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Sample records for active eph controls

  1. PTP-PEST controls EphA3 activation and ephrin-induced cytoskeletal remodelling.

    Mansour, Mariam; Nievergall, Eva; Gegenbauer, Kristina; Llerena, Carmen; Atapattu, Lakmali; Hallé, Maxime; Tremblay, Michel L; Janes, Peter W; Lackmann, Martin

    2016-01-15

    Eph receptors and their corresponding membrane-bound ephrin ligands regulate cell positioning and establish tissue patterns during embryonic and oncogenic development. Emerging evidence suggests that assembly of polymeric Eph signalling clusters relies on cytoskeletal reorganisation and underlies regulation by protein tyrosine phosphatases (PTPs). PTP-PEST (also known as PTPN12) is a central regulator of actin cytoskeletal dynamics. Here, we demonstrate that an N-terminal fragment of PTP-PEST, generated through an ephrinA5-triggered and spatially confined cleavage mediated by caspase-3, attenuates EphA3 receptor activation and its internalisation. Isolation of EphA3 receptor signalling clusters within intact plasma membrane fragments obtained by detergent-free cell fractionation reveals that stimulation of cells with ephrin triggers effective recruitment of this catalytically active truncated form of PTP-PEST together with key cytoskeletal and focal adhesion proteins. Importantly, modulation of actin polymerisation using pharmacological and dominant-negative approaches affects EphA3 phosphorylation in a similar manner to overexpression of PTP-PEST. We conclude that PTP-PEST regulates EphA3 activation both by affecting cytoskeletal remodelling and through its direct action as a PTP controlling EphA3 phosphorylation, indicating its multifaceted regulation of Eph signalling. PMID:26644181

  2. Reelin induces EphB activation

    Elisabeth Bouché; Mario I Romero-Ortega; Mark Henkemeyer; Timothy Catchpole; Jost Leemhuis; Michael Frotscher; Petra May

    2013-01-01

    The integration of newborn neurons into functional neuronal networks requires migration of cells to their final position in the developing brain,the growth and arborization of neuronal processes and the formation of synaptic contacts with other neurons.A central player among the signals that coordinate this complex sequence of differentiation events is the secreted glycoprotein Reelin,which also modulates synaptic plasticity,learning and memory formation in the adult brain.Binding of Reelin to ApoER2 and VLDL receptor,two members of the LDL receptor family,initiates a signaling cascade involving tyrosine phosphorylation of the intracellular cytoplasmic adaptor protein Disabled-l,which targets the neuronal cytoskeleton and ultimately controls the positioning of neurons throughout the developing brain.However,it is possible that Reelin signals interact with other receptor-mediated signaling cascades to regulate different aspects of brain development and plasticity.EphB tyrosine kinases regulate cell adhesion and repulsion-dependent processes via bidirectional signaling through ephrin B transmembrane proteins.Here,we demonstrate that Reelin binds to the extracellular domains of EphB transmembrane proteins,inducing receptor clustering and activation of EphB forward signaling in neurons,independently of the ‘classical' Reelin receptors,ApoER2 and VLDLR.Accordingly,mice lacking EphB1 and EphB2 display a positioning defect of CA3 hippocampal pyramidal neurons,similar to that in Reelin-deficient mice,and this cell migration defect depends on the kinase activity of EphB proteins.Together,our data provide biochemical and functional evidence for signal integration between Reelin and EphB forward signaling.

  3. Lithocholic acid is an Eph-ephrin ligand interfering with Eph-kinase activation.

    Carmine Giorgio

    Full Text Available Eph-ephrin system plays a central role in a large variety of human cancers. In fact, alterated expression and/or de-regulated function of Eph-ephrin system promotes tumorigenesis and development of a more aggressive and metastatic tumour phenotype. In particular EphA2 upregulation is correlated with tumour stage and progression and the expression of EphA2 in non-transformed cells induces malignant transformation and confers tumorigenic potential. Based on these evidences our aim was to identify small molecules able to modulate EphA2-ephrinA1 activity through an ELISA-based binding screening. We identified lithocholic acid (LCA as a competitive and reversible ligand inhibiting EphA2-ephrinA1 interaction (Ki =  49 µM. Since each ephrin binds many Eph receptors, also LCA does not discriminate between different Eph-ephrin binding suggesting an interaction with a highly conserved region of Eph receptor family. Structurally related bile acids neither inhibited Eph-ephrin binding nor affected Eph phosphorylation. Conversely, LCA inhibited EphA2 phosphorylation induced by ephrinA1-Fc in PC3 and HT29 human prostate and colon adenocarcinoma cell lines (IC(50  = 48 and 66 µM, respectively without affecting cell viability or other receptor tyrosine-kinase (EGFR, VEGFR, IGFR1β, IRKβ activity. LCA did not inhibit the enzymatic kinase activity of EphA2 at 100 µM (LANCE method confirming to target the Eph-ephrin protein-protein interaction. Finally, LCA inhibited cell rounding and retraction induced by EphA2 activation in PC3 cells. In conclusion, our findings identified a hit compound useful for the development of molecules targeting ephrin system. Moreover, as ephrin signalling is a key player in the intestinal cell renewal, our work could provide an interesting starting point for further investigations about the role of LCA in the intestinal homeostasis.

  4. EphA4 expression promotes network activity and spine maturation in cortical neuronal cultures

    Clifford Meredith A

    2011-05-01

    Full Text Available Abstract Background Neurons form specific connections with targets via synapses and patterns of synaptic connectivity dictate neural function. During development, intrinsic neuronal specification and environmental factors guide both initial formation of synapses and strength of resulting connections. Once synapses form, non-evoked, spontaneous activity serves to modulate connections, strengthening some and eliminating others. Molecules that mediate intercellular communication are particularly important in synaptic refinement. Here, we characterize the influences of EphA4, a transmembrane signaling molecule, on neural connectivity. Results Using multi-electrode array analysis on in vitro cultures, we confirmed that cortical neurons mature and generate spontaneous circuit activity as cells differentiate, with activity growing both stronger and more patterned over time. When EphA4 was over-expressed in a subset of neurons in these cultures, network activity was enhanced: bursts were longer and were composed of more spikes than in control-transfected cultures. To characterize the cellular basis of this effect, dendritic spines, the major excitatory input site on neurons, were examined on transfected neurons in vitro. Strikingly, while spine number and density were similar between conditions, cortical neurons with elevated levels of EphA4 had significantly more mature spines, fewer immature spines, and elevated colocalization with a mature synaptic marker. Conclusions These results demonstrate that experimental elevation of EphA4 promotes network activity in vitro, supporting spine maturation, producing more functional synaptic pairings, and promoting more active circuitry.

  5. Cell adhesion and EGFR activation regulate EphA2 expression in cancer

    Larsen, Alice Bjerregaard; Stockhausen, Marie-Thérése; Poulsen, Hans Skovgaard

    2010-01-01

    largely unknown. Here we show that the expression of EphA2 in in vitro cultured cells, is restricted to cells growing adherently and that adhesion-induced EphA2 expression is dependent upon activation of the epidermal growth factor receptor (EGFR), mitogen activated protein kinase kinase (MEK) and Src...... family kinases (SRC). Moreover, the results show that adhesion-induced EGFR activation and EphA2 expression is affected by interactions with extracellular matrix (ECM) proteins working as integrin ligands. Stimulation with the EphA2 ligand, ephrinA1 inhibited ERK phosphorylation and cancer cell viability....... These effects were however abolished by activation of the EGF-receptor ligand system favoring Ras/MAPK signaling and cell proliferation. Based on our results, we propose a regulatory mechanism where cell adhesion induces EGFR kinase activation and EphA2 expression; and where the effect of ephrinA1...

  6. EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion

    Sikkema, Arend H.; den Dunnen, Wilfred F. A.; Hulleman, Esther; van Vuurden, Dannis G.; Garcia-Manero, Guillermo; Yang, Hui; Scherpen, Frank J. G.; Kampen, Kim R.; Hoving, Eelco W.; Kamps, Willem A.; Diks, Sander H.; Peppelenbosch, Maikel P.; de Bont, Eve Line S. J. M.

    2012-01-01

    Eph/ephrin signaling has bcen implicated in various types of key cancer-enhancing processes, like migration, proliferation, and angiogenesis. In medulloblastoma, invading tumor cells characteristically lead to early recurrence and a decreased prognosis. Based on kinase-activity profiling data publis

  7. Hypoxia-controlled EphA3 marks a human endometrium-derived multipotent mesenchymal stromal cell that supports vascular growth.

    Catherine To

    Full Text Available Eph and ephrin proteins are essential cell guidance cues that orchestrate cell navigation and control cell-cell interactions during developmental tissue patterning, organogenesis and vasculogenesis. They have been extensively studied in animal models of embryogenesis and adult tissue regeneration, but less is known about their expression and function during human tissue and organ regeneration. We discovered the hypoxia inducible factor (HIF-1α-controlled expression of EphA3, an Eph family member with critical functions during human tumour progression, in the vascularised tissue of regenerating human endometrium and on isolated human endometrial multipotent mesenchymal stromal cells (eMSCs, but not in other highly vascularised human organs. EphA3 affinity-isolation from human biopsy tissue yielded multipotent CD29+/CD73+/CD90+/CD146+ eMSCs that can be clonally propagated and respond to EphA3 agonists with EphA3 phosphorylation, cell contraction, cell-cell segregation and directed cell migration. EphA3 silencing significantly inhibited the ability of transplanted eMSCs to support neovascularisation in immunocompromised mice. In accord with established roles of Eph receptors in mediating interactions between endothelial and perivascular stromal cells during mouse development, our findings suggest that HIF-1α-controlled expression of EphA3 on human MSCs functions during the hypoxia-initiated early stages of adult blood vessel formation.

  8. Hypoxia-controlled EphA3 marks a human endometrium-derived multipotent mesenchymal stromal cell that supports vascular growth.

    To, Catherine; Farnsworth, Rae H; Vail, Mary E; Chheang, Chanly; Gargett, Caroline E; Murone, Carmel; Llerena, Carmen; Major, Andrew T; Scott, Andrew M; Janes, Peter W; Lackmann, Martin

    2014-01-01

    Eph and ephrin proteins are essential cell guidance cues that orchestrate cell navigation and control cell-cell interactions during developmental tissue patterning, organogenesis and vasculogenesis. They have been extensively studied in animal models of embryogenesis and adult tissue regeneration, but less is known about their expression and function during human tissue and organ regeneration. We discovered the hypoxia inducible factor (HIF)-1α-controlled expression of EphA3, an Eph family member with critical functions during human tumour progression, in the vascularised tissue of regenerating human endometrium and on isolated human endometrial multipotent mesenchymal stromal cells (eMSCs), but not in other highly vascularised human organs. EphA3 affinity-isolation from human biopsy tissue yielded multipotent CD29+/CD73+/CD90+/CD146+ eMSCs that can be clonally propagated and respond to EphA3 agonists with EphA3 phosphorylation, cell contraction, cell-cell segregation and directed cell migration. EphA3 silencing significantly inhibited the ability of transplanted eMSCs to support neovascularisation in immunocompromised mice. In accord with established roles of Eph receptors in mediating interactions between endothelial and perivascular stromal cells during mouse development, our findings suggest that HIF-1α-controlled expression of EphA3 on human MSCs functions during the hypoxia-initiated early stages of adult blood vessel formation. PMID:25420155

  9. Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor

    Alessio Lodola

    2013-10-01

    Full Text Available The Eph–ephrin system plays a critical role in tumor growth and vascular functions during carcinogenesis. We had previously identified cholanic acid as a competitive and reversible EphA2 antagonist able to disrupt EphA2-ephrinA1 interaction and to inhibit EphA2 activation in prostate cancer cells. Herein, we report the synthesis and biological evaluation of a set of cholanic acid derivatives obtained by conjugation of its carboxyl group with a panel of naturally occurring amino acids with the aim to improve EphA2 receptor inhibition. Structure-activity relationships indicate that conjugation of cholanic acid with linear amino acids of small size leads to effective EphA2 antagonists whereas the introduction of aromatic amino acids reduces the potency in displacement studies. The b-alanine derivative 4 was able to disrupt EphA2-ephrinA1 interaction in the micromolar range and to dose-dependently inhibit EphA2 activation on PC3 cells. These findings may help the design of novel EphA2 antagonists active on cancer cell lines.

  10. Anti-EphA2 Antibodies Decrease EphA2 Protein Levels in Murine CT26 Colorectal and Human MDA-231 Breast Tumors But Do Not Inhibit Tumor Growth

    David Kiewlich

    2006-01-01

    Full Text Available The EphA2 receptor tyrosine kinase has been shown to be over-expressed in cancer and a monoclonal antibody (mAb that activates and down-modulates EphA2 was reported to inhibit the growth of human breast and lung tumor xenografts in nude mice. Reduction of EphA2 levels by treatment with anti-EphA2 siRNA also inhibited tumor growth, suggesting that the anti-tumor effects of these agents are mediated by decreasing the levels of EphA2. As these studies employed human tumor xenograft models in nude mice with reagents whose crossreactivity with murine EphA2 is unknown, we generated a mAb (Ab20 that preferentially binds, activates, and induces the degradation of murine EphA2. Treatment of established murine CT26 colorectal tumors with Ab20 reduced EphA2 protein levels to ~12% of control tumor levels, yet had no effect on tumor growth. CT26 tumor cell colonization of the lung was also not affected by Ab20 administration despite having barely detectable levels of EphA2. We also generated and tested a potent agonistic mAb against human EphA2 (1G9-H7. No inhibition of human MDA-231 breast tumor xenograft growth was observed despite evidence for >85% reduction of EphA2 protein levels in the tumors. These results suggest that molecular characteristics of the tumors in addition to EphA2 over-expression may be important for predicting responsiveness to EphA2-directed therapies.

  11. Ligand stimulation induces clathrin- and Rab5-dependent downregulation of the kinase-dead EphB6 receptor preceded by the disruption of EphB6-Hsp90 interaction.

    Allonby, Odette; El Zawily, Amr M; Freywald, Tanya; Mousseau, Darrell D; Chlan, Jennifer; Anderson, Deborah; Benmerah, Alexandre; Sidhu, Vishaldeep; Babu, Mohan; DeCoteau, John; Freywald, Andrew

    2014-12-01

    Ligand-induced internalisation and subsequent downregulation of receptor tyrosine kinases (RTKs) serve to determine biological outputs of their signalling. Intrinsically kinase-deficient RTKs control a variety of biological responses, however, the mechanism of their downregulation is not well understood and its analysis is focused exclusively on the ErbB3 receptor. The Eph group of RTKs is represented by the EphA and EphB subclasses. Each bears one kinase-inactive member, EphA10 and EphB6, respectively, suggesting an important role for these molecules in the Eph signalling network. While EphB6 effects on cell behaviour have been assessed, the mechanism of its downregulation remains elusive. Our work reveals that EphB6 and its kinase-active relative, and signalling partner, EphB4, are downregulated in a similar manner in response to their common ligand, ephrin-B2. Following stimulation, both receptors are internalised through clathrin-coated pits and are degraded in lysosomes. Their targeting for lysosomal degradation relies on the activity of an early endosome regulator, the Rab5 GTPase, as this process is inhibited in the presence of a Rab5 dominant-negative mutant. EphB6 also interacts with the Hsp90 chaperone and EphB6 downregulation is preceded by their rapid dissociation. Moreover, the inhibition of Hsp90 results in EphB6 degradation, mimicking its ligand-induced downregulation. These processes appear to rely on overlapping mechanisms, since Hsp90 inhibition does not significantly enhance ligand-induced EphB6 elimination. Taken together, our observations define a novel mechanism for intrinsically kinase-deficient RTK downregulation and support an intriguing model, where Hsp90 dissociation acts as a trigger for ligand-induced receptor removal. PMID:25152371

  12. Activation of EphA4 and EphB2 reverse signaling restores the age-associated reduction of self-renewal, migration and actin turnover in human tendon stem/progenitor cells.

    Cvetan ePopov

    2016-01-01

    Full Text Available Tendon tissues, due to their composition and function, are prone to suffer age-related degeneration and diseases as well as to poorly respond to current repair strategies. It has been suggested that local stem cells, named tendon stem/progenitor cells (TSPC, play essential roles in tendon maintenance and healing. Recently, we have shown that TSPC exhibit a distinct age-related phenotype involving transcriptomal shift, poor self-renewal and elevated senescence coupled with reduced cell migration and actin dynamics. Here, we report for the first time the significant downregulation of the ephrin receptors EphA4, EphB2 and B4 and ligands EFNB1 in aged-TSPC (A-TSPC. Rescue experiments, by delivery of target-specific clustered proteins, revealed that activation of EphA4- or EphB2-dependent reverse signaling could restore the migratory ability and normalize the actin turnover of A-TSPC. However, only EphA4-Fc stimulation improved A-TSPC cell proliferation to levels comparable to young-TSPC (Y-TSPC. Hence, our novel data suggests that decreased expression of ephrin receptors during tendon aging and degeneration limits the establishment of appropriate cell-cell interactions between TSPC and significantly diminished their proliferation, motility and actin turnover. Taken together, we could propose that this mechanism might be contributing to the inferior and delayed tendon healing common for aged individuals.

  13. EphA4 Activation of c-Abl Mediates Synaptic Loss and LTP Blockade Caused by Amyloid-β Oligomers

    M. Vargas, Lina; Leal, Nancy; Estrada, Lisbell D.; González, Adrian; Serrano, Felipe; Araya, Katherine; Gysling, Katia; Inestrosa, Nibaldo C.; Pasquale, Elena B.; Alvarez, Alejandra R.

    2014-01-01

    The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-β oligomers (AβOs) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for AβOs-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by AβOs. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to AβOs, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to AβOs. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by AβOs. According to this results, the EphA4 antagonistic peptide KYL and c-Abl inhibitor STI prevented i) dendritic spine reduction, ii) the blocking of LTP induction and iii) neuronal apoptosis caused by AβOs. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by AβOs. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by AβOs. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients. PMID:24658113

  14. Multimodal Eph/Ephrin signaling controls several phases of urogenital development.

    Peuckert, Christiane; Aresh, Bejan; Holenya, Pavlo; Adams, Derek; Sreedharan, Smitha; Porthin, Annika; Andersson, Louise; Pettersson, Hanna; Wölfl, Stefan; Klein, Rüdiger; Oxburgh, Leif; Kullander, Klas

    2016-08-01

    A substantial portion of the human population is affected by urogenital birth defects resulting from a failure in ureter development. Although recent research suggests roles for several genes in facilitating the ureter/bladder connection, the underlying molecular mechanisms remain poorly understood. Signaling via Eph receptor tyrosine kinases is involved in several developmental processes. Here we report that impaired Eph/Ephrin signaling in genetically modified mice results in severe hydronephrosis caused by defective ureteric bud induction, ureter maturation, and translocation. Our data imply that ureter translocation requires apoptosis in the urogenital sinus and inhibition of proliferation in the common nephric duct. These processes were disturbed in EphA4/EphB2 compound knockout mice and were accompanied by decreased ERK-2 phosphorylation. Using a set of Eph, Ephrin, and signaling-deficient mutants, we found that during urogenital development, different modes of Eph/Ephrin signaling occur at several sites with EphrinB2 and EphrinA5 acting in concert. Thus, Eph/Ephrin signaling should be considered in the etiology of congenital kidney and urinary tract anomalies. PMID:27344203

  15. EphA2 Mutation in Lung Squamous Cell Carcinoma Promotes Increased Cell Survival, Cell Invasion, Focal Adhesions, and Mammalian Target of Rapamycin Activation*

    Faoro, Leonardo; Singleton, Patrick A.; Cervantes, Gustavo M.; Lennon, Frances E.; Choong, Nicholas W.; Kanteti, Rajani; Ferguson, Benjamin D.; Husain, Aliya N.; Tretiakova, Maria S.; Ramnath, Nithya; Vokes, Everett E.; Salgia, Ravi

    2010-01-01

    Non-small cell lung cancer (NSCLC) has a poor prognosis and improved therapies are needed. Expression of EphA2 is increased in NSCLC metastases. In this study, we investigated EphA2 mutations in NSCLC and examined molecular pathways involved in NSCLC. Tumor and cell line DNA was sequenced. One EphA2 mutation was modeled by expression in BEAS2B cells, and functional and biochemical studies were conducted. A G391R mutation was detected in H2170 and 2/28 squamous cell carcinoma patient samples. EphA2 G391R caused constitutive activation of EphA2 with increased phosphorylation of Src, cortactin, and p130Cas. Wild-type (WT) and G391R cells had 20 and 40% increased invasiveness; this was attenuated with knockdown of Src, cortactin, or p130Cas. WT and G391R cells demonstrated a 70% increase in focal adhesion area. Mammalian target of rapamycin (mTOR) phosphorylation was increased in G391R cells with increased survival (55%) compared with WT (30%) and had increased sensitivity to rapamycin. A recurrent EphA2 mutation is present in lung squamous cell carcinoma and increases tumor invasion and survival through activation of focal adhesions and actin cytoskeletal regulatory proteins as well as mTOR. Further study of EphA2 as a therapeutic target is warranted. PMID:20360610

  16. EphA2 mutation in lung squamous cell carcinoma promotes increased cell survival, cell invasion, focal adhesions, and mammalian target of rapamycin activation.

    Faoro, Leonardo; Singleton, Patrick A; Cervantes, Gustavo M; Lennon, Frances E; Choong, Nicholas W; Kanteti, Rajani; Ferguson, Benjamin D; Husain, Aliya N; Tretiakova, Maria S; Ramnath, Nithya; Vokes, Everett E; Salgia, Ravi

    2010-06-11

    Non-small cell lung cancer (NSCLC) has a poor prognosis and improved therapies are needed. Expression of EphA2 is increased in NSCLC metastases. In this study, we investigated EphA2 mutations in NSCLC and examined molecular pathways involved in NSCLC. Tumor and cell line DNA was sequenced. One EphA2 mutation was modeled by expression in BEAS2B cells, and functional and biochemical studies were conducted. A G391R mutation was detected in H2170 and 2/28 squamous cell carcinoma patient samples. EphA2 G391R caused constitutive activation of EphA2 with increased phosphorylation of Src, cortactin, and p130(Cas). Wild-type (WT) and G391R cells had 20 and 40% increased invasiveness; this was attenuated with knockdown of Src, cortactin, or p130(Cas). WT and G391R cells demonstrated a 70% increase in focal adhesion area. Mammalian target of rapamycin (mTOR) phosphorylation was increased in G391R cells with increased survival (55%) compared with WT (30%) and had increased sensitivity to rapamycin. A recurrent EphA2 mutation is present in lung squamous cell carcinoma and increases tumor invasion and survival through activation of focal adhesions and actin cytoskeletal regulatory proteins as well as mTOR. Further study of EphA2 as a therapeutic target is warranted. PMID:20360610

  17. Vaccination with EphA2-derived T cell-epitopes promotes immunity against both EphA2-expressing and EphA2-negative tumors

    Hatano Manabu

    2004-11-01

    Full Text Available Abstract Background A novel tyrosine kinase receptor EphA2 is expressed at high levels in advanced and metastatic cancers. We examined whether vaccinations with synthetic mouse EphA2 (mEphA2-derived peptides that serve as T cell epitopes could induce protective and therapeutic anti-tumor immunity. Methods C57BL/6 mice received subcutaneous (s.c. vaccinations with bone marrow-derived dendritic cells (DCs pulsed with synthetic peptides recognized by CD8+ (mEphA2671–679, mEphA2682–689 and CD4+ (mEphA230–44 T cells. Splenocytes (SPCs were harvested from primed mice to assess the induction of cytotoxic T lymphocyte (CTL responses against syngeneic glioma, sarcoma and melanoma cell lines. The ability of these vaccines to prevent or treat tumor (s.c. injected MCA205 sarcoma or B16 melanoma; i.v. injected B16-BL6 establishment/progression was then assessed. Results Immunization of C57BL/6 mice with mEphA2-derived peptides induced specific CTL responses in SPCs. Vaccination with mEPhA2 peptides, but not control ovalbumin (OVA peptides, prevented the establishment or prevented the growth of EphA2+ or EphA2-negative syngeneic tumors in both s.c. and lung metastasis models. Conclusions These data indicate that mEphA2 can serve as an attractive target against which to direct anti-tumor immunity. The ability of mEphA2 vaccines to impact EphA2-negative tumors such as the B16 melanoma may suggest that such beneficial immunity may be directed against alternative EphA2+ target cells, such as the tumor-associated vascular endothelial cells.

  18. EphB4 as a therapeutic target in mesothelioma

    Malignant pleural mesothelioma (MPM) often develops decades following exposure to asbestos. Current best therapy produces a response in only half of patients, and the median survival with this therapy remains under a year. A search for novel targets and therapeutics is underway, and recently identified targets include VEGF, Notch, and EphB4-Ephrin-B2. Each of these targets has dual activity, promoting tumor cell growth as well as tumor angiogenesis. We investigated EphB4 expression in 39 human mesothelioma tissues by immunohistochemistry. Xenograft tumors established with human mesothelioma cells were treated with an EphB4 inhibitor (monomeric soluble EphB4 fused to human serum albumin, or sEphB4-HSA). The combinatorial effect of sEphB4-HSA and biologic agent was also studied. EphB4 was overexpressed in 72% of mesothelioma tissues evaluated, with 85% of epithelioid and 38% of sarcomatoid subtypes demonstrating overexpression. The EphB4 inhibitor sEphB4-HSA was highly active as a single agent to inhibit tumor growth, accompanied by tumor cell apoptosis and inhibition of PI3K and Src signaling. Combination of sEphB4-HSA and the anti-VEGF antibody (Bevacizumab) was superior to each agent alone and led to complete tumor regression. EphB4 is a potential therapeutic target in mesothelioma. Clinical investigation of sEphB4-HSA as a single agent and in combination with VEGF inhibitors is warranted

  19. Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling

    North, Hilary A.; Zhao, Xiumei; Kolk, Sharon M.; Clifford, Meredith A.; Ziskind, Daniela M.; Donoghue, Maria J.

    2009-01-01

    Summary Eph receptors are widely expressed during cerebral cortical development, yet a role for Eph signaling in the generation of cells during corticogenesis has not been shown. Cortical progenitor cells selectively express one receptor, EphA4, and reducing EphA4 signaling in cultured progenitors suppressed proliferation, decreasing cell number. In vivo, EphA4-/- cortex had a reduced area, fewer cells and less cell division compared with control cortex. To understand the effects of EphA4 signaling in corticogenesis, EphA4-mediated signaling was selectively depressed or elevated in cortical progenitors in vivo. Compared with control cells, cells with reduced EphA4 signaling were rare and mitotically inactive. Conversely, overexpression of EphA4 maintained cells in their progenitor states at the expense of subsequent maturation, enlarging the progenitor pool. These results support a role for EphA4 in the autonomous promotion of cell proliferation during corticogenesis. Although most ephrins were undetectable in cortical progenitors, ephrin B1 was highly expressed. Our analyses demonstrate that EphA4 and ephrin B1 bind to each other, thereby initiating signaling. Furthermore, overexpression of ephrin B1 stimulated cell division of neighboring cells, supporting the hypothesis that ephrin B1-initiated forward signaling of EphA4 promotes cortical cell division. PMID:19542359

  20. Coordinated Eph-ephrin signaling guides migration and axon targeting in the avian auditory system

    Allen-Sharpley Michelle R

    2012-08-01

    Full Text Available Abstract Background In the avian sound localization circuit, nucleus magnocellularis (NM projects bilaterally to nucleus laminaris (NL, with ipsilateral and contralateral NM axon branches directed to dorsal and ventral NL dendrites, respectively. We previously showed that the Eph receptor EphB2 is expressed in NL neuropil and NM axons during development. Here we tested whether EphB2 contributes to NM-NL circuit formation. Results We found that misexpression of EphB2 in embryonic NM precursors significantly increased the number of axon targeting errors from NM to contralateral NL in a cell-autonomous manner when forward signaling was impaired. We also tested the effects of inhibiting forward signaling of different Eph receptor subclasses by injecting soluble unclustered Fc-fusion proteins at stages when NM axons are approaching their NL target. Again we found an increase in axon targeting errors compared to controls when forward signaling was impaired, an effect that was significantly increased when both Eph receptor subclasses were inhibited together. In addition to axon targeting errors, we also observed morphological abnormalities of the auditory nuclei when EphB2 forward signaling was increased by E2 transfection, and when Eph-ephrin forward signaling was inhibited by E6-E8 injection of Eph receptor fusion proteins. Conclusions These data suggest that EphB signaling has distinct functions in axon guidance and morphogenesis. The results provide evidence that multiple Eph receptors work synergistically in the formation of precise auditory circuitry.

  1. Inhibition of VEGF-Dependent Multistage Carcinogenesis by Soluble EphA Receptors

    Nikki Cheng

    2003-09-01

    Full Text Available Elevated expression of Eph receptors has long been correlated with the growth of solid tumors. However, the functional role of this family of receptor tyrosine kinases in carcinogenesis and tumor angiogenesis has not been well characterized. Here we report that soluble EphA receptors inhibit tumor angiogenesis and tumor progression in vivo in the RIP-Tag transgenic model of vascular endothelial growth factor (VEGF-dependent multistage pancreatic islet cell carcinoma. Soluble EphA receptors delivered either by a transgene or an osmotic minipump inhibited the formation of angiogenic islet, a premalignant lesion, reduced tumor volume of solid islet cell carcinoma. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor volume but increased tumor and endothelial cell apoptosis in vivo. In addition, soluble EphA receptors inhibited VEGF and βTC tumor cell-conditioned medium-induced endothelial cell migration in vitro and VEGF-induced cornea angiogenesis in vivo. A dominant negative EphA2 mutant inhibited—whereas a gain-of-function EphA2 mutant enhanced—tumor cell-induced endothelial cell migration, suggesting that EphA2 receptor activation is required for tumor cell-endothelial cell interaction. These data provide functional evidence for EphA class receptor regulation of VEGF-dependent tumor angiogenesis, suggesting that the EphA signaling pathway may represent an attractive novel target for antiangiogenic therapy in cancer.

  2. Dancing with the dead: Eph receptors and their kinase-null partners.

    Truitt, Luke; Freywald, Andrew

    2011-04-01

    Eph receptor tyrosine kinases and their ligands, ephrins, are membrane proteins coordinating a wide range of biological functions both in developing embryos and in adult multicellular organisms. Numerous studies have implicated Eph receptors in the induction of opposing responses, including cell adhesion or repulsion, support or inhibition of cell proliferation and cell migration, and progression or suppression of multiple malignancies. Similar to other receptor tyrosine kinases, Eph receptors rely on their ability to catalyze tyrosine phosphorylation for signal transduction. Interestingly, however, Eph receptors also actively utilize three kinase-deficient receptor tyrosine kinases, EphB6, EphA10, and Ryk, in their signaling network. The accumulating evidence suggests that the unusual flexibility of the Eph family, allowing it to initiate antagonistic responses, might be partially explained by the influence of the kinase-dead participants and that the exact outcome of an Eph-mediated action is likely to be defined by the balance between the signaling of catalytically potent and catalytically null receptors. We discuss in this minireview the emerging functions of the kinase-dead EphB6, EphA10, and Ryk receptors both in normal biological responses and in malignancy, and analyze currently available information related to the molecular mechanisms of their action in the context of the Eph family. PMID:21455264

  3. Discovery and characterization of a novel cyclic peptide that effectively inhibits ephrin binding to the EphA4 receptor and displays anti-angiogenesis activity.

    Xiaofeng Han

    Full Text Available The EphA4 receptor tyrosine kinase regulates a variety of physiological and pathological processes during neural development and the formation of tumor blood vessels; thus, it represents a new and promising therapeutic target. We used a combination of phage peptide display and computer modeling/docking approaches and discovered a novel cyclic nonapeptide, now designated TYY. This peptide selectively inhibits the binding of the ephrinA5 ligand with EphA4 and significantly blocks angiogenesis in a 3D matrigel culture system. Molecular docking reveals that TYY recognizes the same binding pocket on EphA4 that the natural ephrin ligand binds to and that the Tyr3 and Tyr4 side chains of TYY are both critical for the TYY/EphA4 interaction. The discovery of TYY introduces a valuable probe of EphA4 function and a new lead for EphA4-targeted therapeutic development.

  4. Targeting EphA3 inhibits cancer growth by disrupting the tumor stromal microenvironment.

    Vail, Mary E; Murone, Carmel; Tan, April; Hii, Linda; Abebe, Degu; Janes, Peter W; Lee, Fook-Thean; Baer, Mark; Palath, Varghese; Bebbington, Christopher; Yarranton, Geoffrey; Llerena, Carmen; Garic, Slavisa; Abramson, David; Cartwright, Glenn; Scott, Andrew M; Lackmann, Martin

    2014-08-15

    Eph receptor tyrosine kinases are critical for cell-cell communication during normal and oncogenic tissue patterning and tumor growth. Somatic mutation profiles of several cancer genomes suggest EphA3 as a tumor suppressor, but its oncogenic expression pattern and role in tumorigenesis remain largely undefined. Here, we report unexpected EphA3 overexpression within the microenvironment of a range of human cancers and mouse tumor xenografts where its activation inhibits tumor growth. EphA3 is found on mouse bone marrow-derived cells with mesenchymal and myeloid phenotypes, and activation of EphA3(+)/CD90(+)/Sca1(+) mesenchymal/stromal cells with an EphA3 agonist leads to cell contraction, cell-cell segregation, and apoptosis. Treatment of mice with an agonistic α-EphA3 antibody inhibits tumor growth by severely disrupting the integrity and function of newly formed tumor stroma and microvasculature. Our data define EphA3 as a novel target for selective ablation of the tumor microenvironment and demonstrate the potential of EphA3 agonists for anticancer therapy. PMID:25125683

  5. Expression profile of Eph receptors and ephrin ligands in healthy human B lymphocytes and chronic lymphocytic leukemia B-cells.

    Alonso-C, Luis M; Trinidad, Eva M A; de Garcillan, Beatriz; Ballesteros, Monica; Castellanos, Milagros; Cotillo, Ignacio; Muñoz, Juan J; Zapata, Agustin G

    2009-03-01

    Increasing information relates some Eph receptors and their ligands, ephrins (EFN), with the immune system. Herein, we found that normal B-cells from peripheral blood (PB) and lymph nodes (LN) showed a differential expression of certain Eph/EFN members, some of them being modulated upon in vitro stimulation including EFNA1, EFNA4, EphB6 and EphA10. In contrast, PB CLL B-cells showed a more heterogeneous Eph/EFN profile than their normal PB B-cell counterparts, expressing Eph/EFN members frequently found within the LN and activated B-cells, specially EFNA4, EphB6 and EphA10. Two of them, EphB6 and EFNA4 were further related with the clinical course of CLL patients. EphB6 expression correlated with a high content of ZAP-70 mRNA and a poor prognosis. High serum levels of a soluble EFNA4 isoform positively correlated with increasing peripheral blood lymphocyte counts and lymphadenopathy. These findings suggest that Eph/EFN might be relevant in normal B-cell biology and could represent new potential prognostic markers and therapeutic targets for CLL. PMID:18819711

  6. Antibodies binding the ADAM10 substrate recognition domain inhibit Eph function.

    Atapattu, Lakmali; Saha, Nayanendu; Llerena, Carmen; Vail, Mary E; Scott, Andrew M; Nikolov, Dimitar B; Lackmann, Martin; Janes, Peter W

    2012-12-15

    The ADAM10 transmembrane metalloprotease cleaves a variety of cell surface proteins that are important in disease, including ligands for receptor tyrosine kinases of the erbB and Eph families. ADAM10-mediated cleavage of ephrins, the ligands for Eph receptors, is suggested to control Eph/ephrin-mediated cell-cell adhesion and segregation, important during normal developmental processes, and implicated in tumour neo-angiogenesis and metastasis. We previously identified a substrate-binding pocket in the ADAM10 C domain that binds the EphA/ephrin-A complex thereby regulating ephrin cleavage. We have now generated monoclonal antibodies specifically recognising this region of ADAM10, which inhibit ephrin cleavage and Eph/ephrin-mediated cell function, including ephrin-induced Eph receptor internalisation, phosphorylation and Eph-mediated cell segregation. Our studies confirm the important role of ADAM10 in cell-cell interactions mediated by both A- and B-type Eph receptors, and suggest antibodies against the ADAM10 substrate-recognition pocket as promising therapeutic agents, acting by inhibiting cleavage of ephrins and potentially other ADAM10 substrates. PMID:23108669

  7. Evidence that the EphA2 receptor exacerbates ischemic brain injury.

    John Thundyil

    Full Text Available Ephrin (Eph signaling within the central nervous system is known to modulate axon guidance, synaptic plasticity, and to promote long-term potentiation. We investigated the potential involvement of EphA2 receptors in ischemic stroke-induced brain inflammation in a mouse model of focal stroke. Cerebral ischemia was induced in male C57Bl6/J wild-type (WT and EphA2-deficient (EphA2(-/- mice by middle cerebral artery occlusion (MCAO; 60 min, followed by reperfusion (24 or 72 h. Brain infarction was measured using triphenyltetrazolium chloride staining. Neurological deficit scores and brain infarct volumes were significantly less in EphA2(-/- mice compared with WT controls. This protection by EphA2 deletion was associated with a comparative decrease in brain edema, blood-brain barrier damage, MMP-9 expression and leukocyte infiltration, and higher expression levels of the tight junction protein, zona occludens-1. Moreover, EphA2(-/- brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3 and BAX, and higher levels of the anti-apoptotic protein, Bcl-2 as compared to WT group. We confirmed that isolated WT cortical neurons express the EphA2 receptor and its ligands (ephrin-A1-A3. Furthermore, expression of all four proteins was increased in WT primary cortical neurons following 24 h of glucose deprivation, and in the brains of WT mice following stroke. Glucose deprivation induced less cell death in primary neurons from EphA2(-/- compared with WT mice. In conclusion, our data provide the first evidence that the EphA2 receptor directly contributes to blood-brain barrier damage and neuronal death following ischemic stroke.

  8. Generation and characterization of a bispecific diabody targeting both EPH receptor A10 and CD3.

    Kamada, Haruhiko; Taki, Shintaro; Nagano, Kazuya; Inoue, Masaki; Ando, Daisuke; Mukai, Yohei; Higashisaka, Kazuma; Yoshioka, Yasuo; Tsutsumi, Yasuo; Tsunoda, Shin-ichi

    2015-01-24

    The EPH receptor A10 (EphA10) is up-regulated in breast cancer but is not normally expressed in healthy tissue, thus it has been suggested that EphA10 may be a useful target for cancer therapy. This study reports a diabody, an antibody derivative binding two different target molecules, EphA10 expressed in tumor cells and CD3 expressed in T cells, which showed T cell dependent-cytotoxicity. The diabody, which has His-tagged and FLAG-tagged chains, was expressed in Escherichia coli and purified in both heterodimer (Db-1) and homodimer (Db-2) formulations by liquid chromatography. Flow cytometry analysis using EphA10-expressing cells showed that binding activity of heterodimers was stronger than that of homodimers. Addition of diabodies to PBMC cultures resulted in T-cell mediated redirected lysis, and the bioactivity was consistent with the stronger binding activity of heterodimeric diabody formulations. Our results indicate that diabodies recognizing both EphA10 and CD3 could have a range of potential applications in cancer therapy, such as breast cancers that express the EPH receptor A10, especially triple negative breast cancer. PMID:25528586

  9. Exosomes mediate cell contact-independent ephrin-Eph signaling during axon guidance.

    Gong, Jingyi; Körner, Roman; Gaitanos, Louise; Klein, Rüdiger

    2016-07-01

    The cellular release of membranous vesicles known as extracellular vesicles (EVs) or exosomes represents a novel mode of intercellular communication. Eph receptor tyrosine kinases and their membrane-tethered ephrin ligands have very important roles in such biologically diverse processes as neuronal development, plasticity, and pathological diseases. Until now, it was thought that ephrin-Eph signaling requires direct cell contact. Although the biological functions of ephrin-Eph signaling are well understood, our mechanistic understanding remains modest. Here we report the release of EVs containing Ephs and ephrins by different cell types, a process requiring endosomal sorting complex required for transport (ESCRT) activity and regulated by neuronal activity. Treatment of cells with purified EphB2(+) EVs induces ephrinB1 reverse signaling and causes neuronal axon repulsion. These results indicate a novel mechanism of ephrin-Eph signaling independent of direct cell contact and proteolytic cleavage and suggest the participation of EphB2(+) EVs in neural development and synapse physiology. PMID:27354374

  10. Characterization of a novel Eph receptor tyrosine kinase, EphA10, expressed in testis.

    Aasheim, Hans-Christian; Patzke, Sebastian; Hjorthaug, Hanne Sagsveen; Finne, Eivind Farmen

    2005-05-25

    In mammals, 14 members of the Eph receptor tyrosine kinase family have been described so far. Here we present a not yet described member of this family denoted EphA10. We report the identification of three putative EphA10 isoforms: one soluble and two transmembrane isoforms. One of the latter isoforms lacked the sterile alpha motif commonly found in Eph receptors. The gene encoding EphA10 is located on chromosome 1p34 and expression studies show that EphA10 mRNA is mainly expressed in testis. Binding studies to ephrin ligands suggests that this receptor belongs to the EphA subclass of Eph receptors binding mainly to ephrin-A ligands. PMID:15777695

  11. Impaired EphA4 signaling leads to congenital hydronephrosis, renal injury, and hypertension

    Sällström, Johan; Peuckert, Christiane; Gao, Xiang; Larsson, Erik; Nilsson, Anders; Jensen, Boye L; Onozato, Maristela L; Persson, A Erik G; Kullander, Klas; Carlström, Mattias

    2013-01-01

    and renal injuries, similar to that of experimental hydronephrosis. Ultrasound and Doppler techniques were used to visualize renal impairment in the adult mice. Telemetric blood pressure measurements were performed in EphA4(gf/gf) mice and littermate controls (EphA4(+/+)) during normal (0.7% Na......Experimental hydronephrosis induced by partial ureteral obstruction at 3 wk of age causes hypertension and renal impairment in adult rats and mice. Signaling by Ephrin receptors (Eph) and their ligands (ephrins) importantly regulates embryonic development. Genetically modified mice, where the...

  12. EphB2 in the Medial Prefrontal Cortex Regulates Vulnerability to Stress.

    Zhang, Ruo-Xi; Han, Ying; Chen, Chen; Xu, Ling-Zhi; Li, Jia-Li; Chen, Na; Sun, Cheng-Yu; Chen, Wen-Hao; Zhu, Wei-Li; Shi, Jie; Lu, Lin

    2016-09-01

    The ephrin B2 (EphB2) receptor is a tyrosine kinase receptor that is associated with synaptic development and maturation. It has recently been implicated in cognitive deficits and anxiety. However, still unknown is the involvement of EphB2 in the vulnerability to stress. In the present study, we observed decreases in EphB2 levels and their downstream molecules in the medial prefrontal cortex (mPFC) but not in the orbitofrontal cortex (OFC) in mice that were susceptible to chronic social defeat stress. The activation of EphB2 receptors with EphrinB1-Fc in the mPFC produced stress-resistant and antidepressant-like behavioral effects in susceptible mice that lasted for at least 10 days. EphB2 receptor knockdown by short-hairpin RNA in the mPFC increased the susceptibility to stress and induced depressive-like behaviors in a subthreshold chronic social defeat stress paradigm. These behavioral effects were associated with changes in the phosphorylation of cofilin and membrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking and the expression of some synaptic proteins in the mPFC. We also found that EphB2 regulated stress-induced spine remodeling in the mPFC. Altogether, these results indicate that EphB2 is a critical regulator of stress vulnerability and might be a potential target for the treatment of depression. PMID:27103064

  13. Cell-specific information processing in segregating populations of Eph receptor ephrin-expressing cells

    Jørgensen, Claus; Sherman, Andrew; Chen, Ginny I; Pasculescu, Adrian; Poliakov, Alexei; Hsiung, Marilyn; Larsen, Brett; Wilkinson, David G; Linding, Rune; Pawson, Tony

    2009-01-01

    Cells have self-organizing properties that control their behavior in complex tissues. Contact between cells expressing either B-type Eph receptors or their transmembrane ephrin ligands initiates bidirectional signals that regulate cell positioning. However, simultaneously investigating how...... information is processed in two interacting cell types remains a challenge. We implemented a proteomic strategy to systematically determine cell-specific signaling networks underlying EphB2- and ephrin-B1-controlled cell sorting. Quantitative mass spectrometric analysis of mixed populations of EphB2- and...... revealed that signaling between mixed EphB2- and ephrin-B1-expressing cells is asymmetric and that the distinct cell types use different tyrosine kinases and targets to process signals induced by cell-cell contact. We provide systems- and cell-specific network models of contact-initiated signaling between...

  14. Does Rac GTPase Play a Role in EphA4 Signaling in Xenopus Embroys?

    Durand, Ashley

    2008-01-01

    Full Text Available In embryonic development, many cells migrate in order to correctly form new structures. One way that guidance of this migration occurs is via a repulsion mechanism involving the Eph family of receptors. Signaling through these receptors activates the repulsive mechanism that limits which tissues can interact with each other. The repulsion mechanism is not well understood, but involves the reorganization of the actin cytoskeleton and a loss of cell-cell adhesion. Activation of the EphA4 signaling pathway in Xenopus laevis embryos has been shown to cause the repulsion mechanism. the Rho family of GTPases consisting of Cdc42, Rho, and Rac, has been linked to the reorganization of the actin cytoskeleton and Rho has been demonstrated to be part of the EphA4 pathway. The hypothesis to be tested in this study is that activation of Rac is also part of the EphA4 pathway. To test this hypothesis, mutant Rac RNA coding for constitutively active Rac (caRac was injected into Xenopus laevis embryos to determine if Rac activation can mimic EphA4 signaling. As the concentration of RNA coding for caRac increased, the degree of cellular dissociation also increased. While further experimentation must be doe to make a conclusive determination, it is possible that the activation of Rac is a part of EphA4 signaling.

  15. Exosomes expand the sphere of influence of Eph receptors and ephrins.

    Pasquale, Elena B

    2016-07-01

    Membrane-anchored Eph receptors and ephrins represent a ubiquitous intercellular communication system that typically engages at sites of cell-cell contact to initiate bidirectional signaling. Gong et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201601085) show that cells can deploy the EphB2 receptor on exosomes to activate ephrinB signaling and collapse the growth cones of distant neurons. PMID:27354377

  16. EphA2 silencing in nasopharyngeal carcinoma leads to decreased proliferation, invasion and increased sensitization to paclitaxel.

    Tan, Pingqing; Liu, Yong; Yu, Changyun; Su, Zhongwu; Li, Guo; Zhou, Xiaojuan; Huang, Donghai; Zhang, Xin; Qiu, Yuanzheng; Tian, Yongquan

    2012-09-01

    EphA2 is frequently overexpressed and functionally altered in a variety of human cancers. However, its roles in human nasopharyngeal carcinoma (NPC) remain unclear. To investigate the roles of EphA2 in the development and progression of NPC, we initially evaluated the expression pattern of EphA2 protein in NPC tissues using western blotting and CCK-8 assay. Fluorescence-activated cell sorting analysis and invasion assay were conducted to observe the effects of EphA2 inhibition in vivo. Our results demonstrated that EphA2 was overexpressed in NPC specimens and the expression of EphA2 was significantly associated with T classification, advanced clinical stage and lymph node metastasis. Moreover, human NPC 5-8F cells were infected with lentiviral vector-mediated EphA2-specific shRNA, which resulted in the significant inhibition of cell growth, invasion of 5-8F cells and markedly enhanced the sensitivity of 5-8F cells to the chemotherapeutic agent paclitaxel in vitro. Collectively, our results demonstrate that EphA2 is involved in malignant cell behavior and is a potential therapeutic target in human NPC. PMID:23741245

  17. Comparative integromics on Eph family.

    Katoh, Masuko; Katoh, Masaru

    2006-05-01

    EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4 and EPHB6 are EPH family receptors for Ephrin family ligands. Ephrin/EPH signaling pathway networks with the WNT signaling pathway during embryogenesis, tissue regeneration, and carcinogenesis. TCF/LEF-binding sites within the promoter region of human EPH family members were searched for by using bioinformatics and human intelligence. Because five TCF/LEF-binding sites were identified within the 5'-promoter region of the EPHA7 gene, comparative genomics analyses on EPHA7 orthologs were further performed. EPHA7-MANEA-FHL5 locus at human chromosome 6q16.1 and EPHA10-MANEAL-FHL3 locus at human chromosome 1p34.3 were paralogous regions within the human genome. Human EPHA7 mRNA was expressed in embryonic stem (ES) cells, neural tissues, duodenal cancer and parathyroid tumors, while mouse Epha7 mRNA was expressed in fertilized egg, Rathke's pouche, visual cortex, pituitary gland, other neural tissues, pancreas, lung tumors and mammary tumors. The chimpanzee EPHA7 gene and cow Epha7 gene were identified within NW_107969.1 and AC155055.2 genome sequences, respectively. Five TCF/LEF-binding sites within human EPHA7 promoter were conserved in the chimpanzee EPHA7 promoter, and three TCF/LEF-binding sites in the cow Epha7 promoter, but none in the mouse Epha7 promoter. Primates and cow EPHA7 orthologs were identified as evolutionarily conserved targets of the WNT/beta-catenin signaling pathway. D6S1056 microsatellite marker within EPHA7 gene is deleted in prostate cancer. Deletion and/or promoter CpG hypermethylation could explain the EPHA7 down-regulation in human tumors. EPHA7 is a target of systems medicine, especially in the fields of regenerative medicine and oncology. PMID:16596241

  18. Interaction between EGFR and EphA2

    Larsen, Alice Bjerregaard

    2010-01-01

    including those originating from the brain, breast, cervix, colon, head and neck, kidney, lung, esophagus, ovary, prostate, skin and stomach. Moreover, high EphA2 expression has been correlated with increased tumor volume, short overall survival and increasing evidence also suggest that EphA2 is involved in......Enhanced or altered epidermal growth factor receptor (EGFR) activity has been reported in many human cancers and several molecular targeting therapies has been developed. However, despite intense research, therapies targeting EGFR have shown conflicting results in clinical studies, indicating the...... involvement of other important molecular players. Several different EGFR mutations have been reported in cancer, one of which is the cancer specific type III EGFR deletion mutant (EGFRvIII, de2-7EGFR, ¿EGFR). In a global search for EGFR and EGFRvIII regulated genes we identified the receptor tyrosine kinase...

  19. Expression and functional effects of Eph receptor tyrosine kinase A family members on Langerhans like dendritic cells

    Finne Eivind

    2004-06-01

    Full Text Available Abstract Background The Eph receptors are the largest receptor tyrosine kinase family. Several family members are expressed in hematopoietic cells. Previously, the expression of a member of this family, EphA2, was identified on dendritic like cells in tonsils. We therefore specifically examined the expression of EphA2 on in vitro generated dendritic cells. Results In this study, expression of the EphA2 receptor was identified on in vitro generated Langerhans like dendritic cells compared to in vitro generated dendritic cells. We show that ligand induced engagement of the EphA2 receptor leads to receptor autophosphorylation indicating a functional receptor signaling pathway in these cells. We also observe phosphorylation and dephosphorylation of distinct proteins following ligand activation of EphA receptors. In co-stimulation assays, receptor-ligand interaction reduces the capacity of the Langerhans like dendritic cells to stimulate resting CD4+ T cells. Conclusion Engagement of EphA receptor tyrosine kinases on Langerhans like dendritic cells induces signaling as shown by tyrosine phosphorylation and dephosphorylation of distinct proteins. Furthermore this engagement renders the cells less capable of stimulating CD4+ T cells.

  20. Restriction of Receptor Movement Alters Cellular Response: Physical Force Sensing by EphA2

    Salaita, Khalid; Nair, Pradeep M; Petit, Rebecca S; Neve, Richard M; Das, Debopriya; Gray, Joe W; Groves, Jay T

    2009-09-09

    Activation of the EphA2 receptor tyrosine kinase by ephrin-A1 ligands presented on apposed cell surfaces plays important roles in development and exhibits poorly understood functional alterations in cancer. We reconstituted this intermembrane signaling geometry between live EphA2-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1. Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EphA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EphA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease 10. Quantitative analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines reveals characteristic differences that strongly correlate with invasion potential. These observations reveal a mechanism for spatio-mechanical regulation of EphA2 signaling pathways.

  1. EphA receptors regulate prostate cancer cell dissemination through Vav2–RhoA mediated cell–cell repulsion

    Jennifer Batson

    2014-05-01

    Full Text Available Metastatic prostate cancer cells display EphB receptor-mediated attraction when they contact stromal fibroblasts but EphA-driven repulsion when they contact one another. The impact of these ‘social’ interactions between cells during cancer cell invasion and the signalling mechanisms downstream of Eph receptors are unclear. Here we show that EphA receptors regulate prostate cancer cell dissemination in a 2D dispersal assay and in a 3D cancer cell spheroid assay. We show that EphA receptors signal via the exchange factor Vav2 to activate RhoA and that both Vav2 and RhoA are required for prostate cancer cell–cell repulsion. Furthermore, we find that in EphA2/EphA4, Vav2 or RhoA siRNA-treated cells, contact repulsion can be restored by partial microtubule destabilisation. We propose that EphA–Vav2–RhoA-mediated repulsion between contacting cancer cells at the tumour edge could enhance their local invasion away from the primary tumour.

  2. Protein dynamics at Eph receptor-ligand interfaces as revealed by crystallography, NMR and MD simulations

    The role of dynamics in protein functions including signal transduction is just starting to be deciphered. Eph receptors with 16 members divided into A- and B- subclasses are respectively activated by 9 A- and B-ephrin ligands. EphA4 is the only receptor capable of binding to all 9 ephrins and small molecules with overlapped interfaces. We first determined the structures of the EphA4 ligand binding domain (LBD) in two crystals of P1 space group. Noticeably, 8 EphA4 molecules were found in one asymmetric unit and consequently from two crystals we obtained 16 structures, which show significant conformational variations over the functionally critical A-C, D-E, G-H and J-K loops. The 16 new structures, together with previous 9 ones, can be categorized into two groups: closed and open forms which resemble the uncomplexed and complexed structures of the EphA4 LBD respectively. To assess whether the conformational diversity over the loops primarily results from the intrinsic dynamics, we initiated 30-ns molecular dynamics (MD) simulations for both closed and open forms. The results indicate that the loops do have much higher intrinsic dynamics, which is further unravelled by NMR H/D exchange experiments. During simulations, the open form has the RMS deviations slightly larger than those of the closed one, suggesting the open form may be less stable in the absence of external contacts. Furthermore, no obvious exchange between two forms is observed within 30 ns, implying that they are dynamically separated. Our study provides the first experimental and computational result revealing that the intrinsic dynamics are most likely underlying the conformational diversity observed for the EphA4 LBD loops mediating the binding affinity and specificity. Interestingly, the open conformation of the EphA4 LBD is slightly unstable in the absence of it natural ligand ephrins, implying that the conformational transition from the closed to open has to be driven by the high

  3. EphA7在炎症状态下人牙髓组织中的表达和意义%Expression and significance of EphA7 in inflamed human dental pulp

    赵俊杰; 兰卫东; 董迎春

    2015-01-01

    AIM:To investigate the role of EphA7 gene in pulp inflammation and odontogenic pain. METHODS:18 healthy controls,18 asymptomatic and 18 symptomatic irreversible pulpitis human dental pulps were included in the study.The protein expression of EphA7 was detected by immunohistochemistry and western blotting re-spectively.RESULTS:In healthy samples,immunohistochemical staining showed that positive EphA7 expression was only in vascular endothelial cells and odontoblasts.In the inflammatory pulps ,EphA7 expression increased significant-ly.In addition to vascular endothelial cells and odontoblasts,EphA7 positive staining was also detected in fibroblasts, inflammatory cells and nerve fiber tissues.Western blotting analysis showed that EphA7 expression increased signifi-cantly in pulpitis samples compared with healthy controls.In symptomatic irreversible pulpitis samples,EphA7 expres-sion was significantly higher than those in asymptomatic ones.CONCLUSION:EphA7 gene may be a marker reflec-ting inflammatory and pain state of human dental pulp.%目的:探讨EphA7基因在牙髓的炎症反应和牙源性疼痛中的作用及意义。方法:收集健康牙髓、具有疼痛症状的牙髓炎牙髓和无疼痛症状的牙髓炎牙髓各18例,分别采用免疫组化染色和Western印迹法检测EphA7蛋白在不同状态牙髓组织中的表达水平。结果:免疫组化染色显示:EphA7在健康牙髓中仅阳性表达于血管内皮细胞和成牙本质细胞;而在炎症牙髓中,EphA7的表达显著升高,除阳性表达于上述细胞外,同时还阳性表达于成纤维细胞、炎症细胞以及神经纤维组织中。Western印迹法检测结果显示:与健康牙髓相比,牙髓炎牙髓中EphA7蛋白的表达水平显著增高(P<0.05),具有疼痛症状的牙髓中EphA7蛋白的表达水平显著高于无疼痛症状的牙髓(P<0.05)。结论:EphA7基因可能是反映牙髓组织炎症活动和疼痛状态的一个标记物。

  4. EphB2 SNPs and sporadic prostate cancer risk in African American men.

    Christiane M Robbins

    Full Text Available The EphB2 gene has been implicated as a tumor suppressor gene somatically altered in both prostate cancer (PC and colorectal cancer. We have previously shown an association between an EphB2 germline nonsense variant and risk of familial prostate cancer among African American Men (AAM. Here we set out to test the hypothesis that common variation within the EphB2 locus is associated with increased risk of sporadic PC in AAM. We genotyped a set of 341 single nucleotide polymorphisms (SNPs encompassing the EphB2 locus, including known and novel coding and noncoding variants, in 490 AA sporadic PC cases and 567 matched controls. Single marker-based logistical regression analyses revealed seven EphB2 SNPs showing statistically significant association with prostate cancer risk in our population. The most significant association was achieved for a novel synonymous coding SNP, TGen-624, (Odds Ratio (OR  = 0.22; 95% Confidence Interval (CI 0.08-0.66, p = 1×10(-5. Two other SNPs also show significant associations toward a protective effect rs10465543 and rs12090415 (p = 1×10(-4, OR = 0.49 and 0.7, respectively. Two additional SNPs revealed trends towards an increase in risk of prostate cancer, rs4612601 and rs4263970 (p = 0.001, OR = 1.35 and 1.31, respectively. Furthermore, haplotype analysis revealed low levels of linkage disequilibrium within the region, with two blocks being associated with prostate cancer risk among our population. These data suggest that genetic variation at the EphB2 locus may increase risk of sporadic PC among AAM.

  5. Differential roles for EphA and EphB signaling in segregation and patterning of central vestibulocochlear nerve projections.

    Michelle R Allen-Sharpley

    Full Text Available Auditory and vestibular afferents enter the brainstem through the VIIIth cranial nerve and find targets in distinct brain regions. We previously reported that the axon guidance molecules EphA4 and EphB2 have largely complementary expression patterns in the developing avian VIIIth nerve. Here, we tested whether inhibition of Eph signaling alters central targeting of VIIIth nerve axons. We first identified the central compartments through which auditory and vestibular axons travel. We then manipulated Eph-ephrin signaling using pharmacological inhibition of Eph receptors and in ovo electroporation to misexpress EphA4 and EphB2. Anterograde labeling of auditory afferents showed that inhibition of Eph signaling did not misroute axons to non-auditory target regions. Similarly, we did not find vestibular axons within auditory projection regions. However, we found that pharmacologic inhibition of Eph receptors reduced the volume of the vestibular projection compartment. Inhibition of EphB signaling alone did not affect auditory or vestibular central projection volumes, but it significantly increased the area of the auditory sensory epithelium. Misexpression of EphA4 and EphB2 in VIIIth nerve axons resulted in a significant shift of dorsoventral spacing between the axon tracts, suggesting a cell-autonomous role for the partitioning of projection areas along this axis. Cochlear ganglion volumes did not differ among treatment groups, indicating the changes seen were not due to a gain or loss of cochlear ganglion cells. These results suggest that Eph-ephrin signaling does not specify auditory versus vestibular targets but rather contributes to formation of boundaries for patterning of inner ear projections in the hindbrain.

  6. A Novel Extracellular Hsp90 Mediated Co-Receptor Function for LRP1 Regulates EphA2 Dependent Glioblastoma Cell Invasion

    Udhayakumar Gopal; Bohonowych, Jessica E.; Carla Lema-Tome; Angen Liu; Elizabeth Garrett-Mayer; Bingcheng Wang; Isaacs, Jennifer S.

    2011-01-01

    BACKGROUND: Extracellular Hsp90 protein (eHsp90) potentiates cancer cell motility and invasion through a poorly understood mechanism involving ligand mediated function with its cognate receptor LRP1. Glioblastoma multiforme (GBM) represents one of the most aggressive and lethal brain cancers. The receptor tyrosine kinase EphA2 is overexpressed in the majority of GBM specimens and is a critical mediator of GBM invasiveness through its AKT dependent activation of EphA2 at S897 (P-EphA2(S897)). ...

  7. RINL, guanine nucleotide exchange factor Rab5-subfamily, is involved in the EphA8-degradation pathway with odin.

    Hiroaki Kajiho

    Full Text Available The Rab family of small guanosine triphosphatases (GTPases plays a vital role in membrane trafficking. Its active GTP-bound state is driven by guanine nucleotide-exchange factors (GEFs. Ras and Rab interactor (or Ras interaction/interference-like (RINL, which contains a conserved VPS9 domain critical for GEF action, was recently identified as a new Rab5 subfamily GEF in vitro. However, its detailed function and interacting molecules have not yet been fully elucidated. Here we found that RINL has GEF activity for the Rab5 subfamily proteins by measuring their GTP-bound forms in cultured cells. We also found that RINL interacts with odin, a member of the ankyrin-repeat and sterile-alpha motif (SAM domain-containing (Anks protein family. In addition, the Eph tyrosine kinase receptor EphA8 formed a ternary complex with both RINL and odin. Interestingly, RINL expression in cultured cells reduced EphA8 levels in a manner dependent on both its GEF activity and interaction with odin. In addition, knockdown of RINL increased EphA8 level in HeLa cells. Our findings suggest that RINL, as a GEF for Rab5 subfamily, is implicated in the EphA8-degradation pathway via its interaction with odin.

  8. A novel extracellular Hsp90 mediated co-receptor function for LRP1 regulates EphA2 dependent glioblastoma cell invasion.

    Udhayakumar Gopal

    Full Text Available BACKGROUND: Extracellular Hsp90 protein (eHsp90 potentiates cancer cell motility and invasion through a poorly understood mechanism involving ligand mediated function with its cognate receptor LRP1. Glioblastoma multiforme (GBM represents one of the most aggressive and lethal brain cancers. The receptor tyrosine kinase EphA2 is overexpressed in the majority of GBM specimens and is a critical mediator of GBM invasiveness through its AKT dependent activation of EphA2 at S897 (P-EphA2(S897. We explored whether eHsp90 may confer invasive properties to GBM via regulation of EphA2 mediated signaling. PRINCIPAL FINDINGS: We find that eHsp90 signaling is essential for sustaining AKT activation, P-EphA2(S897, lamellipodia formation, and concomitant GBM cell motility and invasion. Furthermore, eHsp90 promotes the recruitment of LRP1 to EphA2 in an AKT dependent manner. A finding supported by biochemical methodology and the dual expression of LRP1 and P-EphA2(S897 in primary and recurrent GBM tumor specimens. Moreover, hypoxia mediated facilitation of GBM motility and invasion is dependent upon eHsp90-LRP1 signaling. Hypoxia dramatically elevated surface expression of both eHsp90 and LRP1, concomitant with eHsp90 dependent activation of src, AKT, and EphA2. SIGNIFICANCE: We herein demonstrate a novel crosstalk mechanism involving eHsp90-LRP1 dependent regulation of EphA2 function. We highlight a dual role for eHsp90 in transducing signaling via LRP1, and in facilitating LRP1 co-receptor function for EphA2. Taken together, our results demonstrate activation of the eHsp90-LRP1 signaling axis as an obligate step in the initiation and maintenance of AKT signaling and EphA2 activation, thereby implicating this pathway as an integral component contributing to the aggressive nature of GBM.

  9. Periostin: A Downstream Mediator of EphB4-Induced Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells

    Fei Zhang

    2016-01-01

    Full Text Available Erythropoietin-producing hepatocyte B4 (EphB4 has been reported to be a key molecular switch in the regulation of bone homeostasis, but the underlying mechanism remains poorly understood. In this study, we investigated the role of EphB4 in regulating the expression of periostin (POSTN within bone marrow-derived mesenchymal stem cells (MSCs and assessed its effect and molecular mechanism of osteogenic induction in vitro. Treatment with ephrinB2-FC significantly increased the expression of POSTN in MSCs, and the inhibition of EphB4 could abrogate this effect. In addition, osteogenic markers were upregulated especially in MSCs overexpressing EphB4. To elucidate the underlying mechanism of cross talk between EphB4 and the Wnt pathway, we detected the change in protein expression of phosphorylated-glycogen synthase kinase 3β-serine 9 (p-GSK-3β-Ser9 and β-catenin, as well as the osteogenic markers Runx2 and COL1. The results showed that GSK-3β activation and osteogenic marker expression levels were downregulated by ephrinB2-FC treatment, but these effects were inhibited by blocking integrin αvβ3 in MSCs. Our findings demonstrate that EphB4 can promote osteogenic differentiation of MSCs via upregulation of POSTN expression. It not only helps to reveal the interaction mechanism between EphB4 and Wnt pathway but also brings a better understanding of EphB4/ephrinB2 signaling in bone homeostasis.

  10. EphCOM: Practical Ephemeral Communications (How to implement ephemeral data with only primary Internet services)

    Project, The Ephemeral Data

    2010-01-01

    The Internet never forgets and data lingers virtually forever. Private data created by users is frequently disseminated around the Internet and users often lose the control and ownership of their contents. This increasing diffusion of private data over the Internet motivates the need for ephemeral data, i.e. time-bounded data that cannot be accessed after a userspecified expiration time. This paper explores and formalizes the concept of Ephemeral Data Systems, systems that prevent an adversary from accessing expired contents. We present EphCOM, a practical Ephemeral Data System that supports ephemeral data using only a primary Internet service, namely the Domain Name Service (DNS). Our proposal leverages DNS servers caching mechanisms. EphCOM does not rely on any Trusted Platform Modules (TPM), peer-to-peer networks, or centralized servers, and is transparent to existing applications and services. It allows users to closely control data lifetime. We analyze its security and show, through extensive and large-s...

  11. COMPLEMENTARY EXPRESSION OF EphA7 AND SCO-SPONDIN DURING POSTERIOR COMMISSURE DEVELOPMENT

    Karen eStanic

    2014-06-01

    Full Text Available Bilaterally symmetric organisms need to exchange information between the two sides of their bodies in order to integrate sensory inputs and coordinate motor control. This exchange occurs through commissures formed by neurons that project axons across the midline to the contralateral side of the central nervous system. The posterior commissure is the first transversal axonal tract of the embryonic vertebrate brain. It is located in the dorsal portion of the prosomere 1, at the caudal diencephalon. The axons of the posterior commissure principally come from neurons of ventrolateral and dorsolateral pretectal nuclei (parvocellular and magnocellular nucleus of the posterior commissure, respectively that extend their axons toward the dorsal region. The trajectory of these axons can be divided into the following three stages: 1 dorsal axon extension towards the lateral roof plate; 2 fasciculation in the lateral roof plate; and 3 midline decision of turning to the ipsilateral side or continuing to the opposite side. The mechanisms and molecules that guide the axons during these steps are unknown. In the present work, immunohistochemical and in situ hybridization analyses were performed, with results suggesting the participation of EphA7 in guiding axons from the ventral to the dorsal region of the prosomere 1 through the generation of an axonal corridor limited by repulsive EphA7 walls. At the lateral roof plate, the axons became fasciculated in presence of SCO-spondin until reaching the midline. Finally, EphA7 expression was observed in the diencephalic midline roof plate, specifically in the region where some axons turn to the ipsilateral side, suggesting its participation in this decision. In summary, the present work proposes a mechanism of posterior commissure formation orchestrated by the complementary expression of the axon guidance cues SCO-spondin and EphA7.

  12. Eph receptor A10 has a potential as a target for a prostate cancer therapy.

    Nagano, Kazuya; Yamashita, Takuya; Inoue, Masaki; Higashisaka, Kazuma; Yoshioka, Yasuo; Abe, Yasuhiro; Mukai, Yohei; Kamada, Haruhiko; Tsutsumi, Yasuo; Tsunoda, Shin-ichi

    2014-07-18

    We recently identified Eph receptor A10 (EphA10) as a novel breast cancer-specific protein. Moreover, we also showed that an in-house developed anti-EphA10 monoclonal antibody (mAb) significantly inhibited proliferation of breast cancer cells, suggesting EphA10 as a promising target for breast cancer therapy. However, the only other known report for EphA10 was its expression in the testis at the mRNA level. Therefore, the potency of EphA10 as a drug target against cancers other than the breast is not known. The expression of EphA10 in a wide variety of cancer cells was studied and the potential of EphA10 as a drug target was evaluated. Screening of EphA10 mRNA expression showed that EphA10 was overexpressed in breast cancer cell lines as well as in prostate and colon cancer cell lines. Thus, we focused on prostate cancers in which EphA10 expression was equivalent to that in breast cancers. As a result, EphA10 expression was clearly shown in clinical prostate tumor tissues as well as in cell lines at the mRNA and protein levels. In order to evaluate the potential of EphA10 as a drug target, we analyzed complement-dependent cytotoxicity effects of anti-EphA10 mAb and found that significant cytotoxicity was mediated by the expression of EphA10. Therefore, the idea was conceived that the overexpression of EphA10 in prostate cancers might have a potential as a target for prostate cancer therapy, and formed the basis for the studies reported here. PMID:24924629

  13. Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5.

    Garry Jason Forse

    Full Text Available The Eph receptor tyrosine kinase/ephrin ligand system regulates a wide spectrum of physiological processes, while its dysregulation has been implicated in cancer progression. The human EphA3 receptor is widely upregulated in the tumor microenvironment and is highly expressed in some types of cancer cells. Furthermore, EphA3 is among the most highly mutated genes in lung cancer and it is also frequently mutated in other cancers. We report the structure of the ligand-binding domain of the EphA3 receptor in complex with its preferred ligand, ephrin-A5. The structure of the complex reveals a pronounced tilt of the ephrin-A5 ligand compared to its orientation when bound to the EphA2 and EphB2 receptors and similar to its orientation when bound to EphA4. This tilt brings an additional area of ephrin-A5 into contact with regions of EphA3 outside the ephrin-binding pocket thereby enlarging the size of the interface, which is consistent with the high binding affinity of ephrin-A5 for EphA3. This large variation in the tilt of ephrin-A5 bound to different Eph receptors has not been previously observed for other ephrins.

  14. Eph receptor A10 has a potential as a target for a prostate cancer therapy

    Nagano, Kazuya [Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085 (Japan); Yamashita, Takuya [Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085 (Japan); Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Inoue, Masaki [Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085 (Japan); Higashisaka, Kazuma [Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085 (Japan); Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Yoshioka, Yasuo [Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085 (Japan); Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); The Center of Advanced Medical Engineering and Informatics, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Abe, Yasuhiro [Cancer Biology Research Center, Sanford Research/USD, 2301 E. 60th Street N, Sioux Falls, SD 57104 (United States); Mukai, Yohei [Laboratory of Innovative Antibody Engineering and Design, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085 (Japan); Kamada, Haruhiko [Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085 (Japan); The Center of Advanced Medical Engineering and Informatics, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); and others

    2014-07-18

    Highlights: • EphA10 mRNA is overexpressed in breast, prostate and colon cancer cell lines. • EphA10 is overexpressed in clinical prostate tumors at mRNA and protein levels. • Anti-EphA10 antibodies were cytotoxic on EphA10-positive prostate cancer cells. - Abstract: We recently identified Eph receptor A10 (EphA10) as a novel breast cancer-specific protein. Moreover, we also showed that an in-house developed anti-EphA10 monoclonal antibody (mAb) significantly inhibited proliferation of breast cancer cells, suggesting EphA10 as a promising target for breast cancer therapy. However, the only other known report for EphA10 was its expression in the testis at the mRNA level. Therefore, the potency of EphA10 as a drug target against cancers other than the breast is not known. The expression of EphA10 in a wide variety of cancer cells was studied and the potential of EphA10 as a drug target was evaluated. Screening of EphA10 mRNA expression showed that EphA10 was overexpressed in breast cancer cell lines as well as in prostate and colon cancer cell lines. Thus, we focused on prostate cancers in which EphA10 expression was equivalent to that in breast cancers. As a result, EphA10 expression was clearly shown in clinical prostate tumor tissues as well as in cell lines at the mRNA and protein levels. In order to evaluate the potential of EphA10 as a drug target, we analyzed complement-dependent cytotoxicity effects of anti-EphA10 mAb and found that significant cytotoxicity was mediated by the expression of EphA10. Therefore, the idea was conceived that the overexpression of EphA10 in prostate cancers might have a potential as a target for prostate cancer therapy, and formed the basis for the studies reported here.

  15. Eph receptor A10 has a potential as a target for a prostate cancer therapy

    Highlights: • EphA10 mRNA is overexpressed in breast, prostate and colon cancer cell lines. • EphA10 is overexpressed in clinical prostate tumors at mRNA and protein levels. • Anti-EphA10 antibodies were cytotoxic on EphA10-positive prostate cancer cells. - Abstract: We recently identified Eph receptor A10 (EphA10) as a novel breast cancer-specific protein. Moreover, we also showed that an in-house developed anti-EphA10 monoclonal antibody (mAb) significantly inhibited proliferation of breast cancer cells, suggesting EphA10 as a promising target for breast cancer therapy. However, the only other known report for EphA10 was its expression in the testis at the mRNA level. Therefore, the potency of EphA10 as a drug target against cancers other than the breast is not known. The expression of EphA10 in a wide variety of cancer cells was studied and the potential of EphA10 as a drug target was evaluated. Screening of EphA10 mRNA expression showed that EphA10 was overexpressed in breast cancer cell lines as well as in prostate and colon cancer cell lines. Thus, we focused on prostate cancers in which EphA10 expression was equivalent to that in breast cancers. As a result, EphA10 expression was clearly shown in clinical prostate tumor tissues as well as in cell lines at the mRNA and protein levels. In order to evaluate the potential of EphA10 as a drug target, we analyzed complement-dependent cytotoxicity effects of anti-EphA10 mAb and found that significant cytotoxicity was mediated by the expression of EphA10. Therefore, the idea was conceived that the overexpression of EphA10 in prostate cancers might have a potential as a target for prostate cancer therapy, and formed the basis for the studies reported here

  16. EphB4 localises to the nucleus of prostate cancer cells

    The EphB4 receptor tyrosine kinase is over-expressed in a variety of different epithelial cancers including prostate where it has been shown to be involved in survival, migration and angiogenesis. We report here that EphB4 also resides in the nucleus of prostate cancer cell lines. We used in silico methods to identify a bipartite nuclear localisation signal (NLS) in the extracellular domain and a monopartite NLS sequence in the intracellular kinase domain of EphB4. To determine whether both putative NLS sequences were functional, fragments of the EphB4 sequence containing each NLS were cloned to create EphB4NLS-GFP fusion proteins. Localisation of both NLS-GFP proteins to the nuclei of transfected cells was observed, demonstrating that EphB4 contains two functional NLS sequences. Mutation of the key amino residues in both NLS sequences resulted in diminished nuclear accumulation. As nuclear translocation is often dependent on importins we confirmed that EphB4 and importin-α can interact. To assess if nuclear EphB4 could be implicated in gene regulatory functions potential EphB4-binding genomic loci were identified using chromatin immunoprecipitation and Lef1 was confirmed as a potential target of EphB4-mediated gene regulation. These novel findings add further complexity to the biology of this important cancer-associated receptor. - Highlights: • The EphB4 protein can be found in the nucleus of prostate cancer cell lines. • EphB4 contains two functional nuclear localisation signals. • Chromatin immunoprecipitation has identified potential genome sequences to which EphB4 binds. • Lef1 is a confirmed target for EphB4-mediated gene regulation

  17. EphB4 localises to the nucleus of prostate cancer cells

    Mertens-Walker, Inga, E-mail: inga.mertenswalker@qut.edu.au [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Australian Prostate Cancer Research Centre—Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD (Australia); Lisle, Jessica E. [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Australian Prostate Cancer Research Centre—Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD (Australia); Nyberg, William A. [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Stephens, Carson R. [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Australian Prostate Cancer Research Centre—Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD (Australia); Burke, Leslie [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Rutkowski, Raphael; Herington, Adrian C.; Stephenson, Sally-Anne [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Australian Prostate Cancer Research Centre—Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD (Australia)

    2015-04-10

    The EphB4 receptor tyrosine kinase is over-expressed in a variety of different epithelial cancers including prostate where it has been shown to be involved in survival, migration and angiogenesis. We report here that EphB4 also resides in the nucleus of prostate cancer cell lines. We used in silico methods to identify a bipartite nuclear localisation signal (NLS) in the extracellular domain and a monopartite NLS sequence in the intracellular kinase domain of EphB4. To determine whether both putative NLS sequences were functional, fragments of the EphB4 sequence containing each NLS were cloned to create EphB4NLS-GFP fusion proteins. Localisation of both NLS-GFP proteins to the nuclei of transfected cells was observed, demonstrating that EphB4 contains two functional NLS sequences. Mutation of the key amino residues in both NLS sequences resulted in diminished nuclear accumulation. As nuclear translocation is often dependent on importins we confirmed that EphB4 and importin-α can interact. To assess if nuclear EphB4 could be implicated in gene regulatory functions potential EphB4-binding genomic loci were identified using chromatin immunoprecipitation and Lef1 was confirmed as a potential target of EphB4-mediated gene regulation. These novel findings add further complexity to the biology of this important cancer-associated receptor. - Highlights: • The EphB4 protein can be found in the nucleus of prostate cancer cell lines. • EphB4 contains two functional nuclear localisation signals. • Chromatin immunoprecipitation has identified potential genome sequences to which EphB4 binds. • Lef1 is a confirmed target for EphB4-mediated gene regulation.

  18. A paradigm shift in EPH receptor interaction: biological relevance of EPHB6 interaction with EPHA2 and EPHB2 in breast carcinoma cell lines.

    Fox, Brian P; Kandpal, Raj P

    2011-01-01

    EPH receptors are the largest known family of receptor tyrosine kinases characterized in humans. These proteins are involved in axon guidance, tissue organization, synaptic plasticity, vascular development and the progression of various diseases including cancer. The varied biological effects of EPH receptors are mediated in part by the expression of these proteins and their intracellular binding proteins. The ability of EPH molecules to form heterodimers within their own class has been suggested, although not exhaustively characterized. We have clarified this phenomenon by showing that EPHB6, a kinase-deficient receptor, can interact with EPHB2 in mammalian cells, and more significantly EPHB6 interacts with EPHA2. However, EPHB6 does not interact with another kinase-deficient receptor, EPHA10. The interaction between EPHB6 and EPHA2 is the first demonstration of an A-type receptor interacting with a B-type receptor. Furthermore, we correlated relative expression of EPHB6, EPHB2 and EPHA2 with non-invasive and invasive phenotypes of breast tumor cell lines. Our results indicate that tumor invasiveness-suppressing activity of EPHB6 is mediated by its ability to sequester other kinase-sufficient and oncogenic EPH receptors. These observations suggest that cellular phenotypes may, in part, be attributed to a combinatorial expression of EPH receptors and heteromeric interactions among the same class, as well as between two classes, of EPH receptors. Our results also suggest that EPHA10 may transduce signals by interacting with other kinase-sufficient receptors in a similar manner. PMID:21737611

  19. Bidirectional signalling between EphA2 and ephrinA1 increases tubular cell attachment, laminin secretion and modulates erythropoietin expression after renal hypoxic injury.

    Rodriguez, Stéphane; Rudloff, Stefan; Koenig, Katrin Franziska; Karthik, Swapna; Hoogewijs, David; Huynh-Do, Uyen

    2016-08-01

    Acute kidney injury (AKI) is common in hospitalized patients and has a poor prognosis, the severity of AKI being linked to progression to chronic kidney disease. This stresses the need to search for protective mechanisms during the acute phase. We investigated kidney repair after hypoxic injury using a rat model of renal artery branch ligation, which led to an oxygen gradient vertical to the corticomedullary axis. Three distinct zones were observed: tubular necrosis, infarction border zone and preserved normal tissue. EphA2 is a receptor tyrosine kinase with pivotal roles in cell architecture, migration and survival, upon juxtacrine contact with its membrane-bound ligand EphrinA1. Following hypoxia, EphA2 was up-regulated in cortical and medullary tubular cells, while EphrinA1 was up-regulated in interstitial cells adjacent to peritubular capillaries. Moreover, erythropoietin (EPO) messenger RNA (mRNA) was strongly expressed in the border zone of infarcted kidney within the first 6 h. To gain more insight into the biological impact of EphA2 and EphrinA1 up-regulation, we activated the signalling pathways in vitro using recombinant EphrinA1/Fc or EphA2/Fc proteins. Stimulation of EphA2 forward signalling in the proximal tubular cell line HK2 increased cell attachment and laminin secretion at the baso-lateral side. Conversely, activation of reverse signalling through EphrinA1 expressed by Hep3B cells promoted EPO production at both the transcriptional and protein level. Strikingly, in co-culture experiments, juxtacrine contact between EphA2 expressing MDCK and EphrinA1 expressing Hep3B was sufficient to induce a significant up-regulation of EPO mRNA production in the latter cells, even in the absence of hypoxic conditions. The synergistic effects of EphA2 and hypoxia led to a 15-20-fold increase of EPO expression. Collectively, our results suggest an important role of EphA2/EphrinA1 signalling in kidney repair after hypoxic injury through stimulation of (i) tubular

  20. EPH-classifications in Geometry, Algebra, Analysis and Arithmetic

    Rastegar, Arash

    2015-01-01

    Trichotomy of Elliptic-Parabolic-Hyperbolic appears in many different areas of mathematics. All of these are named after the very first example of trichotomy, which is formed by ellipses, parabolas, and hyperbolas as conic sections. We try to understand if these classifications are justified and if similar mathematical phenomena is shared among different cases EPH-classification is used.

  1. Potential clinical relevance of Eph receptors and ephrin ligands expressed in prostate carcinoma cell lines.

    Fox, Brian P; Tabone, Christopher J; Kandpal, Raj P

    2006-04-21

    The family of Eph and ephrin receptors is involved in a variety of functions in normal cells, and the alterations in their expression profiles have been observed in several cancers. We have compared the transcripts for Eph receptors and ephrin ligands in cell lines established from normal prostate epithelium and several carcinoma cell lines isolated from prostate tumors of varying degree of metastasis. These cell lines included NPTX, CTPX, LNCaP, DU145, PC-3, and PC-3ML. The cell lines displayed characteristic pattern of expression for specific Eph receptors and ephrin ligands, thus allowing identification of Eph receptor signatures for a particular cell line. The sensitivity of these transcripts to genome methylation is also investigated by treating the cells with 5-aza-2'-deoxycytidine. The comparison of expression profiles revealed that normal prostate and primary prostate tumor cell lines differ in the expression of EphA3, EphB3, and ephrin A3 that are over-expressed in normal prostate. Furthermore, the transcript levels for EphA1 decrease progressively from normal prostate to primary prostate tumor cell line and metastatic tumor cells. A converse relationship was observed for ephrin B2. The treatment of cells with 5-aza-2'-deoxycytidine revealed the sensitivity of EphA3, EphA10, EphB3, and EphB6 to methylation status of genomic DNA. The utility of methylation specific PCR to identify prostate tumor cells and the importance of specific Eph receptors and ephrin ligands in initiation and progression of prostate tumor are discussed. PMID:16516143

  2. Immunohistochemical demonstration of EphA2 processing by MT1-MMP in invasive cutaneous squamous cell carcinoma.

    Tatsukawa, Ryoko; Koga, Kaori; Aoki, Mikiko; Koshikawa, Naohiko; Imafuku, Shinichi; Nakayama, Juichiro; Nabeshima, Kazuki

    2016-07-01

    Erythropoietin-producing hepatocellular receptor-2 (EphA2) overexpression is prevalent in many types of human cancers, and it has been reported that high EphA2 expression is correlated with malignancy. Recent studies revealed that processing of EphA2 by cleaving off the N-terminal portion by membrane-type 1 matrix metalloproteinase (MT1-MMP) promotes invasion via stimulation of Ras in cancer cells in vitro. The objectives of this study were to investigate the presence and role of EphA2 processing in cutaneous squamous cell carcinoma (SCC) tissues. EphA2 (C-terminal and N-terminal) and MT1-MMP expression patterns and levels were analyzed immunohistochemically in SCC (n = 70) and Bowen disease (BD; n = 20). Levels of MT1-MMP and EphA2 expression were evaluated using digital image analysis. Proximity between MT1-MMP and EphA2 in cancer cells and its effect on EphA2 processing were investigated using a combination of in situ proximity ligation assay (PLA) and Western blotting. Immunohistochemical analyses showed that levels of EphA2 N-terminal expression were significantly lower than those of EphA2 C-terminal expression in SCC, whereas levels of EphA2 C- and N-terminal expression were similar in BD. Western blotting showed processed EphA2 fragments in human SCC tissues. Expression levels of MT1-MMP, EphA2, and processed EphA2 fragments were higher in SCC than BD. Proximity between MT1-MMP and EphA2 in SCC was demonstrated by in situ PLA. Our results suggest possible involvement of MT1-MMP processing of EphA2 in invasiveness of cutaneous SCC. PMID:27056569

  3. Isolation and Characterization of a Monobody with a Fibronectin Domain III Scaffold That Specifically Binds EphA2.

    Seung-Hwan Park

    Full Text Available Monobodies are binding scaffold proteins originating from a human fibronectin domain III (Fn3 scaffold that can be easily engineered with specificity and affinity. Human EphA2 (hEphA2 is an early detection marker protein for various tumors including lung, breast, and colon cancer. In this study, we isolated two hEphA2-specific monobodies (E1 and E10 by screening a yeast surface display library. They showed the same amino acid sequence except in the DE loop and had high affinity (~2 nM Kd against hEphA2. E1 bound only hEphA2 and mEphA2, although it bound hEphA2 with an affinity 2-fold higher than that of mEphA2. However, E10 also bound the mEphA6 and mEphA8 homologs as well as hEphA2 and mEphA2. Thus, E1 but not E10 was highly specific for hEphA2. E1 specifically bound human cells and xenograft tumor tissues expressing hEphA on the cell surface. In vivo optical imaging showed strong targeting of Cy5.5-labeled E1 to mouse tumor tissue induced by PC3 cells, a human prostate cancer cell line that expresses a high level of hEphA2. In conclusion, the highly specific monobody E1 is useful as a hEphA2 probe candidate for in vivo diagnosis and therapy.

  4. EphA7 signaling guides cortical dendritic development and spine maturation

    Clifford, Meredith A.; Athar, Wardah; Leonard, Carrie E.; Russo, Alexandra; Sampognaro, Paul J.; Van der Goes, Marie-Sophie; Burton, Denver A.; Zhao, Xiumei; Lalchandani, Rupa R.; Sahin, Mustafa; Vicini, Stefano; Donoghue, Maria J.

    2014-01-01

    The process by which excitatory neurons are generated and mature during the development of the cerebral cortex occurs in a stereotyped manner; coordinated neuronal birth, migration, and differentiation during embryonic and early postnatal life are prerequisites for selective synaptic connections that mediate meaningful neurotransmission in maturity. Normal cortical function depends upon the proper elaboration of neurons, including the initial extension of cellular processes that lead to the formation of axons and dendrites and the subsequent maturation of synapses. Here, we examine the role of cell-based signaling via the receptor tyrosine kinase EphA7 in guiding the extension and maturation of cortical dendrites. EphA7, localized to dendritic shafts and spines of pyramidal cells, is uniquely expressed during cortical neuronal development. On patterned substrates, EphA7 signaling restricts dendritic extent, with Src and Tsc1 serving as downstream mediators. Perturbation of EphA7 signaling in vitro and in vivo alters dendritic elaboration: Dendrites are longer and more complex when EphA7 is absent and are shorter and simpler when EphA7 is ectopically expressed. Later in neuronal maturation, EphA7 influences protrusions from dendritic shafts and the assembling of synaptic components. Indeed, synaptic function relies on EphA7; the electrophysiological maturation of pyramidal neurons is delayed in cultures lacking EphA7, indicating that EphA7 enhances synaptic function. These results provide evidence of roles for Eph signaling, first in limiting the elaboration of cortical neuronal dendrites and then in coordinating the maturation and function of synapses. PMID:24707048

  5. Dexamethasone Regulates EphA5, a Potential Inhibitory Factor with Osteogenic Capability of Human Bone Marrow Stromal Cells

    Tsuyoshi Yamada

    2016-01-01

    Full Text Available We previously demonstrated the importance of quality management procedures for the handling of human bone marrow stromal cells (hBMSCs and provided evidence for the existence of osteogenic inhibitor molecules in BMSCs. One candidate inhibitor is the ephrin type-A receptor 5 (EphA5, which is expressed in hBMSCs and upregulated during long-term culture. In this study, forced expression of EphA5 diminished the expression of osteoblast phenotypic markers. Downregulation of endogenous EphA5 by dexamethasone treatment promoted osteoblast marker expression. EphA5 could be involved in the normal growth regulation of BMSCs and could be a potential marker for replicative senescence. Although Eph forward signaling stimulated by ephrin-B-Fc promoted the expression of ALP mRNA in BMSCs, exogenous addition of EphA5-Fc did not affect the ALP level. The mechanism underlying the silencing of EphA5 in early cultures remains unclear. EphA5 promoter was barely methylated in hBMSCs while histone deacetylation could partially suppress EphA5 expression in early-passage cultures. In repeatedly passaged cultures, the upregulation of EphA5 independent of methylation could competitively inhibit osteogenic signal transduction pathways such as EphB forward signaling. Elucidation of the potential inhibitory function of EphA5 in hBMSCs may provide an alternative approach for lineage differentiation in cell therapy strategies and regenerative medicine.

  6. Expression of Eph receptor A10 is correlated with lymph node metastasis and stage progression in breast cancer patients

    Nagano, Kazuya; Kanasaki, So-ichiro; Yamashita, Takuya; Maeda, Yuka; Inoue, Masaki; Higashisaka, Kazuma; Yoshioka, Yasuo; Abe, Yasuhiro; Mukai, Yohei; Kamada, Haruhiko; Tsutsumi, Yasuo; Tsunoda, Shin-ichi

    2013-01-01

    Eph receptor A10 (EphA10) is a valuable breast cancer marker that is highly expressed in breast cancer tissues by comparison with normal breast tissues, as we previously reported. However, the role of EphA10 expression in breast cancer is not well understood. Here, we have analyzed the expression of EphA10 at the mRNA- and protein-level in clinical breast cancer tissues and then evaluated the relationship with clinicopathological parameters for each sample. EphA10 mRNA expression was quantifi...

  7. EphA2 is a key effector of the MEK/ERK/RSK pathway regulating glioblastoma cell proliferation.

    Hamaoka, Yuho; Negishi, Manabu; Katoh, Hironori

    2016-08-01

    EphA2, a member of the Eph receptor tyrosine kinases, is frequently overexpressed in a variety of malignancies, including glioblastoma, and its expression is correlated with poor prognosis. EphA2 acts as a tumor promoter through a ligand ephrin-independent mechanism, which requires phosphorylation of EphA2 on serine 897 (S897), leading to increased cell migration and invasion. In this study, we show that ligand-independent EphA2 signaling occurs downstream of the MEK/ERK/RSK pathway and mediates epidermal growth factor (EGF)-induced cell proliferation in glioblastoma cells. Suppression of EphA2 expression by long-term exposure to ligand ephrinA1 or EphA2-targeted shRNA inhibited EGF-induced cell proliferation. Stimulation of the cells with EGF induced EphA2 S897 phosphorylation, which was suppressed by MEK and RSK inhibitors, but not by phosphatidylinositol 3-kinase (PI3K) and Akt inhibitors. The RSK inhibitor or RSK2-targeted shRNA also suppressed EGF-induced cell proliferation. Furthermore, overexpression of wild-type EphA2 promoted cell proliferation without EGF stimulation, whereas overexpression of EphA2-S897A mutant suppressed EGF- or RSK2-induced proliferation. Taken together, these results suggest that EphA2 is a key downstream target of the MEK/ERK/RSK signaling pathway in the regulation of glioblastoma cell proliferation. PMID:27132626

  8. Investigation of the expression of the EphB4 receptor tyrosine kinase in prostate carcinoma

    Douglas Evelyn L

    2005-09-01

    Full Text Available Abstract Background The EphB4 receptor tyrosine kinase has been reported as increased in tumours originating from several different tissues and its expression in a prostate cancer xenograft model has been reported. Methods RT-PCR, western blotting and immunohistochemical techniques were used to examine EphB4 expression and protein levels in human prostate cancer cell lines LNCaP, DU145 and PC3. Immunohistochemistry was also used to examine localisation of EphB4 in tissue samples from 15 patients with prostate carcinomas. Results All three prostate cancer cell lines expressed the EphB4 gene and protein. EphB4 immunoreactivity in vivo was significantly greater in human prostate cancers as compared with matched normal prostate epithelium and there appeared to be a trend towards increased expression with higher grade disease. Conclusion EphB4 is expressed in prostate cancer cell lines with increased expression in human prostate cancers when compared with matched normal tissue. EphB4 may therefore be a useful anti-prostate cancer target.

  9. Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer

    Hewett Peter J; Douglas Evelyn L; Slomka Stefan; Stephenson Sally-Anne; Hardingham Jennifer E

    2001-01-01

    Abstract Background We have used commercially available cDNA arrays to identify EphB4 as a gene that is up-regulated in colon cancer tissue when compared with matched normal tissue from the same patient. Results Quantitative RT-PCR analysis of the expression of the EphB4 gene has shown that its expression is increased in 82% of tumour samples when compared with the matched normal tissue from the same patient. Using immunohistochemistry and Western analysis techniques with an EphB4-specific an...

  10. EphB2 SNPs and Sporadic Prostate Cancer Risk in African American Men

    Christiane M Robbins; Stanley Hooker; Kittles, Rick A.; John D. Carpten

    2011-01-01

    The EphB2 gene has been implicated as a tumor suppressor gene somatically altered in both prostate cancer (PC) and colorectal cancer. We have previously shown an association between an EphB2 germline nonsense variant and risk of familial prostate cancer among African American Men (AAM). Here we set out to test the hypothesis that common variation within the EphB2 locus is associated with increased risk of sporadic PC in AAM. We genotyped a set of 341 single nucleotide polymorphisms (SNPs) enc...

  11. A novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells

    Wang, Si; Placzek, William J.; Stebbins, John L.; Mitra, Sayantan; Noberini, Roberta; Koolpe, Mitchell; Zhang, Ziming; Dahl, Russell; Pasquale, Elena B.; Pellecchia, Maurizio

    2012-01-01

    The efficacy of anti-cancer drugs is often limited by their systemic toxicities and adverse side effects. We report that the EphA2 receptor is over-expressed preferentially in several human cancer cell lines compared to normal tissues and that an EphA2 targeting peptide (YSAYPDSVPMMS) can be effective in delivering anti-cancer agents to such tumors. Hence, we report on the synthesis and characterizations of a novel EphA2-targeting agent conjugated with the chemotherapeutic drug paclitaxel. We...

  12. Efficiency in Controlling Activities

    Van Nguyen, Tuyen

    2015-01-01

    Controlling is essential for financial success of corporations. An efficient controlling system should be implemented in order to manage financial performance from income, expense to profitability. The purpose of the thesis is to provide insight knowledge towards corporate accounting management as well as to propose potential improvement for the existing controlling system of the case company, which is Bosch Rexroth Japan. The theoretical framework creates the knowledge foundation for re...

  13. Structure of the ligand-binding domain of the EphB2 receptor at 2 Å resolution

    The crystal structure of the ligand-binding domain of a receptor tyrosine kinase EphB2, an important mediator of cell-cell communication, has been determined at a resolution of 2 Å. The structure confirms the induced-fit mechanism for the binding of ligands to EphB receptors. Eph tyrosine kinase receptors, the largest group of receptor tyrosine kinases, and their ephrin ligands are important mediators of cell–cell communication regulating cell attachment, shape and mobility. Recently, several Eph receptors and ephrins have also been found to play important roles in the progression of cancer. Structural and biophysical studies have established detailed information on the binding and recognition of Eph receptors and ephrins. The initial high-affinity binding of Eph receptors to ephrin occurs through the penetration of an extended G–H loop of the ligand into a hydrophobic channel on the surface of the receptor. Consequently, the G–H loop-binding channel of Eph receptors is the main target in the search for Eph antagonists that could be used in the development of anticancer drugs and several peptides have been shown to specifically bind Eph receptors and compete with the cognate ephrin ligands. However, the molecular details of the conformational changes upon Eph/ephrin binding have remained speculative, since two of the loops were unstructured in the original model of the free EphB2 structure and their conformational changes upon ligand binding could consequently not be analyzed in detail. In this study, the X-ray structure of unbound EphB2 is reported at a considerably higher 2 Å resolution, the conformational changes that the important receptor loops undergo upon ligand binding are described and the consequences that these findings have for the development of Eph antagonists are discussed

  14. Eph/ephrin signaling maintains the boundary of dorsal forerunner cell cluster during morphogenesis of the zebrafish embryonic left-right organizer.

    Zhang, Junfeng; Jiang, Zheng; Liu, Xingfeng; Meng, Anming

    2016-07-15

    The Kupffer's vesicle (KV) is the so-called left-right organizer in teleost fishes. KV is formed from dorsal forerunner cells (DFCs) and generates asymmetrical signals for breaking symmetry of embryos. It is unclear how DFCs or KV cells are prevented from intermingling with adjacent cells. In this study, we show that the Eph receptor gene ephb4b is highly expressed in DFCs whereas ephrin ligand genes, including efnb2b, are expressed in cells next to the DFC cluster during zebrafish gastrulation. ephb4b knockdown or mutation and efnb2b knockdown cause dispersal of DFCs, a smaller KV and randomization of laterality organs. DFCs often dynamically form lamellipodium-like, bleb-like and filopodium-like membrane protrusions at the interface, which attempt to invade but are bounced back by adjacent non-DFC cells during gastrulation. Upon inhibition of Eph/ephrin signaling, however, the repulsion between DFCs and non-DFC cells is weakened or lost, allowing DFCs to migrate away. Ephb4b/Efnb2b signaling by activating RhoA activity mediates contact and repulsion between DFCs and neighboring cells during gastrulation, preventing intermingling of different cell populations. Therefore, our data uncover an important role of Eph/ephrin signaling in maintaining DFC cluster boundary and KV boundary for normal left-right asymmetrical development. PMID:27287807

  15. Active control of convection

    Bau, H.H. [Univ. of Pennsylvania, Philadelphia, PA (United States)

    1995-12-31

    Using stability theory, numerical simulations, and in some instances experiments, it is demonstrated that the critical Rayleigh number for the bifurcation (1) from the no-motion (conduction) state to the motion state and (2) from time-independent convection to time-dependent, oscillatory convection in the thermal convection loop and Rayleigh-Benard problems can be significantly increased or decreased. This is accomplished through the use of a feedback controller effectuating small perturbations in the boundary data. The controller consists of sensors which detect deviations in the fluid`s temperature from the motionless, conductive values and then direct actuators to respond to these deviations in such a way as to suppress the naturally occurring flow instabilities. Actuators which modify the boundary`s temperature/heat flux are considered. The feedback controller can also be used to control flow patterns and generate complex dynamic behavior at relatively low Rayleigh numbers.

  16. Active Combustion Control Valve Project

    National Aeronautics and Space Administration — Over the past decade, research into active combustion control has yielded impressive results in suppressing thermoacoustic instabilities and widening the...

  17. EphB2 guides axons at the midline and is necessary for normal vestibular function

    Cowan, C. A.; Yokoyama, N.; Bianchi, L. M.; Henkemeyer, M.; Fritzsch, B.

    2000-01-01

    Mice lacking the EphB2 receptor tyrosine kinase display a cell-autonomous, strain-specific circling behavior that is associated with vestibular phenotypes. In mutant embryos, the contralateral inner ear efferent growth cones exhibit inappropriate pathway selection at the midline, while in mutant adults, the endolymph-filled lumen of the semicircular canals is severely reduced. EphB2 is expressed in the endolymph-producing dark cells in the inner ear epithelium, and these cells show ultrastructural defects in the mutants. A molecular link to fluid regulation is provided by demonstrating that PDZ domain-containing proteins that bind the C termini of EphB2 and B-ephrins can also recognize the cytoplasmic tails of anion exchangers and aquaporins. This suggests EphB2 may regulate ionic homeostasis and endolymph fluid production through macromolecular associations with membrane channels that transport chloride, bicarbonate, and water.

  18. Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer

    Hewett Peter J

    2001-12-01

    Full Text Available Abstract Background We have used commercially available cDNA arrays to identify EphB4 as a gene that is up-regulated in colon cancer tissue when compared with matched normal tissue from the same patient. Results Quantitative RT-PCR analysis of the expression of the EphB4 gene has shown that its expression is increased in 82% of tumour samples when compared with the matched normal tissue from the same patient. Using immunohistochemistry and Western analysis techniques with an EphB4-specific antibody, we also show that this receptor is expressed in the epithelial cells of the tumour tissue and either not at all, or in only low levels, in the normal tissue. Conclusion The results presented here supports the emerging idea that Eph receptors play a role in tumour formation and suggests that further elucidation of this signalling pathway may identify useful targets for cancer treatment therapies.

  19. Deletion of the EphA2 receptor exacerbates myocardial injury and the progression of ischemic cardiomyopathy

    JitkaA. I.Virag

    2014-04-01

    Full Text Available EphrinA1-EphA-receptor signaling is protective during myocardial infarction (MI. The EphA2-receptor (EphA2-R potentially mediates cardiomyocyte survival. To determine the role of the EphA2-R in acute non-reperfused myocardial injury in vivo, infarct size, inflammatory cell density, NF-κB, p-AKT/Akt, and MMP-2 protein levels, and changes in ephrinA1/EphA2-R gene expression profile were assessed 4 days post-MI in B6129 wild-type (WT and EphA2-R-mutant (EphA2-R-M mice lacking a functional EphA2-R. Fibrosis, capillary density, morphometry of left ventricular chamber and infarct dimensions, and cardiac function also were measured 4 weeks post-MI to determine the extent of ventricular remodeling. EphA2-R-M infarct size and area of residual necrosis were 31.7% and 113% greater than WT hearts, respectively. Neutrophil and macrophage infiltration were increased by 46% and 84% in EphA2-R-M hearts compared with WT, respectively. NF-κB protein expression was 1.9-fold greater in EphA2-R-M hearts at baseline and 56% less NF-κB after infarction compared with WT. EphA6 gene expression was 2.5-fold higher at baseline and increased 9.8-fold 4 days post-MI in EphA2-R-M hearts compared with WT. EphrinA1 gene expression in EphA2-R-M hearts was unchanged at baseline and decreased by 42% 4 days post- MI compared with WT hearts. EphA2-R-M hearts had 66.7% less expression of total Akt protein and 59% less p-Akt protein than WT hearts post-MI. EphA2-R-M hearts 4 weeks post-MI had increased chamber dilation and interstitial fibrosis and decreased MMP-2 expression and capillary density compared with WT. In conclusion, the EphA2-R is necessary to appropriately modulate the inflammatory response and severity of early injury during acute MI, thereby influencing the progression of ischemic cardiomyopathy.

  20. Eph Receptor and Ephrin Signaling in Developing and Adult Brain of the Honeybee (Apis mellifera)

    Vidovic, Maria; Nighorn, Alan; Koblar, Simon; Maleszka, Ryszard

    2007-01-01

    Roles for Eph receptor tyrosine kinase and ephrin signaling in vertebrate brain development are well established. Their involvement in the modulation of mammalian synaptic structure and physiology is also emerging. However, less is known of their effects on brain development and their function in adult invertebrate nervous systems. Here, we report on the characterization of Eph receptor and ephrin orthologs in the honeybee, Apis mellifera (Am), and their role in learning and memory. In situ h...

  1. Active weld control

    Powell, Bradley W.; Burroughs, Ivan A.

    1994-01-01

    Through the two phases of this contract, sensors for welding applications and parameter extraction algorithms have been developed. These sensors form the foundation of a weld control system which can provide action weld control through the monitoring of the weld pool and keyhole in a VPPA welding process. Systems of this type offer the potential of quality enhancement and cost reduction (minimization of rework on faulty welds) for high-integrity welding applications. Sensors for preweld and postweld inspection, weld pool monitoring, keyhole/weld wire entry monitoring, and seam tracking were developed. Algorithms for signal extraction were also developed and analyzed to determine their application to an adaptive weld control system. The following sections discuss findings for each of the three sensors developed under this contract: (1) weld profiling sensor; (2) weld pool sensor; and (3) stereo seam tracker/keyhole imaging sensor. Hardened versions of these sensors were designed and built under this contract. A control system, described later, was developed on a multiprocessing/multitasking operating system for maximum power and flexibility. Documentation for sensor mechanical and electrical design is also included as appendices in this report.

  2. Automaticity or active control

    Tudoran, Ana Alina; Olsen, Svein Ottar

    This study addresses the quasi-moderating role of habit strength in explaining action loyalty. A model of loyalty behaviour is proposed that extends the traditional satisfaction–intention–action loyalty network. Habit strength is conceptualised as a cognitive construct to refer to the psychologic......, respectively, between intended loyalty and action loyalty. At high levels of habit strength, consumers are more likely to free up cognitive resources and incline the balance from controlled to routine and automatic-like responses....

  3. Active Control of Suspension Bridges

    Thoft-Christensen, Palle

    In this paper some recent research on active control of very long suspension bridges, is presented. The presentation is based on research work at Aalborg University, Denmark. The active control system is based on movable flaps attached to the bridge girder. Wind load on bridges with or without...... flaps attached to the girder is briefly presented. A simple active control system is discussed. Results from wind tunnel experiments with a bridge section show that flaps can be used effectively to control bridge girder vibrations. Flutter conditions for suspension bridges with and without flaps are...

  4. EphA4 receptor tyrosine kinase is a modulator of onset and disease severity of experimental autoimmune encephalomyelitis (EAE.

    Kathryn M Munro

    Full Text Available The EphA4 receptor tyrosine kinase is a major regulator of axonal growth and astrocyte reactivity and is a possible inflammatory mediator. Given that multiple sclerosis (MS is primarily an inflammatory demyelinating disease and in mouse models of MS, such as experimental autoimmune encephalomyelitis (EAE, axonal degeneration and reactive gliosis are prominent clinical features, we hypothesised that endogenous EphA4 could play a role in modulating EAE. EAE was induced in EphA4 knockout and wildtype mice using MOG peptide immunisation and clinical severity and histological features of the disease were then compared in lumbar spinal cord sections. EphA4 knockout mice exhibited a markedly less severe clinical course than wildtype mice, with a lower maximum disease grade and a slightly later onset of clinical symptoms. Numbers of infiltrating T cells and macrophages, the number and size of the lesions, and the extent of astrocytic gliosis were similar in both genotypes; however, EphA4 knockout mice appeared to have decreased axonal pathology. Blocking of EphA4 in wildtype mice by administration of soluble EphA4 (EphA4-Fc as a decoy receptor following induction of EAE produced a delay in onset of clinical symptoms; however, most mice had clinical symptoms of similar severity by 22 days, indicating that EphA4 blocking treatment slowed early EAE disease evolution. Again there were no apparent differences in histopathology. To determine whether the role of EphA4 in modulating EAE was CNS mediated or due to an altered immune response, MOG primed T cells from wildtype and EphA4 knockout mice were passively transferred into naive recipient mice and both were shown to induce disease of equivalent severity. These results are consistent with a non-inflammatory, CNS specific, deleterious effect of EphA4 during neuroinflammation that results in axonal pathology.

  5. Convergent Evolution of Head Crests in Two Domesticated Columbids Is Associated with Different Missense Mutations in EphB2.

    Vickrey, Anna I; Domyan, Eric T; Horvath, Martin P; Shapiro, Michael D

    2015-10-01

    Head crests are important display structures in wild bird species and are also common in domesticated lineages. Many breeds of domestic rock pigeon (Columba livia) have crests of reversed occipital feathers, and this recessive trait is associated with a nonsynonymous coding mutation in the intracellular kinase domain of EphB2 (Ephrin receptor B2). The domestic ringneck dove (Streptopelia risoria) also has a recessive crested morph with reversed occipital feathers, and interspecific crosses between crested doves and pigeons produce crested offspring, suggesting a similar genetic basis for this trait in both species. We therefore investigated EphB2 as a candidate for the head crest phenotype of ringneck doves and identified a nonsynonymous coding mutation in the intracellular kinase domain that is significantly associated with the crested morph. This mutation is over 100 amino acid positions away from the crest mutation found in rock pigeons, yet both mutations are predicted to negatively affect the function of ATP-binding pocket. Furthermore, bacterial toxicity assays suggest that "crest" mutations in both species severely impact kinase activity. We conclude that head crests are associated with different mutations in the same functional domain of the same gene in two different columbid species, thereby representing striking evolutionary convergence in morphology and molecules. PMID:26104009

  6. Development of radio tracers for the radiopharmaceutical characterization of Eph receptors; Entwicklung von Radiotracern fuer die radiopharmakologische Charakterisierung von Eph-Rezeptoren

    Pretze, Marc

    2014-06-17

    In the frame of the thesis fundamental work was performed for two F-18 fluorination agents including a trial to use small molecules as radiotracers. Peptide and small molecules ware labeled with F-18 that are based on selective extra and intra cellular inhibitors foe Eph receptors. Eph receptors are supposed to be an adequate target for tumor diagnostics and therapy. The new potential radiotracer shows high in vitro stability (rat plasma) and was tested with melanoma cell lines. The used peptide sequences are discussed in detail.

  7. Expression of Eph receptor A10 is correlated with lymph node metastasis and stage progression in breast cancer patients

    Eph receptor A10 (EphA10) is a valuable breast cancer marker that is highly expressed in breast cancer tissues by comparison with normal breast tissues, as we previously reported. However, the role of EphA10 expression in breast cancer is not well understood. Here, we have analyzed the expression of EphA10 at the mRNA- and protein-level in clinical breast cancer tissues and then evaluated the relationship with clinicopathological parameters for each sample. EphA10 mRNA expression was quantified by real-time polymerase chain reaction using complimentary DNA (cDNA) samples derived from breast cancer patients. Lymph node (LN) metastasis and stage progression were significantly correlated with EphA10 expression at the mRNA level (P = 0.0091 and P = 0.034, respectively). Furthermore, immunohistochemistry (IHC) staining of breast cancer tissue microarrays (TMAs) revealed that EphA10 expression at the protein level was also associated with LN metastasis and stage progression (P = 0.016 and P = 0.011, respectively). These results indicate that EphA10 expression might play a role in tumor progression and metastasis. Our findings will help elucidate the role of EphA10 in clinical breast cancer progression

  8. Expression of Eph receptor A10 is correlated with lymph node metastasis and stage progression in breast cancer patients.

    Nagano, Kazuya; Kanasaki, So-Ichiro; Yamashita, Takuya; Maeda, Yuka; Inoue, Masaki; Higashisaka, Kazuma; Yoshioka, Yasuo; Abe, Yasuhiro; Mukai, Yohei; Kamada, Haruhiko; Tsutsumi, Yasuo; Tsunoda, Shin-Ichi

    2013-12-01

    Eph receptor A10 (EphA10) is a valuable breast cancer marker that is highly expressed in breast cancer tissues by comparison with normal breast tissues, as we previously reported. However, the role of EphA10 expression in breast cancer is not well understood. Here, we have analyzed the expression of EphA10 at the mRNA- and protein-level in clinical breast cancer tissues and then evaluated the relationship with clinicopathological parameters for each sample. EphA10 mRNA expression was quantified by real-time polymerase chain reaction using complimentary DNA (cDNA) samples derived from breast cancer patients. Lymph node (LN) metastasis and stage progression were significantly correlated with EphA10 expression at the mRNA level (P = 0.0091 and P = 0.034, respectively). Furthermore, immunohistochemistry (IHC) staining of breast cancer tissue microarrays (TMAs) revealed that EphA10 expression at the protein level was also associated with LN metastasis and stage progression (P = 0.016 and P = 0.011, respectively). These results indicate that EphA10 expression might play a role in tumor progression and metastasis. Our findings will help elucidate the role of EphA10 in clinical breast cancer progression. PMID:24403271

  9. miR-204 downregulates EphB2 in aging mouse hippocampal neurons.

    Danka Mohammed, Chand Parvez; Rhee, Hwanseok; Phee, Bong-Kwan; Kim, Kunhyung; Kim, Hee-Jin; Lee, Hyehyeon; Park, Jung Hoon; Jung, Jung Hee; Kim, Jeong Yeon; Kim, Hyoung-Chin; Park, Sang Ki; Nam, Hong Gil; Kim, Keetae

    2016-04-01

    Hippocampal synaptic function and plasticity deteriorate with age, often resulting in learning and memory deficits. As MicroRNAs (miRNAs) are important regulators of neuronal protein expression, we examined whether miRNAs may contribute to this age-associated decline in hippocampal function. We first compared the small RNA transcriptome of hippocampal tissues from young and old mice. Among 269 hippocampal miRNAs, 80 were differentially expressed (≥ twofold) among the age groups. We focused on 36 miRNAs upregulated in the old mice compared with those in the young mice. The potential targets of these 36 miRNAs included 11 critical Eph/Ephrin synaptic signaling components. The expression levels of several genes in the Eph/Ephrin pathway, including EphB2, were significantly downregulated in the aged hippocampus. EphB2 is a known regulator of synaptic plasticity in hippocampal neurons, in part by regulating the surface expression of the NMDA receptor NR1 subunit. We found that EphB2 is a direct target of miR-204 among miRNAs that were upregulated with age. The transfection of primary hippocampal neurons with a miR-204 mimic suppressed both EphB2 mRNA and protein expression and reduced the surface expression of NR1. Transfection of miR-204 also decreased the total expression of NR1. miR-204 induces senescence-like phenotype in fully matured neurons as evidenced by an increase in p16-positive cells. We suggest that aging is accompanied by the upregulation of miR-204 in the hippocampus, which downregulates EphB2 and results in reduced surface and total NR1 expression. This mechanism may contribute to age-associated decline in hippocampal synaptic plasticity and the related cognitive functions. PMID:26799631

  10. Modeling development in retinal afferents: retinotopy, segregation, and ephrinA/EphA mutants.

    Keith B Godfrey

    Full Text Available During neural development, neurons extend axons to target areas of the brain. Through processes of growth, branching and retraction these axons establish stereotypic patterns of connectivity. In the visual system, these patterns include retinotopic organization and the segregation of individual axons onto different subsets of target neurons based on the eye of origin (ocular dominance or receptive field type (ON or OFF. Characteristic disruptions to these patterns occur when neural activity or guidance molecule expression is perturbed. In this paper we present a model that explains how these developmental patterns might emerge as a result of the coordinated growth and retraction of individual axons and synapses responding to position-specific markers, trophic factors and spontaneous neural activity. This model derives from one presented earlier (Godfrey et al., 2009 but which is here extended to account for a wider range of phenomena than previously described. These include ocular dominance and ON-OFF segregation and the results of altered ephrinA and EphA guidance molecule expression. The model takes into account molecular guidance factors, realistic patterns of spontaneous retinal wave activity, trophic molecules, homeostatic mechanisms, axon branching and retraction rules and intra-axonal signaling mechanisms that contribute to the survival of nearby synapses on an axon. We show that, collectively, these mechanisms can account for a wider range of phenomena than previous models of retino-tectal development.

  11. Optical control of antibacterial activity

    Velema, Willem A.; van der Berg, Jan Pieter; Hansen, Mickel J.; Szymanski, Wiktor; Driessen, Arnold J. M.; Feringa, Ben L.

    2013-11-01

    Bacterial resistance is a major problem in the modern world, stemming in part from the build-up of antibiotics in the environment. Novel molecular approaches that enable an externally triggered increase in antibiotic activity with high spatiotemporal resolution and auto-inactivation are highly desirable. Here we report a responsive, broad-spectrum, antibacterial agent that can be temporally activated with light, whereupon it auto-inactivates on the scale of hours. The use of such a ‘smart’ antibiotic might prevent the build-up of active antimicrobial material in the environment. Reversible optical control over active drug concentration enables us to obtain pharmacodynamic information. Precisely localized control of activity is achieved, allowing the growth of bacteria to be confined to defined patterns, which has potential for the development of treatments that avoid interference with the endogenous microbial population in other parts of the organism.

  12. The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target

    Ferguson, Benjamin D.; Liu, Ren; Rolle, Cleo E.; Tan, Yi-Hung Carol; Krasnoperov, Valery; Kanteti, Rajani; Tretiakova, Maria S.; Cervantes, Gustavo M.; Hasina, Rifat; Hseu, Robyn D.; Iafrate, A. John; Karrison, Theodore; Ferguson, Mark K.; Husain, Aliya N.; Faoro, Leonardo; Vokes, Everett E.; Gill, Parkash S.; Salgia, Ravi

    2013-01-01

    Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted. PMID:23844053

  13. Active control: Wind turbine model

    Bindner, H.

    1999-01-01

    This report is a part of the reporting of the work done in the project 'Active Control of Wind Turbines'. This project aim is to develop a simulation model for design of control systems for turbines with pitch control and to use that model to designcontrollers. This report describes the model...... developed for controller design and analysis. Emphasis has been put on establishment of simple models describing the dynamic behavior of the wind turbine in adequate details for controller design. This hasbeen done with extensive use of measurements as the basis for selection of model complexity and model....... The models are all formulated as linear differential equations. The models are validated throughcomparisons with measurements performed on a Vestas WD 34 400 kW wind turbine. It is shown from a control point of view simple linear models can be used to describe the dynamic behavior of a pitch...

  14. Fractional active disturbance rejection control.

    Li, Dazi; Ding, Pan; Gao, Zhiqiang

    2016-05-01

    A fractional active disturbance rejection control (FADRC) scheme is proposed to improve the performance of commensurate linear fractional order systems (FOS) and the robust analysis shows that the controller is also applicable to incommensurate linear FOS control. In FADRC, the traditional extended states observer (ESO) is generalized to a fractional order extended states observer (FESO) by using the fractional calculus, and the tracking differentiator plus nonlinear state error feedback are replaced by a fractional proportional-derivative controller. To simplify controller tuning, the linear bandwidth-parameterization method has been adopted. The impacts of the observer bandwidth ωo and controller bandwidth ωc on system performance are then analyzed. Finally, the FADRC stability and frequency-domain characteristics for linear single-input single-output FOS are analyzed. Simulation results by FADRC and ADRC on typical FOS are compared to demonstrate the superiority and effectiveness of the proposed scheme. PMID:26928516

  15. ABOUT CONTROLLING OF SCIENTIFIC ACTIVITY

    Mukhin V. V.

    2014-06-01

    Full Text Available We have selected the new area of controlling - scientific activity controlling. We consider some problems of development in this field, primarily the problem of selection of key performance indicators. It’s been founded that administrative measures stimulated the pursuit of a number of articles published in scientific journals hinders the development of science. Methodological errors - emphasis on citation indexes, impact factors, etc. - lead to wrong management decisions. As the experience of the UK, an expertise should be applied in the management of science. The article briefly discusses some of the drawbacks of the system of scientific specialties. It is proposed to expand research on the science of science and scientific activity controlling. We have also discussed the problems of controlling in applied research organizations

  16. Eph receptors and ephrin class B ligands are expressed at tissue boundaries in Hydra vulgaris.

    Tischer, Susanne; Reineck, Mona; Söding, Johannes; Münder, Sandra; Böttger, Angelika

    2013-01-01

    Eph receptors and ephrins are important players in axon guidance, cell sorting and boundary formation. Both the receptors and the ligands are integrated transmembrane proteins and signalling is bidirectional. The prevalent outcome of signal transduction is repulsion of adjacent cells or cell populations. Eph/ephrins have been identified in all multicellular animals from human to sponge, their functions however appear to have been altered during evolution. Here we have identified four Eph receptors and three class B ligands in the cnidarian Hydra vulgaris, indicating that those are the evolutionary older ones. In situ hybridisation experiments revealed a striking complementarity of expression of receptors and ligands in tentacles and in developing buds. This suggests that the original function of ephrin signalling may have been in epithelial cell adhesion and the formation of tissue boundaries. PMID:24307295

  17. Eph receptor and ephrin signaling in developing and adult brain of the honeybee (Apis mellifera).

    Vidovic, Maria; Nighorn, Alan; Koblar, Simon; Maleszka, Ryszard

    2007-02-01

    Roles for Eph receptor tyrosine kinase and ephrin signaling in vertebrate brain development are well established. Their involvement in the modulation of mammalian synaptic structure and physiology is also emerging. However, less is known of their effects on brain development and their function in adult invertebrate nervous systems. Here, we report on the characterization of Eph receptor and ephrin orthologs in the honeybee, Apis mellifera (Am), and their role in learning and memory. In situ hybridization for mRNA expression showed a uniform distribution of expression of both genes across the developing pupal and adult brain. However, in situ labeling with Fc fusion proteins indicated that the AmEphR and Amephrin proteins were differentially localized to cell body regions in the mushroom bodies and the developing neuropiles of the antennal and optic lobes. In adults, AmEphR protein was localized to regions of synaptic contacts in optic lobes, in the glomeruli of antennal lobes, and in the medial lobe of the mushroom body. The latter two regions are involved in olfactory learning and memory in the honeybee. Injections of EphR-Fc and ephrin-Fc proteins into the brains of adult bees, 1 h before olfactory conditioning of the proboscis extension reflex, significantly reduced memory 24 h later. Experimental amnesia in the group injected with ephrin-Fc was apparent 1 h post-training. Experimental amnesia was also induced by post-training injections with ephrin-Fc suggesting a role in recall. This is the first demonstration that Eph molecules function to regulate the formation of memory in insects. PMID:17443785

  18. Adaptive feedback active noise control

    Kuo, Sen M.; Vijayan, Dipa

    Feedforward active noise control (ANC) systems use a reference sensor that senses a reference input to the controller. This signal is assumed to be unaffected by the secondary source and is a good measure of the undesired noise to be cancelled by the system. The reference sensor may be acoustic (e.g., microphone) or non-acoustic (e.g., tachometer, optical transducer). An obvious problem when using acoustic sensors is that the reference signal may be corrupted by the canceling signal generated by the secondary source. This problem is known as acoustic feedback. One way of avoiding this is by using a feedback active noise control (FANC) system which dispenses with the reference sensor. The FANC technique originally proposed by Olson and May employs a high gain negative feedback amplifier. This system suffered from the drawback that the error microphone had to be placed very close to the loudspeaker. The operation of the system was restricted to low frequency range and suffered from instability due to the possibility of positive feedback. Feedback systems employing adaptive filtering techniques for active noise control were developed. This paper presents the FANC system modeled as an adaptive prediction scheme.

  19. Novel Active Combustion Control Valve

    Caspermeyer, Matt

    2014-01-01

    This project presents an innovative solution for active combustion control. Relative to the state of the art, this concept provides frequency modulation (greater than 1,000 Hz) in combination with high-amplitude modulation (in excess of 30 percent flow) and can be adapted to a large range of fuel injector sizes. Existing valves often have low flow modulation strength. To achieve higher flow modulation requires excessively large valves or too much electrical power to be practical. This active combustion control valve (ACCV) has high-frequency and -amplitude modulation, consumes low electrical power, is closely coupled with the fuel injector for modulation strength, and is practical in size and weight. By mitigating combustion instabilities at higher frequencies than have been previously achieved (approximately 1,000 Hz), this new technology enables gas turbines to run at operating points that produce lower emissions and higher performance.

  20. Comparative Analysis of Virtual Screening Approaches in the Search for Novel EphA2 Receptor Antagonists

    Donatella Callegari

    2015-09-01

    Full Text Available The EphA2 receptor and its ephrin-A1 ligand form a key cell communication system, which has been found overexpressed in many cancer types and involved in tumor growth. Recent medicinal chemistry efforts have identified bile acid derivatives as low micromolar binders of the EphA2 receptor. However, these compounds suffer from poor physicochemical properties, hampering their use in vivo. The identification of compounds able to disrupt the EphA2-ephrin-A1 complex lacking the bile acid scaffold may lead to new pharmacological tools suitable for in vivo studies. To identify the most promising virtual screening (VS protocol aimed at finding novel EphA2 antagonists, we investigated the ability of both ligand-based and structure-based approaches to retrieve known EphA2 antagonists from libraries of decoys with similar molecular properties. While ligand-based VSs were conducted using UniPR129 and ephrin-A1 ligand as reference structures, structure-based VSs were performed with Glide, using the X-ray structure of the EphA2 receptor/ephrin-A1 complex. A comparison of enrichment factors showed that ligand-based approaches outperformed the structure-based ones, suggesting ligand-based methods using the G-H loop of ephrin-A1 ligand as template as the most promising protocols to search for novel EphA2 antagonists.

  1. Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients

    Rose Frank

    2008-03-01

    Full Text Available Abstract Background Malignant gliomas are lethal cancers, highly dependent on angiogenesis and treatment options and prognosis still remain poor for patients with recurrent glioblastoma multiforme (GBM. Ephs and ephrins have many well-defined functions during embryonic development of central nervous system such as axon mapping, neural crest cell migration, hindbrain segmentation and synapse formation as well as physiological and abnormal angiogenesis. Accumulating evidence indicates that Eph and ephrins are frequently overexpressed in different tumor types including GBM. However, their role in tumorigenesis remains controversial, as both tumor growth promoter and suppressor potential have been ascribed to Eph and ephrins while the function of EphA7 in GBM pathogenesis remains largely unknown. Methods In this study, we investigated the immunohistochemical expression of EphA7 in a series of 32 primary and recurrent GBM and correlated it with clinical pathological parameters and patient outcome. In addition, intratumor microvascular density (MVD was quantified by immunostaining for endothelial cell marker von Willebrand factor (vWF. Results Overexpression of EphA7 protein was predictive of the adverse outcome in GBM patients, independent of MVD expression (p = 0.02. Moreover, high density of MVD as well as higher EphA7 expression predicted the disease outcome more accurately than EphA7 variable alone (p = 0.01. There was no correlation between MVD and overall survival or recurrence-free survival (p > 0.05. However, a statistically significant correlation between lower MVD and tumor recurrence was observed (p = 0.003. Conclusion The immunohistochemical assessment of tissue EphA7 provides important prognostic information in GBM and would justify its use as surrogate marker to screen patients for tyrosine kinase inhibitor therapy.

  2. Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients

    Malignant gliomas are lethal cancers, highly dependent on angiogenesis and treatment options and prognosis still remain poor for patients with recurrent glioblastoma multiforme (GBM). Ephs and ephrins have many well-defined functions during embryonic development of central nervous system such as axon mapping, neural crest cell migration, hindbrain segmentation and synapse formation as well as physiological and abnormal angiogenesis. Accumulating evidence indicates that Eph and ephrins are frequently overexpressed in different tumor types including GBM. However, their role in tumorigenesis remains controversial, as both tumor growth promoter and suppressor potential have been ascribed to Eph and ephrins while the function of EphA7 in GBM pathogenesis remains largely unknown. In this study, we investigated the immunohistochemical expression of EphA7 in a series of 32 primary and recurrent GBM and correlated it with clinical pathological parameters and patient outcome. In addition, intratumor microvascular density (MVD) was quantified by immunostaining for endothelial cell marker von Willebrand factor (vWF). Overexpression of EphA7 protein was predictive of the adverse outcome in GBM patients, independent of MVD expression (p = 0.02). Moreover, high density of MVD as well as higher EphA7 expression predicted the disease outcome more accurately than EphA7 variable alone (p = 0.01). There was no correlation between MVD and overall survival or recurrence-free survival (p > 0.05). However, a statistically significant correlation between lower MVD and tumor recurrence was observed (p = 0.003). The immunohistochemical assessment of tissue EphA7 provides important prognostic information in GBM and would justify its use as surrogate marker to screen patients for tyrosine kinase inhibitor therapy

  3. Active control of the noise

    The problems of acoustic noise are more and more preponderant in the measure in that the amount of equipment and industrial machinery is increased such as fans, transformers, compressors etc. the use of devices passive mechanics for the reduction of the noise is effective and very appreciated because its effects embrace a wide range of acoustic frequency. However, to low frequencies, such devices become too big and expensive besides that present a tendency to do not effective. The control of active noise, CAN, using the electronic generation anti-noise, constitutes an interesting solution to the problem because their operation principle allows achieving an appreciable reduction of the noise by means of the use of compact devices. The traditional techniques for the control of acoustic noise like barriers and silenced to attenuate it, are classified as passive and their works has been accepted as norm as for the treatment of problems of noise it refers. Such techniques are considered in general very effective in the attenuation of noise of wide band. However, for low frequency, the required passive structures are too big and expensive; also, their effectiveness diminishes flagrantly, that which makes them impractical in many applications. The active suppression is profiled like a practical alternative for the reduction of acoustic noise. The idea in the active treatment of the noise it contemplates the use of a device electro-acoustic, like a speaker for example that it cancels to the noise by the generation of sounds of Same width and of contrary phase (anti-noise). The cancellation phenomenon is carried out when the ant-noise combines acoustically with the noise, what is in the cancellation of both sounds. The effectiveness of the cancellation of the primary source of noise depends on the precision with which the width and the phase of the generated ant-noise are controlled. The active control of noise, ANC (activates noise control), it is being investigated for

  4. Controlling Spatiotemporal Chaos in Active Dissipative-Dispersive Nonlinear Systems

    Gomes, Susana; Pradas, Marc; Kalliadasis, Serafim; Papageorgiou, Demetrios; Pavliotis, Grigorios

    2015-11-01

    We present a novel generic methodology for the stabilization and control of infinite-dimensional dynamical systems exhibiting low-dimensional spatiotemporal chaos. The methodology is exemplified with the generalized Kuramoto-Sivashinsky equation, the simplest possible prototype that retains that fundamental elements of any nonlinear process involving wave evolution. The equation is applicable on a wide variety of systems including falling liquid films and plasma waves with dispersion due to finite banana width. We show that applying the appropriate choice of time-dependent feedback controls via blowing and suction, we are able to stabilize and/or control all stable or unstable solutions, including steady solutions, travelling waves and spatiotemporal chaos, but also use the controls obtained to stabilize the solutions to more general long wave models. We acknowledge financial support from Imperial College through a Roth PhD studentship, Engineering and Physical Sciences Research Council of the UK through Grants No. EP/H034587, EP/J009636, EP/K041134, EP/L020564 and EP/L024926 and European Research Council via Advanced Grant No. 247031.

  5. Graded and discontinuous EphA-ephrinB expression patterns in the developing auditory brainstem.

    Wallace, Matthew M; Harris, J Aaron; Brubaker, Donald Q; Klotz, Caitlyn A; Gabriele, Mark L

    2016-05-01

    Eph-ephrin interactions guide topographic mapping and pattern formation in a variety of systems. In contrast to other sensory pathways, their precise role in the assembly of central auditory circuits remains poorly understood. The auditory midbrain, or inferior colliculus (IC) is an intriguing structure for exploring guidance of patterned projections as adjacent subdivisions exhibit distinct organizational features. The central nucleus of the IC (CNIC) and deep aspects of its neighboring lateral cortex (LCIC, Layer 3) are tonotopically-organized and receive layered inputs from primarily downstream auditory sources. While less is known about more superficial aspects of the LCIC, its inputs are multimodal, lack a clear tonotopic order, and appear discontinuous, terminating in modular, patch/matrix-like distributions. Here we utilize X-Gal staining approaches in lacZ mutant mice (ephrin-B2, -B3, and EphA4) to reveal EphA-ephrinB expression patterns in the nascent IC during the period of projection shaping that precedes hearing onset. We also report early postnatal protein expression in the cochlear nuclei, the superior olivary complex, the nuclei of the lateral lemniscus, and relevant midline structures. Continuous ephrin-B2 and EphA4 expression gradients exist along frequency axes of the CNIC and LCIC Layer 3. In contrast, more superficial LCIC localization is not graded, but confined to a series of discrete ephrin-B2 and EphA4-positive Layer 2 modules. While heavily expressed in the midline, much of the auditory brainstem is devoid of ephrin-B3, including the CNIC, LCIC Layer 2 modular fields, the dorsal nucleus of the lateral lemniscus (DNLL), as well as much of the superior olivary complex and cochlear nuclei. Ephrin-B3 LCIC expression appears complementary to that of ephrin-B2 and EphA4, with protein most concentrated in presumptive extramodular zones. Described tonotopic gradients and seemingly complementary modular/extramodular patterns suggest Eph

  6. A Digital Controller for Active Aeroelastic Controls

    Ueda, Tetsuhiko; MUROTA, Katsuichi; 上田, 哲彦; 室田, 勝一

    1989-01-01

    A high-speed digital controller for aeroelastic controls was designed and made. The purpose was to minimize adverse phase lag which is inevitably produced by the CPU time of digital processing. The delay deteriorates control performances on rather rapid phenomena like aircraft flutter. With fix-point operation the controller realized 417 microseconds of throughput time including the A/D and D/A conversion. This corresponds to a high sampling rate of 2.4kHz. The controller furnishes two channe...

  7. Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients

    Rose Frank; You An; Juricko Janko; Fokas Emmanouil; Wang Lin-Fang; Pagenstecher Axel; Engenhart-Cabillic Rita; An Han-Xiang

    2008-01-01

    Abstract Background Malignant gliomas are lethal cancers, highly dependent on angiogenesis and treatment options and prognosis still remain poor for patients with recurrent glioblastoma multiforme (GBM). Ephs and ephrins have many well-defined functions during embryonic development of central nervous system such as axon mapping, neural crest cell migration, hindbrain segmentation and synapse formation as well as physiological and abnormal angiogenesis. Accumulating evidence indicates that Eph...

  8. Endothelial-Specific EphA4 Negatively Regulates Native Pial Collateral Formation and Re-Perfusion following Hindlimb Ischemia

    Okyere, Benjamin; Giridhar, Kaavya; Hazy, Amanda; Chen, Miao; Keimig, David; Bielitz, Robert C.; Xie, Hehuang; He, Jia-Qiang; Huckle, William R.; Theus, Michelle H.

    2016-01-01

    Leptomeningeal anastomoses play a critical role in regulating vascular re-perfusion following obstruction, however, the mechanisms regulating their development remains under investingation. Our current findings indicate that EphA4 receptor is a novel negative regulator of collaterogenesis. We demonstrate that EphA4 is highly expressed on pial arteriole collaterals at post-natal day (P) 1 and 7, then significantly reduced by P21. Endothelial cell (EC)-specific loss of EphA4, EphA4f/f/Tie2::Cre (KO), resulted in an increase in the density but not diameter of pial collaterals compared to WT mice. ECs isolated from KO mice displayed a 3-fold increase in proliferation, enhanced migration, tube formation and elevated levels of phospho(p)-Akt compared to WT ECs. Attenuating p-Akt, using LY294002, reduced the proliferative and migration effects in the KO ECs. RNAseq analysis also revealed altered expression patterns for genes that regulate cell proliferation, vascular development, extracellular matrix and immune-mediate responses, namely MCP-1, MMP2 and angiopoietin-1. Lastly, we show that induction of hindlimb ischemia resulted in accelerated re-perfusion, collateral remodeling and reduced tissue necrosis in the absence of EC-specific EphA4 compared to WT mice. These findings demonstrate a novel role for EphA4 in the early development of the pial collateral network and suggests a role in regulating vascular remodeling after obstruction. PMID:27467069

  9. Active Spacecraft Potential Control Investigation

    Torkar, K.; Nakamura, R.; Tajmar, M.; Scharlemann, C.; Jeszenszky, H.; Laky, G.; Fremuth, G.; Escoubet, C. P.; Svenes, K.

    2016-03-01

    In tenuous plasma the floating potential of sunlit spacecraft reaches tens of volts, positive. The corresponding field disturbs measurements of the ambient plasma by electron and ion sensors and can reduce micro-channel plate lifetime in electron detectors owing to large fluxes of attracted photoelectrons. Also the accuracy of electric field measurements may suffer from a high spacecraft potential. The Active Spacecraft Potential Control (ASPOC) neutralizes the spacecraft potential by releasing positive charge produced by indium ion emitters. The method has been successfully applied on other spacecraft such as Cluster and Double Star. Two ASPOC units are present on each spacecraft. Each unit contains four ion emitters, whereby one emitter per instrument is operated at a time. ASPOC for the Magnetospheric Multiscale (MMS) mission includes new developments in the design of the emitters and the electronics. New features include the use of capillaries instead of needles, new materials for the emitters and their internal thermal insulators, an extended voltage and current range of the electronics, both for ion emission and heating purposes, and a more capable control software. This enables lower spacecraft potentials, higher reliability, and a more uniform potential structure in the spacecraft's sheath compared to previous missions. Results from on-ground testing demonstrate compliance with requirements. Model calculations confirm the findings from previous applications that the plasma measurements will not be affected by the beam's space charge. Finally, the various operating modes to adapt to changing boundary conditions are described along with the main data products.

  10. Expression of EphB4 and EphrinB2 in retinoblastoma and their significance%视网膜母细胞瘤中EphB4和EphrinB2的表达及意义

    耿祥娥; 赵玉斌; 张少华; 吕杰; 徐治伟; 王金清

    2012-01-01

    目的 探讨EphB4和EphrinB2的蛋白在视网膜母细胞瘤中的表达及其意义.方法 应用免疫组织化学SP法测定10例正常视网膜组织和40例视网膜母细胞瘤标本中EphB4和EphrinB2的表达水平,分析其与性别、临床分期、分化程度和视神经浸润的关系.结果(1)EphB4和EphrinB2蛋白表达的阳性率,在正常视网膜组织中分别为5%和2.5%,40例视网膜母细胞瘤标本中分别为77.5%和67.5%.EphB4和EphrinB2在视网膜母细胞瘤组织中的阳性率与显著高于正常视网膜组织中的阳性率(P<0.05).(2)EphB4和EphrinB2的蛋白在视网膜母细胞瘤的阳性表达率与肿瘤组织的临床分期、分化程度及视神经浸润显著相关(P<0.05).(3)EphB4和EphrinB2的蛋白在视网膜母细胞瘤组织中的阳性表达显著相关(P<0.05).结论 EphB4和EphrinB2可能在视网膜母细胞瘤的发生和发展过程中起重要作用,可作为评价视网膜母细胞瘤的浸润及预后的标志物.%Objective To investigate the protein expressions of EphB4 and EphrinB2 in retinoblastoma and to study their significance.Methods The expression of EphB4 and EphrinB2 was examined immunohistochemistrically by SP method in tissues of 10 normal retina and 40 patients with retinoblastoma and to study their relationship with gender,clinical stage,differentiation and optic nerve infiltration.Results 1.The protein expression of EphB4 and EphrinB2 observed in the normal tissues of retina was 5% and 2.5% respectively.In the 40 retinoblastoma cases,the positive rate of them was 77.5% and 67.5% respectively.The positive rate of EphB4 and EphrinB2 in retinoblastoma was higher than that in the normal retina(P<0.05).2.The positive expression of EphB4 and EphrinB2 protein were associated with clinical stage,differentiation and optic nerve infiltration(P<0.05).3.The positive expression of EphB4 and EphrinB2 protein in retinoblastoma was positively correlated(P<0.05).Conclusions Eph

  11. EphA1基因可控性双稳转内皮祖细胞系EPCsTet-On-EphA1SiRNA的建立%To construct an EphA1 gene regulatable endothelia progenitor cells (EPCs) by Tet-On system

    陈钢; 金炜东; 王怡; 施红旗; 余正平; 周蒙滔; 杨文军

    2012-01-01

    Objective To develop the EPCsTet-On-EphAlSiRNA cell line which can regulate the EphA1 gene expression by doxycycline. Methods EPCs were transfected with pWHE146 vector by liposome transfection reagent. The transfected cells were screened in medium containing G418 and G418-resistant clones were isolated. All individual G418-resistant clones were selected by transient transfection with plasmid pTRE-hyg-luc. And the low background and high induction of luciferase in response to doxycycline clones were selected. The isolated clones were named EPCsTet" On. Followed, EPCsTefOn cells were transfected with pTHE-EphAlSiRNA vector by liposome transfection reagent. The transfected cells were selected in medium containing hygromycin(hyg) and the double'stable cell lines(G418- and hyg-resistant) EPCsTet-On-EphAlSiRNA were isolated. Induced by doxycycline, RT-PCR and Western blotting were used to test the expression of EphAl. Results Low background and high induction EPCsTet-On-EphAlSiRNA were established successfully. EphA1 mRNA could be induced to down-expressed in EPCsTet-On-EphAlSiRNA by doxycycline. Compared with no doxycycline group which has statistical significance(P< 0.05). In addition the expression rate of EphAl was decreased significantly by doxycycline in a concentration-dependent manner. Conclusion The double-stable cell line EPCsTet-On-EphAlSiRNA waw successfully established, which could be induced EphA 1 dowrrexpressed by doxycycline and provided an ideal experimental platform for further study of EPCs in angiogenesis of liver cancer.%目的 建立可调控EphA1基因表达的内皮祖细胞系EPCsTetOn-EphAl1SiRNA.方法 将pWHE146质粒转染到内皮祖细胞系中,筛选出稳定表达的细胞克隆;扩增后瞬时转染pTRE-hyg-luc质粒,强力霉素诱导表达后,检测荧光素酶活性,挑选出高表达、低背景的受强力霉素调控的EPCsTet-On细胞株;再将重组质粒pTRE-EphA1SiRNA转染入EPCsTet-On细胞株,筛选出稳定表达细

  12. Design, Synthesis and Bio-evaluation of an EphA2-based Targeted Delivery System

    Barile, Elisa; Wang, Si; Das, Swadesh K.; Noberini, Roberta; Dahl, Russell; Stebbins, John L.; Pasquale, Elena B.; Fisher, Paul B.; Pellecchia, Maurizio

    2014-01-01

    We recently described a new targeted delivery system based on specific EphA2 receptor targeting peptides conjugated with the chemotherapeutic agent paclitaxel. In this manuscript we investigate the chemical determinants responsible for the stability and degradation of these agents in plasma. Introducing modifications in both the peptide and the linker between the peptide and paclitaxel, resulted in drug conjugates that are both long-lived in rat plasma and that markedly reduced tumor size in ...

  13. Active interaction control for civil structures

    Wang, Luo-Jia

    1997-01-01

    This thesis presents a civil engineering approach to active control for civil structures. The proposed control technique, termed Active Interaction Control (AIC), utilizes dynamic interactions between different structures, or components of the same structure, to reduce the resonance response of the controlled or primary structure under earthquake excitations. The primary control objective of AIC is to minimize the maximum story drift of the primary structure. This is accomplished by timing th...

  14. Cooperative Control Method of Active and Semiactive Control: New Framework for Vibration Control

    Kazuhiko Hiramoto

    2014-01-01

    A new control design framework for vibration control, the cooperative control of active and semiactive control, is proposed in the paper. In the cooperative control, a structural system having both of an actuator and a semiactive control device, for example, MR damper and so forth, is defined as the control object. In the proposed control approach, the higher control performance is aimed by the cooperative control between the active control with the actuator and the semiactive control with th...

  15. Microglial control of neuronal activity

    Catherine eBéchade

    2013-03-01

    Full Text Available Fine-tuning of neuronal activity was thought to be a neuron-autonomous mechanism until the discovery that astrocytes are active players of synaptic transmission. The involvement of astrocytes has changed our understanding of the roles of non-neuronal cells and shed new light on the regulation of neuronal activity. Microglial cells are the macrophages of the brain and they have been mostly investigated as immune cells. However recent data discussed in this review support the notion that, similarly to astrocytes, microglia are involved in the regulation of neuronal activity. For instance, in most, if not all, brain pathologies a strong temporal correlation has long been known to exist between the pathological activation of microglia and dysfunction of neuronal activity. Recent studies have convincingly shown that alteration of microglial function is responsible for pathological neuronal activity. This causal relationship has also been demonstrated in mice bearing loss-of-function mutations in genes specifically expressed by microglia. In addition to these long-term regulations of neuronal activity, recent data show that microglia can also rapidly regulate neuronal activity, thereby acting as partners of neurotransmission.

  16. Vibration control of active structures an introduction

    Preumont, Andre

    2002-01-01

    This text is an introduction to the dynamics of active structures and to the feedback control of lightly damped flexible structures. The emphasis is placed on basic issues and simple control strategies that work.

  17. Developing Internal Controls through Activities

    Barnes, F. Herbert

    2009-01-01

    Life events can include the Tuesday afternoon cooking class with the group worker or the Saturday afternoon football game, but in the sense that Fritz Redl thought of them, these activities are only threads in a fabric of living that includes all the elements of daily life: playing, working, school-based learning, learning through activities,…

  18. Anti-tumour effects of antibodies targeting the extracellular cysteine-rich region of the receptor tyrosine kinase EphB4.

    Stephenson, Sally-Anne; Douglas, Evelyn L; Mertens-Walker, Inga; Lisle, Jessica E; Maharaj, Mohanan S N; Herington, Adrian C

    2015-04-10

    EphB4 is a membrane-bound receptor tyrosine kinase (RTK) commonly over-produced by many epithelial cancers but with low to no expression in most normal adult tissues. EphB4 over-production promotes ligand-independent signaling pathways that increase cancer cell viability and stimulate migration and invasion. Several studies have shown that normal ligand-dependent signaling is tumour suppressive and therefore novel therapeutics which block the tumour promoting ligand-independent signaling and/or stimulate tumour suppressive ligand-dependent signaling will find application in the treatment of cancer. An EphB4-specific polyclonal antibody, targeting a region of 200 amino acids in the extracellular portion of EphB4, showed potent in vitro anti-cancer effects measured by an increase in apoptosis and a decrease in anchorage independent growth. Peptide exclusion was used to identify the epitope targeted by this antibody within the cysteine-rich region of the EphB4 protein, a sequence defined as a potential ligand interacting interface. Addition of antibody to cancer cells resulted in phosphorylation and subsequent degradation of the EphB4 protein, suggesting a mechanism that is ligand mimetic and tumour suppressive. A monoclonal antibody which specifically targets this identified extracellular epitope of EphB4 significantly reduced breast cancer xenograft growth in vivo confirming that EphB4 is a useful target for ligand-mimicking antibody-based anti-cancer therapies. PMID:25831049

  19. Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells.

    Wu, Bainan; Wang, Si; De, Surya K; Barile, Elisa; Quinn, Bridget A; Zharkikh, Irina; Purves, Angela; Stebbins, John L; Oshima, Robert G; Fisher, Paul B; Pellecchia, Maurizio

    2015-07-23

    The development of novel, targeted delivery agents for anti-cancer therapies requires the design and optimization of potent and selective tumor-targeting agents that are stable and amenable to conjugation with chemotherapeutic drugs. While short peptides represent potentially an excellent platform for these purposes, they often get degraded and are eliminated too rapidly in vivo. In this study, we used a combination of nuclear magnetic resonance-guided structure-activity relationships along with biochemical and cellular studies to derive a novel tumor-homing agent, named 123B9, targeting the EphA2 tyrosine kinase receptor ligand-binding domain. Conjugating 123B9 to the chemotherapeutic drug paclitaxel (PTX) via a stable linker results in an agent that is significantly more effective than the unconjugated drug in both a pancreatic cancer xenograft model and a melanoma lung colonization and metastases model. Hence, 123B9 could represent a promising strategy for the development of novel targeted therapies for cancer. PMID:26165155

  20. Synthesis and structure of silicon-, germanium-, and tin-containing tungsten complexes of carbynes (ButO)3W ≡ C-EPh3 and [ButO)3W ≡ C]2EPh2 (E = Si, Ge, Sn)

    New carbyne complexes of tungsten (ButO)3W ≡ C-SiEPh3 and [ButO)3W ≡ C]2EPh2 (E = Si, Ge, Sn) were prepared in individual crystal state with 48-80% yield using reaction of (ButO)6W2 with Ph3SiC ≡ CPr or Ph2E(C ≡ CPr)2. The structure of previously synthesized compounds, i.e. (ButO)3W ≡ C-E'Ph3 (E' = Ge, Sn), and of the new complexes was identified by the method of X-ray diffraction analysis

  1. SLIDING MODE CONTROL FOR ACTIVE AUTOMOBILE SUSPENSIONS

    1998-01-01

    Nonlinear control methods are presented based on theory of sliding mode control (SMC) or variable structure control (VSC) for application to active automobile suspensions. Requirements of reducing manufacturing cost and energy consumption of the active suspension system may be satisfiedby reasonable design of the sliding surface and hydraulic servo system. Emphasis is placed on the study of the discrete sliding mode control method (DSMC) applicable for a new sort of speed on-off solenoid valves of anti-dust capability and low price. Robustness and effectiveness of the feedback linearized controller in typical road conditions are demonstrated by numerical results fora quarter-car suspension model.

  2. Active vibration control of lightweight floor systems

    Baader, J.; Fontana, M.

    2016-04-01

    Wide-span and lightweight floors are often prone to structural vibrations due to their low resonance frequency and poor material damping. Their dynamic behaviour can be improved using passive, semi-active or active vibration control devices. The following article proposes a novel method for the controller synthesis for active vibration control. An existing passive TMD (tuned mass damper) is modelled and equipped with an actuator in order to provide more efficient damping. Using an iterative optimization approach under constraints, an optimal controller is found which minimizes a quadratic cost function in frequency domain. A simulation of an existing test bench shows that the active vibration control device is able to provide increased damping compared to the passive TMD.

  3. Active Control of Fan Noise

    Nobuhiko YAMASAKI; Hirotoshi TAJIMA

    2008-01-01

    In the wake-rotor interaction fan noise, a number of the interacting modes at the blade passing frequency (BPF)and its harmonics are generated which are prescribed by the number of stator and rotor blades etc. In the present study, the dominant mode is tried to be suppressed by the secondary sound from the loudspeaker actuators. One of the novel features of the present system is the adoption of the control board with the Field Programmable Gate Array (FPGA) hardware and the LabVIEW software to synchronize the circumferentially installed loudspeaker actuators with the relative location of rotational blades under arbitrary fan rotational speeds. The experiments were conducted under the conditions of three rotational speeds of 2004, 3150, and 4002 [rpm]. The reduction in the sound pressure level (SPL) was observed for all three rotational speeds. The sound pressure level at the BPF was reduced approximately 13 [dB] for 2004 [rpm] case, but not so large reduction was attained for other cases probably due to the inefficiency of the loudspeaker actuators at high frequencies

  4. Manually controlled neutron-activation system

    Johns, R. A.; Carothers, G. A.

    1982-01-01

    A manually controlled neutron activation system, the Manual Reactor Activation System, was designed and built and has been operating at one of the Savannah River Plant's production reactors. With this system, samples can be irradiated for up to 24 hours and pneumatically transferred to a shielded repository for decay until their activity is low enough for them to be handled at a radiobench. The Manual Reactor Activation System was built to provide neutron activation of solid waste forms for the Alternative Waste Forms Leach Testing Program. Neutron activation of the bulk sample prior to leaching permits sensitive multielement radiometric analyses of the leachates.

  5. DSP Control of Line Hybrid Active Filter

    Dan, Stan George; Benjamin, Doniga Daniel; Magureanu, R.;

    2005-01-01

    Active Power Filters have been intensively explored in the past decade. Hybrid active filters inherit the efficiency of passive filters and the improved performance of active filters, and thus constitute a viable improved approach for harmonic compensation. In this paper a parallel hybrid filter...... is studied for current harmonic compensation. The hybrid filter is formed by a single tuned Le filter and a small-rated power active filter, which are directly connected in series without any matching transformer. Thus the required rating of the active filter is much smaller than a conventional standalone...... active filter. Simulation and experimental results obtained in laboratory confirmed the validity and effectiveness of the control....

  6. Active Power Filter Using Predicted Current Control

    Xiaojie, Y.; Pivoňka, P.; Valouch, Viktor

    2001-01-01

    Roč. 46, č. 1 (2001), s. 41-50. ISSN 0001-7043 Institutional research plan: CEZ:AV0Z2057903 Keywords : active power filter * control strategy Subject RIV: JA - Electronics ; Optoelectronics, Electrical Engineering

  7. Active Noise Control in Propeller Aircraft

    Johansson, Sven; Claesson, Ingvar

    2001-01-01

    A noisy environment dominated by low frequency noise can often be improved through the use of active noise control. This situation arises naturally in propeller aircraft where the propellers induce periodic low frequency noise inside the cabin. The cabin noise is typically rather high, and the passenger flight comfort could be improved considerably if this level were significantly reduced. This paper addresses same design aspects for multiple-reference active noise control systems based on th...

  8. Semi-active control of dynamically excited structures using active interaction control

    Zhang, Yunfeng

    2001-01-01

    This thesis presents a family of semi-active control algorithms termed Active Interaction Control (AIC) used for response control of dynamically excited structures. The AIC approach has been developed as a semi﷓active means of protecting building structures against large earthquakes. The AIC algorithms include the Active Interface Damping (AID), Optimal Connection Strategy (OCS), and newly developed Tuned Interaction Damping (TID) algorithms. All of the AIC algorithms are founded upon ...

  9. Active load control techniques for wind turbines.

    van Dam, C.P. (University of California, Davis, CA); Berg, Dale E.; Johnson, Scott J. (University of California, Davis, CA)

    2008-07-01

    This report provides an overview on the current state of wind turbine control and introduces a number of active techniques that could be potentially used for control of wind turbine blades. The focus is on research regarding active flow control (AFC) as it applies to wind turbine performance and loads. The techniques and concepts described here are often described as 'smart structures' or 'smart rotor control'. This field is rapidly growing and there are numerous concepts currently being investigated around the world; some concepts already are focused on the wind energy industry and others are intended for use in other fields, but have the potential for wind turbine control. An AFC system can be broken into three categories: controls and sensors, actuators and devices, and the flow phenomena. This report focuses on the research involved with the actuators and devices and the generated flow phenomena caused by each device.

  10. Active and passive vibration control of structures

    Spelsberg-Korspeter, Gottfried

    2014-01-01

    Active and Passive Vibration Control of Structures form an issue of very actual interest in many different fields of engineering, for example in the automotive and aerospace industry, in precision engineering (e.g. in large telescopes), and also in civil engineering. The papers in this volume bring together engineers of different background, and it fill gaps between structural mechanics, vibrations and modern control theory.  Also links between the different applications in structural control are shown.

  11. Active control of vibrations in pedestrian bridges

    Álvaro Cunha; Carlos Moutinho

    1999-01-01

    This paper, apart from making a brief general reference to vibration problems in pedestrian bridges, as well as to the form of modelling of dynamic pedestrian loads, presents the use of a predictive control strategy for the numerical simulation of the dynamic response of actively controlled structures of this type. The consideration of this control strategy permitted the development of a computational model, which was applied to the study of a pedestrian cable-stayed bridge, in order to show ...

  12. Control of nucleus accumbens activity with neurofeedback

    Greer, Stephanie M.; Trujillo, Andrew J.; Glover, Gary H.; Knutson, Brian

    2014-01-01

    The nucleus accumbens (NAcc) plays critical roles in healthy motivation and learning, as well as in psychiatric disorders (including schizophrenia and attention deficit hyperactivity disorder). Thus, techniques that confer control of NAcc activity might inspire new therapeutic interventions. By providing second-to-second temporal resolution of activity in small subcortical regions, functional magnetic resonance imaging (fMRI) can resolve online changes in NAcc activity, which can then be pres...

  13. Adaptive control of active filter using DSP

    In order to reduce output-voltage ripple of power supply, an active filter is necessary. In this paper, the active filter with DSP is proposed. The waveform from active filter can be flexibly improved by DSP programming. The output-voltage ripple can be enough reduced by mixing frequency components of the input-voltage ripple. The result of adaptive control using LMS algorism is presented. The improvement by using filtered-X method is discussed. (author)

  14. Wind Turbine Rotors with Active Vibration Control

    Svendsen, Martin Nymann

    This thesis presents a framework for structural modeling, analysis and active vibration damping of rotating wind turbine blades and rotors. A structural rotor model is developed in terms of finite beam elements in a rotating frame of reference. The element comprises a representation of general...... that these are geometrically well separated. For active vibration control in three-bladed wind turbine rotors the present work presents a resonance-based method for groups of one collective and two whirling modes. The controller is based on the existing resonant format and introduces a dual system...... system. As in the method for non-rotating systems, an explicit procedure for optimal calibration of the controller gains is established. The control system is applied to an 86m wind turbine rotor by means of active strut actuator mechanisms. The prescribed additional damping ratios are reproduced almost...

  15. THE CONTROL AND EVALUATION OF PROMOTIONAL ACTIVITIES

    Felicia Sabou

    2012-01-01

    Full Text Available The paper focused on importance and benefits of control and evaluation of marketing activities. The control of efficiency review the assessment of the resources for marketing activity, checking also the efficiency of the human resources, advertising, promotion activities and distribution activities. In the analyse of human resources the most important ratio are: the average of costumers visits on a day, the number of custom order received from 100 visits, the number of new customers from a period, the number of lost customers from a period, the marketing human expenditures from all the sales.The strategic control is made to check if the objectives and the company strategy are adapted to the marketing environment.

  16. High Affinity Binders to EphA2 Isolated from Abdurin Scaffold Libraries; Characterization, Binding and Tumor Targeting

    Ullman, Christopher; Mathonet, Pascale; Oleksy, Arkadiusz; Diamandakis, Agata; Tomei, Licia; Demartis, Anna; Nardi, Chiara; Sambucini, Sonia; Missineo, Antonino; Alt, Karen; Hagemeyer, Christoph E.; Harris, Matt; Hedt, Amos; Weis, Roland; Gehlsen, Kurt R.

    2015-01-01

    Abdurins are a novel antibody-like scaffold derived from the engineering of a single isolated CH2 domain of human IgG. Previous studies established the prolonged serum half-life of Abdurins, the result of a retained FcRn binding motif. Here we present data on the construction of large, diverse, phage-display and cell-free DNA display libraries and the isolation of high affinity binders to the cancer target, membrane-bound ephrin receptor tyrosine kinase class A2 (EphA2). Antigen binding regions were created by designing combinatorial libraries into the structural loops and Abdurins were selected using phage display methods. Initial binders were reformatted into new maturation libraries and low nanomolar binders were isolated using cell-free DNA display, CIS display. Further characterization confirmed binding of the Abdurins to both human and murine EphA2 proteins and exclusively to cell lines that expressed EphA2, followed by rapid internalization. Two different EphA2 binders were labeled with 64Cu, using a bifunctional MeCOSar chelator, and administered to mice bearing tumors from transplanted human prostate cancer cells, followed by PET/CT imaging. The anti-EphA2 Abdurins localized in the tumors as early as 4 hours after injection and continued to accumulate up to 48 hours when the imaging was completed. These data demonstrate the ability to isolate high affinity binders from the engineered Abdurin scaffold, which retain a long serum half-life, and specifically target tumors in a xenograft model. PMID:26313909

  17. Adaptive Piezoelectric Absorber for Active Vibration Control

    Sven Herold

    2016-02-01

    Full Text Available Passive vibration control solutions are often limited to working reliably at one design point. Especially applied to lightweight structures, which tend to have unwanted vibration, active vibration control approaches can outperform passive solutions. To generate dynamic forces in a narrow frequency band, passive single-degree-of-freedom oscillators are frequently used as vibration absorbers and neutralizers. In order to respond to changes in system properties and/or the frequency of excitation forces, in this work, adaptive vibration compensation by a tunable piezoelectric vibration absorber is investigated. A special design containing piezoelectric stack actuators is used to cover a large tuning range for the natural frequency of the adaptive vibration absorber, while also the utilization as an active dynamic inertial mass actuator for active control concepts is possible, which can help to implement a broadband vibration control system. An analytical model is set up to derive general design rules for the system. An absorber prototype is set up and validated experimentally for both use cases of an adaptive vibration absorber and inertial mass actuator. Finally, the adaptive vibration control system is installed and tested with a basic truss structure in the laboratory, using both the possibility to adjust the properties of the absorber and active control.

  18. Active control for performance enhancement of electrically controlled rotor

    Lu Yang; Wang Chao

    2015-01-01

    Electrically controlled rotor (ECR) system has the potential to enhance the rotor perfor-mance by applying higher harmonic flap inputs. In order to explore the feasibility and effectiveness for ECR performance enhancement using closed-loop control method, firstly, an ECR rotor perfor-mance analysis model based on helicopter flight dynamic model is established, which can reflect the performance characteristics of ECR helicopter at high advance ratio. Based on the simulation platform, an active control method named adaptive T-matrix algorithm is adopted to explore the feasibility and effectiveness for ECR performance enhancement. The simulation results verify the effectiveness of this closed-loop control method. For the sample ECR helicopter, about 3%rotor power reduction is obtained with the optimum 2/rev flap inputs at the advance ratio of 0.34. And through analyzing the distributions of attack of angle and drag in rotor disk, the underlying physical essence of ECR power reduction is cleared. Furthermore, the influence of the key control parameters, including convergence factor and weighting matrix, on the effectiveness of closed-loop control for ECR performance enhancement is explored. Some useful results are summarized, which can be used to direct the future active control law design of ECR performance enhancement.

  19. Active control for performance enhancement of electrically controlled rotor

    Lu Yang

    2015-10-01

    Full Text Available Electrically controlled rotor (ECR system has the potential to enhance the rotor performance by applying higher harmonic flap inputs. In order to explore the feasibility and effectiveness for ECR performance enhancement using closed-loop control method, firstly, an ECR rotor performance analysis model based on helicopter flight dynamic model is established, which can reflect the performance characteristics of ECR helicopter at high advance ratio. Based on the simulation platform, an active control method named adaptive T-matrix algorithm is adopted to explore the feasibility and effectiveness for ECR performance enhancement. The simulation results verify the effectiveness of this closed-loop control method. For the sample ECR helicopter, about 3% rotor power reduction is obtained with the optimum 2/rev flap inputs at the advance ratio of 0.34. And through analyzing the distributions of attack of angle and drag in rotor disk, the underlying physical essence of ECR power reduction is cleared. Furthermore, the influence of the key control parameters, including convergence factor and weighting matrix, on the effectiveness of closed-loop control for ECR performance enhancement is explored. Some useful results are summarized, which can be used to direct the future active control law design of ECR performance enhancement.

  20. Active control of ionized boundary layers

    Mendes, R V

    1997-01-01

    The challenging problems, in the field of control of chaos or of transition to chaos, lie in the domain of infinite-dimensional systems. Access to all variables being impossible in this case and the controlling action being limited to a few collective variables, it will not in general be possible to drive the whole system to the desired behaviour. A paradigmatic problem of this type is the control of the transition to turbulence in the boundary layer of fluid motion. By analysing a boundary layer flow for an ionized fluid near an airfoil, one concludes that active control of the transition amounts to the resolution of an generalized integro-differential eigenvalue problem. To cope with the required response times and phase accuracy, electromagnetic control, whenever possible, seems more appropriate than mechanical control by microactuators.

  1. Capital Control, Debt Financing and Innovative Activity

    Czarnitzki, Dirk; Kraft, Kornelius

    2009-01-01

    "The present paper discusses the effects of dispersed versus concentrated capital ownership on investment into innovative activity. While the market for equity capital might exert insufficient control on top managements’ behavior, this weakness may be mitigated by a suitable degree of debt financing. We report the results of an empirical study on the determinants of innovative activity measured by patent applications. Using a large sample of German manufacturing firms, we find that companies ...

  2. Span of Control and Span of Activity

    Oriana Bandiera; Andrea Prat; Raffaella Sadun; Julie Wulf

    2012-01-01

    For both practitioners and researchers, span of control plays an important role in defining and understanding the role of the CEO. In this paper, we combine organizational chart information for a sample of 65 companies with detailed data on how their CEOs allocate their work time, which we define as their span of activity. Span of activity provides a direct measure of the CEO's management style, including the attention devoted to specific subordinates and functions, the time devoted to indivi...

  3. Active Vibration Control of Piezolaminated Smart Beams

    V. Balamurugan

    2001-04-01

    Full Text Available This paper deals with the active vibration control of beam like structures with distributed piezoelectric sensor and actuator layers bonded on top and bottom surfaces of the beam. A finite element model based on Euler-Bernoulli beam theory has been developed. The contribution of the piezoelectric sensor and actuator layers on the mass and stiffness of the beam is considered. Three types of classical control strategies, namely direct proportional feedback, constant-gain negative velocity feedback and Lyapunov feedback and an optimal control strategy, linear quadratic regulator (LQR scheme are applied to study their control effectiveness. Also, the control performance with different types of loading, such as impulse loading, step loading, harmonic and random loading is studied

  4. A Dynamic Absorber With Active Vibration Control

    Huang, S.-J.; Lian, R.-J.

    1994-12-01

    The design and construction of a dynamic absorber incorporating active vibration control is described. The absorber is a two-degrees-of-freedom spring — lumped mass system sliding on a guide pillar, with two internal vibration disturbance sources. Both the main mass and the secondary absorber mass are acted on by DC servo motors, respectively, to suppress the vibration amplitude. The state variable technique is used to model this dynamic system and a decoupling PID control method is used. First, the discrete time state space model is identified by using the commercial software MATLAB. Then the decoupling controller of this multi-input/multi-output system is derived from the identified model. Finally the results of some experiments are presented. The experimental results show that the system is effective in suppressing vibration. Also, the performance of this control strategy for position tracking control is evaluated based on experimental data.

  5. MODELING MERCURY CONTROL WITH POWDERED ACTIVATED CARBON

    The paper presents a mathematical model of total mercury removed from the flue gas at coal-fired plants equipped with powdered activated carbon (PAC) injection for Mercury control. The developed algorithms account for mercury removal by both existing equipment and an added PAC in...

  6. DNA-based control of protein activity.

    Engelen, W; Janssen, B M G; Merkx, M

    2016-03-01

    DNA has emerged as a highly versatile construction material for nanometer-sized structures and sophisticated molecular machines and circuits. The successful application of nucleic acid based systems greatly relies on their ability to autonomously sense and act on their environment. In this feature article, the development of DNA-based strategies to dynamically control protein activity via oligonucleotide triggers is discussed. Depending on the desired application, protein activity can be controlled by directly conjugating them to an oligonucleotide handle, or expressing them as a fusion protein with DNA binding motifs. To control proteins without modifying them chemically or genetically, multivalent ligands and aptamers that reversibly inhibit their function provide valuable tools to regulate proteins in a noncovalent manner. The goal of this feature article is to give an overview of strategies developed to control protein activity via oligonucleotide-based triggers, as well as hurdles yet to be taken to obtain fully autonomous systems that interrogate, process and act on their environments by means of DNA-based protein control. PMID:26812623

  7. Adenoviruses Using the Cancer Marker EphA2 as a Receptor In Vitro and In Vivo by Genetic Ligand Insertion into Different Capsid Scaffolds

    Behr, Michael; Kaufmann, Johanna K.; Ketzer, Patrick; Engelhardt, Sarah; Mück-Häusl, Martin; Okun, Pamela M.; Petersen, Gabriele; Neipel, Frank; Hassel, Jessica C.; Ehrhardt, Anja; Enk, Alexander H.; Nettelbeck, Dirk M.

    2014-01-01

    Adenoviral gene therapy and oncolysis would critically benefit from targeted cell entry by genetically modified capsids. This requires both the ablation of native adenovirus tropism and the identification of ligands that remain functional in virus context. Here, we establish cell type-specific entry of HAdV-5-based vectors by genetic ligand insertion into a chimeric fiber with shaft and knob domains of the short HAdV-41 fiber (Ad5T/41sSK). This fiber format was reported to ablate transduction in vitro and biodistribution to the liver in vivo. We show that the YSA peptide, binding to the pan-cancer marker EphA2, can be inserted into three positions of the chimeric fiber, resulting in strong transduction of EphA2-positive but not EphA2-negative cells of human melanoma biopsies and of tumor xenografts after intratumoral injection. Transduction was blocked by soluble YSA peptide and restored for EphA2-negative cells after recombinant EphA2 expression. The YSA peptide could also be inserted into three positions of a CAR binding-ablated HAdV-5 fiber enabling specific transduction; however, the Ad5T/41sSK format was superior in vivo. In conclusion, we establish an adenovirus capsid facilitating functional insertion of targeting peptides and a novel adenovirus using the tumor marker EphA2 as receptor with high potential for cancer gene therapy and viral oncolysis. PMID:24760010

  8. Adenoviruses using the cancer marker EphA2 as a receptor in vitro and in vivo by genetic ligand insertion into different capsid scaffolds.

    Michael Behr

    Full Text Available Adenoviral gene therapy and oncolysis would critically benefit from targeted cell entry by genetically modified capsids. This requires both the ablation of native adenovirus tropism and the identification of ligands that remain functional in virus context. Here, we establish cell type-specific entry of HAdV-5-based vectors by genetic ligand insertion into a chimeric fiber with shaft and knob domains of the short HAdV-41 fiber (Ad5T/41sSK. This fiber format was reported to ablate transduction in vitro and biodistribution to the liver in vivo. We show that the YSA peptide, binding to the pan-cancer marker EphA2, can be inserted into three positions of the chimeric fiber, resulting in strong transduction of EphA2-positive but not EphA2-negative cells of human melanoma biopsies and of tumor xenografts after intratumoral injection. Transduction was blocked by soluble YSA peptide and restored for EphA2-negative cells after recombinant EphA2 expression. The YSA peptide could also be inserted into three positions of a CAR binding-ablated HAdV-5 fiber enabling specific transduction; however, the Ad5T/41sSK format was superior in vivo. In conclusion, we establish an adenovirus capsid facilitating functional insertion of targeting peptides and a novel adenovirus using the tumor marker EphA2 as receptor with high potential for cancer gene therapy and viral oncolysis.

  9. Active control of transmitted sound in buildings

    Thompsett, Russell Harvey George

    The problem of noise from neighbours has increased dramatically over the last few years. Many of the noise complaints are due to the high level, low frequency noise from modern stereo equipment, and are often described in terms of the low frequency characteristics of the music; the repetitive, booming, bass beat. The objective of this research was to establish the feasibility of applying active noise control to alleviate this problem. The initial approach was to evaluate the possibility of exploiting the dominance of individual modes in the response of rooms at low frequency to effect global control. However, initial investigations using a modal model of the sound field revealed that this would be difficult due to the contribution of many acoustic modes excited off resonance. This conclusion was supported by measurements of acoustic room responses in typical buildings, illustrating a non-resonant characteristic. Consequently, attention was turned to the feasibility of using local active control systems to create zones of quiet by concentrating control at a specific location near the observers ears, for example in a seat headrest, or near the pillows of a bed. The lack of a reference signal in either approach requires the use of a feedback control strategy. With a typically non-resonant system, the predictability in the disturbance necessary for successful feedback control must be contained in the primary excitation, namely the music. Examples of different music styles were investigated and of those with the potential to be a nuisance surprisingly few were significantly more predictable than a random disturbance. As expected the most encouraging control performance simulations were found for modern dance music, with a strong repetitive beat. A real-time, local controller was demonstrated in the laboratory with such a disturbance signal and the properties of the quiet zone were measured. The subjective response when hearing the controller in operation was found to be

  10. Active control of multiple resistive wall modes

    A two-dimensional array of saddle coils at Mc poloidal and Nc toroidal positions is used on the EXTRAP T2R reversed-field pinch (Brunsell P R et al 2001 Plasma Phys. Control. Fusion 43 1457) to study active control of resistive wall modes (RWMs). Spontaneous growth of several RWMs with poloidal mode number m = 1 and different toroidal mode number n is observed experimentally, in agreement with linear MHD modelling. The measured plasma response to a controlled coil field and the plasma response computed using the linear circular cylinder MHD model are in quantitative agreement. Feedback control introduces a linear coupling of modes with toroidal mode numbers n, n' that fulfil the condition |n - n'| = Nc. Pairs of coupled unstable RWMs are present in feedback experiments with an array of Mc x Nc = 4 x 16 coils. Using intelligent shell feedback, the coupled modes are generally not controlled even though the field is suppressed at the active coils. A better suppression of coupled modes may be achieved in the case of rotating modes by using the mode control feedback scheme with individually set complex gains. In feedback with a larger array of Mc x Nc = 4 x 32 coils, the coupling effect largely disappears, and with this array, the main internal RWMs n = -11, -10, +5, +6 are all simultaneously suppressed throughout the discharge (7-8 wall times). With feedback there is a two-fold extension of the pulse length, compared to discharges without feedback

  11. Actively controlled vibration welding system and method

    Cai, Wayne W.; Kang, Bongsu; Tan, Chin-An

    2013-04-02

    A vibration welding system includes a controller, welding horn, an active material element, and anvil assembly. The assembly may include an anvil body connected to a back plate and support member. The element, e.g., a piezoelectric stack or shape memory alloy, is positioned with respect to the assembly. The horn vibrates in a desirable first direction to form a weld on a work piece. The element controls any vibrations in a second direction by applying calibrated response to the anvil body in the second direction. A method for controlling undesirable vibrations in the system includes positioning the element with respect to the anvil assembly, connecting the anvil body to the support member through the back plate, vibrating the horn in a desirable first direction, and transmitting an input signal to the element to control vibration in an undesirable second direction.

  12. Control Systems Cyber Security Standards Support Activities

    Robert Evans

    2009-01-01

    The Department of Homeland Security’s Control Systems Security Program (CSSP) is working with industry to secure critical infrastructure sectors from cyber intrusions that could compromise control systems. This document describes CSSP’s current activities with industry organizations in developing cyber security standards for control systems. In addition, it summarizes the standards work being conducted by organizations within the sector and provides a brief listing of sector meetings and conferences that might be of interest for each sector. Control systems cyber security standards are part of a rapidly changing environment. The participation of CSSP in the development effort for these standards has provided consistency in the technical content of the standards while ensuring that information developed by CSSP is included.

  13. 基于药效团模型及虚拟筛选方法发现 EphB4全新抑制剂%Discovery of noveI EphB4 inhibitors based on pharmacophore modeIing and virtuaI screening techniques

    邵鑫; 衣倩颖; 杨春蕾

    2016-01-01

    The objective of this paper is to discover new potent inhibitors against EphB4 for cancer therapy via computer-aided drug design strategies including building 3D-QSAR models,virtual screening and molecular doc-king means.The first step is to generate pharmacophore models based on Catalyst/HypoGen algorithm.The best model,Hypo1,has the highest Correl value (0.96),the lowest RMS value (0.89),the closest total cost (101.26) to fixed cost (89.20),and the best Δcost (89.14).Subsequently,Hypo1 was subjected to test set validation and Fischer′s randomization verification and then was used as a 3D query to screen database.In order to further nar-row the number of hits,drug-likeness screening and molecular docking techniques were applied.Finally,23 novel molecules with diverse scaffolds were selected as possible candidates against EphB4 for further studies based on predicted activity analysis,docking scores,and binding modes analysis methods.%采用计算机模拟手段,通过建立3D-QSAR 模型、虚拟筛选及分子对接方法发现恶性肿瘤治疗靶标 EphB4潜在的抑制剂。首先,通过 Catalyst/HypoGen 算法建立药效团模型。其中最好的模型 Hypo1具有最高的科雷尔值(Correl 值):0.96,最低的 RMS 值:0.89,与固定消耗值(fixed cost):89.20,最接近的总消耗值(total cost):101.26,和最高的Δ消耗值(Δcost 值):89.14。随后,Hypo1经过测试集验证及 Fischer 随机验证,并用于筛选化合物数据库。然后利用类药性筛选及分子对接手段进一步减少分子数量。最终,根据预测活性分析、对接得分值及结合模式分析,得到23个具有全新骨架的化合物作为 EphB4的潜在抑制剂可用于后续研究。

  14. BWR startup and shutdown activity transport control

    This paper summarizes BWR industry experience on good practices for controlling the transport of corrosion product activity during shutdowns, particularly refueling outages, and for startup chemistry control to minimize IGSCC (intergranular stress corrosion cracking). For shutdown, overall goals are to minimize adverse impacts of crud bursts and the time required to remove activated corrosion products from the reactor coolant during the shutdown process prior to refueling, and to assist plants in predicting and controlling radiation exposure during outages. For startup, the overall goals are to highlight conditions during early heatup and startup when sources of reactor coolant oxidants are high, when there is a greater likelihood for chemical excursions associated with refueling outage work activities, and when hydrogen injection is not available to mitigate IGSCC due to system design limitations. BWR water chemistry has changed significantly in recent years with the adoption of hydrogen water chemistry, zinc addition and noble metal chemical applications. These processes have, in some instances, resulted in significant activity increases during shutdown evolutions, which together with reduced time for cleanup because of shorter outages, has consequently increased outage radiation exposure. A review several recent outages shows that adverse effects from these conditions can be minimized, leading to the set of good practice recommendations for shutdown chemistry control. Most plants lose the majority of their hydrogen availability hours during early startup because feedwater hydrogen injection systems were not originally designed to inject hydrogen below 20% power. Hydrogen availability has improved through modifications to inject hydrogen at lower power levels, some near 5%. However, data indicate that IGSCC is accelerated during early startup, when dissolved oxygen and hydrogen peroxide levels are high and reactor coolant temperatures are in the 300 to 400 oF (

  15. Active Control of Long Bridges Using Flaps

    Hansen, H. I.; Thoft-Christensen, Palle

    The main problem in designing ultra-long span suspension bridges is flutter. A solution to this problem might be to introduce an active flap control system to increase the flutter wind velocity. The investigated flap control system consists of flaps integrated in the bridge girder so each flap is...... different flap configurations for a bridge section model by using aerodynamic derivatives for a flat plate. The example shows that different flap configurations can either increase or decrease the flutter wind velocity. for optimal flap configurations flutter will not occur....

  16. Jacket Substructure Fatigue Mitigation through Active Control

    Hanis, Tomas; Natarajan, Anand

    As offshore wind farms are being installed farther and in deeper waters offshore, new, and more sophisticated marine substructures such as jackets need to be used. Herein, a 10MW wind turbine mounted on a jacket sub structure at a mean water depth of 50 meters is investigated with regards to the...... fatigue design loads on the braces of the jacket. Since large wind turbines of 10MW rating have low rotor speeds (p), the modal frequencies of the sub structures approach 3p at low wind speeds, which leads to a modal coupling and resonance. Therefore an active control system is developed which provides...... sufficient structural damping and consequently a fatigue reduction at the substructure. The resulting reduction in fatigue design loads on the jacket structure based on the active control system is presented....

  17. Active Noise Control in Forest Machines

    Forsgren, Fredrik

    2011-01-01

    Achieving a low noise level is of great interest to the forest machine industry. Traditionally this is obtained by using passive noise reduction, i.e. by using materials for sound isolation and sound absorption. Especially designs to attenuate low frequency noise tend to be bulky and impractical from an installation point of view. An alternative solution to the problem is to use active noise control (ANC). The basic principle of ANC is to generate an anti-noise signal designed to destructivel...

  18. Active noise control for high frequencies

    Kaymak, E; Atherton, MA; Rotter, KRG; Millar, B.

    2006-01-01

    There are many applications that can benefit from Active Noise Control (ANC) such as in aircraft cabins and air conditioning ducts, i.e. in situations where technology interferes with human hearing in a harmful way or disrupts communication. Headsets with analogue ANC circuits have been used in the armed forces for attenuating frequencies below 1 kHz, which when combined with passive filtering offers protection across the whole frequency range of human hearing. A dental surgery is also a nois...

  19. Active Thermal Control System Development for Exploration

    Westheimer, David

    2007-01-01

    All space vehicles or habitats require thermal management to maintain a safe and operational environment for both crew and hardware. Active Thermal Control Systems (ATCS) perform the functions of acquiring heat from both crew and hardware within a vehicle, transporting that heat throughout the vehicle, and finally rejecting that energy into space. Almost all of the energy used in a space vehicle eventually turns into heat, which must be rejected in order to maintain an energy balance and temperature control of the vehicle. For crewed vehicles, Active Thermal Control Systems are pumped fluid loops that are made up of components designed to perform these functions. NASA has been actively developing technologies that will enable future missions or will provide significant improvements over the state of the art technologies. These technologies have are targeted for application on the Crew Exploration Vehicle (CEV), or Orion, and a Lunar Surface Access Module (LSAM). The technologies that have been selected and are currently under development include: fluids that enable single loop ATCS architectures, a gravity insensitive vapor compression cycle heat pump, a sublimator with reduced sensitivity to feedwater contamination, an evaporative heat sink that can operate in multiple ambient pressure environments, a compact spray evaporator, and lightweight radiators that take advantage of carbon composites and advanced optical coatings.

  20. Active Control of Shear Thickening in Suspensions

    Lin, Neil Y C; Cates, Michael E; Sun, Jin; Cohen, Itai

    2016-01-01

    Shear thickening, an increase of viscosity with shear rate, is a ubiquitous phenomena in suspended materials that has implications for broad technological applications. Controlling this thickening behavior remains a major challenge and has led to empirical strategies ranging from altering the particle surfaces and shape to modifying the solvent properties. However, none of these methods allow for active control of flow properties during shear itself. Here, we demonstrate that by strategic imposition of a high-frequency and low-amplitude shear perturbation orthogonal to the primary shearing flow, we can largely eradicate shear thickening. The orthogonal shear effectively becomes a regulator for controlling thickening in the suspension, allowing the viscosity to be reduced by up to two decades on demand. In a separate setup, we show that such effects can be induced by simply agitating the sample transversely to the primary shear direction. Overall, the ability of in situ manipulation of shear thickening paves a...

  1. Active control of electric potential of spacecraft

    Goldstein, R.

    1977-01-01

    Techniques are discussed for controlling the potential of a spacecraft by means of devices which release appropriate charged particles from the spacecraft to the environment. Attention is given to electron emitters, ion emitters, a basic electron emitter arrangement, techniques for sensing electric field or potential, and flight experiments on active potential control. It is recommended to avoid differential charging on spacecraft surfaces because it can severely affect the efficacy of emitters. Discharging the frame of a spacecraft with dielectric surfaces involves the risk of stressing the dielectric material excessively. The spacecraft should, therefore, be provided with grounded conductive surfaces. It is pointed out that particles released by control systems can return to the spacecraft.

  2. Regional expression and ultrastructural localization of EphA7 in the hippocampus and cerebellum of adult rat.

    Amegandjin, Clara A; Jammow, Wafaa; Laforest, Sylvie; Riad, Mustapha; Baharnoori, Moogeh; Badeaux, Frédérique; DesGroseillers, Luc; Murai, Keith K; Pasquale, Elena B; Drolet, Guy; Doucet, Guy

    2016-08-15

    EphA7 is expressed in the adult central nervous system (CNS), where its roles are yet poorly defined. We mapped its distribution using in situ hybridization (ISH) and immunohistochemistry (IHC) combined with light (LM) and electron microscopy (EM) in adult rat and mouse brain. The strongest ISH signal was in the hippocampal pyramidal and granule cell layers. Moderate levels were detected in habenula, striatum, amygdala, the cingulate, piriform and entorhinal cortex, and in cerebellum, notably the Purkinje cell layer. The IHC signal distribution was consistent with ISH results, with transport of the protein to processes, as exemplified in the hippocampal neuropil layers and weakly stained pyramidal cell layers. In contrast, in the cerebellum, the Purkinje cell bodies were the most strongly immunolabeled elements. EM localized the cell surface-expression of EphA7 essentially in postsynaptic densities (PSDs) of dendritic spines and shafts, and on some astrocytic leaflets, in both hippocampus and cerebellum. Perikaryal and dendritic labeling was mostly intracellular, associated with the synthetic and trafficking machineries. Immunopositive vesicles were also observed in axons and axon terminals. Quantitative analysis in EM showed significant differences in the frequency of labeled elements between regions. Notably, labeled dendrites were ∼3-5 times less frequent in cerebellum than in hippocampus, but they were individually endowed with ∼10-40 times higher frequencies of PSDs, on their shafts and spines. The cell surface localization of EphA7, being preferentially in PSDs, and in perisynaptic astrocytic leaflets, provides morphologic evidence that EphA7 plays key roles in adult CNS synaptic maintenance, plasticity, or function. J. Comp. Neurol. 524:2462-2478, 2016. © 2016 Wiley Periodicals, Inc. PMID:26780036

  3. Bidirectional Signaling through EphrinA2-EphA2 Enhances Osteoclastogenesis and Suppresses Osteoblastogenesis*S⃞

    Irie, Naoko; Takada, Yasunari; Watanabe, Yoshihiko; Matsuzaki, Yumi; Naruse, Chie; Asano, Masahide; Iwakura, Yoichiro; Suda, Toshio; Matsuo, Koichi

    2009-01-01

    Bone is remodeled constantly throughout life by bone-resorbing osteoclasts and bone-forming osteoblasts. To maintain bone volume and quality, differentiation of osteoclasts and osteoblasts is tightly regulated through communication between and within these two cell lineages. Previously we reported that cell-cell interaction mediated by ephrinB2 ligand on osteoclasts and EphB4 receptor on osteoblasts generates bidirectional anti-osteoclastogenic and pro-osteoblastogenic...

  4. Coordinated Voltage Control of Active Distribution Network

    Xie Jiang

    2016-01-01

    Full Text Available This paper presents a centralized coordinated voltage control method for active distribution network to solve off-limit problem of voltage after incorporation of distributed generation (DG. The proposed method consists of two parts, it coordinated primal-dual interior point method-based voltage regulation schemes of DG reactive powers and capacitors with centralized on-load tap changer (OLTC controlling method which utilizes system’s maximum and minimum voltages, to improve the qualified rate of voltage and reduce the operation numbers of OLTC. The proposed coordination has considered the cost of capacitors. The method is tested using a radial edited IEEE-33 nodes distribution network which is modelled using MATLAB.

  5. Controller modification applied for active fault detection

    Niemann, Hans Henrik; Stoustrup, Jakob; Poulsen, Niels Kjølstad

    2014-01-01

    This paper is focusing on active fault detection (AFD) for parametric faults in closed-loop systems. This auxiliary input applied for the fault detection will also disturb the external output and consequently reduce the performance of the controller. Therefore, only small auxiliary inputs are used...... modify the feedback controller with a minor effect on the external output in the fault free case. Further, in the faulty case, the signature of the auxiliary input can be optimized. This is obtained by using a band-pass filter for the YJBK parameter that is only effective in a small frequency range where...... the frequency for the auxiliary input is selected. This gives that it is possible to apply an auxiliary input with a reduced amplitude. An example is included to show the results....

  6. Real Time Vibration Control of Active Suspension System with Active Force Control using Iterative Learning Algorithm

    Kalaivani

    2013-09-01

    Full Text Available This paper presents concurrent vibration control of a laboratory scaled vibration isolator platform with Active Force Control (AFC using Iterative Learning Algorithm (ILA. The work investigates the performance of the traditional Proportional Integral Derivative Controller (PIDC with and without AFC using ILA for vibration suppression. The physical single degree of freedom quarter car has been interfaced with a personal computer using a National Instruments data acquisition card NI USB 6008. The controllers are designed and simulated using LabVIEW simulation software. The results infer that the PIDC with AFC using ILA works superior than the PIDC.

  7. Eph Receptors and Ephrins in Neuron-Astrocyte Communication at Synapses

    MuraiKK; Pasquale EB

    2011-01-01

    神经元-胶质细胞间的相互作用对调节脑内突触联系有重要作用.星形胶质细胞对突触的发育、维 持和可塑性有特别关键、复杂的作用.同样,神经元也对星形胶质细胞的生理功能产生影响.但是,神经元和星形胶质细胞之间相互作用的分子机制尚未完全阐明.近来研究表明,Eph受体酪氨酸激酶及轴突导向因子在突触间接触依赖性神经元-胶质细胞的相互作用中起重要作用.与配体结合后,这2个细胞表面相关蛋白家族成员激活双向信号通路,调节神经元和星形胶质细胞的结构和生理特征.本综述着重探讨Eph受体酪氨酸激酶及轴突导向因子在突触间神经元胶质细胞的相互作用中扮演的角色,并讨论其在突触可塑性、行为及疾病中的潜在作用.%Neuron-glia communication is essential for regulating the properties of synaptic connections in the brain.Astrocytes,in particular,play a critical and complex role in synapse development,maintenance,and plasticity.Likewise,neurons reciprocally influence astrocyte physiology.However,the molecular signaling events that en able astrocytes and neurons to effectively communicate with each other are only partially defined.Recent findings have revealed that Eph receptor tyrosine kinases and ephrins play an important role in contact-dependent neuron-glia communication at synapses.Upon binding,these two families of cell surface-associated proteins trigger bidirectional signaling events that regulate the structural and physiological properties of both neurons and astrocytes.This review will focus on the emerging role of Eph receptors and ephrins in neuron astrocyte interaction at synapses and discuss implications for synaptic plasticity,behavior,and disease.(c) 2010 Wiley-Liss,Inc.

  8. Mesityltellurenyl cations stabilized by triphenylpnictogens [MesTe(EPh(3))](+) (E = P, As, Sb).

    Beckmann, Jens; Bolsinger, Jens; Duthie, Andrew; Finke, Pamela; Lork, Enno; Lüdtke, Carsten; Mallow, Ole; Mebs, Stefan

    2012-11-19

    The homoleptic 1:1 Lewis pair (LP) complex [MesTe(TeMes2)]O3SCF3 (1) featuring the cation [MesTe(TeMes2)](+) (1a) was obtained by the reaction of Mes2Te with HO3SCF3. The reaction of 1 with Ph3E (E = P, As, Sb, Bi) proceeded with substitution of Mes2Te and provided the heteroleptic 1:1 LP complexes [MesTe(EPh3)]O3SCF3 (2, E = P; 3, E = As) and [MesTe(SbPh3)][Ph2Sb(O3SCF3)2] (4) featuring the cations [MesTe(EPh3)](+) (2a, E = P; 3a, E = As; 4a, E = Sb) and the anion [Ph2Sb(O3SCF3)2](-) (4b). In the reaction with Ph3Bi, the crude product contained the cation [MesTe(BiPh3)](+) (5a) and the anion [Ph2Bi(O3SCF3)2](-) (5b); however, the heteroleptic 1:1 LP complex [MesTe(BiPh3)][Ph2Bi(O3SCF3)2] (5) could not be isolated because of its limited stability. Instead, fractional crystallization furnished a large amount of Ph2BiO3SCF3 (6), which was also obtained by the reaction of Ph3Bi with HO3SCF3. The formation of the anions 4b and 5b involves a phenyl group migration from Ph3E (E = Sb, Bi) to the MesTe(+) cation and afforded MesTePh as the byproduct, which was identified in the mother liquor. The heteroleptic 1:1 LP complexes 2-4 were also obtained by the one-pot reaction of Mes2Te, Ph3E (E = P, As, Sb) and HO3SCF3. Compounds 1-4 and 6 were investigated by single-crystal X-ray diffraction. The molecular structures of 1a-4a were used for density functional theory calculations at the B3PW91/TZ level of theory and studied using natural bond order (NBO) analyses as well as real-space bonding descriptors derived from an atoms-in-molecules (AIM) analysis of the theoretically obtained electron density. Additionally, the electron localizability indicator (ELI-D) and the delocalization index are derived from the corresponding pair density. PMID:23134409

  9. Prediction control of active power filters

    王莉娜; 罗安

    2003-01-01

    A prediction method to obtain harmonic reference for active power filter is presented. It is a new use ofthe adaptive predictive filter based on FIR. The delay inherent in digital controller is successfully compensated by u-sing the proposed method, and the computing load is not very large compared with the conventional method. Moreo-ver, no additional hardware is needed. Its DSP-based realization is also presented, which is characterized by time-va-riant rate sampling, quasi synchronous sampling, and synchronous operation among the line frequency, PWM gener-ating and sampling in A/D unit. Synchronous operation releases the limitation on PWM modulation ratio and guar-antees that the electrical noises resulting from the switching operation of IGBTs do not interfere with the sampledcurrent. The simulation and experimental results verify the satisfactory performance of the proposed method.

  10. Ribosome-dependent activation of stringent control.

    Brown, Alan; Fernández, Israel S; Gordiyenko, Yuliya; Ramakrishnan, V

    2016-06-01

    In order to survive, bacteria continually sense, and respond to, environmental fluctuations. Stringent control represents a key bacterial stress response to nutrient starvation that leads to rapid and comprehensive reprogramming of metabolic and transcriptional patterns. In general, transcription of genes for growth and proliferation is downregulated, while those important for survival and virulence are upregulated. Amino acid starvation is sensed by depletion of the aminoacylated tRNA pools, and this results in accumulation of ribosomes stalled with non-aminoacylated (uncharged) tRNA in the ribosomal A site. RelA is recruited to stalled ribosomes and activated to synthesize a hyperphosphorylated guanosine analogue, (p)ppGpp, which acts as a pleiotropic secondary messenger. However, structural information about how RelA recognizes stalled ribosomes and discriminates against aminoacylated tRNAs is missing. Here we present the cryo-electron microscopy structure of RelA bound to the bacterial ribosome stalled with uncharged tRNA. The structure reveals that RelA utilizes a distinct binding site compared to the translational factors, with a multi-domain architecture that wraps around a highly distorted A-site tRNA. The TGS (ThrRS, GTPase and SpoT) domain of RelA binds the CCA tail to orient the free 3' hydroxyl group of the terminal adenosine towards a β-strand, such that an aminoacylated tRNA at this position would be sterically precluded. The structure supports a model in which association of RelA with the ribosome suppresses auto-inhibition to activate synthesis of (p)ppGpp and initiate the stringent response. Since stringent control is responsible for the survival of pathogenic bacteria under stress conditions, and contributes to chronic infections and antibiotic tolerance, RelA represents a good target for the development of novel antibacterial therapeutics. PMID:27279228

  11. Missile flight control using active flexspar actuators

    Barrett, Ron; Gross, R. Steven; Brozoski, Fred

    1996-04-01

    A new type of subsonic missile flight control surface using piezoelectric flexspar actuators is presented. The flexspar design uses an aerodynamic shell which is pivoted at the quarter-chord about a graphite main spar. The shell is pitched up and down by a piezoelectric bender element which is rigidly attached to a base mount and allowed to rotate freely at the tip. The element curvature, shell pitch deflection and torsional stiffness are modeled using laminated plate theory. A one-third scale TOW 2B missile model was used as a demonstration platform. A static wing of the missile was replaced with an active flexspar wing. The 1 in 0964-1726/5/2/002/img1 2.7 in active flight control surface was powered by a bimorph bender with 5 mil PZT-5H sheets. Bench and wind tunnel testing showed good correlation between theory and experiment and static pitch deflections in excess of 0964-1726/5/2/002/img2. A natural frequency of 78.5 rad 0964-1726/5/2/002/img3 with a break frequency of 157 rad 0964-1726/5/2/002/img3 was measured. Wind tunnel tests revealed no flutter or divergence tendencies. Maximum changes in lift coefficient were measured at 0964-1726/5/2/002/img5 which indicates that terminal and initial missile load factors may be increased by approximately 3.1 and 12.6 g respectively, leading to a greatly reduced turn radius of only 2400 ft.

  12. Actively controlled thin-shell space optics

    Denoyer, Keith K.; Flint, Eric M.; Main, John A.; Lindler, Jason E.

    2003-08-01

    Increasingly, scientific and military missions require the use of space-based optical systems. For example, new capabilities are required for imaging terrestrial like planets, for surveillance, and for directed energy applications. Given the difficulties in producing and launching large optics, it is doubtful that refinements of conventional technology will meet future needs, particularly in a cost-effective manner. To meet this need, recent research has been investigating the feasibility of a new class of ultra-lightweight think-skin optical elements that combine recent advances in lightweight thermally formed materials, active materials, and novel sensing and control architectures. If successful, the approach may lead to an order of magnitude reduction in space optics areal density, improved large scale manufacturing capability, and dramatic reductions in manufacturing and launch costs. In a recent effort, a one meter thin-film mirror like structure was fabricated. This paper provides an overview of tools used to model and simulate this structure as well as results from structural dynamic testing. In addition, progress in the area of non-contact global shape control using smart materials is presented.

  13. High performance composites with active stiffness control.

    Tridech, Charnwit; Maples, Henry A; Robinson, Paul; Bismarck, Alexander

    2013-09-25

    High performance carbon fiber reinforced composites with controllable stiffness could revolutionize the use of composite materials in structural applications. Here we describe a structural material, which has a stiffness that can be actively controlled on demand. Such a material could have applications in morphing wings or deployable structures. A carbon fiber reinforced-epoxy composite is described that can undergo an 88% reduction in flexural stiffness at elevated temperatures and fully recover when cooled, with no discernible damage or loss in properties. Once the stiffness has been reduced, the required deformations can be achieved at much lower actuation forces. For this proof-of-concept study a thin polyacrylamide (PAAm) layer was electrocoated onto carbon fibers that were then embedded into an epoxy matrix via resin infusion. Heating the PAAm coating above its glass transition temperature caused it to soften and allowed the fibers to slide within the matrix. To produce the stiffness change the carbon fibers were used as resistance heating elements by passing a current through them. When the PAAm coating had softened, the ability of the interphase to transfer load to the fibers was significantly reduced, greatly lowering the flexural stiffness of the composite. By changing the moisture content in PAAm fiber coating, the temperature at which the PAAm softens and the composites undergo a reduction in stiffness can be tuned. PMID:23978266

  14. Development of a generic activities model of command and control

    Stanton, NA; Baber, C; Walker, GH; Houghton, RJ; McMaster, R.; Stewart, R; Harris, D.; Jenkins, DP; Young, MS; Salmon, PM

    2008-01-01

    This paper reports on five different models of command and control. Four different models are reviewed: a process model, a contextual control model, a decision ladder model and a functional model. Further to this, command and control activities are analysed in three distinct domains: armed forces, emergency services and civilian services. From this analysis, taxonomies of command and control activities are developed that give rise to an activities model of command and control. This model w...

  15. Active controllers and the time duration to learn a task

    Repperger, D. W.; Goodyear, C.

    1986-01-01

    An active controller was used to help train naive subjects involved in a compensatory tracking task. The controller is called active in this context because it moves the subject's hand in a direction to improve tracking. It is of interest here to question whether the active controller helps the subject to learn a task more rapidly than the passive controller. Six subjects, inexperienced to compensatory tracking, were run to asymptote root mean square error tracking levels with an active controller or a passive controller. The time required to learn the task was defined several different ways. The results of the different measures of learning were examined across pools of subjects and across controllers using statistical tests. The comparison between the active controller and the passive controller as to their ability to accelerate the learning process as well as reduce levels of asymptotic tracking error is reported here.

  16. Optimal designs for dose finding studies with an active control

    Benda, Norbert; Bretz, Frank; Dette, Holger; Kiss , Christine

    2011-01-01

    Dose finding studies often compare several doses of a new compound with a marketed standard treatment as an active control. In the past, however, research has focused mostly on experimental designs for placebo-controlled dose finding studies. To the best of our knowledge, optimal designs for dose finding studies with an active control have not been considered so far. As the statistical analysis for an active controlled dose finding study can be formulated in terms of a mixture ...

  17. Force Feedback Control of a Semi-Active Shock Absorber

    Svennerbrandt, Per

    2014-01-01

    Semi-active suspension systems promise to significantly reduce the necessary trade-off be-tween handling and passenger comfort present in conventional suspension systems by enabling active chassis and wheel control. Öhlins Racing AB have developed a semi-active suspension technology known as CES, Continuously controlled Electronic Suspension, based on solenoid control valves which are integrated into specially designed hydraulic dampers, and are currently developing control and estimation sys...

  18. Active control of smart structures : an overall approach

    Nestorović Tamara; Trajkov Miroslav

    2010-01-01

    The paper presents active control of smart structures within a focused frame of piezoelectric applications in active vibration and noise attenuation with potentials for the use in mechanical and civil engineering. An overall approach to active control of piezoelectric structures involves subsequent steps of modeling, control, simulation, experimental verification and implementation. Each of these steps is regarded in details. Different application examples showing the feasibility of the activ...

  19. Management Control of Public and Not-for-Profit Activities

    Hofstede, G.

    1981-01-01

    Traditional approaches to management control usually fail for public and not-for-profit activities. The type of control applicable to such activities depends on four criteria: are objectives unambiguous, outputs measurable, effects of interventions known, and is the activity repetitive? Depending on where activities stand with regard to these criteria, the control applicable corresponds to one of six different types: routine, expert, trial-and-error, intuitive, judgemental, or political contr...

  20. Low Activity Waste Feed Process Control Strategy

    The primary purpose of this document is to describe the overall process control strategy for monitoring and controlling the functions associated with the Phase 1B high-level waste feed delivery. This document provides the basis for process monitoring and control functions and requirements needed throughput the double-shell tank system during Phase 1 high-level waste feed delivery. This document is intended to be used by (1) the developers of the future Process Control Plan and (2) the developers of the monitoring and control system

  1. Low Activity Waste Feed Process Control Strategy

    STAEHR, T.W.

    2000-06-14

    The primary purpose of this document is to describe the overall process control strategy for monitoring and controlling the functions associated with the Phase 1B high-level waste feed delivery. This document provides the basis for process monitoring and control functions and requirements needed throughput the double-shell tank system during Phase 1 high-level waste feed delivery. This document is intended to be used by (1) the developers of the future Process Control Plan and (2) the developers of the monitoring and control system.

  2. An adaptive active control for the modified Chua's circuit

    In this Letter, it is shown that a couple of the modified Chua's systems with different parameters and initial conditions can be synchronized using active control when the values of parameters both in drive system and response system are known aforehand. Furthermore, an adaptive active control approach is proposed based on Lyapunov stability theory to make the states of two identical Chua's systems with unknown constant parameters be asymptotically synchronized. In addition, the proposed adaptive active control method guarantees that the designed controller is independent to those uncertain parameters. Simulation results by using both active control and adaptive active control are provided, and the feasibility and effectiveness of the proposed adaptive active control are demonstrated

  3. Attitude control with active actuator saturation prevention

    Forbes, James Richard

    2015-02-01

    Spacecraft attitude control in the presence of actuator saturation is considered. The attitude controller developed has two components: a proportional component and an angular velocity component. The proportional control has a special form that depends on the attitude parameterization. The angular velocity control is realized by a strictly positive real system with its own input nonlinearity. The strictly positive real system can filter noise in the angular velocity measurement. With this control architecture the torques applied to the body are guaranteed to be below a predetermined value, thus preventing saturation of the actuators. The closed-loop equilibrium point corresponding to the desired attitude is shown to be asymptotically stable. Additionally, the control law does not require specific knowledge of the body's inertia properties, and is therefore robust to such modelling errors.

  4. Magnetic Levitation Technique for Active Vibration Control

    Hoque, Emdadul; Mizuno, Takeshi

    2010-01-01

    A zero-power controlled magnetic levitation system has been presented in this chapter. The unique characteristic of the zero-power control system is that it can generate negative stiffness with zero control current in the steady-state which is realized in this chapter. The detail characteristics of the levitation system are investigated. Moreover, two major contributions, the stiffness adjustment and nonlinear compensation of the suspension system have been introduced elaborately. Often, ther...

  5. Tuning of active vibration controllers for ACTEX by genetic algorithm

    Kwak, Moon K.; Denoyer, Keith K.

    1999-06-01

    This paper is concerned with the optimal tuning of digitally programmable analog controllers on the ACTEX-1 smart structures flight experiment. The programmable controllers for each channel include a third order Strain Rate Feedback (SRF) controller, a fifth order SRF controller, a second order Positive Position Feedback (PPF) controller, and a fourth order PPF controller. Optimal manual tuning of several control parameters can be a difficult task even though the closed-loop control characteristics of each controller are well known. Hence, the automatic tuning of individual control parameters using Genetic Algorithms is proposed in this paper. The optimal control parameters of each control law are obtained by imposing a constraint on the closed-loop frequency response functions using the ACTEX mathematical model. The tuned control parameters are then uploaded to the ACTEX electronic control electronics and experiments on the active vibration control are carried out in space. The experimental results on ACTEX will be presented.

  6. Active control design of modular tensegrity structures

    Amouri, Sarah; Averseng, Julien; Dubé, Jean-François

    2013-01-01

    In this paper, a general methodology for the design of modular active tensegrity structures is presented. The objectives are to propose systems such as grids or footbridges that would be able to actively damper their first vibration modes and to adapt their geometry using a small number of activators. This approach is validated experimentally on a plane regular tensegrity grid. Using numerical simulation, an application on the model of a modular tensegrity footbridge is presented.

  7. Optimal cooperative control synthesis of active displays

    Garg, S.; Schmidt, D. K.

    1985-01-01

    A technique is developed that is intended to provide a systematic approach to synthesizing display augmentation for optimal manual control in complex, closed-loop tasks. A cooperative control synthesis technique, previously developed to design pilot-optimal control augmentation for the plant, is extended to incorporate the simultaneous design of performance enhancing displays. The technique utilizes an optimal control model of the man in the loop. It is applied to the design of a quickening control law for a display and a simple K/s(2) plant, and then to an F-15 type aircraft in a multi-channel task. Utilizing the closed loop modeling and analysis procedures, the results from the display design algorithm are evaluated and an analytical validation is performed. Experimental validation is recommended for future efforts.

  8. Phase and gain control policies for robust active vibration control of flexible structures

    Zhang, Kai; Scorletti, Gérard; Ichchou, Mohamed; Mieyeville, F.

    2013-01-01

    The interest of this paper is to develop a general and systematic robust control methodology for active vibration control of flexible structures. For this purpose, first phase and gain control policies are proposed to impose qualitative frequency-dependent requirements on the controller to consider a complete set of control objectives. Then the proposed control methodology is developed by employing phase and gain control policies in the dynamic output feedback H∞ control: according to the set...

  9. Nonlinear Predictive Control of Semi-Active Landing Gear System

    Wu, Dongsu; Gu, Hongbin; Liu, Hui

    2010-01-01

    The application of model predictive control and constructive nonlinear control methodology to semi-active landing gear system is studied in this paper. A unified shock absorber mathematical model incorporates solenoid valve’s electromechanical and magnetic dynamics is built to facilitate simulation and controller design. Then we propose a hierarchical control structure to deal with the high nonlinearity. A dual mode model predictive controller as an outer loop controller is developed to gen...

  10. Self-Tuning Active Vibration Control of Flexible Beam Structures

    M.O. Tokhi; Hossain, M A

    1994-01-01

    This paper presents the design and performance evaluation of an adaptive active control mechanism for vibration suppression in flexible beam structures. A cantilever beam system in transverse vibration is considered. First order control finite difference methods are used to study the behaviour of the beam and develop a suitable test and verification platform. An active vibration control algorithm is developed within an adaptive control framework for broadband cancellation of vibration along t...

  11. Brain-Activity-Driven Real-Time Music Emotive Control

    Giraldo, Sergio; Ramirez, Rafael

    2013-01-01

    Active music listening has emerged as a study field that aims to enable listeners to interactively control music. Most of active music listening systems aim to control music aspects such as playback, equalization, browsing, and retrieval, but few of them aim to control expressive aspects of music to convey emotions. In this study our aim is to enrich the music listening experience by allowing listeners to control expressive parameters in music performances using their perceived emotional stat...

  12. Active and Passive Flow Control around Simplified Ground Vehicles

    C.H Bruneau

    2012-01-01

    Full Text Available The aim of this work is to control the flow around ground vehicles by active or/and passive strategies. The active control is achieved by steady, pulsed or closed-loop jets located at the backof the simplified car model. The passive control is performed using porous layers between the solid body and the fluid in order to modify the shear forces. The two previous control methods can be coupled to improve the drag reduction.

  13. Automotive applications of rapid prototyping for active vibration control

    Bohn, C.; Svaricek, F. [Continental Gummi-Werke AG, Hannover (Germany); Karkosch, H.J.; Marienfeld, P.M. [ContiTech Vibration Control GmbH, Hannover (Germany)

    2001-07-01

    This paper presents some recent results of Continental's research and development activities in the area of active vibration control. First, a brief overview of different approaches to active noise and vibration control is given. This is followed by a discussion of the rapid controller prototyping process that is currently being introduced. Finally, some experimental results obtained in cooperation with an automobile manufacturer are presented. These results demonstrate that major noise and vibration attenuation can be achieved through active vibration control in automobiles. (orig.)

  14. Formal Verification of Effectiveness of Control Activities in Business Processes

    Arimoto, Yasuhito; Iida, Shusaku; Futatsugi, Kokichi

    It has been an important issue to deal with risks in business processes for achieving companies' goals. This paper introduces a method for applying a formal method to analysis of risks and control activities in business processes in order to evaluate control activities consistently, exhaustively, and to give us potential to have scientific discussion on the result of the evaluation. We focus on document flows in business activities and control activities and risks related to documents because documents play important roles in business. In our method, document flows including control activities are modeled and it is verified by OTS/CafeOBJ Method that risks about falsification of documents are avoided by control activities in the model. The verification is done by interaction between humans and CafeOBJ system with theorem proving, and it raises potential to discuss the result scientifically because the interaction gives us rigorous reasons why the result is derived from the verification.

  15. Active control of radiated sound using nearfield pressure sensing

    CHEN Ke'an; YIN Xuefei

    2004-01-01

    Based on nearfield sound pressure sensing to pick up error information, an approach for constructing active acoustic structure to effectively reduce radiated sound power at low frequency is proposed. The idea is that a nearfield pressure after active control is used as error signals and transformed into an objective function in adaptive active control process.Firstly sound power expression using near-field pressure radiated from a flexible structure is derived, and then three kind of nearfield pressure based active control strategies, I.e. Minimization of radiated sound power, minimization of sound power for dominant radiation modes and minimization of sound power for modified dominant radiation modes are respectively presented and applied to active control of radiated single and broadband noise. Finally computer simulations on sound power reduction under three strategies are conducted and it is shown that the proposed active control strategies are invalid and considerable reduction in radiated sound power can be achieved.

  16. Recent advances in active control of aircraft cabin noise

    Mathur, Gopal; Fuller, Christopher

    2002-11-01

    Active noise control techniques can provide significant reductions in aircraft interior noise levels without the structural modifications or weight penalties usually associated with passive techniques, particularly for low frequency noise. Our main objective in this presentation is to give a review of active control methods and their applications to aircraft cabin noise reduction with an emphasis on recent advances and challenges facing the noise control engineer in the practical application of these techniques. The active noise control method using secondary acoustic sources, e.g., loudspeakers, as control sources for tonal noise reduction is first discussed with results from an active noise control flight test demonstration. An innovative approach of applying control forces directly to the fuselage structure using piezoelectric actuators, known as active structural acoustic control (ASAC), to control cabin noise is then presented. Experimental results from laboratory ASAC tests conducted on a full-scale fuselage and from flight tests on a helicopter will be discussed. Finally, a hybrid active/passive noise control approach for achieving significant broadband noise reduction will be discussed. Experimental results of control of broadband noise transmission through an aircraft structure will be presented.

  17. Broadband Radiation Modes: Estimation and Active Control

    Berkhoff, Arthur P.

    2002-01-01

    In this paper we give a formulation of the most efficiently radiating vibration patterns of a vibrating body, the radiation modes, in the time domain. The radiation modes can be used to arrive at efficient weighting schemes for an array of sensors in order to reduce the controller dimensionality. Be

  18. Pulley With Active Antifriction Actuator And Control

    Ih, Che-Hang C.; Vivian, Howard C.

    1994-01-01

    Torque actuator and associated control system minimizes effective friction of rotary bearing. Motor exerts compensating torque in response to feedback from external optical sensor. Compensation torque nearly cancels frictional torque of shaft bearings. Also useful in reducing bearing friction in gyro-scopes, galvanometers, torquemeters, accelerometers, earth-motion detectors, and balances.

  19. Selective Activation and Disengagement of Moral Control.

    Bandura, Albert

    1990-01-01

    Analyzes psychological mechanisms by which moral control is selectively disengaged from inhumane conduct in ordinary and unusual circumstances. Explores the symptoms of moral exclusion as described in the literature. Presents categories that unify theory on moral exclusion and contribute practical classifications for use in empirical studies. (JS)

  20. Genetic control of active neural circuits

    Leon Reijmers

    2009-12-01

    Full Text Available The use of molecular tools to study the neurobiology of complex behaviors has been hampered by an inability to target the desired changes to relevant groups of neurons. Specific memories and specific sensory representations are sparsely encoded by a small fraction of neurons embedded in a sea of morphologically and functionally similar cells. In this review we discuss genetics techniques that are being developed to address this difficulty. In several studies the use of promoter elements that are responsive to neural activity have been used to drive long lasting genetic alterations into neural ensembles that are activated by natural environmental stimuli. This approach has been used to examine neural activity patterns during learning and retrieval of a memory, to examine the regulation of receptor trafficking following learning and to functionally manipulate a specific memory trace. We suggest that these techniques will provide a general approach to experimentally investigate the link between patterns of environmentally activated neural firing and cognitive processes such as perception and memory.

  1. Control of optical active borates nanocrystals agglomeration

    I. Cieślik; R. Węgłowski; J. Żmija; K. Kurzydłowski; M. Płocińska; M. Oćwieja

    2013-01-01

    Purpose: The purposes of this study explore the possibility of total control the agglomeration of nanoborates powders. The great potential of PDLCs can be enhanced by using dye-doped or nanoparticles-doped materials, such as borates [1]. It is important to know how to prepare nanoparticles in order to obtain a high level of dispersion in the composites. Otherwise, even small an agglomeration does not give a possibility on the appropriate characteristic of properties and interp...

  2. Active control for turbulent premixed flame simulations

    Bell, John B.; Day, Marcus S.; Grcar, Joseph F.; Lijewski, Michael J.

    2004-03-26

    Many turbulent premixed flames of practical interest are statistically stationary. They occur in combustors that have anchoring mechanisms to prevent blow-off and flashback. The stabilization devices often introduce a level of geometric complexity that is prohibitive for detailed computational studies of turbulent flame dynamics. As a result, typical detailed simulations are performed in simplified model configurations such as decaying isotropic turbulence or inflowing turbulence. In these configurations, the turbulence seen by the flame either decays or, in the latter case, increases as the flame accelerates toward the turbulent inflow. This limits the duration of the eddy evolutions experienced by the flame at a given level of turbulent intensity, so that statistically valid observations cannot be made. In this paper, we apply a feedback control to computationally stabilize an otherwise unstable turbulent premixed flame in two dimensions. For the simulations, we specify turbulent in flow conditions and dynamically adjust the integrated fueling rate to control the mean location of the flame in the domain. We outline the numerical procedure, and illustrate the behavior of the control algorithm. We use the simulations to study the propagation and the local chemical variability of turbulent flame chemistry.

  3. A reduced energy supply strategy in active vibration control

    In this paper, a control strategy is presented and numerically tested. This strategy aims to achieve the potential performance of fully active systems with a reduced energy supply. These energy needs are expected to be comparable to the power demands of semi-active systems, while system performance is intended to be comparable to that of a fully active configuration. The underlying strategy is called 'global semi-active control'. This control approach results from an energy investigation based on management of the optimal control process. Energy management encompasses storage and convenient restitution. The proposed strategy monitors a given active law without any external energy supply by considering purely dissipative and energy-demanding phases. Such a control law is offered here along with an analysis of its properties. A suboptimal form, well adapted for practical implementation steps, is also given. Moreover, a number of numerical experiments are proposed in order to validate test findings

  4. Activity meters permitting direct activity readings for food controls

    Instruments for total gamma activity measurements can only be used, if the calibration factor is known for the radionuclide mixture to be measured in each case. This is determined using spectroscopes calibrated on the basis of reference samples. Inaccuracies of measurement performed on equal volumes are caused by the fact that specific weights vary between foodstuffs and must therefore be made up for by adequate adjustments. As any radioactivity occurring naturally in the specimens cannot be distinguished from manmade radioactivity, it may be impossible to interpret results lower than some 100 Bq/kg for certain samples influenced by potassium (legume, dry milk) or uranium-radium (soil). The instruments incorporate annular receptacles for the samples and NaI(Tl) detectors for the measurement of gamma-emitting radionuclides in liquids, plant materials and foodstuffs, which have a reading for such activities in Bq/l or Bq/kg (Becquerel monitors). (orig./DG)

  5. Geometric control of active collective motion

    Theillard, Maxime; Saintillan, David

    2016-01-01

    Recent experimental studies have shown that confinement can profoundly affect self-organization in semi-dilute active suspensions, leading to striking features such as the formation of steady and spontaneous vortices in circular domains and the emergence of unidirectional pumping motions in periodic racetrack geometries. Motivated by these findings, we analyze the two-dimensional dynamics in confined suspensions of active self-propelled swimmers using a mean-field kinetic theory where conservation equations for the particle configurations are coupled to the forced Navier-Stokes equations for the self-generated fluid flow. In circular domains, a systematic exploration of the parameter space casts light on three distinct states: equilibrium with no flow, stable vortex, and chaotic motion, and the transitions between these are explained and predicted quantitatively using a linearized theory. In periodic racetracks, similar transitions from equilibrium to net pumping to traveling waves to chaos are observed in ag...

  6. Active Vibration Control of Satellite Flexible Structures during Attitude Maneuvers

    Saeed Hemmati; Morteza Shahravi; Keramat Malekzadeh

    2013-01-01

    The purpose of this study is controlling active vibration of satellite flexible structures during attitude maneuvers. A smart structure is a structure which is able to sense and control active reaction to any external factors and stimulation. As it comes from the definition of smart structures, development of this knowledge depends on the materials science development, theories and strategies for control. In materials science, smart materials are developed in such a way that they are able to ...

  7. An active control synchronization for two modified Chua circuits

    Li, Guo-Hui

    2005-03-01

    From modern control theory, an active control method to synchronize two modified Chua circuits with each other, which exhibit chaos, is presented. Some sufficient conditions of linear stability of the chaotic synchronization are obtained from rigorous mathematic justification. On the basis of the state-observer, the controller is analytically deduced using the active control. It is shown that this technique can be applied to achieve synchronization of the two systems with each other, whether they are identical or not. Finally, numerical simulations show the effectiveness of the proposed control scheme.

  8. An active control synchronization for two modified Chua circuits

    Li Guo-Hui

    2005-01-01

    From modern control theory, an active control method to synchronize two modified Chua circuits with each other, which exhibit chaos, is presented. Some sufficient conditions of linear stability of the chaotic synchronization are obtained from rigorous mathematic justification. On the basis of the state-observer, the controller is analytically deduced using the active control. It is shown that this technique can be applied to achieve synchroniztion of the tow systems with each other, whether they are identical or not. Finally, numerical simulations show the effectiveness of the proposed control scheme.

  9. Active control of noise radiation from vibrating structures

    Mørkholt, Jakob

    The thesis is concerned with the active control of randomly vibrating structures by means of feedback control, with particular emphasis on reducing the sound radiation from such structures. A time domain model of the structural and radiation dynamics of an actively controlled plate has been...... developed, based on the theory of radiation filters for estimating the sound radiation from multimodal vibrations. This model has then been used in simulations of optimal feedback control, with special emphasis of the stability margins of the optimal control scheme. Two different methods of designing...

  10. Foundations of Active Control - Active Noise Reduction Helmets

    Elmkjær, Torsten Haaber Leth

    2008-01-01

    regularization. A simplification of this algorithm leads to the MC-αγΠ-NLMS algorithm that is an extended variant of the NLMS algorithm. Off-line simultaneous system identification capabilities of a complex system involving a total 4 secondary paths, 20 feedback paths and 4 control-performance paths is...... obvious input and output channel definition by a finite lumped-elements multi-channel system. Usually, no unique transfer function x exist as the system is not point-wise excited, but excited over an area as in the case of diffuse sound field illumination. A new method for acoustical signal processing...

  11. Active control for single camera SLAM

    Vidal-Calleja, Teresa A.; Davison, Andrew J.; Andrade-Cetto, J.; Murray, David W

    2006-01-01

    In this paper we consider a single hand-held camera performing SLAM at video rate with generic 6DOF motion. The aim is to optimise both the localisation of the sensor and building of the feature map by computing the most appropriate control actions or movements. The actions belong to a discrete set (e.g. go forward, go left, go up, turn right, etc), and are chosen so as to maximise the mutual information gain between posterior states and measurements. Maximising the mutual information helps t...

  12. Controlling the enzymatic activity of a restriction enzyme by light

    Schierling, Benno; Noël, Ann-Josée; Wende, Wolfgang; Hien, Le Thi; Volkov, Eugeny; Kubareva, Elena; Oretskaya, Tatiana; Kokkinidis, Michael; Römpp, Andreas; Spengler, Bernhard; Pingoud, Alfred

    2009-01-01

    For many applications it would be desirable to be able to control the activity of proteins by using an external signal. In the present study, we have explored the possibility of modulating the activity of a restriction enzyme with light. By cross-linking two suitably located cysteine residues with a bifunctional azobenzene derivative, which can adopt a cis- or trans-configuration when illuminated by UV or blue light, respectively, enzymatic activity can be controlled in a reversible manner. T...

  13. An Overview of Active Structural Control under Seismic Loads

    Soong, T.T.; Masri, S. F.; Housner, G. W.

    1991-01-01

    The concept of active structural control as a means of structural protection against seismic loads, developed over the last 20 years, has received considerable attention in recent years. It has now reached the stage where active systems have been installed in full-scale structures. It is the purpose of this paper to provide an overview of this development with special emphasis placed on laboratory experiments using model structures and on full-scale implementation of some active control syste...

  14. Epicondylopathia humeri (EPH) and peritendinitis humeroscapularis (PHS): evaluation of radiation therapy long-term results and literature review

    Background: The effectiveness of radiotherapy (RT) for degenerative inflammatory disorders has been clinically documented in historical studies, but long-term follow-up and assessment with objective criteria are still not available. Patients and methods: From 1986 to 1991, 200 consecutive patients with symptomatic epicondylopathia humeri (EPH, n=104) and peritendinitis humeroscapularis (PHS, n=96) were referred to our clinic. All patients were refractory to conventional therapy prior to irradiation. One hundred fifty-six patients with 192 sites (due to bilateral symptoms) received a full treatment course and were available for long-term follow-up, i.e. 83 patients with 93 elbows and 73 patients with 89 shoulders. The treatment response was evaluated with regard to pain symptoms grouped into five categories (pain at strain, pain at night, persistent pain during daytime, pain at rest and morning stiffness) and four grades (none, mild, moderate and severe) and with regard to established orthopedic scores (Morrey score and Constant and Murley score). The analysis was performed before and 6 weeks after RT and at last follow-up. All joints received two RT series applied in three weekly fractions (EPH, 6x1 Gy (total 12 Gy); PHS, 6x0.5 Gy (total 6 Gy)). The second RT series started 6 weeks after the first RT series. The minimum follow-up was 1 year for both groups and the mean follow-up reached 4 years (range 1-8 years). Results: Fifty elbows (43 patients) and 44 shoulders (39 patients) achieved complete pain relief in all pain categories; 24 elbows and 28 shoulders substantially improved, i.e. had only minor symptoms. Thus, 74 elbows and 72 shoulders responded to RT. Nineteen elbows (17 patients) had surgery after RT due to persisting symptoms or subjective dissatisfaction; 17 shoulders (12 patients) were non-responders and five of those were operated on; seven elbows and one shoulder were completely free of pain after surgery. The mean Morrey score improved by 18 points

  15. Generalized internal model robust control for active front steering intervention

    Wu, Jian; Zhao, Youqun; Ji, Xuewu; Liu, Yahui; Zhang, Lipeng

    2015-03-01

    Because of the tire nonlinearity and vehicle's parameters' uncertainties, robust control methods based on the worst cases, such as H ∞, µ synthesis, have been widely used in active front steering control, however, in order to guarantee the stability of active front steering system (AFS) controller, the robust control is at the cost of performance so that the robust controller is a little conservative and has low performance for AFS control. In this paper, a generalized internal model robust control (GIMC) that can overcome the contradiction between performance and stability is used in the AFS control. In GIMC, the Youla parameterization is used in an improved way. And GIMC controller includes two sections: a high performance controller designed for the nominal vehicle model and a robust controller compensating the vehicle parameters' uncertainties and some external disturbances. Simulations of double lane change (DLC) maneuver and that of braking on split- µ road are conducted to compare the performance and stability of the GIMC control, the nominal performance PID controller and the H ∞ controller. Simulation results show that the high nominal performance PID controller will be unstable under some extreme situations because of large vehicle's parameters variations, H ∞ controller is conservative so that the performance is a little low, and only the GIMC controller overcomes the contradiction between performance and robustness, which can both ensure the stability of the AFS controller and guarantee the high performance of the AFS controller. Therefore, the GIMC method proposed for AFS can overcome some disadvantages of control methods used by current AFS system, that is, can solve the instability of PID or LQP control methods and the low performance of the standard H ∞ controller.

  16. Generalized Internal Model Robust Control for Active Front Steering Intervention

    WU Jian; ZHAO Youqun; JI Xuewu; LIU Yahui; ZHANG Lipeng

    2015-01-01

    Because of the tire nonlinearity and vehicle’s parameters’ uncertainties, robust control methods based on the worst cases, such as H∞, μsynthesis, have been widely used in active front steering control, however, in order to guarantee the stability of active front steering system (AFS) controller, the robust control is at the cost of performance so that the robust controller is a little conservative and has low performance for AFS control. In this paper, a generalized internal model robust control (GIMC) that can overcome the contradiction between performance and stability is used in the AFS control. In GIMC, the Youla parameterization is used in an improved way. And GIMC controller includes two sections:a high performance controller designed for the nominal vehicle model and a robust controller compensating the vehicle parameters’ uncertainties and some external disturbances. Simulations of double lane change (DLC) maneuver and that of braking on split-μroad are conducted to compare the performance and stability of the GIMC control, the nominal performance PID controller and the H∞ controller. Simulation results show that the high nominal performance PID controller will be unstable under some extreme situations because of large vehicle’s parameters variations, H∞ controller is conservative so that the performance is a little low, and only the GIMC controller overcomes the contradiction between performance and robustness, which can both ensure the stability of the AFS controller and guarantee the high performance of the AFS controller. Therefore, the GIMC method proposed for AFS can overcome some disadvantages of control methods used by current AFS system, that is, can solve the instability of PID or LQP control methods and the low performance of the standard H∞controller.

  17. Active structural control with stable fuzzy PID techniques

    Yu, Wen

    2016-01-01

    This book presents a detailed discussion of intelligent techniques to measure the displacement of buildings when they are subjected to vibration. It shows how these techniques are used to control active devices that can reduce vibration 60–80% more effectively than widely used passive anti-seismic systems. After introducing various structural control devices and building-modeling and active structural control methods, the authors propose offset cancellation and high-pass filtering techniques to solve some common problems of building-displacement measurement using accelerometers. The most popular control algorithms in industrial settings, PD/PID controllers, are then analyzed and then combined with fuzzy compensation. The stability of this combination is proven with standard weight-training algorithms. These conditions provide explicit methods for selecting PD/PID controllers. Finally, fuzzy-logic and sliding-mode control are applied to the control of wind-induced vibration. The methods described are support...

  18. Adaptive Current Control with PI-Fuzzy Compound Controller for Shunt Active Power Filter

    Juntao Fei

    2013-01-01

    Full Text Available An adaptive control technology and PI-fuzzy compound control technology are proposed to control an active power filter (APF. AC side current compensation and DC capacitor voltage tracking control strategy are discussed and analyzed. Model reference adaptive controller for the AC side current compensation is derived and established based on Lyapunov stability theory; proportional and integral (PI fuzzy compound controller is designed for the DC side capacitor voltage control. The adaptive current controller based on PI-fuzzy compound system is compared with the conventional PI controller for active power filter. Simulation results demonstrate the feasibility and satisfactory performance of the proposed control strategies. It is shown that the proposed control method has an excellent dynamic performance such as small current tracking error, reduced total harmonic distortion (THD, and strong robustness in the presence of parameters variation and nonlinear load.

  19. Active Vibration Control of Rotor-Bearing Systems

    Blanco-Ortega, Andres; Silva-Navaro, Gerardo; Beltran-Carbajal, Francisco; Vela-Valdes, Luis Gerardo

    2010-01-01

    The active vibration control of a Jeffcott-like rotor through dynamic stiffness control and acceleration scheduling is addressed. The control approach consists of a servomechanism able to move one of the supporting bearings in such a way that the effective rotor length is controlled. As a consequence, the rotor stiffness and natural frequency are modified according to an off-line and smooth trajectory planning of the rotor speed/acceleration in order to reduce the unbalance response when pass...

  20. Wireless sensor networks for active vibration control in automobile structures

    Wireless sensor networks (WSNs) are nowadays widely used in monitoring and tracking applications. This paper presents the feasibility of using WSNs in active vibration control strategies. The method employed here involves active-structural acoustic control using piezoelectric sensors distributed on a car structure. This system aims at being merged with a WSN whose head node collects data and processes control laws so as to command piezoelectric actuators wisely placed on the structure. We will study the feasibility of implementing WSNs in active vibration control and introduce a complete design methodology to optimize hardware/software and control law synergy in mechatronic systems. A design space exploration will be conducted so as to identify the best WSN platform and the resulting impact on control. (paper)

  1. Wireless sensor networks for active vibration control in automobile structures

    Mieyeville, Fabien; Ichchou, Mohamed; Scorletti, Gérard; Navarro, David; Du, Wan

    2012-07-01

    Wireless sensor networks (WSNs) are nowadays widely used in monitoring and tracking applications. This paper presents the feasibility of using WSNs in active vibration control strategies. The method employed here involves active-structural acoustic control using piezoelectric sensors distributed on a car structure. This system aims at being merged with a WSN whose head node collects data and processes control laws so as to command piezoelectric actuators wisely placed on the structure. We will study the feasibility of implementing WSNs in active vibration control and introduce a complete design methodology to optimize hardware/software and control law synergy in mechatronic systems. A design space exploration will be conducted so as to identify the best WSN platform and the resulting impact on control.

  2. Various applications of Active Field Control (AFC)

    Watanabe, Takayuki; Miyazaki, Hideo; Kishinaga, Shinji; Kawakami, Fukushi

    2003-10-01

    AFC is an electro-acoustic enhancement system, which has been under development at Yamaha Corporation. In this paper, several types of various AFC applications are discussed, while referring to representative projects for each application in Japan. (1) Realization of acoustics in a huge hall to classical music program, e.g., Tokyo International Forum. This venue is a multipurpose hall with approximately 5000 seats. AFC achieves loudness and reverberance equivalent to those of a hall with 2500 seats or fewer. (2) Optimization of acoustics for a variety of programs, e.g., Arkas Sasebo. AFC is used to create the optimum acoustics for each program, such as reverberance for classical concerts, acoustical support for opera singers, uniformity throughout the hall from the stage to under-balcony area, etc. (3) Control of room shape acoustical effect, e.g., Osaka Central Public Hall: In this renovation project, preservation of historically important architecture in the original form is required. AFC is installed to vary only the acoustical environment without architectural changes. (4) Assistance with crowd enthusiasm for sports entertainment, e.g., Tokyo Metropolitan Gymnasium. In this venue, which is designed as a very absorptive space for speech intelligibility, AFC is installed to enhance the atmosphere of live sports entertainment.

  3. Active airborne contamination control using electrophoresis

    In spite of our best efforts, radioactive airborne contamination continues to be a formidable problem at many of the Department of Energy (DOE) weapons complex sites. For workers that must enter areas with high levels of airborne contamination, personnel protective equipment (PPE) can become highly restrictive, greatly diminishing productivity. Rather than require even more restrictive PPE for personnel in some situations, the Rocky Flats Plant (RFP) is actively researching and developing methods to aggressively combat airborne contamination hazards using electrophoretic technology. With appropriate equipment, airborne particulates can be effectively removed and collected for disposal in one simple process. The equipment needed to implement electrophoresis is relatively inexpensive, highly reliable, and very compact. Once airborne contamination levels are reduced, less PPE is required and a significant cost savings may be realized through decreased waste and maximized productivity. Preliminary ''cold,'' or non-radioactive, testing results at the RFP have shown the technology to be effective on a reasonable scale, with several potential benefits and an abundance of applications

  4. CLP activities and control in Ireland

    Caroline Walsh

    2011-01-01

    Full Text Available The 10th December 2010 marked a new beginning for Regulation (EC no. 1272/2008 on the classification, labelling and packaging of substances and mixtures (CLP in Ireland with the start of its operational phase. It was on this date that the administrative and enforcement provisions for CLP were encompassed in the new Chemicals Amendment Act, 2010. In this Act, the Health and Safety Authority, known as the "the Authority" is named as Competent Authority (CA for CLP, along with the Minister for Agriculture, Fisheries and Food, in respect of pesticides and plant protection products and the Beaumont Hospital Board with responsibility for receiving information relating to emergency health response. In practice, the Authority has been de facto CA for CLP since its publication on the 31st December 2008, given its role in existing classification and labelling regimes. This article focuses on the work undertaken by the Authority on CLP at a National, European and International level including its implementation, training, helpdesk, guidance, enforcement and awareness raising activities.

  5. Controlled physical activity for functional operability determination

    Luchenkov А.А.

    2014-06-01

    Full Text Available The aim: to use veloergometry test at patients of high anaeshtesiology-operative risk before traumatic operations for functional operability determination. Material and methods: Randomized prospective research with the double "blind" control has been performed at 95 patients of high risk (ASA>III, undergoing long and traumatic operations on thoracic and abdominal organs. Patients have divided into groups without complications and with complications (51 and 44 patients which one day prior to operation have spent veloergometry test (VEMT. Average dynamic pressure (ADP, the general peripheral resistance of vessels (GPRV, a core index (Cl; arterio-venous (a-v difference on oxygen, oxygen delivery to tissues, consumption of oxygen and coefficients extraction oxygen in tissues; energy consumption have been investigated. Statistics has been done by nonparametric methods. Results. In response to veloergometry test in both groups growth of Cl at the expense of a tachycardia and GPRV fall which in complication group remains above norm is noted. In group without complications coefficients extraction oxygen in tissues were normalised, a-v difference on 02 became above norm, in other group — coefficients extraction oxygen in tissues and a-v difference on 02 began to exceed norm, and oxygen consumption has grown almost in 2 times. After VEMT a-v a difference on О and oxygen consumption were essentially above in group with complications. Under the influence of VEMT markecT stabilization of function of vegetative nervous systems (VNS. The number of complications made 39: intraoperation cardiovascular — 23, postoperative respiratory — 16. Clinically important connection (p=0,069 of perioperative complications with growth a-v differences on oxygen and a power interchanging have been received. Conclusion. Thus, the oxygen-energy exchange and the vegetative status can be referred to clinical functional operability determination.

  6. Control of optical active borates nanocrystals agglomeration

    I. Cieślik

    2013-12-01

    Full Text Available Purpose: The purposes of this study explore the possibility of total control the agglomeration of nanoborates powders. The great potential of PDLCs can be enhanced by using dye-doped or nanoparticles-doped materials, such as borates [1]. It is important to know how to prepare nanoparticles in order to obtain a high level of dispersion in the composites. Otherwise, even small an agglomeration does not give a possibility on the appropriate characteristic of properties and interpretation of the results. The deagglomeration methods applied until now give the decrease of agglomeration to a lesser extent than our method. Characteristic size and shape of particles made with sol-gel process is difficult to perform. Design/methodology/approach: Nanopowders samples of YAB and LCBO were prepared with sol-gel method. Deagglomeration process was carried out using acetic acid. The morphology and size of nanopowders were investigated by scanning electron microscopy (SEM. The crystallite sizes were determinated with IPS UA method. Findings: It was confirmed that the acetic acid influence on the decrease of agglomeration. It was also determined of conditions for preparation borates nanopowders samples (concentration acetic acind time and temperature of drying prepared samples. We have proved that a reagent used for deagglomeration process does not affect the structure of the investigated nanoborates used in an experimental. Research limitations/implications: The results can be used to the prepared of nanocompades of borates to observe a morphology and reliable assessment of nanocrystalline size. Originality/value: Our study shows how to prepare a sample of particles to observe morphology and measure the size of nanograins. In our study we found excellent solution, the medium, which not influence the inorganic nanomaterial structure. Result seems to be excellent and very perspective. We have showed as that measurement type influence the results of particles size.

  7. Development of Active Noise Control System for Quieting Transformer Noise

    Lee, Bok Kyu; Song, Seik Young; Choi, Huo Yul [Korea Electric Power Research Institute, Taejon (Korea, Republic of); Yun, Dae Hea; Lee, Hyuk Jae [Korea Electrotechnology Research Institute, Changwon (Korea, Republic of)

    1997-12-31

    The passive noise control technique made use of sound-absorbing or soundproofing materials, so it required a large area and high cost for installation and had a drawback of poor performance at low frequency. Compared to this, the Active Noise Control attenuates noise sound pressure by using secondary source which has same performance ay low-frequency. Furthermore, it is able to save space and expenses. - research on adaptive algorithms - evaluation of global attenuation of the control - computer simulation - real-time Active Noise Control System Hardware Implementation - ANC system setting in the noisy area.

  8. Indirect control of a single-phase active power filter

    Mihai CULEA

    2006-12-01

    Full Text Available The control of shunt active power filters using PWM inverters consists in generating a reference by separating, using different methods, the harmonics to be eliminated. The methods used are time-consuming and need dedicated control and signal processing equipments. To avoid these setbacks a new method is proposed in the paper. The active power filter is a current PWM rectifier with voltage output and with a capacitor on the DC side. The PWM rectifier is controlled so that the sum of its current and the load’s current is a sinusoid. The control block as well as simulation results are presented.

  9. Development of hydraulic brake actuator for active brake control; Active brake seigyoyo yuatsu booster no kaihatsu

    Konishi, Y.; Hattori, M. Sugisawa, M.; Nishii, M. [Aisin Seiki Co. Ltd., Aichi (Japan)

    1997-10-01

    Recently, application of active brake control systems of the vehicle are increasing. (Vehicle stability control, Panic brake assist ) We have developed a new hydraulic brake actuator for active brake control systems. New hydraulic brake actuator is composed of the three parts. (Hydraulic booster unit, Power supply unit, Control valve unit) This report describes the construction of the new hydraulic booster unit. 2 refs., 10 figs.

  10. Application of smart materials to helicopter rotor active control

    Straub, Friedrich K.; Ealey, Mark A.; Schetky, Lawrence M.

    1997-05-01

    Helicopter design is limited by the compromise inherent in meeting hover and forward flight requirements, and the unsteady environment encountered in forward flight. Active control of helicopter rotors using smart material, in-blade actuation can overcome these barriers and provide substantial reductions in noise and vibrations and improved performance. The present study covers the blade/actuator integration and actuator development for a full scale system to demonstrate active control of noise and vibrations as well as inflight blade tracking on the MD Explorer helicopter. A piezoelectric multilayer stack actuator, driving a trailing edge flap, is used for active control. A shape memory alloy torsion actuator, driving a trailing edge trim tab, is used for inflight tracking. Overall, this DARPA sponsored program entails the design, development, and fabrication of the full scale active control rotor system. If successful, an entry in the NASA Ames 40 X 80 foot wind tunnel and flight tests are planned for a follow on program.

  11. Recent results on structural control of an active precision structure

    Chu, C. C.; Fanson, J. L.; Smith, R. S.

    1991-01-01

    This paper describes recent results in structural control of an active precision truss structure at JPL. The goal is to develop practical control methodology and to apply to active truss structures intended for high precision space-based optics applications. The active structure considered incorporates piezoelectric active members which apply control forces internal to the structure and thereby improve the structure's dimensional stability. Two approaches to structural control system design were investigated. The first approach uses only noncollocated measurements of acceleration at the location of a simulated optical component to achieve structural stabilization. The second approach is essentially the same as the first one except that a viscous damper was used in place of a truss member on the structure to improve the dampings of selected flexible modes. The corresponding experimental closed-loop results are presented in this paper.

  12. Perception Neural Networks for Active Noise Control Systems

    Wang Xiaoli

    2012-11-01

    Full Text Available In a response to a growing demand for environments of 70dB or less noise levels, many industrial sectors have focused with some form of noise control system. Active noise control (ANC has proven to be the most effective technology. This paper mainly investigates application of neural network on self-adaptation system in active noise control (ANC. An active silencing control system is made which adopts a motional feedback loudspeaker as not a noise controlling source but a detecting sensor. The working fundamentals and the characteristics of the motional feedback loudspeaker are analyzed in detail. By analyzing each acoustical path, identification based adaptive linear neural network is built. This kind of identifying method can be achieved conveniently. The estimated result of each sound channel matches well with its real sound character, respectively.

  13. Active Vibration Control of a Monopile Offshore Structure

    Nielsen, Søren R. K.; Kirkegaard, Poul Henning; Thesbjerg, L.

    1996-01-01

    structure an active control technique has been proposed in corporation with the consulting company Rambøll, Esbjerg, Denmark. The proposed control technique is based on the relationship between the position of the separation points of the boundary layer flow and the drag term in the wave force on the......, it can be necessary to use an active or a passive vibration control system. However, for a monopile with severe space problems it can be difficult to locate a passive control system such as e.g. a tuned mass damper. Therefore, in order to active control wave introduced vibrations of a monopile...... cylinder. This concept has been experimentally investigated with a test model in stationary flow tests. The idea is to have a large drag coefficient when the cylinder moves opposite of the wave direction implying a relatively large damping excitation. When the structure moves in the wave direction a small...

  14. EphrinA4 mimetic peptide targeted to EphA binding site impairs the formation of long-term fear memory in lateral amygdala

    Dines, M; Lamprecht, R.

    2014-01-01

    Fear conditioning leads to long-term fear memory formation and is a model for studying fear-related psychopathologies conditions such as phobias and posttraumatic stress disorder. Long-term fear memory formation is believed to involve alterations of synaptic efficacy mediated by changes in synaptic transmission and morphology in lateral amygdala (LA). EphrinA4 and its cognate Eph receptors are intimately involved in regulating neuronal morphogenesis, synaptic transmission and plasticity. To a...

  15. EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation

    Margolis, Seth S.; Salogiannis, John; Lipton, David M.; Mandel-Brehm, Caleigh; Wills, Zachary P.; Mardinly, Alan R.; Hu, Linda; Greer, Paul L.; Bikoff, Jay B.; Ho, Hsin-Yi Henry; Soskis, Michael J.; Sahin, Mustafa; Greenberg, Michael E.

    2010-01-01

    The mechanisms that promote excitatory synapse formation and maturation have been extensively studied. However, the molecular events that limit excitatory synapse development so that synapses form at the right time and place and in the correct numbers are less well understood. We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylat...

  16. Active Inference, homeostatic regulation and adaptive behavioural control

    Pezzulo, G; Rigoli, F.; Friston, K.

    2015-01-01

    We review a theory of homeostatic regulation and adaptive behavioural control within the Active Inference framework. Our aim is to connect two research streams that are usually considered independently; namely, Active Inference and associative learning theories of animal behaviour. The former uses a probabilistic (Bayesian) formulation of perception and action, while the latter calls on multiple (Pavlovian, habitual, goal-directed) processes for homeostatic and behavioural control. We offer a...

  17. Vector disparity sensor with vergence control for active vision systems

    Eduardo Ros; Francisco Barranco; Javier Diaz; Sabatini, Silvio P; Agostino Gibaldi

    2012-01-01

    This paper presents an architecture for computing vector disparity for active vision systems as used on robotics applications. The control of the vergence angle of a binocular system allows us to efficiently explore dynamic environments, but requires a generalization of the disparity computation with respect to a static camera setup, where the disparity is strictly 1-D after the image rectification. The interaction between vision and motor control allows us to develop an active sensor that ac...

  18. Active Engine Mounting Control Algorithm Using Neural Network

    Fadly Jashi Darsivan

    2009-01-01

    Full Text Available This paper proposes the application of neural network as a controller to isolate engine vibration in an active engine mounting system. It has been shown that the NARMA-L2 neurocontroller has the ability to reject disturbances from a plant. The disturbance is assumed to be both impulse and sinusoidal disturbances that are induced by the engine. The performance of the neural network controller is compared with conventional PD and PID controllers tuned using Ziegler-Nichols. From the result simulated the neural network controller has shown better ability to isolate the engine vibration than the conventional controllers.

  19. Innovation in Active Vibration Control Strategy of Intelligent Structures

    A. Moutsopoulou

    2014-01-01

    Full Text Available Large amplitudes and attenuating vibration periods result in fatigue, instability, and poor structural performance. In light of past approaches in this field, this paper intends to discuss some innovative approaches in vibration control of intelligent structures, particularly in the case of structures with embedded piezoelectric materials. Control strategies are presented, such as the linear quadratic control theory, as well as more advanced theories, such as robust control theory. The paper presents sufficiently a recognizable advance in knowledge of active vibration control in intelligent structures.

  20. N-(2,4)-dinitrophenyl-L-arginine Interacts with EphB4 and Functions as an EphB4 Kinase Modulator.

    Kamstra, Rhiannon L; Freywald, Andrew; Floriano, Wely B

    2015-10-01

    The erythropoietin-producing hepatocellular carcinoma receptor B4 is a receptor tyrosine kinase whose expression is preserved in various malignancies, including colon, gastric, and breast carcinoma. Hepatocellular carcinoma receptor B4 presence in tumor cells and involvement in cancer suppression makes it a potential therapeutic target for activating compounds. Moreover, modulators of its activity also have a strong potential to be used in diagnosis and therapy monitoring. We used virtual ligand screening to identify novel hepatocellular carcinoma receptor B4 kinase modulators for experimental testing. Three independent assay platforms confirmed that dinitrophenyl-L-arginine is likely to affect the kinase activity of hepatocellular carcinoma receptor B4. An enzyme-coupled spectrophotometric assay has been used to examine this possibility and may prove to be useful for assessing other novel kinase modulator candidates. Overall, our observations suggest that dinitrophenyl-L-arginine has an activating effect on hepatocellular carcinoma receptor B4 and, therefore, more efficient derivatives may have therapeutic effects in tumors where hepatocellular carcinoma receptor B4 exhibits antimalignant properties. The hepatocellular carcinoma receptor B4-activating effect is discussed with respect to previously described mechanisms, using predicted and experimental structures for docked ligands. As a novel kinase activity modulator, dinitrophenyl-L-arginine may provide new insights into molecular mechanisms by which kinases are activated or regulated, and may serve as a lead compound for the generation of novel hepatocellular carcinoma receptor B4-activating therapeutic compounds. PMID:25581780

  1. Active Fault Tolerant Control of Livestock Stable Ventilation System

    Gholami, Mehdi

    2011-01-01

    of the hybrid model are estimated by a recursive estimation algorithm, the Extended Kalman Filter (EKF), using experimental data which was provided by an equipped laboratory. Two methods for active fault diagnosis are proposed. The AFD methods excite the system by injecting a so-called excitation...... degraded performance even in the faulty case. In this thesis, we have designed such controllers for climate control systems for livestock buildings in three steps: Deriving a model for the climate control system of a pig-stable. Designing a active fault diagnosis (AFD) algorithm for different kinds of...... fault. Designing a fault tolerant control scheme for the climate control system. In the first step, a conceptual multi-zone model for climate control of a live-stock building is derived. The model is a nonlinear hybrid model. Hybrid systems contain both discrete and continuous components. The parameters...

  2. Applications of active adaptive noise control to jet engines

    Shoureshi, Rahmat; Brackney, Larry

    1993-01-01

    During phase 2 research on the application of active noise control to jet engines, the development of multiple-input/multiple-output (MIMO) active adaptive noise control algorithms and acoustic/controls models for turbofan engines were considered. Specific goals for this research phase included: (1) implementation of a MIMO adaptive minimum variance active noise controller; and (2) turbofan engine model development. A minimum variance control law for adaptive active noise control has been developed, simulated, and implemented for single-input/single-output (SISO) systems. Since acoustic systems tend to be distributed, multiple sensors, and actuators are more appropriate. As such, the SISO minimum variance controller was extended to the MIMO case. Simulation and experimental results are presented. A state-space model of a simplified gas turbine engine is developed using the bond graph technique. The model retains important system behavior, yet is of low enough order to be useful for controller design. Expansion of the model to include multiple stages and spools is also discussed.

  3. "Active Flux" DTFC-SVM Sensorless Control of IPMSM

    Boldea, Ion; Codruta Paicu, Mihaela; Gheorghe-Daniel, Andreescu,;

    2009-01-01

    This paper proposes an implementation of a motionsensorless control system in wide speed range based on "active flux" observer, and direct torque and flux control with space vector modulation (DTFC-SVM) for the interior permanent magnet synchronous motor (IPMSM), without signal injection. The...

  4. Finite element models applied in active structural acoustic control

    Oude Nijhuis, Marco H.H.; Boer, de André; Rao, Vittal S.

    2002-01-01

    This paper discusses the modeling of systems for active structural acoustic control. The finite element method is applied to model structures including the dynamics of piezoelectric sensors and actuators. A model reduction technique is presented to make the finite element model suitable for controll

  5. Smart Materials and Active Noise and Vibration Control in Vehicles

    Doppenberg, E.J.J.; Berkhoff, A.P.; Overbeek, van M.

    2001-01-01

    The paper presents the results for the reduction of sound radiated from a structure using different control methodologies, and discusses two approaches for active structural acoustic control: the acoustic approach or the vibro-acoustic approach. Integrated actuators in structure material are necessa

  6. A Semi-active Control System for Wind Turbines

    Caterino, N.; Georgakis, Christos T.; Trinchillo, F.; Occhiuzzi, A.

    A semi-active (SA) control system based on the use of smart magnetorheological (MR) dampers to control the structural response of a wind turbine is proposed herein. The innovative approach is based on the implementation and use of a variable-properties base restraint. This is able to modify in re...

  7. Active following fuzzy output feedback sliding mode control of real-vehicle semi-active suspensions

    Liu, H.; Nonami, K.; Hagiwara, T.

    2008-07-01

    Many semi-active suspension systems have been investigated in various literatures in order to achieve lower energy consumption and as good performance as full-active suspension systems. Full-active suspension systems can achieve a good ride quality by actuators; however, their implementation equipments are expensive. The full-active suspensions are perfect from the point of view of control; hence, semi-active control laws with performance similar to full-active controls have attracted the engineering community for their ease and lower cost of implementation. This paper presents a new active following fuzzy output feedback sliding mode control for a real-vehicle semi-active suspension system. The performance of the proposed controller has been verified by comparing it with passive control and also with the full-active target semi-active approximation control method. In the experiment, it was shown that the proposed method has the effectiveness in stabilizing heave, roll and pitch movement of the car body.

  8. Passive and Active Vibration Control of Renewable Energy Structures

    Zhang, Zili

    2015-01-01

    The present thesis deals with fundamental researches on passive and active vibration control of renewable energy structures, and provides useful models for practical applications. Effective and robust vibration control methods have been explored for mitigating the lightly damped edgewise blade vibration and lateral tower vibration, with the main focus on structural control devices. Rigorous theoretical modeling of different dynamic system has been established, based on which detailed design a...

  9. Stability investigation of an airfoil section with active flap control

    Bergami, Leonardo; Gaunaa, Mac

    2010-01-01

    This work presents a method to determine flutter and divergence instability limits for a two-dimensional (2-D) airfoil section fitted with an actively controlled trailing edge flap. This flap consists of a deformable trailing edge, which deformation is governed by control algorithms based on measurements of either heave displacement, local angle of attack or aerodynamic pressure difference measured over the airfoil. The purpose of the controlled deformable flap is to reduce fluctuations in th...

  10. Active vibration control techniques for flexible space structures

    Parlos, Alexander G.; Jayasuriya, Suhada

    1990-01-01

    Two proposed control system design techniques for active vibration control in flexible space structures are detailed. Control issues relevant only to flexible-body dynamics are addressed, whereas no attempt was made to integrate the flexible and rigid-body spacecraft dynamics. Both of the proposed approaches revealed encouraging results; however, further investigation of the interaction of the flexible and rigid-body dynamics is warranted.