Chen, Wu; Xu, Ying; Ji, Shengyue


    The pseudolite system is a good alternative for indoor positioning systems due to its large coverage area and accurate positioning solution. However, for common Global Positioning System (GPS) receivers, the pseudolite system requires some modifications of the user terminals. To solve the problem, this paper proposes a new pseudolite-based indoor positioning system architecture. The main idea is to receive real-world GPS signals, repeat each satellite signal and transmit those using indoor transmitting antennas. The transmitted GPS-like signal can be processed (signal acquisition and tracking, navigation data decoding) by the general receiver and thus no hardware-level modification on the receiver is required. In addition, all Tx can be synchronized with each other since one single clock is used in Rx/Tx. The proposed system is simulated using a software GPS receiver. The simulation results show the indoor positioning system is able to provide high accurate horizontal positioning in both static and dynamic situations. PMID:25938199

  11. Exploiting the natural redundancy of chaotic signals in communication systems (United States)

    Marino; Rosa; Grebogi


    Chaotic signals can be used as carriers of information in communication systems. In this work we describe a simple encoding method that allows one to map any desired bit sequence into a chaotic waveform. The redundancy of the resulting information carrying signal enables us to devise a novel signal reconstruction technique that is able to recover relatively large parts of the chaotic signal starting from just a few samples of it. We show that this technique allows one to increase both the transmission reliability and the transmission rate of a communication system even in the presence of noise.

  12. Regulatory Roles of Metabolites in Cell Signaling Networks

    Institute of Scientific and Technical Information of China (English)

    Feng Li; Wei Xu; Shimin Zhao


    Mounting evidence suggests that cellular metabolites,in addition to being sources of fuel and macromolecular substrates,are actively involved in signaling and epigenetic regulation.Many metabolites,such as cyclic AMP,which regulates phosphorylation/dephosphorylation,have been identified to modulate DNA and histone methylation and protein stability.Metabolite-driven cellular regulation occurs through two distinct mechanisms:proteins allosterically bind or serve as substrates for protein signaling pathways,and metabolites covalently modify proteins to regulate their functions.Such novel protein metabolites include fumarate,succinyl-CoA,propionyl-CoA,butyryl-CoA and crontonyl-CoA.Other metabolites,including α-ketoglutarate,succinate and fumarate,regulate epigenetic processes and cell signaling via protein binding.Here,we summarize recent progress in metabolite-derived post-translational protein modification and metabolite-binding associated signaling regulation.Uncovering metabolites upstream of cell signaling and epigenetic networks permits the linkage of metabolic disorders and human diseases,and suggests that metabolite modulation may be a strategy for innovative therapeutics and disease prevention techniques.

  13. MAPK signal pathways in the regulation of cell proliferation in mammalian cells

    Institute of Scientific and Technical Information of China (English)


    MAPK families play an important role in complex cellular programs like proliferation, differentiation,development, transformation, and apoptosis. At least three MAPK families have been characterized: extracellular signal-regulated kinase (ERK), Jun kinase (JNK/SAPK) and p38 MAPK. The above effects are fulfilled by regulation of cell cycle engine and other cell proliferation related proteins. In this paper we discussed their functions and cooperation with other signal pathways in regulation of cell proliferation.

  14. Interleukin-7 Receptor Signaling Network: An Integrated Systems Perspective

    Institute of Scientific and Technical Information of China (English)

    Megan J. Palmer; Vinay S. Mahajan; Lily C. Trajman; Darrell J. Irvine; Douglas A.Lauffenburger; Jianzhu Chen


    Interleukin-7 (IL-7) is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes. Binding of IL-7 to its cognate receptor, the IL-7 receptor (IL-7R), activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation. There has been much interest in understanding how IL-7 receptor signaling is modulated at multiple interconnected network levels. This review examines how the strength of the signal through the IL-7 receptor is modulated in T and B cells, including the use of shared receptor components, signaling crosstaik, shared interaction domains, feedback loops, integrated gene regulation, muitimerization and ligand competition. We discuss how these network control mechanisms could integrate to govern the properties of IL-7R signaling in lymphocytes in health and disease. Analysis of IL-7receptor signaling at a network level in a systematic manner will allow for a comprehensive approach to understanding the impact of multiple signaling pathways on lymphocyte biology.

  15. Wnt and planar cell polarity signaling in cystic renal disease. (United States)

    Goggolidou, Paraskevi


    Cystic kidney diseases can cause end stage renal disease, affecting millions of individuals worldwide. They may arise early or later in life, are characterized by a spectrum of symptoms and can be caused by diverse genetic defects. The primary cilium, a microtubule-based organelle that can serve as a signaling antenna, has been demonstrated to have a significant role in ensuring correct kidney development and function. In the kidney, one of the signaling pathways that requires the cilium for normal development is Wnt signaling. In this review, the roles of primary cilia in relation to canonical and non-canonical Wnt/PCP signaling in cystic renal disease are described. The evidence of the associations between cilia, Wnt signaling and cystic renal disease is discussed and the significance of planar cell polarity-related mechanisms in cystic kidney disease is presented. Although defective Wnt signaling is not the only cause of renal disease, research is increasingly highlighting its importance, encouraging the development of Wnt-associated diagnostic and prognostic tools for cystic renal disease.

  16. Planar Cell Polarity Signaling Pathway in Congenital Heart Diseases

    Directory of Open Access Journals (Sweden)

    Gang Wu


    Full Text Available Congenital heart disease (CHD is a common cardiac disorder in humans. Despite many advances in the understanding of CHD and the identification of many associated genes, the fundamental etiology for the majority of cases remains unclear. The planar cell polarity (PCP signaling pathway, responsible for tissue polarity in Drosophila and gastrulation movements and cardiogenesis in vertebrates, has been shown to play multiple roles during cardiac differentiation and development. The disrupted function of PCP signaling is connected to some CHDs. Here, we summarize our current understanding of how PCP factors affect the pathogenesis of CHD.

  17. Wnt-Frizzled/planar cell polarity signaling: cellular orientation by facing the wind (Wnt). (United States)

    Yang, Yingzi; Mlodzik, Marek


    The establishment of planar cell polarity (PCP) in epithelial and mesenchymal cells is a critical, evolutionarily conserved process during development and organogenesis. Analyses in Drosophila and several vertebrate model organisms have contributed a wealth of information on the regulation of PCP. A key conserved pathway regulating PCP, the so-called core Wnt-Frizzled PCP (Fz/PCP) signaling pathway, was initially identified through genetic studies of Drosophila. PCP studies in vertebrates, most notably mouse and zebrafish, have identified novel factors in PCP signaling and have also defined cellular features requiring PCP signaling input. These studies have shifted focus to the role of Van Gogh (Vang)/Vangl genes in this molecular system. This review focuses on new insights into the core Fz/Vangl/PCP pathway and recent advances in Drosophila and vertebrate PCP studies. We attempt to integrate these within the existing core Fz/Vangl/PCP signaling framework.

  18. Signals, processes, and systems an interactive multimedia introduction to signal processing

    CERN Document Server

    Karrenberg, Ulrich


    This is a very new concept for learning Signal Processing, not only from the physically-based scientific fundamentals, but also from the didactic perspective, based on modern results of brain research. The textbook together with the DVD form a learning system that provides investigative studies and enables the reader to interactively visualize even complex processes. The unique didactic concept is built on visualizing signals and processes on the one hand, and on graphical programming of signal processing systems on the other. The concept has been designed especially for microelectronics, computer technology and communication. The book allows to develop, modify, and optimize useful applications using DasyLab - a professional and globally supported software for metrology and control engineering. With the 3rd edition, the software is also suitable for 64 bit systems running on Windows 7. Real signals can be acquired, processed and played on the sound card of your computer. The book provides more than 200 pre-pr...

  19. Signals and systems with MATLAB and Simulink modeling

    CERN Document Server

    Karis, Steven, T


    This text contains a comprehensive discussion on continuous and discrete time signals and systems with many MATLABʼ examples. Contents: Elementary Signals, Laplace transformation and its Inverse, Circuit Analysis with the Laplace transformation, State-Space, Impulse Response and Convolution, Fourier Series and Transform, Discrete-Time Signals and the Z transform, Discrete Fourier Transform and FFT, Design of Analog and Digital Filters, and Window Functions Ideal for self-study by students and working professionals.

  20. Novel aspects on signal-transduction in the pancreatic beta-cell. (United States)

    Berggren, Per-Olof; Leibiger, Ingo B


    The glucose-stimulus/insulin-secretion-coupling by the pancreatic beta-cell, which guarantees the maintenance of glucose homeostasis in man, is regulated by a sophisticated interplay between glucose and a plethora of additional factors. Besides other nutrients, incretins, nerval innervation, systemic growth factors as well as autocrine and paracrine regulatory loops within the islet of Langerhans modulate the function of the insulin-producing beta-cell. Although the modulatory role of these factors is well appreciated, the underlying molecular mechanisms involved remain poorly understood. However, in most cases beta-cell membrane receptors coupled primarily to either G-proteins or tyrosine kinases, which subsequently activate respective second messenger cascades, are involved. In the present mini-review we will discuss the role of signaling through some of these receptor-operated effector systems in the light of pancreatic beta-cell signal-transduction.

  1. Specification of Drosophila corpora cardiaca neuroendocrine cells from mesoderm is regulated by Notch signaling.

    Directory of Open Access Journals (Sweden)

    Sangbin Park


    Full Text Available Drosophila neuroendocrine cells comprising the corpora cardiaca (CC are essential for systemic glucose regulation and represent functional orthologues of vertebrate pancreatic α-cells. Although Drosophila CC cells have been regarded as developmental orthologues of pituitary gland, the genetic regulation of CC development is poorly understood. From a genetic screen, we identified multiple novel regulators of CC development, including Notch signaling factors. Our studies demonstrate that the disruption of Notch signaling can lead to the expansion of CC cells. Live imaging demonstrates localized emergence of extra precursor cells as the basis of CC expansion in Notch mutants. Contrary to a recent report, we unexpectedly found that CC cells originate from head mesoderm. We show that Tinman expression in head mesoderm is regulated by Notch signaling and that the combination of Daughterless and Tinman is sufficient for ectopic CC specification in mesoderm. Understanding the cellular, genetic, signaling, and transcriptional basis of CC cell specification and expansion should accelerate discovery of molecular mechanisms regulating ontogeny of organs that control metabolism.

  2. Antagonistic evolution in an aposematic predator-prey signaling system. (United States)

    Speed, Michael P; Franks, Daniel W


    Warning signals within species, such as the bright colors of chemically defended animals, are usually considered mutualistic, monomorphic traits. Such a view is however increasingly at odds with the growing empirical literature, showing nontrivial levels of signal variation within prey populations. Key to understanding this variation, we argue, could be a recognition that toxicity levels frequently vary within populations because of environmental heterogeneity. Inequalities in defense may undermine mutualistic monomorphic signaling, causing evolutionary antagonism between loci that determine appearance of less well-defended and better defended prey forms within species. In this article, we apply a stochastic model of evolved phenotypic plasticity to the evolution of prey signals. We show that when toxicity levels vary, then antagonistic interactions can lead to evolutionary conflict between alleles at different signaling loci, causing signal evolution, "red queen-like" evolutionary chase, and one or more forms of signaling equilibria. A key prediction is that variation in the way that predators use information about toxicity levels in their attack behaviors profoundly affects the evolutionary characteristics of the prey signaling systems. Environmental variation is known to cause variation in many qualities that organisms signal; our approach may therefore have application to other signaling systems.

  3. Vitamin D controls T cell antigen receptor signaling and activation of human T cells

    DEFF Research Database (Denmark)

    von Essen, Marina Rode; Kongsbak-Wismann, Martin; Schjerling, Peter


    Phospholipase C (PLC) isozymes are key signaling proteins downstream of many extracellular stimuli. Here we show that naive human T cells had very low expression of PLC-gamma1 and that this correlated with low T cell antigen receptor (TCR) responsiveness in naive T cells. However, TCR triggering...... led to an upregulation of approximately 75-fold in PLC-gamma1 expression, which correlated with greater TCR responsiveness. Induction of PLC-gamma1 was dependent on vitamin D and expression of the vitamin D receptor (VDR). Naive T cells did not express VDR, but VDR expression was induced by TCR...... signaling via the alternative mitogen-activated protein kinase p38 pathway. Thus, initial TCR signaling via p38 leads to successive induction of VDR and PLC-gamma1, which are required for subsequent classical TCR signaling and T cell activation....

  4. Construction of cell type-specific logic models of signaling networks using CellNOpt. (United States)

    Morris, Melody K; Melas, Ioannis; Saez-Rodriguez, Julio


    Mathematical models are useful tools for understanding protein signaling networks because they provide an integrated view of pharmacological and toxicological processes at the molecular level. Here we describe an approach previously introduced based on logic modeling to generate cell-specific, mechanistic and predictive models of signal transduction. Models are derived from a network encoding prior knowledge that is trained to signaling data, and can be either binary (based on Boolean logic) or quantitative (using a recently developed formalism, constrained fuzzy logic). The approach is implemented in the freely available tool CellNetOptimizer (CellNOpt). We explain the process CellNOpt uses to train a prior knowledge network to data and illustrate its application with a toy example as well as a realistic case describing signaling networks in the HepG2 liver cancer cell line.

  5. Simvastatin impairs growth hormone-activated signal transducer and activator of transcription (STAT signaling pathway in UMR-106 osteosarcoma cells.

    Directory of Open Access Journals (Sweden)

    María Claudia Sandoval-Usme

    Full Text Available Recent studies have demonstrated that statins reduce cell viability and induce apoptosis in various types of cancer cells. The molecular mechanisms underlying these effects are poorly understood. The JAK/STAT pathway plays an important role in the regulation of proliferation and apoptosis in many tissues, and its deregulation is believed to be involved in tumorigenesis and cancer. The physiological activation of STAT proteins by GH is rapid but transient in nature and its inactivation is regulated mainly by the expression of SOCS proteins. UMR-106 osteosarcoma cells express a GH-responsive JAK2/STAT5 signaling pathway, providing an experimental model to study the influence of statins on this system. In this study we investigated the actions of simvastatin on cell proliferation, migration, and invasion on UMR-106 cells and examined whether alterations in GH-stimulated JAK/STAT/SOCS signaling may be observed. Results showed that treatment of osteosarcoma cells with simvastatin at 3 to 10 µM doses decreases cell proliferation, migration, and invasion in a time- and dose-dependent manner. At the molecular level, although the mechanisms used by simvastatin are not entirely clear, the effect of the statin on the reduction of JAK2 and STAT5 phosphorylation levels may partially explain the decrease in the GH-stimulated STAT5 transcriptional activity. This effect correlated with a time- and dose-dependent increase of SOCS-3 expression levels in cells treated with simvastatin, a regulatory role that has not been previously described. Furthermore, the finding that simvastatin is capable of inducing SOCS-3 and CIS genes expression shows the potential of the JAK/STAT pathway as a therapeutic target, reinforcing the efficacy of simvastatin as chemotherapeutic drug for the treatment of osteosarcoma.

  6. Erythropoietin regulates Treg cells in asthma through TGFβ receptor signaling. (United States)

    Wan, Guoshi; Wei, Bing


    Asthma is a chronic inflammatory disorder of the airways, the development of which is suppressed by regulatory T cells (Treg). Erythropoietin (EPO) is originally defined as a hematopoietic growth factor. Recently, the anti-inflammatory effects of EPO in asthma have been acknowledged. However, the underlying mechanisms remain ill-defined. Here, we showed that EPO treatment significantly reduced the severity of an ovalbumin (OVA)-induced asthma in mice, seemingly through promoting Foxp3-mediated activation of Treg cells in OVA-treated mouse lung. The activation of Treg cells resulted from increases in transforming growth factor β1 (TGFβ1), which were mainly produced by M2 macrophages (M2M). In vitro, Co-culture with M2M increased Foxp3 levels in Treg cells and the Treg cell number, in a TGFβ receptor signaling dependent manner. Moreover, elimination of macrophages abolished the therapeutic effects of EPO in vivo. Together, our data suggest that EPO may increase M2M, which activate Treg cells through TGFβ receptor signaling to mitigate the severity of asthma.

  7. NOTE: Automated wavelet denoising of photoacoustic signals for circulating melanoma cell detection and burn image reconstruction (United States)

    Holan, Scott H.; Viator, John A.


    Photoacoustic image reconstruction may involve hundreds of point measurements, each of which contributes unique information about the subsurface absorbing structures under study. For backprojection imaging, two or more point measurements of photoacoustic waves induced by irradiating a biological sample with laser light are used to produce an image of the acoustic source. Each of these measurements must undergo some signal processing, such as denoising or system deconvolution. In order to process the numerous signals, we have developed an automated wavelet algorithm for denoising signals. We appeal to the discrete wavelet transform for denoising photoacoustic signals generated in a dilute melanoma cell suspension and in thermally coagulated blood. We used 5, 9, 45 and 270 melanoma cells in the laser beam path as test concentrations. For the burn phantom, we used coagulated blood in 1.6 mm silicon tube submerged in Intralipid. Although these two targets were chosen as typical applications for photoacoustic detection and imaging, they are of independent interest. The denoising employs level-independent universal thresholding. In order to accommodate nonradix-2 signals, we considered a maximal overlap discrete wavelet transform (MODWT). For the lower melanoma cell concentrations, as the signal-to-noise ratio approached 1, denoising allowed better peak finding. For coagulated blood, the signals were denoised to yield a clean photoacoustic resulting in an improvement of 22% in the reconstructed image. The entire signal processing technique was automated so that minimal user intervention was needed to reconstruct the images. Such an algorithm may be used for image reconstruction and signal extraction for applications such as burn depth imaging, depth profiling of vascular lesions in skin and the detection of single cancer cells in blood samples.

  8. Flash signal evolution in Photinus fireflies: character displacement and signal exploitation in a visual communication system. (United States)

    Stanger-Hall, Kathrin F; Lloyd, James E


    Animal communication is an intriguing topic in evolutionary biology. In this comprehensive study of visual signal evolution, we used a phylogenetic approach to study the evolution of the flash communication system of North American fireflies. The North American firefly genus Photinus contains 35 described species with simple ON-OFF visual signals, and information on habitat types, sympatric congeners, and predators. This makes them an ideal study system to test hypotheses on the evolution of male and female visual signal traits. Our analysis of 34 Photinus species suggests two temporal pattern generators: one for flash duration and one for flash intervals. Reproductive character displacement was a main factor for signal divergence in male flash duration among sympatric Photinus species. Male flash pattern intervals (i.e., the duration of the dark periods between signals) were positively correlated with the number of sympatric Photuris fireflies, which include predators of Photinus. Females of different Photinus species differ in their response preferences to male traits. As in other communication systems, firefly male sexual signals seem to be a compromise between optimizing mating success (sexual selection) and minimizing predation risk (natural selection). An integrative model for Photinus signal evolution is proposed.

  9. Living ordered neural networks as model systems for signal processing (United States)

    Villard, C.; Amblard, P. O.; Becq, G.; Gory-Fauré, S.; Brocard, J.; Roth, S.


    Neural circuit architecture is a fundamental characteristic of the brain, and how architecture is bound to biological functions is still an open question. Some neuronal geometries seen in the retina or the cochlea are intriguing: information is processed in parallel by several entities like in "pooling" networks which have recently drawn the attention of signal processing scientists. These systems indeed exhibit the noise-enhanced processing effect, which is also actively discussed in the neuroscience community at the neuron scale. The aim of our project is to use in-vitro ordered neuron networks as living paradigms to test ideas coming from the computational science. The different technological bolts that have to be solved are enumerated and the first results are presented. A neuron is a polarised cell, with an excitatory axon and a receiving dendritic tree. We present how soma confinement and axon differentiation can be induced by surface functionalization techniques. The recording of large neuron networks, ordered or not, is also detailed and biological signals shown. The main difficulty to access neural noise in the case of weakly connected networks grown on micro electrode arrays is explained. This open the door to a new detection technology suitable for sub-cellular analysis and stimulation, whose development will constitute the next step of this project.

  10. Chemoattractant signaling between tumor cells and macrophages regulates cancer cell migration, metastasis and neovascularization.

    Directory of Open Access Journals (Sweden)

    Chad E Green

    Full Text Available Tumor-associated macrophages are known to influence cancer progression by modulation of immune function, angiogenesis, and cell metastasis, however, little is known about the chemokine signaling networks that regulate this process. Utilizing CT26 colon cancer cells and RAW 264.7 macrophages as a model cellular system, we demonstrate that treatment of CT26 cells with RAW 264.7 conditioned medium induces cell migration, invasion and metastasis. Inflammatory gene microarray analysis indicated CT26-stimulated RAW 264.7 macrophages upregulate SDF-1alpha and VEGF, and that these cytokines contribute to CT26 migration in vitro. RAW 264.7 macrophages also showed a robust chemotactic response towards CT26-derived chemokines. In particular, microarray analysis and functional testing revealed CSF-1 as the major chemoattractant for RAW 264.7 macrophages. Interestingly, in the chick CAM model of cancer progression, RAW 264.7 macrophages localized specifically to the tumor periphery where they were found to increase CT26 tumor growth, microvascular density, vascular disruption, and lung metastasis, suggesting these cells home to actively invading areas of the tumor, but not the hypoxic core of the tumor mass. In support of these findings, hypoxic conditions down regulated CSF-1 production in several tumor cell lines and decreased RAW 264.7 macrophage migration in vitro. Together our findings suggest a model where normoxic tumor cells release CSF-1 to recruit macrophages to the tumor periphery where they secrete motility and angiogenic factors that facilitate tumor cell invasion and metastasis.

  11. Wnt signaling through T-cell factor phosphorylation

    Institute of Scientific and Technical Information of China (English)

    Sergei Y Sokol


    Embryonic signaling pathways often lead to a switch from default repression to transcriptional activation of target genes. A major consequence of Wnt signaling is stabilization of p-catenin, which associates with T-cell factors (TCFs) and 'converts' them from repressors into transcriptional activators. The molecular mechanisms responsible for this conversion remain poorly understood. Several studies have reported on the regulation of TCF by phosphorylation,yet its physiological significance has been unclear: in some cases it appears to promote target gene activation, in oth-ers Wnt-dependent transcription is inhibited. This review focuses on recent progress in the understanding of context-dependent post-translational regulation of TCF function by Wnt signaling.

  12. Pi sensing and signalling: from prokaryotic to eukaryotic cells. (United States)

    Qi, Wanjun; Baldwin, Stephen A; Muench, Stephen P; Baker, Alison


    Phosphorus is one of the most important macronutrients and is indispensable for all organisms as a critical structural component as well as participating in intracellular signalling and energy metabolism. Sensing and signalling of phosphate (Pi) has been extensively studied and is well understood in single-cellular organisms like bacteria (Escherichia coli) and Saccharomyces cerevisiae In comparison, the mechanism of Pi regulation in plants is less well understood despite recent advances in this area. In most soils the available Pi limits crop yield, therefore a clearer understanding of the molecular basis underlying Pi sensing and signalling is of great importance for the development of plants with improved Pi use efficiency. This mini-review compares some of the main Pi regulation pathways in prokaryotic and eukaryotic cells and identifies similarities and differences among different organisms, as well as providing some insight into future research.

  13. A CRISPR-Based Toolbox for Studying T Cell Signal Transduction (United States)

    Chi, Shen; Weiss, Arthur; Wang, Haopeng


    CRISPR/Cas9 system is a powerful technology to perform genome editing in a variety of cell types. To facilitate the application of Cas9 in mapping T cell signaling pathways, we generated a toolbox for large-scale genetic screens in human Jurkat T cells. The toolbox has three different Jurkat cell lines expressing distinct Cas9 variants, including wild-type Cas9, dCas9-KRAB, and sunCas9. We demonstrated that the toolbox allows us to rapidly disrupt endogenous gene expression at the DNA level and to efficiently repress or activate gene expression at the transcriptional level. The toolbox, in combination with multiple currently existing genome-wide sgRNA libraries, will be useful to systematically investigate T cell signal transduction using both loss-of-function and gain-of-function genetic screens. PMID:27057542

  14. A CRISPR-Based Toolbox for Studying T Cell Signal Transduction

    Directory of Open Access Journals (Sweden)

    Shen Chi


    Full Text Available CRISPR/Cas9 system is a powerful technology to perform genome editing in a variety of cell types. To facilitate the application of Cas9 in mapping T cell signaling pathways, we generated a toolbox for large-scale genetic screens in human Jurkat T cells. The toolbox has three different Jurkat cell lines expressing distinct Cas9 variants, including wild-type Cas9, dCas9-KRAB, and sunCas9. We demonstrated that the toolbox allows us to rapidly disrupt endogenous gene expression at the DNA level and to efficiently repress or activate gene expression at the transcriptional level. The toolbox, in combination with multiple currently existing genome-wide sgRNA libraries, will be useful to systematically investigate T cell signal transduction using both loss-of-function and gain-of-function genetic screens.

  15. EGFR signaling regulates cell proliferation, differentiation and morphogenesis during planarian regeneration and homeostasis. (United States)

    Fraguas, Susanna; Barberán, Sara; Cebrià, Francesc


    Similarly to development, the process of regeneration requires that cells accurately sense and respond to their external environment. Thus, intrinsic cues must be integrated with signals from the surrounding environment to ensure appropriate temporal and spatial regulation of tissue regeneration. Identifying the signaling pathways that control these events will not only provide insights into a fascinating biological phenomenon but may also yield new molecular targets for use in regenerative medicine. Among classical models to study regeneration, freshwater planarians represent an attractive system in which to investigate the signals that regulate cell proliferation and differentiation, as well as the proper patterning of the structures being regenerated. Recent studies in planarians have begun to define the role of conserved signaling pathways during regeneration. Here, we extend these analyses to the epidermal growth factor (EGF) receptor pathway. We report the characterization of three epidermal growth factor (EGF) receptors in the planarian Schmidtea mediterranea. Silencing of these genes by RNA interference (RNAi) yielded multiple defects in intact and regenerating planarians. Smed-egfr-1(RNAi) resulted in decreased differentiation of eye pigment cells, abnormal pharynx regeneration and maintenance, and the development of dorsal outgrowths. In contrast, Smed-egfr-3(RNAi) animals produced smaller blastemas associated with abnormal differentiation of certain cell types. Our results suggest important roles for the EGFR signaling in controlling cell proliferation, differentiation and morphogenesis during planarian regeneration and homeostasis.

  16. Spatio-temporal dynamcis of a cell signal cascade with negative feedback (United States)

    Maya Bernal, Jose Luis; Ramirez-Santiago, Guillermo


    We studied the spatio-temporal dynamics of a system of reactio-diffusion equations that models a cell signal transduction pathway with six cycles and negative feedback. The basic cycle consists of the phosphorylation-dephosphorylation of two antagonic proteins. We found two regimes of saturation of the enzimatic reaction in the kinetic parameters space and determined the conditions for the signal propagation in the steady state. The trajectories for which transduction occurs are defined in terms of the ratio of the enzimatic activities. We found that in spite of the negative feedback the cell signal cascade behaves as an amplifier and produces phosphoprotein concentration gradients within the cell. This model behaves also as a noise filter and as a switch. Supported by DGAPA-UNAM Contract IN118410-3.

  17. Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation. (United States)

    Wang, Xi-De; Leow, Ching Ching; Zha, Jiping; Tang, Zhijun; Modrusan, Zora; Radtke, Freddy; Aguet, Michel; de Sauvage, Frederic J; Gao, Wei-Qiang


    Notch pathway is crucial for stem/progenitor cell maintenance, growth and differentiation in a variety of tissues. Using a transgenic cell ablation approach, we found in our previous study that cells expressing Notch1 are crucial for prostate early development and re-growth. Here, we further define the role of Notch signaling in regulating prostatic epithelial cell growth and differentiation using biochemical and genetic approaches in ex vivo or in vivo systems. Treatment of developing prostate grown in culture with inhibitors of gamma-secretase/presenilin, which is required for Notch cleavage and activation, caused a robust increase in proliferation of epithelial cells co-expressing cytokeratin 8 and 14, lack of luminal/basal layer segregation and dramatically reduced branching morphogenesis. Using conditional Notch1 gene deletion mouse models, we found that inactivation of Notch1 signaling resulted in profound prostatic alterations, including increased tufting, bridging and enhanced epithelial proliferation. Cells within these lesions co-expressed both luminal and basal cell markers, a feature of prostatic epithelial cells in predifferentiation developmental stages. Microarray analysis revealed that the gene expression in a number of genetic networks was altered following Notch1 gene deletion in prostate. Furthermore, expression of Notch1 and its effector Hey-1 gene in human prostate adenocarcinomas were found significantly down-regulated compared to normal control tissues. Taken together, these data suggest that Notch signaling is critical for normal cell proliferation and differentiation in the prostate, and deregulation of this pathway may facilitate prostatic tumorigenesis.

  18. Power system small signal stability analysis and control

    CERN Document Server

    Mondal, Debasish; Sengupta, Aparajita


    Power System Small Signal Stability Analysis and Control presents a detailed analysis of the problem of severe outages due to the sustained growth of small signal oscillations in modern interconnected power systems. The ever-expanding nature of power systems and the rapid upgrade to smart grid technologies call for the implementation of robust and optimal controls. Power systems that are forced to operate close to their stability limit have resulted in the use of control devices by utility companies to improve the performance of the transmission system against commonly occurring power system

  19. Simulation of queue with cyclic service in signalized intersection system

    Directory of Open Access Journals (Sweden)

    Muhammad Dermawan Mulyodiputro


    Full Text Available The simulation was implemented by modeling the queue with cyclic service in the signalized intersection system. The service policies used in this study were exhaustive and gated, the model was the M/M/1 queue, the arrival rate used was Poisson distribution and the services rate used was Exponential distribution. In the gated service policy, the server served only vehicles that came before the green signal appears at an intersection. Considered that there were 2 types of exhaustive policy in the signalized intersection system, namely normal exhaustive (vehicles only served during the green signal was still active, and exhaustive (there was the green signal duration addition at the intersection, when the green signal duration at an intersection finished. The results of this queueing simulation program were to obtain characteristics and performance of the system, i.e. average number of vehicles and waiting time of vehicles in the intersection and in the system, as well as system utilities. Then from these values, it would be known which of the cyclic service policies (normal exhaustive, exhaustive and gated was the most suitable when applied to a signalized intersection system

  20. Controlling Cell Functions and Fate with Surfaces and Hydrogels: The Role of Material Features in Cell Adhesion and Signal Transduction

    Directory of Open Access Journals (Sweden)

    Maurizio Ventre


    Full Text Available In their natural environment, cells are constantly exposed to a cohort of biochemical and biophysical signals that govern their functions and fate. Therefore, materials for biomedical applications, either in vivo or in vitro, should provide a replica of the complex patterns of biological signals. Thus, the development of a novel class of biomaterials requires, on the one side, the understanding of the dynamic interactions occurring at the interface of cells and materials; on the other, it requires the development of technologies able to integrate multiple signals precisely organized in time and space. A large body of studies aimed at investigating the mechanisms underpinning cell-material interactions is mostly based on 2D systems. While these have been instrumental in shaping our understanding of the recognition of and reaction to material stimuli, they lack the ability to capture central features of the natural cellular environment, such as dimensionality, remodelling and degradability. In this work, we review the fundamental traits of material signal sensing and cell response. We then present relevant technologies and materials that enable fabricating systems able to control various aspects of cell behavior, and we highlight potential differences that arise from 2D and 3D settings.

  1. Role of cell adhesion signal molecules in hepatocellular carcinoma cell apoptosis

    Institute of Scientific and Technical Information of China (English)

    Jian-Min Su; Li-Ying Wang; Yu-Long Liang; Xi-Liang Zha


    AIM: Cell adhesion molecules and their signal molecules play a very important role in carcinogenesis. The aim of this study is to elucidate the role of these molecules and the signal molecules of integrins and E-cadherins, such as (focal adhesion kinase) FAK, (integrin linked kinase)ILK, and β-catenin in hepatocellular carcinoma cell apoptosis.METHODS: We first synthesized the small molecular compound, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and identified it, by element analysis and 1H NMR. To establish the apoptosis model of the SMMC-7721 hepatocellular carcinoma cell, we treated cells with DCVC in EBSS for different concentrations or for various length times in the presence of 20 μmol/L N,N-diphenyl-p-phenylenediamine,which blocks necrotic cell death and identified this model by flow cytometry and DNA ladder. Then we studied the changes of FAK, ILK, β-catenin, and PKB in this apoptotic model by Western blot.RESULTS: We found that the loss or decrease of cell adhesion signal molecules is an important reason in apoptosis of SMMC-7721 hepatocellular carcinoma cell and the apoptosis of SMMC-7721 cell was preceded by the loss or decrease of FAK, ILK, PKB, and β-catenin or the damage of cell-matrix and cell-cell adhesion.CONCLUSION: Our results suggested that the decrease of adhesion signal molecules, FAK, ILK, PKB, and β-catenin,could induce hepatocellular carcinoma cell apoptosis.

  2. Signal processing method and system for noise removal and signal extraction (United States)

    Fu, Chi Yung; Petrich, Loren


    A signal processing method and system combining smooth level wavelet pre-processing together with artificial neural networks all in the wavelet domain for signal denoising and extraction. Upon receiving a signal corrupted with noise, an n-level decomposition of the signal is performed using a discrete wavelet transform to produce a smooth component and a rough component for each decomposition level. The level smooth component is then inputted into a corresponding neural network pre-trained to filter out noise in that component by pattern recognition in the wavelet domain. Additional rough components, beginning at the highest level, may also be retained and inputted into corresponding neural networks pre-trained to filter out noise in those components also by pattern recognition in the wavelet domain. In any case, an inverse discrete wavelet transform is performed on the combined output from all the neural networks to recover a clean signal back in the time domain.

  3. Auditory signal design for automatic number plate recognition system

    NARCIS (Netherlands)

    Heydra, C.G.; Jansen, R.J.; Van Egmond, R.


    This paper focuses on the design of an auditory signal for the Automatic Number Plate Recognition system of Dutch national police. The auditory signal is designed to alert police officers of suspicious cars in their proximity, communicating priority level and location of the suspicious car and takin

  4. Measurement System for Playout Delay of TV Signals

    NARCIS (Netherlands)

    Kooij, W.J.; Stokking, H.M.; Brandenburg, R. van; Boer, P.T. de


    TV signals are carried towards end-users using different (broadcast) technologies and by different providers. This is causing differences in the playout timing of the TV signal at different locations and devices. Authors have developed a measurement system for measuring the relative playout delay of

  5. Cdc42/N-WASP signaling links actin dynamics to pancreatic beta cell delamination and differentiation

    DEFF Research Database (Denmark)

    Kesavan, Gokul; Lieven, Oliver; Mamidi, Anant;


    to differentiation remains unknown. Using the developing mouse pancreas as a model system, we show that β cell delamination and differentiation are two independent events, which are controlled by Cdc42/N-WASP signaling. Specifically, we show that expression of constitutively active Cdc42 in β cells inhibits β cell......Delamination plays a pivotal role during normal development and cancer. Previous work has demonstrated that delamination and epithelial cell movement within the plane of an epithelium are associated with a change in cellular phenotype. However, how this positional change is linked...

  6. Cell survival signalling through PPARδ and arachidonic acid metabolites in neuroblastoma.

    Directory of Open Access Journals (Sweden)

    Emma Bell

    Full Text Available Retinoic acid (RA has paradoxical effects on cancer cells: promoting cell death, differentiation and cell cycle arrest, or cell survival and proliferation. Arachidonic acid (AA release occurs in response to RA treatment and, therefore, AA and its downstream metabolites may be involved in cell survival signalling. To test this, we inhibited phospholipase A2-mediated AA release, cyclooxygenases and lipoxygenases with small-molecule inhibitors to determine if this would sensitise cells to cell death after RA treatment. The data suggest that, in response to RA, phospholipase A2-mediated release of AA and subsequent metabolism by lipoxygenases is important for cell survival. Evidence from gene expression reporter assays and PPARδ knockdown suggests that lipoxygenase metabolites activate PPARδ. The involvement of PPARδ in cell survival is supported by results of experiments with the PPARδ inhibitor GSK0660 and siRNA-mediated knockdown. Quantitative reverse transcriptase PCR studies demonstrated that inhibition of 5-lipoxygenase after RA treatment resulted in a strong up-regulation of mRNA for PPARδ2, a putative inhibitory PPARδ isoform. Over-expression of PPARδ2 using a tetracycline-inducible system in neuroblastoma cells reduced proliferation and induced cell death. These data provide evidence linking lipoxygenases and PPARδ in a cell survival-signalling mechanism and suggest new drug-development targets for malignant and hyper-proliferative diseases.

  7. Key Signaling Events for Committing Mouse Pluripotent Stem Cells to the Germline Fate. (United States)

    Wang, Jian-Qi; Cao, Wen-Guang


    The process of germline development carries genetic information and preparatory totipotency across generations. The last decade has witnessed remarkable successes in the generation of germline cells from mouse pluripotent stem cells, especially induced germline cells with the capacity for producing viable offspring, suggesting clinical applications of induced germline cells in humans. However, to date, the culture systems for germline induction with accurate sex-specific meiosis and epigenetic reprogramming have not been well-established. In this study, we primarily focus on the mouse model to discuss key signaling events for germline induction. We review mechanisms of competent regulators on primordial germ cell induction and discuss current achievements and difficulties in inducing sex-specific germline development. Furthermore, we review the developmental identities of mouse embryonic stem cells and epiblast stem cells under certain defined culture conditions as it relates to the differentiation process of becoming germline cells.

  8. Knowledge representation model for systems-level analysis of signal transduction networks. (United States)

    Lee, Dong-Yup; Zimmer, Ralf; Lee, Sang-Yup; Hanisch, Daniel; Park, Sunwon


    A Petri-net based model for knowledge representation has been developed to describe as explicitly and formally as possible the molecular mechanisms of cell signaling and their pathological implications. A conceptual framework has been established for reconstructing and analyzing signal transduction networks on the basis of the formal representation. Such a conceptual framework renders it possible to qualitatively understand the cell signaling behavior at systems-level. The mechanisms of the complex signaling network are explored by applying the established framework to the signal transduction induced by potent proinflammatory cytokines, IL-1beta and TNF-alpha The corresponding expert-knowledge network is constructed to evaluate its mechanisms in detail. This strategy should be useful in drug target discovery and its validation.

  9. BPTF transduces MITF-driven prosurvival signals in melanoma cells. (United States)

    Dar, Altaf A; Majid, Shahana; Bezrookove, Vladimir; Phan, Binh; Ursu, Sarah; Nosrati, Mehdi; De Semir, David; Sagebiel, Richard W; Miller, James R; Debs, Robert; Cleaver, James E; Kashani-Sabet, Mohammed


    Microphthalmia-associated transcription factor (MITF) plays a critical and complex role in melanocyte transformation. Although several downstream targets of MITF action have been identified, the precise mechanisms by which MITF promotes melanocytic tumor progression are incompletely understood. Recent studies identified an oncogenic role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression, in part through activation of BCL2, a canonical target of MITF signaling. Analysis of the BPTF promoter identified a putative MITF-binding site, suggesting that MITF may regulate BPTF expression. Overexpression of MITF resulted in up-regulation of BPTF in a panel of melanoma and melanocyte cell lines. shRNA-mediated down-regulation of MITF in melanoma cells was accompanied by down-regulation of BPTF and BPTF-regulated genes (including BCL2) and resulted in reduced proliferative capacity of melanoma cells. The suppression of cell growth mediated by MITF silencing was rescued by overexpression of BPTF cDNA. Binding of MITF to the BPTF promoter was demonstrated using ChIP analysis. MITF overexpression resulted in direct transcriptional activation of BPTF, as evidenced by increased luciferase activity driven by the BPTF promoter. These results indicate that BPTF transduces key prosurvival signals driven by MITF, further supporting its important role in promoting melanoma cell survival and progression.

  10. Omega-3 fatty acids, lipid rafts, and T cell signaling. (United States)

    Hou, Tim Y; McMurray, David N; Chapkin, Robert S


    n-3 polyunsaturated fatty acids (PUFA) have been shown in many clinical studies to attenuate inflammatory responses. Although inflammatory responses are orchestrated by a wide spectrum of cells, CD4(+) T cells play an important role in the etiology of many chronic inflammatory diseases such as inflammatory bowel disease and obesity. In light of recent concerns over the safety profiles of non-steroidal anti-inflammatory drugs (NSAIDs), alternatives such as bioactive nutraceuticals are becoming more attractive. In order for these agents to be accepted into mainstream medicine, however, the mechanisms by which nutraceuticals such as n-3 PUFA exert their anti-inflammatory effects must be fully elucidated. Lipid rafts are nanoscale, dynamic domains in the plasma membrane that are formed through favorable lipid-lipid (cholesterol, sphingolipids, and saturated fatty acids) and lipid-protein (membrane-actin cytoskeleton) interactions. These domains optimize the clustering of signaling proteins at the membrane to facilitate efficient cell signaling which is required for CD4(+) T cell activation and differentiation. This review summarizes novel emerging data documenting the ability of n-3 PUFA to perturb membrane-cytoskeletal structure and function in CD4(+) T cells. An understanding of these underlying mechanisms will provide a rationale for the use of n-3 PUFA in the treatment of chronic inflammation.

  11. Nitric oxide-induced signalling in rat lacrimal acinar cells

    DEFF Research Database (Denmark)

    Looms, Dagnia Karen; Tritsaris, K.; Dissing, S.


    The aim of the present study was to investigate the physiological role of nitric oxide (NO) in mediating secretory processes in rat lacrimal acinar cells. In addition, we wanted to determine whether the acinar cells possess endogenous nitric oxide synthase (NOS) activity by measuring NO productio...... not by itself causing fast transient increases in [Ca2+]i. In addition, we suggest that endogenously produced NO activated by ß-adrenergic receptor stimulation, plays an important role in signalling to the surrounding tissue.......The aim of the present study was to investigate the physiological role of nitric oxide (NO) in mediating secretory processes in rat lacrimal acinar cells. In addition, we wanted to determine whether the acinar cells possess endogenous nitric oxide synthase (NOS) activity by measuring NO production......-adrenergic stimulation and not by a rise in [Ca2+]i alone.   We show that in rat lacrimal acinar cells, NO and cGMP induce Ca2+ release from intracellular stores via G kinase activation. However, the changes in [Ca2+]i are relatively small, suggesting that this pathway plays a modulatory role in Ca2+ signalling, thus...

  12. Vestibular and Attractor Network Basis of the Head Direction Cell Signal in Subcortical Circuits

    Directory of Open Access Journals (Sweden)

    Benjamin J Clark


    Full Text Available Accurate navigation depends on a network of neural systems that encode the moment-to-moment changes in an animal’s directional orientation and location in space. Within this navigation system are head direction (HD cells, which fire persistently when an animal’s head is pointed in a particular direction (Sharp et al., 2001a; Taube, 2007. HD cells are widely thought to underlie an animal’s sense of spatial orientation, and research over the last 25+ years has revealed that this robust spatial signal is widely distributed across subcortical and cortical limbic areas. Much of this work has been directed at understanding the functional organization of the HD cell circuitry, and precisely how this signal is generated from sensory and motor systems. The purpose of the present review is to summarize some of the recent studies arguing that the HD cell circuit is largely processed in a hierarchical fashion, following a pathway involving the dorsal tegmental nuclei → lateral mammillary nuclei → anterior thalamus → parahippocampal and retrosplenial cortical regions. We also review recent work identifying bursting cellular activity in the HD cell circuit after lesions of the vestibular system, and relate these observations to the long held view that attractor network mechanisms underlie HD signal generation. Finally, we summarize the work to date suggesting that this network architecture may reside within the tegmento-mammillary circuit.

  13. Quantitative Phosphoproteomic Analysis of T-Cell Receptor Signaling. (United States)

    Ahsan, Nagib; Salomon, Arthur R


    TCR signaling critically depends on protein phosphorylation across many proteins. Localization of each phosphorylation event relative to the T-cell receptor (TCR) and canonical T-cell signaling proteins will provide clues about the structure of TCR signaling networks. Quantitative phosphoproteomic analysis by mass spectrometry provides a wide-scale view of cellular phosphorylation networks. However, analysis of phosphorylation by mass spectrometry is still challenging due to the relative low abundance of phosphorylated proteins relative to all proteins and the extraordinary diversity of phosphorylation sites across the proteome. Highly selective enrichment of phosphorylated peptides is essential to provide the most comprehensive view of the phosphoproteome. Optimization of phosphopeptide enrichment methods coupled with highly sensitive mass spectrometry workflows significantly improves the sequencing depth of the phosphoproteome to over 10,000 unique phosphorylation sites from complex cell lysates. Here we describe a step-by-step method for phosphoproteomic analysis that has achieved widespread success for identification of serine, threonine, and tyrosine phosphorylation. Reproducible quantification of relative phosphopeptide abundance is provided by intensity-based label-free quantitation. An ideal set of mass spectrometry analysis parameters is also provided that optimize the yield of identified sites. We also provide guidelines for the bioinformatic analysis of this type of data to assess the quality of the data and to comply with proteomic data reporting requirements.

  14. Noise Separation from the Weak Signal Chaotic Detection System

    Directory of Open Access Journals (Sweden)

    Hanjie Gu


    Full Text Available The traditional weak signal chaotic detection system still restricts some technical issues in the situation of the signal with noise, such as poor denoising ability and low detection precision. In this paper, we propose a novel weak signal chaotic detection system based on an improved wavelet transform algorithm. First, the traditional wavelet transform algorithm domain variables have been transformed and discretized to eliminate the redundant transform. Then, based on the discrete optimization, the wavelet coefficients have been optimized by threshold compromise strategy. The improved wavelet transform algorithm is applied in the weak signal chaotic detection system. The noise signal after finite discrete processing is treated as a perturbation of cycle power and put into a chaotic system for detecting weak signal under the noise conditions. The simulation experiments show that the proposed improved wavelet transform algorithm has a better denoising effect than the traditional wavelet transform algorithm. Moreover, the improved algorithm shows better accuracy and higher robustness in the weak signal chaotic detection system.

  15. Differential T cell receptor-mediated signaling in naive and memory CD4 T cells. (United States)

    Farber, D L; Acuto, O; Bottomly, K


    Naive and memory CD4 T cells differ in cell surface phenotype, function, activation requirements, and modes of regulation. To investigate the molecular bases for the dichotomies between naive and memory CD4 T cells and to understand how the T cell receptor (TCR) directs diverse functional outcomes, we investigated proximal signaling events triggered through the TCR/CD3 complex in naive and memory CD4 T cell subsets isolated on the basis of CD45 isoform expression. Naive CD4 T cells signal through TCR/CD3 similar to unseparated CD4 T cells, producing multiple tyrosine-phosphorylated protein species overall and phosphorylating the T cell-specific ZAP-70 tyrosine kinase which is recruited to the CD3zeta subunit of the TCR. Memory CD4 T cells, however, exhibit a unique pattern of signaling through TCR/CD3. Following stimulation through TCR/CD3, memory CD4 T cells produce fewer species of tyrosine-phosphorylated substrates and fail to phosphorylate ZAP-70, yet unphosphorylated ZAP-70 can associate with the TCR/CD3 complex. Moreover, a 26/28-kDa phosphorylated doublet is associated with CD3zeta in resting and activated memory but not in naive CD4 T cells. Despite these differences in the phosphorylation of ZAP-70 and CD3-associated proteins, the ZAP-70-related kinase, p72syk, exhibits similar phosphorylation in naive and memory T cell subsets, suggesting that this kinase could function in place of ZAP-70 in memory CD4 T cells. These results indicate that proximal signals are differentially coupled to the TCR in naive versus memory CD4 T cells, potentially leading to distinct downstream signaling events and ultimately to the diverse functions elicited by these two CD4 T cell subsets.

  16. Fuel cell system with interconnect

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Zhien; Goettler, Richard


    The present invention includes an integrated planar, series connected fuel cell system having electrochemical cells electrically connected via interconnects, wherein the anodes of the electrochemical cells are protected against Ni loss and migration via an engineered porous anode barrier layer.

  17. A Radio Communication System for Neuronal Signals

    Institute of Scientific and Technical Information of China (English)

    Wang Min; Yang Maoquan; Wang Xiaojun; Guang Kui; Zhang Xiao


    To collect neuronal activity data from awake, freely behaving animals, we developed miniature telemetry recording system. The integrated system consists of four major components: l) Microelectrodes and micro-driver assembly, 2) analog front end (AFE), 3) programmable system on chip (PSoC), and 4) ra- dio transceiver and the LabVIEW were used as a platform for the graphic user interface. The result showed the system was able to record and analyze neuronal recordings in freely moving animals and lasted continuously for a time period of a week or more. This is very useful for the study of the interdisciplinary research of neu- roscience and information engineering techniques. The circuits and architecture of the devices can be adapted for neurobiology and research with other small animals.

  18. Novel Small Molecule Inhibitors of Cancer Stem Cell Signaling Pathways. (United States)

    Abetov, Danysh; Mustapova, Zhanar; Saliev, Timur; Bulanin, Denis; Batyrbekov, Kanat; Gilman, Charles P


    The main aim of oncologists worldwide is to understand and then intervene in the primary tumor initiation and propagation mechanisms. This is essential to allow targeted elimination of cancer cells without altering normal mitotic cells. Currently, there are two main rival theories describing the process of tumorigenesis. According to the Stochastic Model, potentially any cell, once defunct, is capable of initiating carcinogenesis. Alternatively the Cancer Stem Cell (CSC) Model posits that only a small fraction of undifferentiated tumor cells are capable of triggering carcinogenesis. Like healthy stem cells, CSCs are also characterized by a capacity for self-renewal and the ability to generate differentiated progeny, possibly mediating treatment resistance, thus leading to tumor recurrence and metastasis. Moreover, molecular signaling profiles are similar between CSCs and normal stem cells, including Wnt, Notch and Hedgehog pathways. Therefore, development of novel chemotherapeutic agents and proteins (e.g., enzymes and antibodies) specifically targeting CSCs are attractive pharmaceutical candidates. This article describes small molecule inhibitors of stem cell pathways Wnt, Notch and Hedgehog, and their recent chemotherapy clinical trials.

  19. Modelling of Signal - Level Crossing System

    Directory of Open Access Journals (Sweden)

    Daniel Novak


    Full Text Available The author presents an object-oriented model of a railway level-crossing system created for the purpose of functional requirements specification. Unified Modelling Language (UML, version 1.4, which enables specification, visualisation, construction and documentation of software system artefacts, was used. The main attention was paid to analysis and design phases. The former phase resulted in creation of use case diagrams and sequential diagrams, the latter in creation of class/object diagrams and statechart diagrams.

  20. A diterpenoid derivative 15-oxospiramilactone inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Wei Wang; Haiyang Liu; Sheng Wang; Xiaojiang Hao; Lin Li


    The Wnt/β-catenin signaling pathway is a highly conserved pathway in organism evolution and regulates many biological processes. Aberrant activation of the Wnt/β-catenin signaling pathway is closely related to tumorigenesis.In order to identify potent small molecules to treat the over-activated Wnt signaling-mediated cancer, such as colon cancer, we established a mammalian cell line-based reporter gene screening system. The screen revealed a diterpenoid derivative, 15-oxospiramilactone(NC043)that inhibits Wnt3a or LiCl-stimulated Top-flash reporter activity in HEK293T cells and growth of colon cancer cells, SW480 and Caco-2. Treatment of SW480 cells with NC043 led to decreases in the mRNA and/or protein expression of Wnt target genes Axin2, Cyclin Dl and Survivin, as well as decreases in the protein levels of Cdc25c and Cdc2.NC043 did not affect the cytosol-nuclear distribution and protein level of soluble β-catenin, but decreased β-catenin/TCF4 association in SW480 cells. Moreover, NC043 inhibited anchorage-independent growth and xenograft tumorigenesis of SW480 cells. Collectively these results demonstrate that NC043 is a novel small molecule that inhibits canonical Wnt signaling downstream of P-catenin stability and may be a potential compound for treating colorectal cancer.

  1. Sonic hedgehog signaling coordinates the proliferation and differentiation of neural stem/progenitor cells by regulating cell cycle kinetics during development of the neocortex. (United States)

    Komada, Munekazu


    Sonic hedgehog (Shh) acts as a morphogen in normal development of various vertebrate tissues and organs. Shh signaling is essential for patterning and cell-fate specification, particularly in the central nervous system. Shh signaling plays different roles depending on its concentration, area, and timing of exposure. During the development of the neocortex, a low level of Shh is expressed in the neural stem/progenitor cells as well as in mature neurons in the dorsal telencephalon. Shh signaling in neocortex development has been shown to regulate cell cycle kinetics of radial glial cells and intermediate progenitor cells, thereby maintaining the proliferation, survival and differentiation of neurons in the neocortex. During the development of the telencephalon, endogenous Shh signaling is involved in the transition of slow-cycling neural stem cells to fast-cycling neural progenitor cells. It seems that high-level Shh signaling in the ventral telencephalon is essential for ventral specification, while low-level Shh signaling in the dorsal telencephalon plays important roles in the fine-tuning of cell cycle kinetics. The Shh levels and multiple functions of Shh signaling are important for proper corticogenesis in the developing brain. The present paper discusses the roles of Shh signaling in the proliferation and differentiation of neural stem/progenitor cells.

  2. An implantable CMOS signal conditioning system for recording nerve signals with cuff electrodes

    DEFF Research Database (Denmark)

    Papathanasiou, Konstantinos; Lehmann, Torsten


    We propose a system architecture for recording nerve signals with cuff electrodes and develop the key component in this system, the small-input, low-noise, low-power, high-gain amplifier. The amplifier is implemented using a mixture of weak- and strong-inversion transistors and a special off-set ......-set compensation technique; its performance is validated using Spice simulations....

  3. Non-Neuronal Cells in the Hypothalamic Adaptation to Metabolic Signals (United States)

    Freire-Regatillo, Alejandra; Argente-Arizón, Pilar; Argente, Jesús; García-Segura, Luis Miguel; Chowen, Julie A.


    Although the brain is composed of numerous cell types, neurons have received the vast majority of attention in the attempt to understand how this organ functions. Neurons are indeed fundamental but, in order for them to function correctly, they rely on the surrounding “non-neuronal” cells. These different cell types, which include glia, epithelial cells, pericytes, and endothelia, supply essential substances to neurons, in addition to protecting them from dangerous substances and situations. Moreover, it is now clear that non-neuronal cells can also actively participate in determining neuronal signaling outcomes. Due to the increasing problem of obesity in industrialized countries, investigation of the central control of energy balance has greatly increased in attempts to identify new therapeutic targets. This has led to interesting advances in our understanding of how appetite and systemic metabolism are modulated by non-neuronal cells. For example, not only are nutrients and hormones transported into the brain by non-neuronal cells, but these cells can also metabolize these metabolic factors, thus modifying the signals reaching the neurons. The hypothalamus is the main integrating center of incoming metabolic and hormonal signals and interprets this information in order to control appetite and systemic metabolism. Hence, the factors transported and released from surrounding non-neuronal cells will undoubtedly influence metabolic homeostasis. This review focuses on what is known to date regarding the involvement of different cell types in the transport and metabolism of nutrients and hormones in the hypothalamus. The possible involvement of non-neuronal cells, in particular glial cells, in physiopathological outcomes of poor dietary habits and excess weight gain are also discussed. PMID:28377744

  4. Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells. (United States)

    Rodríguez-Hernández, A; Navarro-Villarán, E; González, R; Pereira, S; Soriano-De Castro, L B; Sarrias-Giménez, A; Barrera-Pulido, L; Álamo-Martínez, J M; Serrablo-Requejo, A; Blanco-Fernández, G; Nogales-Muñoz, A; Gila-Bohórquez, A; Pacheco, D; Torres-Nieto, M A; Serrano-Díaz-Canedo, J; Suárez-Artacho, G; Bernal-Bellido, C; Marín-Gómez, L M; Barcena, J A; Gómez-Bravo, M A; Padilla, C A; Padillo, F J; Muntané, J


    Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.

  5. Slit/Robo1 signaling regulates neural tube development by balancing neuroepithelial cell proliferation and differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Guang; Li, Yan; Wang, Xiao-yu [Key Laboratory for Regenerative Medicine of The Ministry of Education, Department of Histology and Embryology, School of Medicine, Jinan University, Guangzhou 510632 (China); Han, Zhe [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Chuai, Manli [College of Life Sciences Biocentre, University of Dundee, Dundee DD1 5EH (United Kingdom); Wang, Li-jing [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Ho Lee, Kenneth Ka [Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin (Hong Kong); Geng, Jian-guo, E-mail: [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109 (United States); Yang, Xuesong, E-mail: [Key Laboratory for Regenerative Medicine of The Ministry of Education, Department of Histology and Embryology, School of Medicine, Jinan University, Guangzhou 510632 (China)


    Formation of the neural tube is the morphological hallmark for development of the embryonic central nervous system (CNS). Therefore, neural tube development is a crucial step in the neurulation process. Slit/Robo signaling was initially identified as a chemo-repellent that regulated axon growth cone elongation, but its role in controlling neural tube development is currently unknown. To address this issue, we investigated Slit/Robo1 signaling in the development of chick neCollege of Life Sciences Biocentre, University of Dundee, Dundee DD1 5EH, UKural tube and transgenic mice over-expressing Slit2. We disrupted Slit/Robo1 signaling by injecting R5 monoclonal antibodies into HH10 neural tubes to block the Robo1 receptor. This inhibited the normal development of the ventral body curvature and caused the spinal cord to curl up into a S-shape. Next, Slit/Robo1 signaling on one half-side of the chick embryo neural tube was disturbed by electroporation in ovo. We found that the morphology of the neural tube was dramatically abnormal after we interfered with Slit/Robo1 signaling. Furthermore, we established that silencing Robo1 inhibited cell proliferation while over-expressing Robo1 enhanced cell proliferation. We also investigated the effects of altering Slit/Robo1 expression on Sonic Hedgehog (Shh) and Pax7 expression in the developing neural tube. We demonstrated that over-expressing Robo1 down-regulated Shh expression in the ventral neural tube and resulted in the production of fewer HNK-1{sup +} migrating neural crest cells (NCCs). In addition, Robo1 over-expression enhanced Pax7 expression in the dorsal neural tube and increased the number of Slug{sup +} pre-migratory NCCs. Conversely, silencing Robo1 expression resulted in an enhanced Shh expression and more HNK-1{sup +} migrating NCCs but reduced Pax7 expression and fewer Slug{sup +} pre-migratory NCCs were observed. In conclusion, we propose that Slit/Robo1 signaling is involved in regulating neural tube


    Institute of Scientific and Technical Information of China (English)

    Ying ZHOU; Yuqiang WU


    The paper addresses the global output tracking of a class of multi-input multi-output(MIMO) nonlinear systems affected by disturbances, which are generated by a known exosystem. An adaptive controller is designed based on the proposed observer and the backstepping approach to asymptotically track arbitrary reference signal and to guarantee the boundedness of all the signals in the closed loop system. Finally, the numerical simulation results illustrate the effectiveness of the proposed scheme.

  7. 4th International Conference on Communications, Signal Processing, and Systems

    CERN Document Server

    Mu, Jiasong; Wang, Wei; Zhang, Baoju


    This book brings together papers presented at the 4th International Conference on Communications, Signal Processing, and Systems, which provides a venue to disseminate the latest developments and to discuss the interactions and links between these multidisciplinary fields. Spanning topics ranging from Communications, Signal Processing and Systems, this book is aimed at undergraduate and graduate students in Electrical Engineering, Computer Science and Mathematics, researchers and engineers from academia and industry as well as government employees (such as NSF, DOD, DOE, etc).

  8. Digital signal processing in power system protection and control

    CERN Document Server

    Rebizant, Waldemar; Wiszniewski, Andrzej


    Digital Signal Processing in Power System Protection and Control bridges the gap between the theory of protection and control and the practical applications of protection equipment. Understanding how protection functions is crucial not only for equipment developers and manufacturers, but also for their users who need to install, set and operate the protection devices in an appropriate manner. After introductory chapters related to protection technology and functions, Digital Signal Processing in Power System Protection and Control presents the digital algorithms for signal filtering, followed

  9. Wearable Systems for Service based on Physiological Signals. (United States)

    Ryoo, Dong-Wan; Kim, Young-Sung; Lee, Jeun-Woo


    Many researches for useful status information on humans have been done using the bio-signals. The bio-signal acquisition systems can be used to connect a user and a ubiquitous computing environment. The ubiquitous computing environment has to give various services anywhere, anytime. Consequently, ubiquitous computing requires new technology, such as a new user interface, dynamic service mechanism based on context and mobility support, which is different from technology used in desktop environment. To do this, we developed a wearable system, which can sense physiological data, determine emotional status and execute service based on the emotion. In this paper, we described wearable systems for personalized service based on physiological signals. The wearable system is composed of three subsystems, the physiological data sensing subsystem, the human status awareness subsystem and the service management subsystem. The physiological data sensing subsystem senses PPG, GSR and SKT signals from the data glove and sends the data to a wearable system using Bluetooth. The human status awareness subsystem in the wearable system receives the data from bio-sensors and determines emotional status using nonlinear mapping and rule-base. After determining emotion, the service management subsystem activates proper service automatically, and the service management subsystem can provide personalized service for users based on acquired bio-signals. Also, we presented various feature extraction using bio-signals such as PPG, GSR, SKT considering mobility, and emotion recognition of human status for the ubiquitous computing service.

  10. Chloroquine inhibits human CD4+ T-cell activation by AP-1 signaling modulation (United States)

    Schmidt, Ralf L. J.; Jutz, Sabrina; Goldhahn, Katrin; Witzeneder, Nadine; Gerner, Marlene C.; Trapin, Doris; Greiner, Georg; Hoermann, Gregor; Steiner, Guenter; Pickl, Winfried F.; Burgmann, Heinz; Steinberger, Peter; Ratzinger, Franz; Schmetterer, Klaus G.


    Chloroquine (CQ) is widely used as an anti-inflammatory therapeutic for rheumatic diseases. Although its modes of action on the innate immune system are well described, there is still insufficient knowledge about its direct effects on the adaptive immune system. Thus, we evaluated the influence of CQ on activation parameters of human CD4+ T-cells. CQ directly suppressed proliferation, metabolic activity and cytokine secretion of T-cells following anti-CD3/anti-CD28 activation. In contrast, CQ showed no effect on up-regulation of T-cell activation markers. CQ inhibited activation of all T helper cell subsets, although IL-4 and IL-13 secretion by Th2 cells were less influenced compared to other Th-specific cytokines. Up to 10 μM, CQ did not reduce cell viability, suggesting specific suppressive effects on T-cells. These properties of CQ were fully reversible in re-stimulation experiments. Analyses of intracellular signaling showed that CQ specifically inhibited autophagic flux and additionally activation of AP-1 by reducing phosphorylation of c-JUN. This effect was mediated by inhibition of JNK catalytic activity. In summary, we characterized selective and reversible immunomodulatory effects of CQ on human CD4+ T-cells. These findings provide new insights into the biological actions of JNK/AP-1 signaling in T-cells and may help to expand the therapeutic spectrum of CQ. PMID:28169350

  11. Ca²⁺ signaling and regulation of fluid secretion in salivary gland acinar cells. (United States)

    Ambudkar, Indu S


    Neurotransmitter stimulation of plasma membrane receptors stimulates salivary gland fluid secretion via a complex process that is determined by coordinated temporal and spatial regulation of several Ca(2+) signaling processes as well as ion flux systems. Studies over the past four decades have demonstrated that Ca(2+) is a critical factor in the control of salivary gland function. Importantly, critical components of this process have now been identified, including plasma membrane receptors, calcium channels, and regulatory proteins. The key event in activation of fluid secretion is an increase in intracellular [Ca(2+)] ([Ca(2+)]i) triggered by IP3-induced release of Ca(2+) from ER via the IP3R. This increase regulates the ion fluxes required to drive vectorial fluid secretion. IP3Rs determine the site of initiation and the pattern of [Ca(2+)]i signal in the cell. However, Ca(2+) entry into the cell is required to sustain the elevation of [Ca(2+)]i and fluid secretion. This Ca(2+) influx pathway, store-operated calcium influx pathway (SOCE), has been studied in great detail and the regulatory mechanisms as well as key molecular components have now been identified. Orai1, TRPC1, and STIM1 are critical components of SOCE and among these, Ca(2+) entry via TRPC1 is a major determinant of fluid secretion. The receptor-evoked Ca(2+) signal in salivary gland acinar cells is unique in that it starts at the apical pole and then rapidly increases across the cell. The basis for the polarized Ca(2+) signal can be ascribed to the polarized arrangement of the Ca(2+) channels, transporters, and signaling proteins. Distinct localization of these proteins in the cell suggests compartmentalization of Ca(2+) signals during regulation of fluid secretion. This chapter will discuss new concepts and findings regarding the polarization and control of Ca(2+) signals in the regulation of fluid secretion.

  12. Emergency vehicle traffic signal preemption system (United States)

    Bachelder, Aaron D. (Inventor); Foster, Conrad F. (Inventor)


    An emergency vehicle traffic light preemption system for preemption of traffic lights at an intersection to allow safe passage of emergency vehicles. The system includes a real-time status monitor of an intersection which is relayed to a control module for transmission to emergency vehicles as well as to a central dispatch office. The system also provides for audio warnings at an intersection to protect pedestrians who may not be in a position to see visual warnings or for various reasons cannot hear the approach of emergency vehicles. A transponder mounted on an emergency vehicle provides autonomous control so the vehicle operator can attend to getting to an emergency and not be concerned with the operation of the system. Activation of a priority-code (i.e. Code-3) situation provides communications with each intersection being approached by an emergency vehicle and indicates whether the intersection is preempted or if there is any conflict with other approaching emergency vehicles. On-board diagnostics handle various information including heading, speed, and acceleration sent to a control module which is transmitted to an intersection and which also simultaneously receives information regarding the status of an intersection. Real-time communications and operations software allow central and remote monitoring, logging, and command of intersections and vehicles.

  13. Microglia antioxidant systems and redox signaling

    DEFF Research Database (Denmark)

    Vilhardt, F; Haslund-Vinding, J; Jaquet, V;


    't stand alone however, and are not always pernicious. We discuss in general terms, and where available in microglia, GSH synthesis and relation to cystine import and glutamate export, and the thioredoxin system as the most important antioxidative defense mechanism, and further, we discuss in the context...

  14. Intraspecific evolution of the intercellular signaling network underlying a robust developmental system. (United States)

    Milloz, Josselin; Duveau, Fabien; Nuez, Isabelle; Félix, Marie-Anne


    Many biological systems produce an invariant output when faced with stochastic or environmental variation. This robustness of system output to variation affecting the underlying process may allow for "cryptic" genetic evolution within the system without change in output. We studied variation of cell fate patterning of Caenorhabditis elegans vulva precursors, a developmental system that relies on a simple intercellular signaling network and yields an invariant output of cell fates and lineages among C. elegans wild isolates. We first investigated the system's genetic variation in C. elegans by means of genetic tools and cell ablation to break down its buffering mechanisms. We uncovered distinct architectures of quantitative variation along the Ras signaling cascade, including compensatory variation, and differences in cell sensitivity to induction along the anteroposterior axis. In the unperturbed system, we further found variation between isolates in spatio-temporal dynamics of Ras pathway activity, which can explain the phenotypic differences revealed upon perturbation. Finally, the variation mostly affects the signaling pathways in a tissue-specific manner. We thus demonstrate and characterize microevolution of a developmental signaling network. In addition, our results suggest that the vulva genetic screens would have yielded a different mutation spectrum, especially for Wnt pathway mutations, had they been performed in another C. elegans genetic background.

  15. Sensors and signal transduction pathways in vertebrate cell volume regulation

    DEFF Research Database (Denmark)

    Hoffmann, Else K; Pedersen, Stine F


    will be discussed. In contrast to the simple pathway of osmosensing in yeast, cells from vertebrate organisms appear to exhibit multiple volume sensing systems, the specific mechanism(s) activated being cell type- and stimulus-dependent. Candidate sensors include integrins and growth factor receptors, while other...

  16. On eukaryotic intelligence: signaling system's guidance in the evolution of multicellular organization. (United States)

    Marijuán, Pedro C; del Moral, Raquel; Navarro, Jorge


    Communication with the environment is an essential characteristic of the living cell, even more when considering the origins and evolution of multicellularity. A number of changes and tinkering inventions were necessary in the evolutionary transition between prokaryotic and eukaryotic cells, which finally made possible the appearance of genuine multicellular organisms. In the study of this process, however, the transformations experimented by signaling systems themselves have been rarely object of analysis, obscured by other more conspicuous biological traits: incorporation of mitochondria, segregated nucleus, introns/exons, flagellum, membrane systems, etc. Herein a discussion of the main avenues of change from prokaryotic to eukaryotic signaling systems and a review of the signaling resources and strategies underlying multicellularity will be attempted. In the expansion of prokaryotic signaling systems, four main systemic resources were incorporated: molecular tools for detection of solutes, molecular tools for detection of solvent (Donnan effect), the apparatuses of cell-cycle control, and the combined system endocytosis/cytoskeleton. The multiple kinds of enlarged, mixed pathways that emerged made possible the eukaryotic revolution in morphological and physiological complexity. The massive incorporation of processing resources of electro-molecular nature, derived from the osmotic tools counteracting the Donnan effect, made also possible the organization of a computational tissue with huge information processing capabilities: the nervous system. In the central nervous systems of vertebrates, and particularly in humans, neurons have achieved both the highest level of molecular-signaling complexity and the highest degree of information-processing adaptability. Theoretically, it can be argued that there has been an accelerated pace of evolutionary change in eukaryotic signaling systems, beyond the other general novelties introduced by eukaryotic cells in their

  17. Using Heterologous COS-7 Cells to Identify Semaphorin-Signaling Components. (United States)

    Sakurai, Atsuko; Doçi, Colleen L; Gutkind, J Silvio


    Semaphorins are a family of membrane-bound and secreted type of proteins which were initially identified as chemorepulsive axon guidance molecules. Plexins and neuropilins are two major receptor families of semaphorins, and their common downstream targets are the actin cytoskeleton and cell-to-extracellular matrix adhesions. Semaphorins promote the collapse of growth cones by inducing rapid changes in the cytoskeleton and disassembly of focal adhesion structures. When transfected with appropriate receptors, non-neuronal COS-7 cells exhibit a similar cell collapse phenotype upon semaphorin stimulation. This heterologous system using COS-7 cells has been developed and widely used to investigate semaphorin-signaling pathways. In this chapter, we describe a COS-7 collapse assay protocol used to identify semaphorin-signaling components and a method to produce recombinant class 3 semaphorin proteins.

  18. Massive MIMO Systems: Signal Processing Challenges and Research Trends


    de Lamare, R.C.


    This article presents a tutorial on multiuser multiple-antenna wireless systems with a very large number of antennas, known as massive multi-input multi-output (MIMO) systems. Signal processing challenges and future trends in the area of massive MIMO systems are presented and key application scenarios are detailed. A linear algebra approach is considered for the description of the system and data models of massive MIMO architectures. The operational requirements of massive MIMO systems are di...

  19. Arsenic inhibits hedgehog signaling during P19 cell differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jui Tung [Environmental Toxicology Program, Clemson University, 132 Long Hall, Clemson, SC 29634 (United States); Bain, Lisa J., E-mail: [Environmental Toxicology Program, Clemson University, 132 Long Hall, Clemson, SC 29634 (United States); Department of Biological Sciences, Clemson University, 132 Long Hall, Clemson, SC 29634 (United States)


    Arsenic is a toxicant found in ground water around the world, and human exposure mainly comes from drinking water or from crops grown in areas containing arsenic in soils or water. Epidemiological studies have shown that arsenic exposure during development decreased intellectual function, reduced birth weight, and altered locomotor activity, while in vitro studies have shown that arsenite decreased muscle and neuronal cell differentiation. The sonic hedgehog (Shh) signaling pathway plays an important role during the differentiation of both neurons and skeletal muscle. The purpose of this study was to investigate whether arsenic can disrupt Shh signaling in P19 mouse embryonic stem cells, leading to changes muscle and neuronal cell differentiation. P19 embryonic stem cells were exposed to 0, 0.25, or 0.5 μM of sodium arsenite for up to 9 days during cell differentiation. We found that arsenite exposure significantly reduced transcript levels of genes in the Shh pathway in both a time and dose-dependent manner. This included the Shh ligand, which was decreased 2- to 3-fold, the Gli2 transcription factor, which was decreased 2- to 3-fold, and its downstream target gene Ascl1, which was decreased 5-fold. GLI2 protein levels and transcriptional activity were also reduced. However, arsenic did not alter GLI2 primary cilium accumulation or nuclear translocation. Moreover, additional extracellular SHH rescued the inhibitory effects of arsenic on cellular differentiation due to an increase in GLI binding activity. Taken together, we conclude that arsenic exposure affected Shh signaling, ultimately decreasing the expression of the Gli2 transcription factor. These results suggest a mechanism by which arsenic disrupts cell differentiation. - Highlights: • Arsenic exposure decreases sonic hedgehog pathway-related gene expression. • Arsenic decreases GLI2 protein levels and transcriptional activity in P19 cells. • Arsenic exposure does not alter the levels of SHH

  20. Interleukin 4: signalling mechanisms and control of T cell differentiation. (United States)

    Paul, W E


    Interleukin 4 (IL-4) is a pleiotropic type I cytokine that controls both growth and differentiation among haemopoietic and non-haemopoietic cells. Its receptor is a heterodimer. One chain, the IL-4R alpha chain, binds IL-4 with high affinity and determines the nature of the biochemical signals that are induced. The second chain, gamma c, is required for the induction of such signals. IL-4-mediated growth depends upon activation events that involve phosphorylation of Y497 of IL-4R alpha, leading to the binding and phosphorylation of 4PS/IRS-2 in haemopoietic cells and of IRS-1 in non-haemopoietic cells. By contrast, IL-4-mediated differentiation events depend upon more distal regions of the IL-4R alpha chain that include a series of STAT-6 binding sites. The distinctive roles of these receptor domains was verified by receptor-reconstruction experiments. The 'growth' and 'differentiation' domains of the IL-4R alpha chain, independently expressed as chimeric structures with a truncated version of the IL-2R beta chain, were shown to convey their functions to the hybrid receptor. The critical role of STAT-6 in IL-4-mediated gene activation and differentiation was made clear by the finding that lymphocytes from STAT-6 knockout mice are strikingly deficient in these functions but have retained the capacity to grow, at least partially, in response to IL-4. IL-4 plays a central role in determining the phenotype of naive CD4+ T cells. In the presence of IL-4, newly primed naive T cells develop into IL-4 producers while in its absence they preferentially become gamma-interferon (IFN-gamma) producers. Recently, a specialized subpopulation of T cells, CD4+/NK1.1+ cells, has been shown to produce large amounts of IL-4 upon stimulation. Two examples of mice with deficiencies in these cells are described--beta 2-microglobulin knockout mice and SJL mice. Both show defects in the development of IL-4-producing cells and in the increase in serum IgE in response to stimulation with the

  1. Roles of 1,25(OH2D3 and Vitamin D Receptor in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus by Regulating the Activation of CD4+ T Cells and the PKCδ/ERK Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Xiao-Jie He


    Full Text Available Background/Aims: The study aims to elucidate the roles of 1,25(OH2D3 and vitamin D receptor (VDR in the pathogenesis of rheumatoid arthritis (RA and systemic lupus erythematosus (SLE by regulating the activation of CD4+ T cells and the PKCδ/ERK signaling pathway. Methods: From January 2013 to December 2015, a total of 130 SLE patients, 137 RA patients and 130 healthy controls were selected in this study. Serum levels of 1,25(OH2D3 and VDR mRNA expression were detected by ELISA and real-time fluorescence quantitative PCR (RT-qPCR. Density gradient centrifugation was performed to separate peripheral blood mononuclear cells (PBMCs. CD4+ T cells were separated using magnetic activated cell sorting (MACS. CD4+T cells in logarithmic growth phase were collected and assigned into 9 groups: the normal control group, the normal negative control (NC group, the VDR siRNA group, the RA control group, the RA NC group, the VDR over-expressed RA group, the SLE control group, the SLE NC group, and the VDR over-expressed SLE group. The mRNA and protein expressions of VDR, PKCδ, ERK1/2, CD11a, CD70 and CD40L were detected by RT-qPCR and Western blotting. Bisulfite genomic sequencing was conducted to monitor the methylation status of CD11a, CD70 and CD40L. Results: Compared with healthy controls, serum 1,25(OH2D3 level and VDR mRNA expression in peripheral blood were decreased in SLE patients and RA patients. With the increase of concentrations of 1,25(OH2D3 treatment, the VDR mRNA expression and DNA methylation levels of CD11a, CD70 and CD40L were declined, while the expressions of PKCδ, ERK1/2, CD11a, CD70 and CD40L were elevated in SLE, RA and normal CD4+T cells. Compared with the SLE contro, RA control, SLE NC and RA NC groups, the expressions of PKCδ, ERK1/2, CD11a, CD70 and CD40L decreased but DNA methylation levels of CD11a, CD70 and CD40L increased in the VDR over-expressed SLE group and VDR over-expressed RA group. However, compared with the normal

  2. Distinct roles of Shh and Fgf signaling in regulating cell proliferation during zebrafish pectoral fin development

    Directory of Open Access Journals (Sweden)

    Neumann Carl J


    Full Text Available Abstract Background Cell proliferation in multicellular organisms must be coordinated with pattern formation. The major signaling pathways directing pattern formation in the vertebrate limb are well characterized, and we have therefore chosen this organ to examine the interaction between proliferation and patterning. Two important signals for limb development are members of the Hedgehog (Hh and Fibroblast Growth Factor (Fgf families of secreted signaling proteins. Sonic hedgehog (Shh directs pattern formation along the anterior/posterior axis of the limb, whereas several Fgfs in combination direct pattern formation along the proximal/distal axis of the limb. Results We used the genetic and pharmacological amenability of the zebrafish model system to dissect the relative importance of Shh and Fgf signaling in regulating proliferation during development of the pectoral fin buds. In zebrafish mutants disrupting the shh gene, proliferation in the pectoral fin buds is initially normal, but later is strongly reduced. Correlating with this reduction, Fgf signaling is normal at early stages, but is later lost in shh mutants. Furthermore, pharmacological inhibition of Hh signaling for short periods has little effect on either Fgf signaling, or on expression of G1- and S-phase cell-cycle genes, whereas long periods of inhibition lead to the downregulation of both. In contrast, even short periods of pharmacological inhibition of Fgf signaling lead to strong disruption of proliferation in the fin buds, without affecting Shh signaling. To directly test the ability of Fgf signaling to regulate proliferation in the absence of Shh signaling, we implanted beads soaked with Fgf protein into shh mutant fin buds. We find that Fgf-soaked beads rescue proliferation in the pectoral find buds of shh mutants, indicating that Fgf signaling is sufficient to direct proliferation in zebrafish fin buds in the absence of Shh. Conclusion Previous studies have shown that both

  3. An adaptive signal compression system with pre-specified reconstruction quality and compression rate. (United States)

    Tümer, M Borahan; Demir, Mert C


    Two essential properties of a signal compression method are the compression rate and the distance between the original signal and the reconstruction from the compressed signal. These two properties are used to assess the performance and quality of the method. In a recent work [B. Tümer, B. Demiröz, Lecture Notes in Computer Science-Computer and Information Sciences, volume 2869, chapter Signal Compression Using Growing Cell Structures: A Transformational Approach, Springer Verlag, 2003, pp. 952-959], an adaptive signal compression system (ACS) is presented which defines the performance of the system as a function of the system complexity, system sensitivity and data size. For a compression method, it is desirable to formulate the performance of the system as a function of the system complexity and sensitivity to optimize the performance of the system. It would be further desirable to express the reconstruction quality in terms of the same system parameters so as to know up front what compression rate to end up with for a specific reconstruction quality. In this work, we modify ACS such that the modified ACS (MACS) estimates the reconstruction quality for a given system complexity and sensitivity. Once this relation is identified it is possible to optimize either compression rate or reconstruction quality with respect to system sensitivity and system complexity while limiting the other one.

  4. Tissue-Specific Gain of RTK Signalling Uncovers Selective Cell Vulnerability during Embryogenesis.

    Directory of Open Access Journals (Sweden)

    Yannan Fan

    Full Text Available The successive events that cells experience throughout development shape their intrinsic capacity to respond and integrate RTK inputs. Cellular responses to RTKs rely on different mechanisms of regulation that establish proper levels of RTK activation, define duration of RTK action, and exert quantitative/qualitative signalling outcomes. The extent to which cells are competent to deal with fluctuations in RTK signalling is incompletely understood. Here, we employ a genetic system to enhance RTK signalling in a tissue-specific manner. The chosen RTK is the hepatocyte growth factor (HGF receptor Met, an appropriate model due to its pleiotropic requirement in distinct developmental events. Ubiquitously enhanced Met in Cre/loxP-based Rosa26(stopMet knock-in context (Del-R26(Met reveals that most tissues are capable of buffering enhanced Met-RTK signalling thus avoiding perturbation of developmental programs. Nevertheless, this ubiquitous increase of Met does compromise selected programs such as myoblast migration. Using cell-type specific Cre drivers, we genetically showed that altered myoblast migration results from ectopic Met expression in limb mesenchyme rather than in migrating myoblasts themselves. qRT-PCR analyses show that ectopic Met in limbs causes molecular changes such as downregulation in the expression levels of Notum and Syndecan4, two known regulators of morphogen gradients. Molecular and functional studies revealed that ectopic Met expression in limb mesenchyme does not alter HGF expression patterns and levels, but impairs HGF bioavailability. Together, our findings show that myoblasts, in which Met is endogenously expressed, are capable of buffering increased RTK levels, and identify mesenchymal cells as a cell type vulnerable to ectopic Met-RTK signalling. These results illustrate that embryonic cells are sensitive to alterations in the spatial distribution of RTK action, yet resilient to fluctuations in signalling levels of an

  5. Bactericidal Antibiotics Increase Hydroxyphenyl Fluorescein Signal by Altering Cell Morphology

    DEFF Research Database (Denmark)

    Paulander, Wilhelm; Wang, Ying; Folkesson, Sven Anders;


    It was recently proposed that for bactericidal antibiotics a common killing mechanism contributes to lethality involving indirect stimulation of hydroxyl radical (OH center dot) formation. Flow cytometric detection of OH center dot by hydroxyphenyl fluorescein (HPF) probe oxidation was used...... to support this hypothesis. Here we show that increased HPF signals in antibiotics-exposed bacterial cells are explained by fluorescence associated with increased cell size, and do not reflect reactive oxygen species (ROS) concentration. Independently of antibiotics, increased fluorescence was seen...... for elongated cells expressing the oxidative insensitive green fluorescent protein (GFP). Although our data question the role of ROS in lethality of antibiotics other research approaches point to important interplays between basic bacterial metabolism and antibiotic susceptibility. To underpin...

  6. Bactericidal antibiotics increase hydroxyphenyl fluorescein signal by altering cell morphology.

    Directory of Open Access Journals (Sweden)

    Wilhelm Paulander

    Full Text Available It was recently proposed that for bactericidal antibiotics a common killing mechanism contributes to lethality involving indirect stimulation of hydroxyl radical (OH• formation. Flow cytometric detection of OH• by hydroxyphenyl fluorescein (HPF probe oxidation was used to support this hypothesis. Here we show that increased HPF signals in antibiotics-exposed bacterial cells are explained by fluorescence associated with increased cell size, and do not reflect reactive oxygen species (ROS concentration. Independently of antibiotics, increased fluorescence was seen for elongated cells expressing the oxidative insensitive green fluorescent protein (GFP. Although our data question the role of ROS in lethality of antibiotics other research approaches point to important interplays between basic bacterial metabolism and antibiotic susceptibility. To underpin such relationships, methods for detecting bacterial metabolites at a cellular level are needed.

  7. Differential T Cell Cytokine Receptivity and Not Signal Quality Distinguishes IL-6 and IL-10 Signaling during Th17 Differentiation. (United States)

    Jones, Lindsay L; Alli, Rajshekhar; Li, Bofeng; Geiger, Terrence L


    How a large number of cytokines differentially signal through a small number of signal transduction pathways is not well resolved. This is particularly true for IL-6 and IL-10, which act primarily through STAT3 yet induce dissimilar transcriptional programs leading alternatively to pro- and anti-inflammatory effects. Kinetic differences in signaling, sustained to IL-10 and transient to IL-6, are critical to this in macrophages. T cells are also key targets of IL-6 and IL-10, yet how differential signaling in these cells leads to divergent cellular fates is unclear. We show that, unlike for macrophages, signal duration cannot explain the distinct effects of these cytokines in T cells. Rather, naive, activated, activated-rested, and memory CD4(+) T cells differentially express IL-6 and IL-10 receptors in an activation state-dependent manner, and this impacts downstream cytokine effects. We show a dominant role for STAT3 in IL-6-mediated Th17 subset maturation. IL-10 cannot support Th17 differentiation because of insufficient cytokine receptivity rather than signal quality. Enforced expression of IL-10Rα on naive T cells permits an IL-10-generated STAT3 signal equivalent to that of IL-6 and equally capable of promoting Th17 formation. Similarly, naive T cell IL-10Rα expression also allows IL-10 to mimic the effects of IL-6 on both Th1/Th2 skewing and Tfh cell differentiation. Our results demonstrate a key role for the regulation of receptor expression rather than signal quality or duration in differentiating the functional outcomes of IL-6 and IL-10 signaling, and identify distinct signaling properties of these cytokines in T cells compared with myeloid cells.

  8. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. (United States)

    Seda, Vaclav; Mraz, Marek


    The physiology of B cells is intimately connected with the function of their B-cell receptor (BCR). B-cell lymphomas frequently (dys)regulate BCR signalling and thus take advantage of this pre-existing pathway for B-cell proliferation and survival. This has recently been underscored by clinical trials demonstrating that small molecules (fosfamatinib, ibrutinib, idelalisib) inhibiting BCR-associated kinases (SYK, BTK, PI3K) have an encouraging clinical effect. Here we describe the current knowledge of the specific aspects of BCR signalling in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukaemia (CLL) and normal B cells. Multiple factors can contribute to BCR pathway (dys)regulation in these malignancies and the activation of 'chronic' or 'tonic' BCR signalling. In lymphoma B cells, the balance of initiation, amplitude and duration of BCR activation can be influenced by a specific immunoglobulin structure, the expression and mutations of adaptor molecules (like GAB1, BLNK, GRB2, CARD11), the activity of kinases (like LYN, SYK, PI3K) or phosphatases (like SHIP-1, SHP-1 and PTEN) and levels of microRNAs. We also discuss the crosstalk of BCR with other signalling pathways (NF-κB, adhesion through integrins, migration and chemokine signalling) to emphasise that the 'BCR inhibitors' target multiple pathways interconnected with BCR, which might explain some of their clinical activity.

  9. CellTracks cell analysis system for rare cell detection

    NARCIS (Netherlands)

    Kagan, Michael T.; Trainer, Michael N.; Bendele, Teresa; Rao, Chandra; Horton, Allen; Tibbe, Arjan G.; Greve, Jan; Terstappen, Leon W.M.M.


    The CellTracks system is a Compact Disk-based cell analyzer that, similar to flow cytometry, differentiates cells that are aligned while passing through focused laser beams. In CellTracks, only immuno-magnetically labeled cells are aligned and remain in position for further analysis. This feature is

  10. Mouse bone marrow stromal cells differentiate to neuron-like cells upon inhibition of BMP signaling. (United States)

    Saxena, Monika; Prashar, Paritosh; Yadav, Prem Swaroop; Sen, Jonaki


    Bone marrow stromal cells (BMSCs) are a source of autologous stem cells that have the potential for undergoing differentiation into multiple cell types including neurons. Although the neuronal differentiation of mesenchymal stem cells has been studied for a long time, the molecular players involved are still not defined. Here we report that the genetic deletion of two members of the bone morphogenetic protein (Bmp) family, Bmp2 and Bmp4 in mouse BMSCs causes their differentiation into cells with neuron-like morphology. Surprisingly these cells expressed certain markers characteristic of both neuronal and glial cells. Based on this observation, we inhibited BMP signaling in mouse BMSCs through a brief exposure to Noggin protein which also led to their differentiation into cells expressing both neuronal and glial markers. Such cells seem to have the potential for further differentiation into subtypes of neuronal and glial cells and thus could be utilized for cell-based therapeutic applications.

  11. Science Signaling Podcast for 3 May 2016: Innate lymphoid cell plasticity. (United States)

    Vivier, Eric; Golub, Rachel; VanHook, Annalisa M


    This Podcast features an interview with Rachel Golub and Eric Vivier, authors of two Research Articles that appear in the 3 May 2016 issue of Science Signaling, about plasticity of innate lymphoid cells (ILCs). ILCs are related to the T cells and B cells of the adaptive immune system, and they regulate immune responses by secreting cytokines. ILCs are a heterogeneous population of cells that can be classified into several subtypes. Type 3 ILCs (ILC3s) can be further subdivided into distinct subpopulations. Chea et al found that Notch signaling controlled the relative proportions of different ILC3 subtypes in the mouse intestine. A related study by Viant et al reports that the Notch and transforming growth factor-β (TGF-β) signaling pathways antagonize one another to control the balance between different subsets of ILC3s. Both studies demonstrate that ILC3 fate is plastic and can be influenced by signals present in the microenvironment of these tissue-resident cells.Listen to Podcast.

  12. Brassinosteroid signaling directs formative cell divisions and protophloem differentiation in Arabidopsis root meristems. (United States)

    Kang, Yeon Hee; Breda, Alice; Hardtke, Christian S


    Brassinosteroids (BRs) trigger an intracellular signaling cascade through its receptors BR INSENSITIVE 1 (BRI1), BRI1-LIKE 1 (BRL1) and BRL3. Recent studies suggest that BR-independent inputs related to vascular differentiation, for instance root protophloem development, modulate downstream BR signaling components. Here, we report that protophloem sieve element differentiation is indeed impaired in bri1 brl1 brl3 mutants, although this effect might not be mediated by canonical downstream BR signaling components. We also found that their small meristem size is entirely explained by reduced cell elongation, which is, however, accompanied by supernumerary formative cell divisions in the radial dimension. Thus, reduced cell expansion in conjunction with growth retardation, because of the need to accommodate supernumerary formative divisions, can account for the overall short root phenotype of BR signaling mutants. Tissue-specific re-addition of BRI1 activity partially rescued subsets of these defects through partly cell-autonomous, partly non-cell-autonomous effects. However, protophloem-specific BRI1 expression essentially rescued all major bri1 brl1 brl3 root meristem phenotypes. Our data suggest that BR perception in the protophloem is sufficient to systemically convey BR action in the root meristem context.

  13. Predicted molecular signaling guiding photoreceptor cell migration following transplantation into damaged retina (United States)

    Unachukwu, Uchenna John; Warren, Alice; Li, Ze; Mishra, Shawn; Zhou, Jing; Sauane, Moira; Lim, Hyungsik; Vazquez, Maribel; Redenti, Stephen


    To replace photoreceptors lost to disease or trauma and restore vision, laboratories around the world are investigating photoreceptor replacement strategies using subretinal transplantation of photoreceptor precursor cells (PPCs) and retinal progenitor cells (RPCs). Significant obstacles to advancement of photoreceptor cell-replacement include low migration rates of transplanted cells into host retina and an absence of data describing chemotactic signaling guiding migration of transplanted cells in the damaged retinal microenvironment. To elucidate chemotactic signaling guiding transplanted cell migration, bioinformatics modeling of PPC transplantation into light-damaged retina was performed. The bioinformatics modeling analyzed whole-genome expression data and matched PPC chemotactic cell-surface receptors to cognate ligands expressed in the light-damaged retinal microenvironment. A library of significantly predicted chemotactic ligand-receptor pairs, as well as downstream signaling networks was generated. PPC and RPC migration in microfluidic ligand gradients were analyzed using a highly predicted ligand-receptor pair, SDF-1α - CXCR4, and both PPCs and RPCs exhibited significant chemotaxis. This work present a systems level model and begins to elucidate molecular mechanisms involved in PPC and RPC migration within the damaged retinal microenvironment.

  14. Signalling pathways induced in cells exposed to medium from irradiated cells

    Energy Technology Data Exchange (ETDEWEB)

    Lyng, F.M.; Maguire, P. (Radiation and Environmental Science Centre, Focas Institute, Dublin Institute of Technology, Dublin (Ireland)); McClean, B.; Seymour, C.; Mothersill, C. (St Luke' s Hospital, Dublin (Ireland))


    In recent years, radiation induced bystander effects have been reported in cells which were not themselves irradiated but were either in the vicinity of irradiated cells or exposed to medium from irradiated cells. The effects have been clearly shown to occur both in vivo and in vitro. This work has led to a paradigm shift in radiobiology over the last 5 - 10 years. The target theory of radiation induced effects is now being challenged because of an increasing number of studies which demonstrate non(DNA)-targeted effects. These effects appear to be particularly important at low doses. Considerable evidence now exists relating to radiation-induced bystander effects but the mechanisms involved in the transduction of the signal are still unclear. Cell - cell communication through gap junctions and / or secretion of a cytotoxic factor into the medium are thought to be involved in the transduction of the bystander signal. Oxidative metabolism has been shown to be important in both mechanisms. Signalling pathways leading to apoptosis, such as calcium, MAP kinase, mitochondrial and reactive oxygen species (ROS) signalling are discussed. The importance of oxidative metabolism and calcium signalling in bystander responses are demonstrated. Further investigations of these signalling pathways may aid in the identification of novel therapeutic targets. (orig.)

  15. Mammary stem cells and breast cancer--role of Notch signalling. (United States)

    Farnie, Gillian; Clarke, Robert B


    Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair. Evidence shows that breast stem cells are multipotent and can self renew, which are key characteristics of stem cells, and a single cell enriched with cell surface markers has the ability to grow a fully functional mammary gland in vivo. Many groups have extrapolated the cancer stem cell hypothesis from the haematopoietic system to solid cancers, where using in vitro culture techniques and in vivo transplant models have established evidence of cancer stem cells in colon, pancreas, prostate, brain and breast cancers. In the report we describe the evidence for breast cancer stem cells; studies consistently show that stem cell like and breast cancer initiating populations can be enriched using cell surface makers CD44+/CD24- and have upregulated genes which include Notch. Notch signalling has been highlighted as a pathway involved in the development of the breast and is frequently dysregulated in invasive breast cancer. We have investigated the role of Notch in a pre-invasive breast lesion, ductal carcinoma in situ (DCIS), and have found that aberrant activation of Notch signalling is an early event in breast cancer. High expression of Notch 1 intracellular domain (NICD) in DCIS also predicted a reduced time to recurrence 5 years after surgery. Using a non-adherent sphere culture technique we have grown DCIS mammospheres from primary DCIS tissue, where self-renewal capacity, measured by the number of mammosphere initiating cells, were increased from normal breast tissue. A gamma-secretase inhibitor, DAPT, which inhibits all four Notch receptors and a Notch 4 neutralising antibody were shown to reduce DCIS mammosphere formation, indicating that Notch signalling and other stem cell self-renewal pathways may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.

  16. Responses of macrophages to the danger signals released from necrotic cells. (United States)

    Kimura, Toshifumi; Kobayashi, Shuhei; Hanihara-Tatsuzawa, Fumito; Sayama, Aoi; MaruYama, Takashi; Muta, Tatsushi


    The immune system maintains homeostasis by recognizing and responding to cell death caused by various stresses. The immune response is considered to be elicited by 'danger signals' released from necrotic cells. However, the identity of the danger signals remains elusive. In this study, we focused on the expression of chemokines by macrophages stimulated with necrotic cells. In mouse bone-marrow-derived macrophages, the chemokine monocyte chemoattractant protein (MCP)-3 was induced at both the mRNA and protein levels in response to heat-killed murine cells. The induction of MCP-3 was also observed in MyD88-deficient macrophages, indicating that Toll-like receptors and the IL-1 receptor are not involved in this response. Consistent with this observation, the activation of NF-κB was not detected in RAW264.7 macrophages stimulated with necrotic cells. Treatments with proteinase K, DNaseI or RNaseA did not affect the ' STIMULATING ACTIVITY': of necrotic cells. In contrast, treatment with apyrase, which removes phosphates from nucleoside tri- and di-phosphates, abolished the inducing activity. Purified UDP at 30 µM concentration elicited similar induction of MCP-3 in RAW264.7 macrophages. Small interfering RNA-mediated knock-down of the UDP receptor P2Y6 in RAW264.7 cells significantly reduced the induction of MCP-3 in response to necrotic cells, but not its induction by lipopolysaccharide. Furthermore, ectopic expression of the P2Y6 receptor in HEK293 cells conferred responsiveness to necrotic cells. These results suggest that UDP released by necrotic cells plays a critical role as an endogenous danger signal and that P2Y6 is required for the induction of MCP-3 in response to necrotic cells.

  17. Retinal bipolar cells: temporal filtering of signals from cone photoreceptors. (United States)

    Burkhardt, Dwight A; Fahey, Patrick K; Sikora, Michael A


    The temporal dynamics of the response of neurons in the outer retina were investigated by intracellular recording from cones, bipolar, and horizontal cells in the intact, light-adapted retina of the tiger salamander (Ambystoma tigrinum), with special emphasis on comparing the two major classes of bipolars cells, the ON depolarizing bipolars (Bd) and the OFF hyperpolarizing bipolars (Bh). Transfer functions were computed from impulse responses evoked by a brief light flash on a steady background of 20 cd/m(2). Phase delays ranged from about 89 ms for cones to 170 ms for Bd cells, yielding delays relative to that of cones of about 49 ms for Bh cells and 81 ms for Bd cells. The difference between Bd and Bh cells, which may be due to a delay introduced by the second messenger G-protein pathway unique to Bd cells, was further quantified by latency measurements and responses to white noise. The amplitude transfer functions of the outer retinal neurons varied with light adaptation in qualitative agreement with results for other vertebrates and human vision. The transfer functions at 20 cd/m(2) were predominantly low pass with 10-fold attenuation at about 13, 14, 9.1, and 7.7 Hz for cones, horizontal, Bh, and Bd cells, respectively. The transfer function from the cone voltage to the bipolar voltage response, as computed from the above measurements, was low pass and approximated by a cascade of three low pass RC filters ("leaky integrators"). These results for cone-->bipolar transmission are surprisingly similar to recent results for rod-->bipolar transmission in salamander slice preparations. These and other findings suggest that the rate of vesicle replenishment rather than the rate of release may be a common factor shaping synaptic signal transmission from rods and cones to bipolar cells.

  18. Sunitinib activates Axl signaling in renal cell cancer. (United States)

    van der Mijn, Johannes C; Broxterman, Henk J; Knol, Jaco C; Piersma, Sander R; De Haas, Richard R; Dekker, Henk; Pham, Thang V; Van Beusechem, Victor W; Halmos, Balazs; Mier, James W; Jiménez, Connie R; Verheul, Henk M W


    Mass spectrometry-based phosphoproteomics provides a unique unbiased approach to evaluate signaling network in cancer cells. The tyrosine kinase inhibitor sunitinib is registered as treatment for patients with renal cell cancer (RCC). We investigated the effect of sunitinib on tyrosine phosphorylation in RCC tumor cells to get more insight in its mechanism of action and thereby to find potential leads for combination treatment strategies. Sunitinib inhibitory concentrations of proliferation (IC50) of 786-O, 769-p and A498 RCC cells were determined by MTT-assays. Global tyrosine phosphorylation was measured by LC-MS/MS after immunoprecipitation with the antiphosphotyrosine antibody p-TYR-100. Phosphoproteomic profiling of 786-O cells yielded 1519 phosphopeptides, corresponding to 675 unique proteins including 57 different phosphorylated protein kinases. Compared to control, incubation with sunitinib at its IC50 of 2 µM resulted in downregulation of 86 phosphopeptides including CDK5, DYRK3, DYRK4, G6PD, PKM and LDH-A, while 94 phosphopeptides including Axl, FAK, EPHA2 and p38α were upregulated. Axl- (y702), FAK- (y576) and p38α (y182) upregulation was confirmed by Western Blot in 786-O and A498 cells. Subsequent proliferation assays revealed that inhibition of Axl with a small molecule inhibitor (R428) sensitized 786-O RCC cells and immortalized endothelial cells to sunitinib up to 3 fold. In conclusion, incubation with sunitinib of RCC cells causes significant upregulation of multiple phosphopeptides including Axl. Simultaneous inhibition of Axl improves the antitumor activity of sunitinib. We envision that evaluation of phosphoproteomic changes by TKI treatment enables identification of new targets for combination treatment strategies.

  19. Signal Processing in Large Systems: a New Paradigm

    CERN Document Server

    Couillet, Romain


    For a long time, signal processing applications, and most particularly detection and parameter estimation methods, have relied on the limiting behaviour of test statistics and estimators, as the number n of observations of a population grows large comparatively to the population size N, i.e. n>>N. Modern technological and societal advances now demand the study of sometimes extremely large populations, while simultaneously requiring fast signal processing due to accelerated system dynamics; this results in not-so-large practical ratios n/N, sometimes even smaller than one. A disruptive change in classical signal processing methods has therefore been initiated in the past ten years, mostly spurred by the field of large dimensional random matrix theory. The early literature in random matrix theory for signal processing applications is however scarce and highly technical. This tutorial proposes an accessible methodological introduction to the modern tools of random matrix theory and to the signal processing metho...

  20. Medical Signal-Conditioning and Data-Interface System (United States)

    Braun, Jeffrey; Jacobus, charles; Booth, Scott; Suarez, Michael; Smith, Derek; Hartnagle, Jeffrey; LePrell, Glenn


    A general-purpose portable, wearable electronic signal-conditioning and data-interface system is being developed for medical applications. The system can acquire multiple physiological signals (e.g., electrocardiographic, electroencephalographic, and electromyographic signals) from sensors on the wearer s body, digitize those signals that are received in analog form, preprocess the resulting data, and transmit the data to one or more remote location(s) via a radiocommunication link and/or the Internet. The system includes a computer running data-object-oriented software that can be programmed to configure the system to accept almost any analog or digital input signals from medical devices. The computing hardware and software implement a general-purpose data-routing-and-encapsulation architecture that supports tagging of input data and routing the data in a standardized way through the Internet and other modern packet-switching networks to one or more computer(s) for review by physicians. The architecture supports multiple-site buffering of data for redundancy and reliability, and supports both real-time and slower-than-real-time collection, routing, and viewing of signal data. Routing and viewing stations support insertion of automated analysis routines to aid in encoding, analysis, viewing, and diagnosis.

  1. Multistep phosphorylation systems: tunable components of biological signaling circuits. (United States)

    Valk, Evin; Venta, Rainis; Ord, Mihkel; Faustova, Ilona; Kõivomägi, Mardo; Loog, Mart


    Multisite phosphorylation of proteins is a powerful signal processing mechanism that plays crucial roles in cell division and differentiation as well as in disease. We recently demonstrated a novel phenomenon in cell cycle regulation by showing that cyclin-dependent kinase-dependent multisite phosphorylation of a crucial substrate is performed sequentially in the N-to-C terminal direction along the disordered protein. The process is controlled by key parameters, including the distance between phosphorylation sites, the distribution of serines and threonines in sites, and the position of docking motifs. According to our model, linear patterns of phosphorylation along disordered protein segments determine the signal-response function of a multisite phosphorylation switch. Here we discuss the general advantages and engineering principles of multisite phosphorylation networks as processors of kinase signals. We also address the idea of using the mechanistic logic of linear multisite phosphorylation networks to design circuits for synthetic biology applications.

  2. Reconstruction of the temporal signaling network in Salmonella-infected human cells

    Directory of Open Access Journals (Sweden)

    Gungor eBudak


    Full Text Available Salmonella enterica is a bacterial pathogen that usually infects its host through food sources. Translocation of the pathogen proteins into the host cells leads to changes in the signaling mechanism either by activating or inhibiting the host proteins. Using high-throughput ‘omic’ technologies, changes in the signaling components can be quantified at different levels; however, experimental hits are usually incomplete to represent the whole signaling system as some driver proteins stay hidden within the experimental data. Given that the bacterial infection modifies the response network of the host, more coherent view of the underlying biological processes and the signaling networks can be obtained by using a network modeling approach based on the reverse engineering principles in which a confident region from the protein interactome is found by inferring hits from the omic experiments. In this work, we have used a published temporal phosphoproteomic dataset of Salmonella-infected human cells and reconstructed the temporal signaling network of the human host by integrating the interactome and the phosphoproteomic datasets. We have combined two well-established network modeling frameworks, the Prize-collecting Steiner Forest (PCSF approach and the Integer Linear Programming (ILP based edge inference approach. The resulting network conserves the information on temporality, direction of interactions, while revealing hidden entities in the signaling, such as the SNARE binding, mTOR signaling, immune response, cytoskeleton organization, and apoptosis pathways. Targets of the Salmonella effectors in the host cells such as CDC42, RHOA, 14-3-3δ, Syntaxin family, Oxysterol-binding proteins were included in the reconstructed signaling network although they were not present in the initial phosphoproteomic data. We believe that integrated approaches have a high potential for the identification of clinical targets in infectious diseases, especially in the

  3. Evolution of stalk/spore ratio in a social amoeba: cell-to-cell interaction via a signaling chemical shaped by cheating risk. (United States)

    Uchinomiya, Kouki; Iwasa, Yoh


    The social amoeba (or cellular slime mold) is a model system for cell cooperation. When food is depleted in the environment, cells aggregate together. Some of these cells become stalks, raising spores to aid in their dispersal. Differentiation-inducing factor-1 (DIF-1) is a signaling chemical produced by prespore cells and decomposed by prestalk cells. It affects the rate of switching between prestalk and prespore cells, thereby achieving a stable stalk/spore ratio. In this study we analyzed the evolution of the stalk/spore ratio. Strains may differ in the production and decomposition rates of the signaling chemical, and in the sensitivity of cells to switch in response to the signaling chemical exposure. When two strains with the same stalk/spore ratio within their own fruiting body are combined into a single fruiting body, one strain may develop into prespores to a greater degree than the other. Direct evolutionary simulations and quantitative genetic dynamics demonstrate that if a fruiting body is always formed by a single strain, the cells evolve to produce less signaling chemical and become more sensitive to the signaling chemical due to the cost of producing the chemical. In contrast, if a fruiting body is formed by multiple strains, the cells evolve to become less sensitive to the signaling chemical and produce more signaling chemical in order to reduce the risk of being exploited. In contrast, the stalk-spore ratio is less likely to be affected by small cheating risk.

  4. Enhancing the GLP-1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells


    Li, Yazhou; Tweedie, David; Mattson, Mark P.; Holloway, Harold W.; Greig, Nigel H.


    Increasing evidence suggests that glucagon-like peptide-1 (GLP-1), an incretin hormone of current interest in type 2 diabetes, is neuroprotective in both cell culture and animal models. To characterize the neuroprotective properties of GLP-1 and associated underlying mechanisms, we over-expressed the GLP-1 receptor (R) on human neuroblastoma SH-SY5Y cells to generate a neuronal culture system featuring enhanced GLP-1R signaling. In GLP-1R over-expressing SH-SY5Y (SH-hGLP-1R#9) cells, GLP-1 an...

  5. Planar cell polarity signaling in collective cell movements during morphogenesis and disease. (United States)

    Muñoz-Soriano, Verónica; Belacortu, Yaiza; Paricio, Nuria


    Collective and directed cell movements are crucial for diverse developmental processes in the animal kingdom, but they are also involved in wound repair and disease. During these processes groups of cells are oriented within the tissue plane, which is referred to as planar cell polarity (PCP). This requires a tight regulation that is in part conducted by the PCP pathway. Although this pathway was initially characterized in flies, subsequent studies in vertebrates revealed a set of conserved core factors but also effector molecules and signal modulators, which build the fundamental PCP machinery. The PCP pathway in Drosophila regulates several developmental processes involving collective cell movements such as border cell migration during oogenesis, ommatidial rotation during eye development, and embryonic dorsal closure. During vertebrate embryogenesis, PCP signaling also controls collective and directed cell movements including convergent extension during gastrulation, neural tube closure, neural crest cell migration, or heart morphogenesis. Similarly, PCP signaling is linked to processes such as wound repair, and cancer invasion and metastasis in adults. As a consequence, disruption of PCP signaling leads to pathological conditions. In this review, we will summarize recent findings about the role of PCP signaling in collective cell movements in flies and vertebrates. In addition, we will focus on how studies in Drosophila have been relevant to our understanding of the PCP molecular machinery and will describe several developmental defects and human disorders in which PCP signaling is compromised. Therefore, new discoveries about the contribution of this pathway to collective cell movements could provide new potential diagnostic and therapeutic targets for these disorders.

  6. Experimental demonstration of bindingless signal delivery in human cells via microfluidics (United States)

    Kuo, Ching-Te; Chuang, Fang-Tzu; Wu, Pei-Yi; Lin, Yueh-Chien; Liu, Hao-Kai; Huang, Guan-Syuan; Tsai, Tzu-Ching; Chi, Cheng-Yu; Wo, Andrew M.; Lee, Hsinyu; Lee, Si-Chen


    The cellular signal transduction is commonly believed to rely on the direct "contact" or "binding" of the participating molecule reaction that depends positively on the corresponding molecule concentrations. In living systems, however, it is somewhat difficult to precisely match the corresponding rapid "binding," depending on the probability of molecular collision, existing in the cellular receptor-ligand interactions. Thus, a question arises that if there is another mechanism (i.e., bindingless) that could promote this signal communication. According to this hypothesis, we report a cellular model based on the examination of intracellular calcium concentration to explore whether the unidentified signal delivery in cells exists, via a microfluidic device. This device was designed to isolate the cells from directly contacting with the corresponding ligands/molecules by the particular polydimethylsiloxane (PDMS) membranes with different thicknesses. Results show a significant increment of calcium mobilization in human prostate cancer PC-3 cells by the stimulation of endothelin-1, even up to a separated distance of 95 μm. In addition, these stimulated signals exhibited a bump-shaped characteristics depending on the membrane thickness. When the PDMS membrane is capped by SiO2, a particular trait that resembles the ballistic signal conduction was observed. A theoretical model was developed to describe the signal transport process across the PDMS membrane. Taken together, these results indicate that the unidentified signal (ligand structural information) delivery could occur in cells and be examined by the proposed approach, exhibiting a bindingless communication manner. Moreover, this approach and our finding may offer new opportunities to establish a robust and cost-effective platform for the study of cellular biology and new drug development.

  7. Blockage of Notch Signaling Inhibits the Migration and Proliferation of Retinal Pigment Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Weiwei Liu


    Full Text Available The Notch signaling is an evolutionarily conserved cell-cell communication pathway that plays critical roles in the proliferation, survival, apoptosis, and fate determination of mammalian cells. Retinal pigment epithelial (RPE cells are responsible for supporting the function of the neural retina and maintaining vision. This study investigated the function of Notch signaling in RPE cells. We found that the members of the Notch signaling pathway components were differentially expressed in RPE cells. Furthermore, blockage of Notch signaling inhibited the migration and proliferation of RPE cells and reduced the expression levels of certain Notch signaling target genes, including HES1, MYC, HEY2, and SOX9. Our data reveal a critical role of Notch signaling in RPE cells, suggesting that targeting Notch signaling may provide a novel approach for the treatment of ophthalmic diseases related to RPE cells.

  8. The contribution of cell-cell signaling and motility to bacterial biofilm formation

    DEFF Research Database (Denmark)

    Shrout, Joshua D; Tolker-Nielsen, Tim; Givskov, Michael;


    Many bacteria grow attached to a surface as biofilms. Several factors dictate biofilm formation, including responses by the colonizing bacteria to their environment. Here we review how bacteria use cell-cell signaling (also called quorum sensing) and motility during biofilm formation. Specificall...

  9. Cell-surface signaling in Pseudomonas: stress responses, iron transport, and pathogenicity. (United States)

    Llamas, María A; Imperi, Francesco; Visca, Paolo; Lamont, Iain L


    Membrane-spanning signaling pathways enable bacteria to alter gene expression in response to extracytoplasmic stimuli. Many such pathways are cell-surface signaling (CSS) systems, which are tripartite molecular devices that allow Gram-negative bacteria to transduce an extracellular stimulus into a coordinated transcriptional response. Typically, CSS systems are composed of the following: (1) an outer membrane receptor, which senses the extracellular stimulus; (2) a cytoplasmic membrane-spanning protein involved in signal transduction from the periplasm to the cytoplasm; and (3) an extracytoplasmic function (ECF) sigma factor that initiates expression of the stimulus-responsive gene(s). Members of genus Pseudomonas provide a paradigmatic example of how CSS systems contribute to the global control of gene expression. Most CSS systems enable self-regulated uptake of iron via endogenous (pyoverdine) or exogenous (xenosiderophores, heme, and citrate) carriers. Some are also implicated in virulence, biofilm formation, and cell-cell interactions. Incorporating insights from the well-characterized alginate regulatory circuitry, this review will illustrate common themes and variations at the level of structural and functional properties of Pseudomonas CSS systems. Control of the expression and activity of ECF sigma factors are central to gene regulation via CSS, and the variety of intrinsic and extrinsic factors influencing these processes will be discussed.

  10. Cell swelling and ion redistribution assessed with intrinsic optical signals

    Directory of Open Access Journals (Sweden)



    Full Text Available Cell volume changes are associated with alterations of intrinsic optical signals (IOS. In submerged brain slices in vitro, afferent stimulation induces an increase in light transmission. As assessed by measurement of the largely membrane impermeant ion tetramethylammonium (TMA in the extracellular space, these IOS correlate with the extent and time course of the change of the extracellular space size. They have a high signal to noise ratio and allow measurements of IOS changes in the order of a few percent. Under conditions of reduced net KCl uptake (low Cl solution a directed spatial buffer mechanism (K syphoning can be demonstrated in the neocortex with widening of the extracellular space in superficial layers associated with a reduced light transmission and an increase of extracellular K concentration. The nature of the IOS under pathophysiological conditions is less clear. Spreading depressions first cause an increase of light transmission, then a decrease. Such a decrease has also been observed following application of NMDA where it was associated with structural damage. Pharmacological analyses suggest that under physiological conditions changes of extracellular space size are mainly caused by astrocytic volume changes while with strong stimuli and under pathophysiological conditions also neuronal swelling occurs. With reflected light usually signals opposite to those observed with transmitted light are seen. Recording of IOS from interface slices gives very complex signals since under these conditions an increase of light transmission has been reported to be superimposed by a decrease of the signal due to mechanical lensing effects of the slice surface. Depending on the method of measurement and the exact conditions, several mechanisms may contribute to IOS. Under well defined conditions IOS are a useful supplementary tool to monitor changes of extracellular volume both in space and time.

  11. Outage performance of cognitive radio systems with Improper Gaussian signaling

    KAUST Repository

    Amin, Osama


    Improper Gaussian signaling has proved its ability to improve the achievable rate of the systems that suffer from interference compared with proper Gaussian signaling. In this paper, we first study impact of improper Gaussian signaling on the performance of the cognitive radio system by analyzing the outage probability of both the primary user (PU) and the secondary user (SU). We derive exact expression of the SU outage probability and upper and lower bounds for the PU outage probability. Then, we design the SU signal by adjusting its transmitted power and the circularity coefficient to minimize the SU outage probability while maintaining a certain PU quality-of-service. Finally, we evaluate the proposed bounds and adaptive algorithms by numerical results.

  12. DMPD: Signals and receptors involved in recruitment of inflammatory cells. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 7744810 Signals and receptors involved in recruitment of inflammatory cells. Ben-Ba...ow Signals and receptors involved in recruitment of inflammatory cells. PubmedID 7744810 Title Signals and r...eceptors involved in recruitment of inflammatory cells. Authors Ben-Baruch A, Mic

  13. Clustering in Cell Cycle Dynamics with General Response/Signaling Feedback

    CERN Document Server

    Young, Todd; Buckalew, Richard; Moses, Gregory; Boczko, Erik; 10.1016/j.jtbi.2011.10.002.


    Motivated by experimental and theoretical work on autonomous oscillations in yeast, we analyze ordinary differential equations models of large populations of cells with cell-cycle dependent feedback. We assume a particular type of feedback that we call Responsive/Signaling (RS), but do not specify a functional form of the feedback. We study the dynamics and emergent behaviour of solutions, particularly temporal clustering and stability of clustered solutions. We establish the existence of certain periodic clustered solutions as well as "uniform" solutions and add to the evidence that cell-cycle dependent feedback robustly leads to cell-cycle clustering. We highlight the fundamental differences in dynamics between systems with negative and positive feedback. For positive feedback systems the most important mechanism seems to be the stability of individual isolated clusters. On the other hand we find that in negative feedback systems, clusters must interact with each other to reinforce coherence. We conclude fr...

  14. Development of a new model system to dissect isoform specific Akt signalling in adipocytes (United States)

    Kajno, Esi; McGraw, Timothy E.; Gonzalez, Eva


    Protein kinase B (Akt) kinases are critical signal transducers mediating insulin action. Genetic studies revealed that Akt1 and Akt2 signalling differentially contribute to sustain lipid and glucose homoeostasis; however Akt isoform-specific effectors remain elusive due to the lack of a suitable model system to mechanistically interrogate Akt isoform-specific signalling. To overcome those technical limitations we developed a novel model system that provides acute and specific control of signalling by Akt isoforms. We generated mutants of Akt1 and Akt2 resistant to the allosteric Akt inhibitor MK-2206. We then developed adipocyte cell lines, in which endogenous Akt1 or Akt2 has been replaced by their corresponding drug-resistant Akt mutant. Treatment of those cells with MK-2206 allowed for acute and specific control of either Akt1 or Akt2 function. Our data showed that Akt1W80A and Akt2W80A mutants are resistant to MK-2206, dynamically regulated by insulin and able to signal to Akt downstream effectors. Analyses of insulin action in this cellular system showed that Akt1 and Akt2 are both able to mediate insulin regulation of the transcription factor forkhead box O1 (FoxO1) and the glucose transporter 4 (GLUT4), revealing a redundant role for these Akt kinases in the control of glucose transport into fat cells. In contrast, Akt1 signalling is uniquely required for adipogenesis, by controlling the mitotic clonal expansion (MCE) of pre-adipocytes that precedes white adipose cell differentiation. Our data provide new insights into the role of Akt kinases in glucose transport and adipogenesis and support our model system as a valuable tool for the biochemical characterization of signalling by specific Akt isoforms. PMID:25856301

  15. Signal structure of the Chinese Area Positioning System

    Institute of Scientific and Technical Information of China (English)


    Proper signal structure is very important in the navigation, positioning, and time services of a satellite navigation system. In this paper, the carrier wave characteristics, ranging code functions, BOC modulation, navigation data rate, the error-correcting methods, and signal channel resource allocation are discussed in terms of the technical characteristics of the transforming satellite navigation system and the resources of communication satellites. The results show that dual-frequency of C band in the Chinese Area Positioning System (CAPS), compound ranging code, a combination of the coarse code and precise code, BOC modulation, separate-channel transmission of different users are compatible with the satellite navigation system at present. The experiments show that the current signal structure can meet the demand of CAPS.

  16. Regulation of Dense-Core Granule Replenishment by Autocrine BMP Signalling in Drosophila Secondary Cells. (United States)

    Redhai, Siamak; Hellberg, Josephine E E U; Wainwright, Mark; Perera, Sumeth W; Castellanos, Felix; Kroeger, Benjamin; Gandy, Carina; Leiblich, Aaron; Corrigan, Laura; Hilton, Thomas; Patel, Benjamin; Fan, Shih-Jung; Hamdy, Freddie; Goberdhan, Deborah C I; Wilson, Clive


    Regulated secretion by glands and neurons involves release of signalling molecules and enzymes selectively concentrated in dense-core granules (DCGs). Although we understand how many secretagogues stimulate DCG release, how DCG biogenesis is then accelerated to replenish the DCG pool remains poorly characterised. Here we demonstrate that each prostate-like secondary cell (SC) in the paired adult Drosophila melanogaster male accessory glands contains approximately ten large DCGs, which are loaded with the Bone Morphogenetic Protein (BMP) ligand Decapentaplegic (Dpp). These DCGs can be marked in living tissue by a glycophosphatidylinositol (GPI) lipid-anchored form of GFP. In virgin males, BMP signalling is sporadically activated by constitutive DCG secretion. Upon mating, approximately four DCGs are typically released immediately, increasing BMP signalling, primarily via an autocrine mechanism. Using inducible knockdown specifically in adult SCs, we show that secretion requires the Soluble NSF Attachment Protein, SNAP24. Furthermore, mating-dependent BMP signalling not only promotes cell growth, but is also necessary to accelerate biogenesis of new DCGs, restoring DCG number within 24 h. Our analysis therefore reveals an autocrine BMP-mediated feedback mechanism for matching DCG release to replenishment as secretion rates fluctuate, and might explain why in other disease-relevant systems, like pancreatic β-cells, BMP signalling is also implicated in the control of secretion.

  17. The ubiquitin–proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer

    Directory of Open Access Journals (Sweden)

    Voutsadakis Ioannis A


    Full Text Available Abstract Epithelial to Mesenchymal transition (EMT in cancer, a process permitting cancer cells to become mobile and metastatic, has a signaling hardwire forged from development. Multiple signaling pathways that regulate carcinogenesis enabling characteristics in neoplastic cells such as proliferation, resistance to apoptosis and angiogenesis are also the main players in EMT. These pathways, as almost all cellular processes, are in their turn regulated by ubiquitination and the Ubiquitin-Proteasome System (UPS. Ubiquitination is the covalent link of target proteins with the small protein ubiquitin and serves as a signal to target protein degradation by the proteasome or to other outcomes such as endocytosis, degradation by the lysosome or specification of cellular localization. This paper reviews signal transduction pathways regulating EMT and being regulated by ubiquitination.

  18. Digital Signal Processor System for AC Power Drivers


    Ovidiu Neamtu


    DSP (Digital Signal Processor) is the bestsolution for motor control systems to make possible thedevelopment of advanced motor drive systems. The motorcontrol processor calculates the required motor windingvoltage magnitude and frequency to operate the motor atthe desired speed. A PWM (Pulse Width Modulation)circuit controls the on and off duty cycle of the powerinverter switches to vary the magnitude of the motorvoltages.

  19. Digital Signal Processor System for AC Power Drivers

    Directory of Open Access Journals (Sweden)

    Ovidiu Neamtu


    Full Text Available DSP (Digital Signal Processor is the bestsolution for motor control systems to make possible thedevelopment of advanced motor drive systems. The motorcontrol processor calculates the required motor windingvoltage magnitude and frequency to operate the motor atthe desired speed. A PWM (Pulse Width Modulationcircuit controls the on and off duty cycle of the powerinverter switches to vary the magnitude of the motorvoltages.

  20. Serotonergic chemosensory neurons modify the C. elegans immune response by regulating G-protein signaling in epithelial cells.

    Directory of Open Access Journals (Sweden)

    Alexandra Anderson

    Full Text Available The nervous and immune systems influence each other, allowing animals to rapidly protect themselves from changes in their internal and external environment. However, the complex nature of these systems in mammals makes it difficult to determine how neuronal signaling influences the immune response. Here we show that serotonin, synthesized in Caenorhabditis elegans chemosensory neurons, modulates the immune response. Serotonin released from these cells acts, directly or indirectly, to regulate G-protein signaling in epithelial cells. Signaling in these cells is required for the immune response to infection by the natural pathogen Microbacterium nematophilum. Here we show that serotonin signaling suppresses the innate immune response and limits the rate of pathogen clearance. We show that C. elegans uses classical neurotransmitters to alter the immune response. Serotonin released from sensory neurons may function to modify the immune system in response to changes in the animal's external environment such as the availability, or quality, of food.

  1. Planar cell polarity signalling controls cell division orientation during zebrafish gastrulation. (United States)

    Gong, Ying; Mo, Chunhui; Fraser, Scott E


    Oriented cell division is an integral part of pattern development in processes ranging from asymmetric segregation of cell-fate determinants to the shaping of tissues. Despite proposals that it has an important function in tissue elongation, the mechanisms regulating division orientation have been little studied outside of the invertebrates Caenorhabditis elegans and Drosophila melanogaster. Here, we have analysed mitotic divisions during zebrafish gastrulation using in vivo confocal imaging and found that cells in dorsal tissues preferentially divide along the animal-vegetal axis of the embryo. Establishment of this animal-vegetal polarity requires the Wnt pathway components Silberblick/Wnt11, Dishevelled and Strabismus. Our findings demonstrate an important role for non-canonical Wnt signalling in oriented cell division during zebrafish gastrulation, and indicate that oriented cell division is a driving force for axis elongation. Furthermore, we propose that non-canonical Wnt signalling has a conserved role in vertebrate axis elongation, orienting both cell intercalation and mitotic division.

  2. Lipopolysaccharide-induced multinuclear cells: Increased internalization of polystyrene beads and possible signals for cell fusion

    Energy Technology Data Exchange (ETDEWEB)

    Nakanishi-Matsui, Mayumi, E-mail:; Yano, Shio; Futai, Masamitsu


    Highlights: •LPS induces multinuclear cells from murine macrophage-derived RAW264.7 cells. •Large beads are internalized by cells actively fusing to become multinuclear. •The multinuclear cell formation is inhibited by anti-inflammatory cytokine, IL10. •Signal transduction for cell fusion is different from that for inflammation. -- Abstract: A murine macrophage-derived line, RAW264.7, becomes multinuclear on stimulation with lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria. These multinuclear cells internalized more polystyrene beads than mononuclear cells or osteoclasts (Nakanishi-Matsui, M., Yano, S., Matsumoto, N., and Futai, M., 2012). In this study, we analyzed the time courses of cell fusion in the presence of large beads. They were internalized into cells actively fusing to become multinuclear. However, the multinuclear cells once formed showed only low phagocytosis activity. These results suggest that formation of the multinuclear cells and bead internalization took place simultaneously. The formation of multinuclear cells was blocked by inhibitors for phosphoinositide 3-kinase, phospholipase C, calcineurin, and c-Jun N-terminal kinase. In addition, interleukin 6 and 10 also exhibited inhibitory effects. These signaling molecules and cytokines may play a crucial role in the LPS-induced multinuclear cell formation.

  3. Xanthohumol inhibits the extracellular signal regulated kinase (ERK) signalling pathway and suppresses cell growth of lung adenocarcinoma cells. (United States)

    Sławińska-Brych, Adrianna; Zdzisińska, Barbara; Dmoszyńska-Graniczka, Magdalena; Jeleniewicz, Witold; Kurzepa, Jacek; Gagoś, Mariusz; Stepulak, Andrzej


    Aberrant activation of the Ras/MEK/ERK signaling pathway has been frequently observed in non-small-cell lung carcinoma (NSCLC) and its important role in cancer progression and malignant transformation has been documented. Hence, the ERK1/2 kinase cascade becomes a potential molecular target in cancer treatment. Xanthohumol (XN, a prenylated chalcone derived from hope cones) is known to possess a broad spectrum of chemopreventive and anticancer activities. In our studies, the MTT and BrdU assays revealed that XN demonstrated greater antiproliferative activity against A549 lung adenocarcinoma cells than against the lung adenocarcinoma H1563 cell line. We observed that XN was able to suppress the activities of ERK1/2 and p90RSK kinases, followed by inhibition of phosphorylation and activation of the CREB protein. Additionally, the XN treatment of the cancer cells caused upregulation of key cell cycle regulators p53 and p21 as well as downregulation of cyclin D1. As a result, the cytotoxic effect of XN was attributed to the cell cycle arrest at G1 phase and induction of apoptosis indicated by increased caspase-3 activity. Thus, XN might be a promising anticancer drug candidate against lung carcinomas.

  4. Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion

    Energy Technology Data Exchange (ETDEWEB)

    Loomans, Holli A. [Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Andl, Claudia D., E-mail: [Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Digestive Disease Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States)


    In recent years, a significant amount of research has examined the controversial role of activin A in cancer. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, is best characterized for its function during embryogenesis in mesoderm cell fate differentiation and reproduction. During embryogenesis, TGFβ superfamily ligands, TGFβ, bone morphogenic proteins (BMPs) and activins, act as potent morphogens. Similar to TGFβs and BMPs, activin A is a protein that is highly systemically expressed during early embryogenesis; however, post-natal expression is overall reduced and remains under strict spatiotemporal regulation. Of importance, normal post-natal expression of activin A has been implicated in the migration and invasive properties of various immune cell types, as well as endometrial cells. Aberrant activin A signaling during development results in significant morphological defects and premature mortality. Interestingly, activin A has been found to have both oncogenic and tumor suppressor roles in cancer. Investigations into the role of activin A in prostate and breast cancer has demonstrated tumor suppressive effects, while in lung and head and neck squamous cell carcinoma, it has been consistently shown that activin A expression is correlated with increased proliferation, invasion and poor patient prognosis. Activin A signaling is highly context-dependent, which is demonstrated in studies of epithelial cell tumors and the microenvironment. This review discusses normal activin A signaling in comparison to TGFβ and highlights how its dysregulation contributes to cancer progression and cell invasion.

  5. Guidance signalling regulates leading edge behaviour during collective cell migration of cardiac cells in Drosophila. (United States)

    Raza, Qanber; Jacobs, J Roger


    Collective cell migration is the coordinated movement of cells, which organize tissues during morphogenesis, repair and some cancers. The motile cell membrane of the advancing front in collective cell migration is termed the Leading Edge. The embryonic development of the vertebrate and Drosophila hearts are both characterized by the coordinated medial migration of a bilateral cluster of mesodermal cells. In Drosophila, the cardioblasts form cohesive bilateral rows that migrate collectively as a unit towards the dorsal midline to form the dorsal vessel. We have characterized the collective cell migration of cardioblasts as an in vivo quantitative model to study the behaviour of the Leading Edge. We investigated whether guidance signalling through Slit and Netrin pathways plays a role in cell migration during heart development. Through time-lapse imaging and quantitative assessment of migratory behaviour of the cardioblasts in loss-of-function mutants, we demonstrate that both Slit and Netrin mediated signals are autonomously and concomitantly required to maximize migration velocity, filopodial and lamellipodial activities. Additionally, we show that another Slit and Netrin receptor, Dscam1, the role of which during heart development was previously unknown, is required for both normal migration of cardioblasts and luminal expansion. Leading edge behaviour analysis revealed a dosage dependent genetic interaction between Slit and Netrin receptors suggesting that downstream signalling through these receptors converge on a common output that increases leading edge activity of the cardioblasts. Finally, we found that guidance signalling maintains the balance between epithelial and mesenchymal characteristics of the migrating cardioblasts.

  6. Planar cell polarity signalling couples cell division and morphogenesis during neurulation. (United States)

    Ciruna, Brian; Jenny, Andreas; Lee, Diana; Mlodzik, Marek; Schier, Alexander F


    Environmental and genetic aberrations lead to neural tube closure defects (NTDs) in 1 out of every 1,000 births. Mouse and frog models for these birth defects have indicated that Van Gogh-like 2 (Vangl2, also known as Strabismus) and other components of planar cell polarity (PCP) signalling might control neurulation by promoting the convergence of neural progenitors to the midline. Here we show a novel role for PCP signalling during neurulation in zebrafish. We demonstrate that non-canonical Wnt/PCP signalling polarizes neural progenitors along the anteroposterior axis. This polarity is transiently lost during cell division in the neural keel but is re-established as daughter cells reintegrate into the neuroepithelium. Loss of zebrafish Vangl2 (in trilobite mutants) abolishes the polarization of neural keel cells, disrupts re-intercalation of daughter cells into the neuroepithelium, and results in ectopic neural progenitor accumulations and NTDs. Remarkably, blocking cell division leads to rescue of trilobite neural tube morphogenesis despite persistent defects in convergence and extension. These results reveal a function for PCP signalling in coupling cell division and morphogenesis at neurulation and indicate a previously unrecognized mechanism that might underlie NTDs.

  7. Transmission of colour and acuity signals by parvocellular cells in marmoset monkeys. (United States)

    Martin, Paul R; Blessing, Esther M; Buzás, Péter; Szmajda, Brett A; Forte, Jason D


    The red-green axis of colour vision evolved recently in primate evolutionary history. Signals serving red-green colour vision travel together with signals serving spatial vision, in the parvocellular (PC) division of the subcortical visual pathway. However, the question of whether receptive fields of PC pathway cells are specialized to transmit red-green colour signals remains unresolved. We addressed this question in single-cell recordings from the lateral geniculate nucleus of anaesthetized marmosets. Marmosets show a high proportion of dichromatic (red-green colour-blind) individuals, allowing spatial and colour tuning properties of PC cells to be directly compared in dichromatic and trichromatic visual systems. We measured spatial frequency tuning for sine gratings that provided selective stimulation of individual photoreceptor types. We found that in trichromatic marmosets, the foveal visual field representation is dominated by red-green colour-selective PC cells. Colour selectivity of PC cells is reduced at greater eccentricities, but cone inputs to centre and surround are biased to create more selectivity than predicted by a purely 'random wiring' model. Thus, one-to-one connections in the fovea are sufficient, but not necessary, to create colour-selective responses. The distribution of spatial tuning properties for achromatic stimuli shows almost complete overlap between PC cells recorded in dichromatic and trichromatic marmosets. These data indicate that transmission of red-green colour signals has been enabled by centre-surround receptive fields of PC cells, and has not altered the capacity of PC cells to serve high-acuity vision at high stimulus contrast.

  8. HIF-1α contributes to proliferation and invasiveness of neuroblastoma cells via SHH signaling. (United States)

    Chen, Sheng; Zhang, Min; Xing, Lili; Wang, Yue; Xiao, Yongtao; Wu, Yeming


    The aim of this study was to investigate the effects of hypoxia-inducible factor-1α (HIF-1α) on the proliferation, migration and invasion of neuroblastoma (NB) cells and the mechanisms involved. We here initially used the real-time polymerase chain reaction (real-time PCR), Western blotting and immunohistochemistry (IHC) to detect the expression of HIF-1α and components of the sonic hedgehog (SHH) signaling pathway in NB cells and human specimens. Subsequently, cell proliferation, migration and invasion were analyzed using the cell counting assay, wound healing assay and Transwell system in two types of human NB cell lines, SH-SY5Y and IMR32. In addition, the role of HIF-1α in NB cells growth was determined in a xenograft nude mouse model. We found that the level of HIF-1α was significantly upregulated during NB progression and was associated with the expression of two components of SHH signaling, SHH and GLI1. We next indicated that the proliferation, migration and invasiveness of SH-SY5Y and IMR32 cells were significantly inhibited by HIF-1α knockdown, which was mediated by small interfering RNAs (siRNAs) targeting against its mRNA. Furthermore, the growth of NB cells in vivo was also suppressed by HIF-1α inhibition. Finally, the pro-migration and proliferative effects of HIF-1α could be reversed by disrupting SHH signaling. In conclusion, our results demonstrated that upregulation of HIF-1α in NB promotes proliferation, migration and invasiveness via SHH signaling.

  9. HIF-1α contributes to proliferation and invasiveness of neuroblastoma cells via SHH signaling.

    Directory of Open Access Journals (Sweden)

    Sheng Chen

    Full Text Available The aim of this study was to investigate the effects of hypoxia-inducible factor-1α (HIF-1α on the proliferation, migration and invasion of neuroblastoma (NB cells and the mechanisms involved. We here initially used the real-time polymerase chain reaction (real-time PCR, Western blotting and immunohistochemistry (IHC to detect the expression of HIF-1α and components of the sonic hedgehog (SHH signaling pathway in NB cells and human specimens. Subsequently, cell proliferation, migration and invasion were analyzed using the cell counting assay, wound healing assay and Transwell system in two types of human NB cell lines, SH-SY5Y and IMR32. In addition, the role of HIF-1α in NB cells growth was determined in a xenograft nude mouse model. We found that the level of HIF-1α was significantly upregulated during NB progression and was associated with the expression of two components of SHH signaling, SHH and GLI1. We next indicated that the proliferation, migration and invasiveness of SH-SY5Y and IMR32 cells were significantly inhibited by HIF-1α knockdown, which was mediated by small interfering RNAs (siRNAs targeting against its mRNA. Furthermore, the growth of NB cells in vivo was also suppressed by HIF-1α inhibition. Finally, the pro-migration and proliferative effects of HIF-1α could be reversed by disrupting SHH signaling. In conclusion, our results demonstrated that upregulation of HIF-1α in NB promotes proliferation, migration and invasiveness via SHH signaling.

  10. Vitamin D Is a Multilevel Repressor of Wnt/β-Catenin Signaling in Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Larriba, María Jesús; González-Sancho, José Manuel; Barbáchano, Antonio; Niell, Núria; Ferrer-Mayorga, Gemma; Muñoz, Alberto, E-mail: [Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Arturo Duperier 4, Madrid 28029 (Spain)


    The Wnt/β-catenin signaling pathway is abnormally activated in most colorectal cancers and in a proportion of other neoplasias. This activation initiates or contributes to carcinogenesis by regulating the expression of a large number of genes in tumor cells. The active vitamin D metabolite 1α,25-dihydroxyvitamin D{sub 3} (1,25(OH){sub 2}D{sub 3}) inhibits Wnt/β-catenin signaling by several mechanisms at different points along the pathway. Additionally, paracrine actions of 1,25(OH){sub 2}D{sub 3} on stromal cells may also repress this pathway in neighbouring tumor cells. Here we review the molecular basis for the various mechanisms by which 1,25(OH){sub 2}D{sub 3} antagonizes Wnt/β-catenin signaling, preferentially in human colon carcinoma cells, and the consequences of this inhibition for the phenotype and proliferation rate. The effect of the vitamin D system on Wnt/β-catenin signaling and tumor growth in animal models will also be commented in detail. Finally, we revise existing data on the relation between vitamin D receptor expression and vitamin D status and the expression of Wnt/β-catenin pathway genes and targets in cancer patients.

  11. Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming human beta cell function (United States)

    Rodriguez-Diaz, Rayner; Dando, Robin; Jacques-Silva, M. Caroline; Fachado, Alberto; Molina, Judith; Abdulreda, Midhat; Ricordi, Camillo; Roper, Stephen D.; Berggren, Per-Olof; Caicedo, Alejandro


    Acetylcholine is a neurotransmitter that plays a major role in the function of the insulin secreting pancreatic beta cell1,2. Parasympathetic innervation of the endocrine pancreas, the islets of Langerhans, has been shown to provide cholinergic input to the beta cell in several species1,3,4, but the role of autonomic innervation in human beta cell function is at present unclear. Here we show that, in contrast to mouse islets, cholinergic innervation of human islets is sparse. Instead, we find that the alpha cells of the human islet provide paracrine cholinergic input to surrounding endocrine cells. Human alpha cells express the vesicular acetylcholine transporter and release acetylcholine when stimulated with kainate or a lowering in glucose concentration. Acetylcholine secretion by alpha cells in turn sensitizes the beta cell response to increases in glucose concentration. Our results demonstrate that in human islets acetylcholine is a paracrine signal that primes the beta cell to respond optimally to subsequent increases in glucose concentration. We anticipate these results to revise models about neural input and cholinergic signaling in the endocrine pancreas. Cholinergic signaling within the islet represents a potential therapeutic target in diabetes5, highlighting the relevance of this advance to future drug development. PMID:21685896

  12. Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death. (United States)

    Laborde, E


    Glutathione transferases (GSTs) are enzymes that catalyze the conjugation of glutathione (GSH) to a variety of electrophilic substances. Their best known role is as cell housekeepers engaged in the detoxification of xenobiotics. Recently, GSTs have also been shown to act as modulators of signal transduction pathways that control cell proliferation and cell death. Their involvement in cancer cell growth and differentiation, and in the development of resistance to anticancer agents, has made them attractive drug targets. This review is focused on the inhibition of GSTs, in particular GSTP1-1, as a potential therapeutic approach for the treatment of cancer and other diseases associated with aberrant cell proliferation.

  13. Notch1-Dll4 signalling and mechanical force regulate leader cell formation during collective cell migration. (United States)

    Riahi, Reza; Sun, Jian; Wang, Shue; Long, Min; Zhang, Donna D; Wong, Pak Kin


    At the onset of collective cell migration, a subset of cells within an initially homogenous population acquires a distinct 'leader' phenotype with characteristic morphology and motility. However, the factors driving the leader cell formation as well as the mechanisms regulating leader cell density during the migration process remain to be determined. Here we use single-cell gene expression analysis and computational modelling to show that the leader cell identity is dynamically regulated by Dll4 signalling through both Notch1 and cellular stress in a migrating epithelium. Time-lapse microscopy reveals that Dll4 is induced in leader cells after the creation of the cell-free region and leader cells are regulated via Notch1-Dll4 lateral inhibition. Furthermore, mechanical stress inhibits Dll4 expression and leader cell formation in the monolayer. Collectively, our findings suggest that a reduction of mechanical force near the boundary promotes Notch1-Dll4 signalling to dynamically regulate the density of leader cells during collective cell migration.

  14. Chaotic oscillator detection system about weak signals in spot welding

    Institute of Scientific and Technical Information of China (English)

    Kai-lei SONG; Zhen LUO; Feng YE; Xin-xin TANG; Shu-xian YUAN


    Spot welding is an efficient and shortcut processing method used in plate, and its quality detection is very important. However, there are many factors affecting the spot welding quality. Because of the low precision of traditional detection methods, spot welding has seldom been used in the aerospace industry which requires high welding quality. In this article, we give a new weak signal detection model based on chaotic oscillators. Using Melnikov methods and Lyapunov exponent, we can determine the critical values when the system enters in and out of chaos. Through lots of numerical simulations, it can be found that the lowest value of the weak sinusoidal signal the system can detect reach 10-11, and its signal-to-noise ratio (SNR) is = 126 dB. Compared with other detection methods, chaos oscillator detection system not only has a lower threshold value, but also is easy to implement in practice. This model thus has good application prospects.

  15. Extracellular matrix stiffness modulates VEGF calcium signaling in endothelial cells: individual cell and population analysis. (United States)

    Derricks, Kelsey E; Trinkaus-Randall, Vickery; Nugent, Matthew A


    Vascular disease and its associated complications are the number one cause of death in the Western world. Both extracellular matrix stiffening and dysfunctional endothelial cells contribute to vascular disease. We examined endothelial cell calcium signaling in response to VEGF as a function of extracellular matrix stiffness. We developed a new analytical tool to analyze both population based and individual cell responses. Endothelial cells on soft substrates, 4 kPa, were the most responsive to VEGF, whereas cells on the 125 kPa substrates exhibited an attenuated response. Magnitude of activation, not the quantity of cells responding or the number of local maximums each cell experienced distinguished the responses. Individual cell analysis, across all treatments, identified two unique cell clusters. One cluster, containing most of the cells, exhibited minimal or slow calcium release. The remaining cell cluster had a rapid, high magnitude VEGF activation that ultimately defined the population based average calcium response. Interestingly, at low doses of VEGF, the high responding cell cluster contained smaller cells on average, suggesting that cell shape and size may be indicative of VEGF-sensitive endothelial cells. This study provides a new analytical tool to quantitatively analyze individual cell signaling response kinetics, that we have used to help uncover outcomes that are hidden within the average. The ability to selectively identify highly VEGF responsive cells within a population may lead to a better understanding of the specific phenotypic characteristics that define cell responsiveness, which could provide new insight for the development of targeted anti- and pro-angiogenic therapies.

  16. Cell signaling by reactive nitrogen and oxygen species in atherosclerosis (United States)

    Patel, R. P.; Moellering, D.; Murphy-Ullrich, J.; Jo, H.; Beckman, J. S.; Darley-Usmar, V. M.


    The production of reactive oxygen and nitrogen species has been implicated in atherosclerosis principally as means of damaging low-density lipoprotein that in turn initiates the accumulation of cholesterol in macrophages. The diversity of novel oxidative modifications to lipids and proteins recently identified in atherosclerotic lesions has revealed surprising complexity in the mechanisms of oxidative damage and their potential role in atherosclerosis. Oxidative or nitrosative stress does not completely consume intracellular antioxidants leading to cell death as previously thought. Rather, oxidative and nitrosative stress have a more subtle impact on the atherogenic process by modulating intracellular signaling pathways in vascular tissues to affect inflammatory cell adhesion, migration, proliferation, and differentiation. Furthermore, cellular responses can affect the production of nitric oxide, which in turn can strongly influence the nature of oxidative modifications occurring in atherosclerosis. The dynamic interactions between endogenous low concentrations of oxidants or reactive nitrogen species with intracellular signaling pathways may have a general role in processes affecting wound healing to apoptosis, which can provide novel insights into the pathogenesis of atherosclerosis.

  17. A four-channel microelectronic system for neural signal regeneration

    Energy Technology Data Exchange (ETDEWEB)

    Xie Shushan; Wang Zhigong; Li Wenyuan [Institute of RF- and OE-ICs, Southeast University, Nanjing 210096 (China); Lue Xiaoying; Pan Haixian, E-mail: [State Key Laboratory of Bio-Electronics, Southeast University, Nanjing 210096 (China)


    This paper presents a microelectronic system which is capable of making a signal record and functional electric stimulation of an injured spinal cord. As a requirement of implantable engineering for the regeneration microelectronic system, the system is of low noise, low power, small size and high performance. A front-end circuit and two high performance OPAs (operational amplifiers) have been designed for the system with different functions, and the two OPAs are a low-noise low-power two-stage OPA and a constant-g{sub m} RTR input and output OPA. The system has been realized in CSMC 0.5-{mu}m CMOS technology. The test results show that the system satisfies the demands of neuron signal regeneration. (semiconductor integrated circuits)

  18. A four-channel microelectronic system for neural signal regeneration

    Institute of Scientific and Technical Information of China (English)

    Xie Shushan; Wang Zhigong; Lü Xiaoying; Li Wenyuan; Pan Haixian


    This paper presents a microelectronic system which is capable of making a signal record and functional electric stimulation of an injured spinal cord. As a requirement of implantable engineering for the regeneration microelectronic system, the system is of low noise, low power, small size and high performance. A front-end circuit and two high performance OPAs (operational amplifiers) have been designed for the system with different functions,and the two OPAs are a low-noise low-power two-stage OPA and a constant-g_m RTR input and output OPA. The system has been realized in CSMC 0.5-μm CMOS technology. The test results show that the system satisfies the demands of neuron signal regeneration.

  19. Study of orexins signal transduction pathways in rat olfactory mucosa and in olfactory sensory neurons-derived cell line Odora: multiple orexin signalling pathways. (United States)

    Gorojankina, Tatiana; Grébert, Denise; Salesse, Roland; Tanfin, Zahra; Caillol, Monique


    Orexins A and B (OxA and OxB) are multifunctional neuropeptides implicated in the regulation of energy metabolism, wakefulness but also in a broad range of motivated behaviours. They signal through two G-protein-coupled receptors: orexin receptor 1 and 2 (Ox1R and Ox2R). The orexins and their receptors are present at all levels of the rat olfactory system: epithelium, bulb, piriform cortex but their signalling mechanisms remain unknown. We have studied orexins signal transduction pathways in the rat olfactory mucosa (OM) and in the Odora cell line derived from olfactory sensory neurons and heterologously expressing Ox1R or Ox2R. We have demonstrated by western blot and RT-PCR that multiple components of adenylyl cyclase (AC) and phospholipase C (PLC) signalling pathways were identical in OM and Odora cells. OxA and OxB induced a weak increase in IP3 in OM; they induced a significant rise in cAMP and IP3 in Odora transfected cells, suggesting the activation of AC and PLC pathways. Both OxA and OxB induced intracellular calcium elevation and transient activation of MAP kinases (ERK42/44) in Odora/Ox1R and Odora/Ox2R cells. These results suggest the existence of multiple orexins signalling pathways in Odora cells and probably in OM, corresponding to different possible roles of these peptides.

  20. Signaling network of dendritic cells in response to pathogens: a community-input supported knowledgebase

    Directory of Open Access Journals (Sweden)

    Nudelman Irina


    Full Text Available Abstract Background Dendritic cells are antigen-presenting cells that play an essential role in linking the innate and adaptive immune systems. Much research has focused on the signaling pathways triggered upon infection of dendritic cells by various pathogens. The high level of activity in the field makes it desirable to have a pathway-based resource to access the information in the literature. Current pathway diagrams lack either comprehensiveness, or an open-access editorial interface. Hence, there is a need for a dependable, expertly curated knowledgebase that integrates this information into a map of signaling networks. Description We have built a detailed diagram of the dendritic cell signaling network, with the goal of providing researchers with a valuable resource and a facile method for community input. Network construction has relied on comprehensive review of the literature and regular updates. The diagram includes detailed depictions of pathways activated downstream of different pathogen recognition receptors such as Toll-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors and nucleotide-binding oligomerization domain-like receptors. Initially assembled using CellDesigner software, it provides an annotated graphical representation of interactions stored in Systems Biology Mark-up Language. The network, which comprises 249 nodes and 213 edges, has been web-published through the Biological Pathway Publisher software suite. Nodes are annotated with PubMed references and gene-related information, and linked to a public wiki, providing a discussion forum for updates and corrections. To gain more insight into regulatory patterns of dendritic cell signaling, we analyzed the network using graph-theory methods: bifan, feedforward and multi-input convergence motifs were enriched. This emphasis on activating control mechanisms is consonant with a network that subserves persistent and coordinated responses to

  1. Quantifying signal dispersion in a hybrid ice core melting system. (United States)

    Breton, Daniel J; Koffman, Bess G; Kurbatov, Andrei V; Kreutz, Karl J; Hamilton, Gordon S


    We describe a microcontroller-based ice core melting and data logging system allowing simultaneous depth coregistration of a continuous flow analysis (CFA) system (for microparticle and conductivity measurement) and a discrete sample analysis system (for geochemistry and microparticles), both supplied from the same melted ice core section. This hybrid melting system employs an ice parcel tracking algorithm which calculates real-time sample transport through all portions of the meltwater handling system, enabling accurate (1 mm) depth coregistration of all measurements. Signal dispersion is analyzed using residence time theory, experimental results of tracer injection tests and antiparallel melting of replicate cores to rigorously quantify the signal dispersion in our system. Our dispersion-limited resolution is 1.0 cm in ice and ~2 cm in firn. We experimentally observe the peak lead phenomenon, where signal dispersion causes the measured CFA peak associated with a given event to be depth assigned ~1 cm shallower than the true event depth. Dispersion effects on resolution and signal depth assignment are discussed in detail. Our results have implications for comparisons of chemistry and physical properties data recorded using multiple instruments and for deconvolution methods of enhancing CFA depth resolution.

  2. The histidine kinase AHK5 integrates endogenous and environmental signals in Arabidopsis guard cells.

    Directory of Open Access Journals (Sweden)

    Radhika Desikan

    Full Text Available BACKGROUND: Stomatal guard cells monitor and respond to environmental and endogenous signals such that the stomatal aperture is continually optimised for water use efficiency. A key signalling molecule produced in guard cells in response to plant hormones, light, carbon dioxide and pathogen-derived signals is hydrogen peroxide (H(2O(2. The mechanisms by which H(2O(2 integrates multiple signals via specific signalling pathways leading to stomatal closure is not known. PRINCIPAL FINDINGS: Here, we identify a pathway by which H(2O(2, derived from endogenous and environmental stimuli, is sensed and transduced to effect stomatal closure. Histidine kinases (HK are part of two-component signal transduction systems that act to integrate environmental stimuli into a cellular response via a phosphotransfer relay mechanism. There is little known about the function of the HK AHK5 in Arabidopsis thaliana. Here we report that in addition to the predicted cytoplasmic localisation of this protein, AHK5 also appears to co-localise to the plasma membrane. Although AHK5 is expressed at low levels in guard cells, we identify a unique role for AHK5 in stomatal signalling. Arabidopsis mutants lacking AHK5 show reduced stomatal closure in response to H(2O(2, which is reversed by complementation with the wild type gene. Over-expression of AHK5 results in constitutively less stomatal closure. Abiotic stimuli that generate endogenous H(2O(2, such as darkness, nitric oxide and the phytohormone ethylene, also show reduced stomatal closure in the ahk5 mutants. However, ABA caused closure, dark adaptation induced H(2O(2 production and H(2O(2 induced NO synthesis in mutants. Treatment with the bacterial pathogen associated molecular pattern (PAMP flagellin, but not elf peptide, also exhibited reduced stomatal closure and H(2O(2 generation in ahk5 mutants. SIGNIFICANCE: Our findings identify an integral signalling function for AHK5 that acts to integrate multiple signals via H

  3. Calcium and cell death signaling in neurodegeneration and aging. (United States)

    Smaili, Soraya; Hirata, Hanako; Ureshino, Rodrigo; Monteforte, Priscila T; Morales, Ana P; Muler, Mari L; Terashima, Juliana; Oseki, Karen; Rosenstock, Tatiana R; Lopes, Guiomar S; Bincoletto, Claudia


    Transient increase in cytosolic (Cac2+) and mitochondrial Ca2+ (Ca m2+) are essential elements in the control of many physiological processes. However, sustained increases in Ca c2+ and Ca m2+ may contribute to oxidative stress and cell death. Several events are related to the increase in Ca m2+, including regulation and activation of a number of Ca2+ dependent enzymes, such as phospholipases, proteases and nucleases. Mitochondria and endoplasmic reticulum (ER) play pivotal roles in the maintenance of intracellular Ca2+ homeostasis and regulation of cell death. Several lines of evidence have shown that, in the presence of some apoptotic stimuli, the activation of mitochondrial processes may lead to the release of cytochrome c followed by the activation of caspases, nuclear fragmentation and apoptotic cell death. The aim of this review was to show how changes in calcium signaling can be related to the apoptotic cell death induction. Calcium homeostasis was also shown to be an important mechanism involved in neurodegenerative and aging processes.

  4. Heparan Sulfate Proteoglycans Regulate Fgf Signaling and Cell Polarity during Collective Cell Migration

    Directory of Open Access Journals (Sweden)

    Marina Venero Galanternik


    Full Text Available Collective cell migration is a highly regulated morphogenetic movement during embryonic development and cancer invasion that involves the precise orchestration and integration of cell-autonomous mechanisms and environmental signals. Coordinated lateral line primordium migration is controlled by the regulation of chemokine receptors via compartmentalized Wnt/β-catenin and fibroblast growth factor (Fgf signaling. Analysis of mutations in two exostosin glycosyltransferase genes (extl3 and ext2 revealed that loss of heparan sulfate (HS chains results in a failure of collective cell migration due to enhanced Fgf ligand diffusion and loss of Fgf signal transduction. Consequently, Wnt/β-catenin signaling is activated ectopically, resulting in the subsequent loss of the chemokine receptor cxcr7b. Disruption of HS proteoglycan (HSPG function induces extensive, random filopodia formation, demonstrating that HSPGs are involved in maintaining cell polarity in collectively migrating cells. The HSPGs themselves are regulated by the Wnt/β-catenin and Fgf pathways and thus are integral components of the regulatory network that coordinates collective cell migration with organ specification and morphogenesis.

  5. Systemic Acquired Resistance and Signal Transduction in Plant

    Institute of Scientific and Technical Information of China (English)

    ZHAO Shu-qing; GUO Jian-bo


    Systemic acquired resistance (SAR), known as the broad-spectrum, inducible plant immunity,is a defense response triggered by pathogen infection. The response starts from the recognition of plant resist-ance (R) with the corresponding avirulence (avr) gene from the pathogen. There are some genes for conver-gence of signals downstream of different R/avr interacting partners into a single signaling pathway. Salicylicacid (SA) is required for the induction of SAR and involved in transducing the signal in target tissues. The SAsignal is transduced through NPR1, a nuclear-localized protein that interacts with transcription factors thatare involved in regulating SA-mediated gene expression. Some chemicals that mimic natural signaling com-pounds can also activate SAR. The application of biochemical activators to agriculture for plant protection is anovel idea for developing green chemical pesticide.

  6. Canonical Wnt signaling promotes early hematopoietic progenitor formation and erythroid specification during embryonic stem cell differentiation.

    Directory of Open Access Journals (Sweden)

    Anuradha Tarafdar

    Full Text Available The generation of hematopoietic stem cells (HSCs during development is a complex process linked to morphogenic signals. Understanding this process is important for regenerative medicine applications that require in vitro production of HSC. In this study we investigated the effects of canonical Wnt/β-catenin signaling during early embryonic differentiation and hematopoietic specification using an embryonic stem cell system. Our data clearly demonstrates that following early differentiation induction, canonical Wnt signaling induces a strong mesodermal program whilst maintaining a degree of stemness potential. This involved a complex interplay between β-catenin/TCF/LEF/Brachyury/Nanog. β-catenin mediated up-regulation of TCF/LEF resulted in enhanced brachyury levels, which in-turn lead to Nanog up-regulation. During differentiation, active canonical Wnt signaling also up-regulated key transcription factors and cell specific markers essential for hematopoietic specification, in particular genes involved in establishing primitive erythropoiesis. This led to a significant increase in primitive erythroid colony formation. β-catenin signaling also augmented early hematopoietic and multipotent progenitor (MPP formation. Following culture in a MPP specific cytokine cocktail, activation of β-catenin suppressed differentiation of the early hematopoietic progenitor population, with cells displaying a higher replating capacity and a propensity to form megakaryocytic erythroid progenitors. This bias towards erythroid lineage commitment was also observed when hematopoietic progenitors were directed to undergo myeloid colony formation. Overall this study underscores the importance of canonical Wnt/β-catenin signaling in mesodermal specification, primitive erythropoiesis and early hematopietic progenitor formation during hematopoietic induction.

  7. Canonical Wnt signaling promotes early hematopoietic progenitor formation and erythroid specification during embryonic stem cell differentiation. (United States)

    Tarafdar, Anuradha; Dobbin, Edwina; Corrigan, Pamela; Freeburn, Robin; Wheadon, Helen


    The generation of hematopoietic stem cells (HSCs) during development is a complex process linked to morphogenic signals. Understanding this process is important for regenerative medicine applications that require in vitro production of HSC. In this study we investigated the effects of canonical Wnt/β-catenin signaling during early embryonic differentiation and hematopoietic specification using an embryonic stem cell system. Our data clearly demonstrates that following early differentiation induction, canonical Wnt signaling induces a strong mesodermal program whilst maintaining a degree of stemness potential. This involved a complex interplay between β-catenin/TCF/LEF/Brachyury/Nanog. β-catenin mediated up-regulation of TCF/LEF resulted in enhanced brachyury levels, which in-turn lead to Nanog up-regulation. During differentiation, active canonical Wnt signaling also up-regulated key transcription factors and cell specific markers essential for hematopoietic specification, in particular genes involved in establishing primitive erythropoiesis. This led to a significant increase in primitive erythroid colony formation. β-catenin signaling also augmented early hematopoietic and multipotent progenitor (MPP) formation. Following culture in a MPP specific cytokine cocktail, activation of β-catenin suppressed differentiation of the early hematopoietic progenitor population, with cells displaying a higher replating capacity and a propensity to form megakaryocytic erythroid progenitors. This bias towards erythroid lineage commitment was also observed when hematopoietic progenitors were directed to undergo myeloid colony formation. Overall this study underscores the importance of canonical Wnt/β-catenin signaling in mesodermal specification, primitive erythropoiesis and early hematopietic progenitor formation during hematopoietic induction.

  8. 1st International Conference on Signal, Networks, Computing, and Systems

    CERN Document Server

    Mohapatra, Durga; Nagar, Atulya; Sahoo, Manmath


    The book is a collection of high-quality peer-reviewed research papers presented in the first International Conference on Signal, Networks, Computing, and Systems (ICSNCS 2016) held at Jawaharlal Nehru University, New Delhi, India during February 25–27, 2016. The book is organized in to two volumes and primarily focuses on theory and applications in the broad areas of communication technology, computer science and information security. The book aims to bring together the latest scientific research works of academic scientists, professors, research scholars and students in the areas of signal, networks, computing and systems detailing the practical challenges encountered and the solutions adopted.

  9. Wearable System for Acquisition and Monitoring of Biological Signals (United States)

    Piccinini, D. J.; Andino, N. B.; Ponce, S. D.; Roberti, MA; López, y. N.


    This paper presents a modular, wearable system for acquisition and wireless transmission of biological signals. Configurable slaves for different signals (such as ECG, EMG, inertial sensors, and temperature) based in the ADS1294 Medical Analog Front End are connected to a Master, based in the CC3200 microcontroller, both from Texas Instruments. The slaves are configurable according to the specific application, providing versatility to the wearable system. The battery consumption is reduced, through a couple of Li-ion batteries and the circuit has also a battery charger. A custom made box was designed and fabricated in a 3D printer, preserving the requirements of low cost, low weight and safety recommendations.

  10. [Regulation of in vitro and in vivo differentiation of mouse embryonic stem cells, embryonic germ cells, and teratocarcinoma cells by TGFb family signaling factors]. (United States)

    Gordeeva, O F; Nikonova, T M; Lifantseva, N V


    The activity of specific signaling and transcription factors determines the cell fate in normal development and in tumor transformation. The transcriptional profiles of gene-components of different branches of TGFbeta family signaling pathways were studied in experimental models of initial stages of three-dimensional in vitro differentiation of embryonic stem cells, embryonic germ cells and teratocarcinoma cells and in teratomas and teratocarcinomas developed after their transplantation into immunodeficient Nude mice. Gene profile analysis of studied cell systems have revealed that expression patterns of ActivinA, Nodal, Lefty1, Lefty2, TGF TGFbeta1, BMP4, and GDF were identical in pluripotent stem cells whereas the mRNAs of all examined genes with the exception of Inhibin betaA/ActivinA were detected in the teratocarcinoma cells. These results indicate that differential activity of signaling pathways of the TGFbeta family factors regulates pluripotent state maintenance and pluripotent stem cell differentiation into the progenitors of three germ layers and extraembryonic structures and that normal expression pattern of TGFbeta family factors is rearranged in embryonic teratocarcinoma cells during tumor growth in vitro and in vivo.

  11. Resolving Early Signaling Events in T-Cell Activation Leading to IL-2 and FOXP3 Transcription

    Directory of Open Access Journals (Sweden)

    Jeffrey P. Perley


    Full Text Available Signal intensity and feedback regulation are known to be major factors in the signaling events stemming from the T-cell receptor (TCR and its various coreceptors, but the exact nature of these relationships remains in question. We present a mathematical model of the complex signaling network involved in T-cell activation with cross-talk between the Erk, calcium, PKC and mTOR signaling pathways. The model parameters are adjusted to fit new and published data on TCR trafficking, Zap70, calcium, Erk and Isignaling. The regulation of the early signaling events by phosphatases, CD45 and SHP1, and the TCR dynamics are critical to determining the behavior of the model. Additional model corroboration is provided through quantitative and qualitative agreement with experimental data collected under different stimulating and knockout conditions. The resulting model is analyzed to investigate how signal intensity and feedback regulation affect TCR- and coreceptor-mediated signal transduction and their downstream transcriptional profiles to predict the outcome for a variety of stimulatory and knockdown experiments. Analysis of the model shows that: (1 SHP1 negative feedback is necessary for preventing hyperactivity in TCR signaling; (2 CD45 is required for TCR signaling, but also partially suppresses it at high expression levels; and (3 elevated FOXP3 and reduced IL-2 signaling, an expression profile often associated with T regulatory cells (Tregs, is observed when the system is subjected to weak TCR and CD28 costimulation or a severe reduction in CD45 activity.

  12. Continuous monitoring of membrane protein micro-domain association during cell signaling

    CERN Document Server

    Huang, Heng


    Central to understanding membrane bound cell signaling is to quantify how the membrane ultra-structure consisting of transient spatial domains modulates signaling and how the signaling influences this ultra-structure. Yet, measuring the association of membrane proteins with domains in living, intact cells poses considerable challenges. Here, we describe a non-destructive method to quantify protein-lipid domain and protein cytoskeleton interactions in single, intact cells enabling continuous monitoring of the protein domains interaction over time during signaling.

  13. Control of microRNA biogenesis and transcription by cell signaling pathways



    A limited set of cell-cell signaling pathways presides over the vast majority of animal developmental events. The typical raison d'etre for signal transduction is to control the transcription of protein-coding genes. However, with the recent appreciation of microRNAs, growing attention has been paid towards understanding how signaling pathways intertwine with microRNA-mediated regulation. This review highlights recent studies that uncover unexpected modes of microRNA regulation by cell signal...

  14. RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells. (United States)

    Dayal, Shubham; Zhou, Jun; Manivannan, Praveen; Siddiqui, Mohammad Adnan; Ahmad, Omaima Farid; Clark, Matthew; Awadia, Sahezeel; Garcia-Mata, Rafael; Shemshedini, Lirim; Malathi, Krishnamurthy


    The interferon antiviral pathways and prostate cancer genetics converge on a regulated endoribonuclease, RNase L. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 (HPC1) to RNASEL. To date, there is no correlation of viral infections with prostate cancer, suggesting that RNase L may play additional roles in tumor suppression. Here, we demonstrate a role of RNase L as a suppressor of androgen receptor (AR) signaling, cell migration and matrix metalloproteinase activity. Using RNase L mutants, we show that its nucleolytic activity is dispensable for both AR signaling and migration. The most prevalent HPC1-associated mutations in RNase L, R462Q and E265X, enhance AR signaling and cell migration. RNase L negatively regulates cell migration and attachment on various extracellular matrices. We demonstrate that RNase L knockdown cells promote increased cell surface expression of integrin β1 which activates Focal Adhesion Kinase-Sarcoma (FAK-Src) pathway and Ras-related C3 botulinum toxin substrate 1-guanosine triphosphatase (Rac1-GTPase) activity to increase cell migration. Activity of matrix metalloproteinase (MMP)-2 and -9 is significantly increased in cells where RNase L levels are ablated. We show that mutations in RNase L found in HPC patients may promote prostate cancer by increasing expression of AR-responsive genes and cell motility and identify novel roles of RNase L as a prostate cancer susceptibility gene.

  15. Suofu Qin’s work on studies of cell survival signaling in cancer and epithelial cells

    Institute of Scientific and Technical Information of China (English)


    Reactive oxygen species (ROS) encompass a variety of diverse chemical species including superoxide anions, hydrogen peroxide, hydroxyl radicals and peroxynitrite, which are mainly produced via mitochondrial oxidative metabolism, enzymatic reactions, and light-initiated lipid peroxidation. Over-production of ROS and/or decrease in the antioxidant capacity cause cells to undergo oxi- dative stress that damages cellular macromolecules such as proteins, lipids, and DNA. Oxidative stress is associated with ageing and the development of agerelated diseases such as cancer and age-related macular degeneration. ROS activate signaling pathways that promote cell survival or lead to cell death, depending on the source and site of ROS production, the specific ROS generated, the concentration and kinetics of ROS generation, and the cell types being challenged. However, how the nature and compartmentalization of ROS contribute to the pathogenesis of individual diseases is poorly understood. Consequently, it is crucial to gain a comprehensive understanding of the molecular bases of cell oxidative stress signaling, which will then provide novel therapeutic opportunities to interfere with disease progression via targeting specific signaling pathways.Currently, Dr. Qin’s work is focused on inflammatory and oxidative stress responses using the retinal pigment epithelial (RPE) cells as a model. The study of RPE cell inflammatory and oxidative stress responses has successfully led to a better understanding of RPE cell biology and identification of potential therapeutic targets.

  16. Menin expression is regulated by transforming growth factor beta signaling in leukemia cells

    Institute of Scientific and Technical Information of China (English)

    ZHANG Hui; LIU Zu-guo; HUA Xian-xin


    Background Menin is a ubiquitously expressed protein encoded by the multiple endocrine neoplasia type 1 (MEN1)gene. Besides its importance in endocrine organs, menin has been shown to interact with the mixed lineage leukemia (MLL) protein, a histone H3 lysine 4 methyltransferase, and plays a critical role in hematopoiesis and leukemogenesis.Previous studies have shown that menin promotes transforming growth factor beta (TGF-β) signaling in endocrine cells.However, little is known regarding the impact of TGF-β pathway on menin in hematopoietic system. Here, with leukemia cell lines generated from conditional MEN1 or TGF-p receptor (TβRII) knockout mouse models, we investigated the possible cross-talk of these two pathways in leukemia cells.Methods MEN1 or TβRII conditional knockout mice were bred and the bone marrow cells were transduced with retroviruses expressing oncogeneic MLL-AF9 (a mixed lineage leukemia fusion protein) to generate two leukemia cell lines. Cell proliferation assays were performed to investigate the effect of TGF-β treatment on MLL-AF9 transformed leukemia cells with/without MEN1 or TβRII excision. Menin protein was detected with Western blotting and mRNA levels of cell proliferation-related genes Cyclin A2 and Cyclin E2 were examined with real-time RT-PCR for each treated sample.In vivo effect of TGF-p signal on menin expression was also investigated in mouse liver tissue after TβRII excision.Results TGF-β not only inhibited the proliferation of wild type MLL-AF9 transformed mouse bone marrow cells, but also up-regulated menin expression in these cells. Moreover, TGF-P failed to further inhibit the proliferation of Men1-null cells as compared to Men1-expressing control cells. Furthermore, excision of TβRII, a vital component in TGF-β signaling pathway, down-regulated menin expression in MLL-AF9 transformed mouse bone marrow cells. In vivo data also confirmed that menin expression was decreased in liver samples of conditional T

  17. Molecular signatures of the primitive prostate stem cell niche reveal novel mesenchymal-epithelial signaling pathways.

    Directory of Open Access Journals (Sweden)

    Roy Blum

    Full Text Available BACKGROUND: Signals between stem cells and stroma are important in establishing the stem cell niche. However, very little is known about the regulation of any mammalian stem cell niche as pure isolates of stem cells and their adjacent mesenchyme are not readily available. The prostate offers a unique model to study signals between stem cells and their adjacent stroma as in the embryonic prostate stem cell niche, the urogenital sinus mesenchyme is easily separated from the epithelial stem cells. Here we investigate the distinctive molecular signals of these two stem cell compartments in a mammalian system. METHODOLOGY/PRINCIPAL FINDINGS: We isolated fetal murine urogenital sinus epithelium and urogenital sinus mesenchyme and determined their differentially expressed genes. To distinguish transcripts that are shared by other developing epithelial/mesenchymal compartments from those that pertain to the prostate stem cell niche, we also determined the global gene expression of epidermis and dermis of the same embryos. Our analysis indicates that several of the key transcriptional components that are predicted to be active in the embryonic prostate stem cell niche regulate processes such as self-renewal (e.g., E2f and Ap2, lipid metabolism (e.g., Srebp1 and cell migration (e.g., Areb6 and Rreb1. Several of the enriched promoter binding motifs are shared between the prostate epithelial/mesenchymal compartments and their epidermis/dermis counterparts, indicating their likely relevance in epithelial/mesenchymal signaling in primitive cellular compartments. Based on differential gene expression we also defined ligand-receptor interactions that may be part of the molecular interplay of the embryonic prostate stem cell niche. CONCLUSIONS/SIGNIFICANCE: We provide a comprehensive description of the transcriptional program of the major regulators that are likely to control the cellular interactions in the embryonic prostatic stem cell niche, many of which may

  18. Calcium signaling properties of a thyrotroph cell line, mouse TαT1 cells. (United States)

    Tomić, Melanija; Bargi-Souza, Paula; Leiva-Salcedo, Elias; Nunes, Maria Tereza; Stojilkovic, Stanko S


    TαT1 cells are mouse thyrotroph cell line frequently used for studies on thyroid-stimulating hormone beta subunit gene expression and other cellular functions. Here we have characterized calcium-signaling pathways in TαT1 cells, an issue not previously addressed in these cells and incompletely described in native thyrotrophs. TαT1 cells are excitable and fire action potentials spontaneously and in response to application of thyrotropin-releasing hormone (TRH), the native hypothalamic agonist for thyrotrophs. Spontaneous electrical activity is coupled to small amplitude fluctuations in intracellular calcium, whereas TRH stimulates both calcium mobilization from intracellular pools and calcium influx. Non-receptor-mediated depletion of intracellular pool also leads to a prominent facilitation of calcium influx. Both receptor and non-receptor stimulated calcium influx is substantially attenuated but not completely abolished by inhibition of voltage-gated calcium channels, suggesting that depletion of intracellular calcium pool in these cells provides a signal for both voltage-independent and -dependent calcium influx, the latter by facilitating the pacemaking activity. These cells also express purinergic P2Y1 receptors and their activation by extracellular ATP mimics TRH action on calcium mobilization and influx. The thyroid hormone triiodothyronine prolongs duration of TRH-induced calcium spikes during 30-min exposure. These data indicate that TαT1 cells are capable of responding to natively feed-forward TRH signaling and intrapituitary ATP signaling with acute calcium mobilization and sustained calcium influx. Amplification of TRH-induced calcium signaling by triiodothyronine further suggests the existence of a pathway for positive feedback effects of thyroid hormones probably in