Canonical and Noncanonical Sites Determine NPT2A Binding Selectivity to NHERF1 PDZ1.

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Tatyana Mamonova

Full Text Available Na+/H+ Exchanger Regulatory Factor-1 (NHERF1 is a scaffolding protein containing 2 PDZ domains that coordinates the assembly and trafficking of transmembrane receptors and ion channels. Most target proteins harboring a C-terminus recognition motif bind more-or-less equivalently to the either PDZ domain, which contain identical core-binding motifs. However some substrates such as the type II sodium-dependent phosphate co-transporter (NPT2A, uniquely bind only one PDZ domain. We sought to define the structural determinants responsible for the specificity of interaction between NHERF1 PDZ domains and NPT2A. By performing all-atom/explicit-solvent molecular dynamics (MD simulations in combination with biological mutagenesis, fluorescent polarization (FP binding assays, and isothermal titration calorimetry (ITC, we found that in addition to canonical interactions of residues at 0 and -2 positions, Arg at the -1 position of NPT2A plays a critical role in association with Glu43 and His27 of PDZ1 that are absent in PDZ2. Experimentally introduced mutation in PDZ1 (Glu43Asp and His27Asn decreased binding to NPT2A. Conversely, introduction of Asp183Glu and Asn167His mutations in PDZ2 promoted the formation of favorable interactions yielding micromolar KDs. The results describe novel determinants within both the PDZ domain and outside the canonical PDZ-recognition motif that are responsible for discrimination of NPT2A between two PDZ domains. The results challenge general paradigms for PDZ recognition and suggest new targets for drug development.

PDZ Protein Regulation of G Protein-Coupled Receptor Trafficking and Signaling Pathways.

Science.gov (United States)

Dunn, Henry A; Ferguson, Stephen S G

2015-10-01

G protein-coupled receptors (GPCRs) contribute to the regulation of every aspect of human physiology and are therapeutic targets for the treatment of numerous diseases. As a consequence, understanding the myriad of mechanisms controlling GPCR signaling and trafficking is essential for the development of new pharmacological strategies for the treatment of human pathologies. Of the many GPCR-interacting proteins, postsynaptic density protein of 95 kilodaltons, disc large, zona occludens-1 (PDZ) domain-containing proteins appear most abundant and have similarly been implicated in disease mechanisms. PDZ proteins play an important role in regulating receptor and channel protein localization within synapses and tight junctions and function to scaffold intracellular signaling protein complexes. In the current study, we review the known functional interactions between PDZ domain-containing proteins and GPCRs and provide insight into the potential mechanisms of action. These PDZ domain-containing proteins include the membrane-associated guanylate-like kinases [postsynaptic density protein of 95 kilodaltons; synapse-associated protein of 97 kilodaltons; postsynaptic density protein of 93 kilodaltons; synapse-associated protein of 102 kilodaltons; discs, large homolog 5; caspase activation and recruitment domain and membrane-associated guanylate-like kinase domain-containing protein 3; membrane protein, palmitoylated 3; calcium/calmodulin-dependent serine protein kinase; membrane-associated guanylate kinase protein (MAGI)-1, MAGI-2, and MAGI-3], Na(+)/H(+) exchanger regulatory factor proteins (NHERFs) (NHERF1, NHERF2, PDZ domain-containing kidney protein 1, and PDZ domain-containing kidney protein 2), Golgi-associated PDZ proteins (Gα-binding protein interacting protein, C-terminus and CFTR-associated ligand), PDZ domain-containing guanine nucleotide exchange factors (GEFs) 1 and 2, regulator of G protein signaling (RGS)-homology-RhoGEFs (PDZ domain-containing RhoGEF and

Molecular determinants for the complex binding specificity of the PDZ domain in PICK1

DEFF Research Database (Denmark)

Madsen, Kenneth L; Beuming, Thijs; Niv, Masha Y

2005-01-01

PICK1 (protein interacting with C kinase 1) contains a single PDZ domain known to mediate interaction with the C termini of several receptors, transporters, ion channels, and kinases. In contrast to most PDZ domains, the PICK1 PDZ domain interacts with binding sequences classifiable as type I (te...

Olfactory receptor signaling is regulated by the post-synaptic density 95, Drosophila discs large, zona-occludens 1 (PDZ) scaffold multi-PDZ domain protein 1.

LENUS (Irish Health Repository)

Dooley, Ruth

2009-12-01

The unique ability of mammals to detect and discriminate between thousands of different odorant molecules is governed by the diverse array of olfactory receptors expressed by olfactory sensory neurons in the nasal epithelium. Olfactory receptors consist of seven transmembrane domain G protein-coupled receptors and comprise the largest gene superfamily in the mammalian genome. We found that approximately 30% of olfactory receptors possess a classical post-synaptic density 95, Drosophila discs large, zona-occludens 1 (PDZ) domain binding motif in their C-termini. PDZ domains have been established as sites for protein-protein interaction and play a central role in organizing diverse cell signaling assemblies. In the present study, we show that multi-PDZ domain protein 1 (MUPP1) is expressed in the apical compartment of olfactory sensory neurons. Furthermore, on heterologous co-expression with olfactory sensory neurons, MUPP1 was shown to translocate to the plasma membrane. We found direct interaction of PDZ domains 1 + 2 of MUPP1 with the C-terminus of olfactory receptors in vitro. Moreover, the odorant-elicited calcium response of OR2AG1 showed a prolonged decay in MUPP1 small interfering RNA-treated cells. We have therefore elucidated the first building blocks of the putative \\'olfactosome\\

A Novel Scheme for DVL-Aided SINS In-Motion Alignment Using UKF Techniques

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Wenqi Wu

2013-01-01

Full Text Available In-motion alignment of Strapdown Inertial Navigation Systems (SINS without any geodetic-frame observations is one of the toughest challenges for Autonomous Underwater Vehicles (AUV. This paper presents a novel scheme for Doppler Velocity Log (DVL aided SINS alignment using Unscented Kalman Filter (UKF which allows large initial misalignments. With the proposed mechanism, a nonlinear SINS error model is presented and the measurement model is derived under the assumption that large misalignments may exist. Since a priori knowledge of the measurement noise covariance is of great importance to robustness of the UKF, the covariance-matching methods widely used in the Adaptive KF (AKF are extended for use in Adaptive UKF (AUKF. Experimental results show that the proposed DVL-aided alignment model is effective with any initial heading errors. The performances of the adaptive filtering methods are evaluated with regards to their parameter estimation stability. Furthermore, it is clearly shown that the measurement noise covariance can be estimated reliably by the adaptive UKF methods and hence improve the performance of the alignment.

INVESTIGATING THE ROLE OF PDZ-DOMAIN INTERACTIONS FOR DOPAMINE TRANSPORTER FUNCTION

DEFF Research Database (Denmark)

Fog, Jacob; Vægter, Christian Bjerggaard; Gether, Ulrik

canonical PDZ domain interactions with proteins such as PICK1. To clarify the actual role of PDZ domain interactions for DAT function we have expressed the wild type DAT and a number of C-terminal mutants either alone or together with PICK1 in HEK293, N2A neuroblastoma and PC12 cells. Data obtained from...

Cooperative phosphoinositide and peptide binding by PSD-95/discs large/ZO-1 (PDZ) domain of polychaetoid, Drosophila zonulin.

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Ivarsson, Ylva; Wawrzyniak, Anna Maria; Wuytens, Gunther; Kosloff, Mickey; Vermeiren, Elke; Raport, Marie; Zimmermann, Pascale

2011-12-30

PDZ domains are well known protein-protein interaction modules that, as part of multidomain proteins, assemble molecular complexes. Some PDZ domains have been reported to interact with membrane lipids, in particular phosphatidylinositol phosphates, but few studies have been aimed at elucidating the prevalence or the molecular details of such interactions. We screened 46 Drosophila PDZ domains for phosphoinositide-dependent cellular localization and discovered that the second PDZ domain of polychaetoid (Pyd PDZ2) interacts with phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)) at the plasma membrane. Surface plasmon resonance binding experiments with recombinant protein established that Pyd PDZ2 interacts with phosphatidylinositol phosphates with apparent affinities in the micromolar range. Electrostatic interactions involving an extended positively charged surface of Pyd PDZ2 are crucial for the PtdIns(4,5)P(2)-dependent membrane interactions as shown by a combination of three-dimensional modeling, mutagenesis, binding, and localization studies. In vivo localization studies further suggested that both lipid and peptide binding contribute to membrane localization. We identified the transmembrane protein Crumbs as a Pyd PDZ2 ligand and probed the relation between peptide and PtdIns(4,5)P(2) binding. Contrary to the prevalent view on PDZ/peptide/lipid binding, we did not find competition between peptide and lipid ligands. Instead, preloading the protein with the 10-mer Crb3 peptide increased the apparent affinity of Pyd PDZ2 for PtdIns(4,5)P(2) 6-fold. Our results suggest that membrane localization of Pyd PDZ2 may be driven by a combination of peptide and PtdIns(4,5)P(2) binding, which raises the intriguing possibility that the domain may coordinate protein- and phospholipid-mediated signals.

Prevalence, specificity and determinants of lipid-interacting PDZ domains from an in-cell screen and in vitro binding experiments.

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Ylva Ivarsson

Full Text Available BACKGROUND: PDZ domains are highly abundant protein-protein interaction modules involved in the wiring of protein networks. Emerging evidence indicates that some PDZ domains also interact with phosphoinositides (PtdInsPs, important regulators of cell polarization and signaling. Yet our knowledge on the prevalence, specificity, affinity, and molecular determinants of PDZ-PtdInsPs interactions and on their impact on PDZ-protein interactions is very limited. METHODOLOGY/PRINCIPAL FINDINGS: We screened the human proteome for PtdInsPs interacting PDZ domains by a combination of in vivo cell-localization studies and in vitro dot blot and Surface Plasmon Resonance (SPR experiments using synthetic lipids and recombinant proteins. We found that PtdInsPs interactions contribute to the cellular distribution of some PDZ domains, intriguingly also in nuclear organelles, and that a significant subgroup of PDZ domains interacts with PtdInsPs with affinities in the low-to-mid micromolar range. In vitro specificity for the head group is low, but with a trend of higher affinities for more phosphorylated PtdInsPs species. Other membrane lipids can assist PtdInsPs-interactions. PtdInsPs-interacting PDZ domains have generally high pI values and contain characteristic clusters of basic residues, hallmarks that may be used to predict additional PtdInsPs interacting PDZ domains. In tripartite binding experiments we established that peptide binding can either compete or cooperate with PtdInsPs binding depending on the combination of ligands. CONCLUSIONS/SIGNIFICANCE: Our screen substantially expands the set of PtdInsPs interacting PDZ domains, and shows that a full understanding of the biology of PDZ proteins will require a comprehensive insight into the intricate relationships between PDZ domains and their peptide and lipid ligands.

Importance of a Conserved Lys/Arg Residue for Ligand/PDZ Domain Interactions as Examined by Protein Semisynthesis

DEFF Research Database (Denmark)

Pedersen, Søren W; Moran, Griffin E; Sereikaité, Vita

2016-01-01

PDZ domains are ubiquitous small protein domains that are mediators of numerous protein-protein interactions, and play a pivotal role in protein trafficking, synaptic transmission, and the assembly of signaling-transduction complexes. In recent years, PDZ domains have emerged as novel and exciting...... drug targets for diseases (in the brain in particular), so understanding the molecular details of PDZ domain interactions is of fundamental importance. PDZ domains bind to a protein partner at either a C-terminal peptide or internal peptide motifs. Here, we examined the importance of a conserved Lys...

An in silico analysis of the binding modes and binding affinities of small molecule modulators of PDZ-peptide interactions.

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Garima Tiwari

Full Text Available Inhibitors of PDZ-peptide interactions have important implications in a variety of biological processes including treatment of cancer and Parkinson's disease. Even though experimental studies have reported characterization of peptidomimetic inhibitors of PDZ-peptide interactions, the binding modes for most of them have not been characterized by structural studies. In this study we have attempted to understand the structural basis of the small molecule-PDZ interactions by in silico analysis of the binding modes and binding affinities of a set of 38 small molecules with known K(i or K(d values for PDZ2 and PDZ3 domains of PSD-95 protein. These two PDZ domains show differential selectivity for these compounds despite having a high degree of sequence similarity and almost identical peptide binding pockets. Optimum binding modes for these ligands for PDZ2 and PDZ3 domains were identified by using a novel combination of semi-flexible docking and explicit solvent molecular dynamics (MD simulations. Analysis of the binding modes revealed most of the peptidomimectic ligands which had high K(i or K(d moved away from the peptide binding pocket, while ligands with high binding affinities remained in the peptide binding pocket. The differential specificities of the PDZ2 and PDZ3 domains primarily arise from differences in the conformation of the loop connecting βB and βC strands, because this loop interacts with the N-terminal chemical moieties of the ligands. We have also computed the MM/PBSA binding free energy values for these 38 compounds with both the PDZ domains from multiple 5 ns MD trajectories on each complex i.e. a total of 228 MD trajectories of 5 ns length each. Interestingly, computational binding free energies show good agreement with experimental binding free energies with a correlation coefficient of approximately 0.6. Thus our study demonstrates that combined use of docking and MD simulations can help in identification of potent inhibitors

Degradation of Human PDZ-Proteins by Human Alphapapillomaviruses Represents an Evolutionary Adaptation to a Novel Cellular Niche

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Van Doorslaer, Koenraad; DeSalle, Rob; Einstein, Mark H.; Burk, Robert D.

2015-01-01

In order to complete their life cycle, papillomaviruses have evolved to manipulate a plethora of cellular pathways. The products of the human Alphapapillomavirus E6 proteins specifically interact with and target PDZ containing proteins for degradation. This viral phenotype has been suggested to play a role in viral oncogenesis. To analyze the association of HPV E6 mediated PDZ-protein degradation with cervical oncogenesis, a high-throughput cell culture assay was developed. Degradation of an epitope tagged human MAGI1 isoform was visualized by immunoblot. The correlation between HPV E6-induced degradation of hMAGI1 and epidemiologically determined HPV oncogenicity was evaluated using a Bayesian approach within a phylogenetic context. All tested oncogenic types degraded the PDZ-containing protein hMAGI1d; however, E6 proteins isolated from several related albeit non-oncogenic viral types were equally efficient at degrading hMAGI1. The relationship between both traits (oncogenicity and PDZ degradation potential) is best explained by a model in which the potential to degrade PDZ proteins was acquired prior to the oncogenic phenotype. This analysis provides evidence that the ancestor of both oncogenic and non-oncogenic HPVs acquired the potential to degrade human PDZ-containing proteins. This suggests that HPV E6 directed degradation of PDZ-proteins represents an ancient ecological niche adaptation. Phylogenetic modeling indicates that this phenotype is not specifically correlated with oncogenic risk, but may act as an enabling phenotype. The role of PDZ protein degradation in HPV fitness and oncogenesis needs to be interpreted in the context of Alphapapillomavirus evolution. PMID:26086730

Degradation of Human PDZ-Proteins by Human Alphapapillomaviruses Represents an Evolutionary Adaptation to a Novel Cellular Niche.

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Koenraad Van Doorslaer

2015-06-01

Full Text Available In order to complete their life cycle, papillomaviruses have evolved to manipulate a plethora of cellular pathways. The products of the human Alphapapillomavirus E6 proteins specifically interact with and target PDZ containing proteins for degradation. This viral phenotype has been suggested to play a role in viral oncogenesis. To analyze the association of HPV E6 mediated PDZ-protein degradation with cervical oncogenesis, a high-throughput cell culture assay was developed. Degradation of an epitope tagged human MAGI1 isoform was visualized by immunoblot. The correlation between HPV E6-induced degradation of hMAGI1 and epidemiologically determined HPV oncogenicity was evaluated using a Bayesian approach within a phylogenetic context. All tested oncogenic types degraded the PDZ-containing protein hMAGI1d; however, E6 proteins isolated from several related albeit non-oncogenic viral types were equally efficient at degrading hMAGI1. The relationship between both traits (oncogenicity and PDZ degradation potential is best explained by a model in which the potential to degrade PDZ proteins was acquired prior to the oncogenic phenotype. This analysis provides evidence that the ancestor of both oncogenic and non-oncogenic HPVs acquired the potential to degrade human PDZ-containing proteins. This suggests that HPV E6 directed degradation of PDZ-proteins represents an ancient ecological niche adaptation. Phylogenetic modeling indicates that this phenotype is not specifically correlated with oncogenic risk, but may act as an enabling phenotype. The role of PDZ protein degradation in HPV fitness and oncogenesis needs to be interpreted in the context of Alphapapillomavirus evolution.

Degradation of Human PDZ-Proteins by Human Alphapapillomaviruses Represents an Evolutionary Adaptation to a Novel Cellular Niche.

Science.gov (United States)

Van Doorslaer, Koenraad; DeSalle, Rob; Einstein, Mark H; Burk, Robert D

2015-06-01

In order to complete their life cycle, papillomaviruses have evolved to manipulate a plethora of cellular pathways. The products of the human Alphapapillomavirus E6 proteins specifically interact with and target PDZ containing proteins for degradation. This viral phenotype has been suggested to play a role in viral oncogenesis. To analyze the association of HPV E6 mediated PDZ-protein degradation with cervical oncogenesis, a high-throughput cell culture assay was developed. Degradation of an epitope tagged human MAGI1 isoform was visualized by immunoblot. The correlation between HPV E6-induced degradation of hMAGI1 and epidemiologically determined HPV oncogenicity was evaluated using a Bayesian approach within a phylogenetic context. All tested oncogenic types degraded the PDZ-containing protein hMAGI1d; however, E6 proteins isolated from several related albeit non-oncogenic viral types were equally efficient at degrading hMAGI1. The relationship between both traits (oncogenicity and PDZ degradation potential) is best explained by a model in which the potential to degrade PDZ proteins was acquired prior to the oncogenic phenotype. This analysis provides evidence that the ancestor of both oncogenic and non-oncogenic HPVs acquired the potential to degrade human PDZ-containing proteins. This suggests that HPV E6 directed degradation of PDZ-proteins represents an ancient ecological niche adaptation. Phylogenetic modeling indicates that this phenotype is not specifically correlated with oncogenic risk, but may act as an enabling phenotype. The role of PDZ protein degradation in HPV fitness and oncogenesis needs to be interpreted in the context of Alphapapillomavirus evolution.

Structure function relations in PDZ-domain-containing proteins ...

Indian Academy of Sciences (India)

G P Manjunath

2017-12-30

Dec 30, 2017 ... Implications for protein networks in cellular signalling ..... However, surface plasmon resonance .... entiate between conformation changes in the PDZ domain or .... NHERF1, through long-range electrostatic and hydrophobic.

Characterization of diverse internal binding specificities of PDZ domains by yeast two-hybrid screening of a special peptide library.

Science.gov (United States)

Mu, Yi; Cai, Pengfei; Hu, Siqi; Ma, Sucan; Gao, Youhe

2014-01-01

Protein-protein interactions (PPIs) are essential events to play important roles in a series of biological processes. There are probably more ways of PPIs than we currently realized. Structural and functional investigations of weak PPIs have lagged behind those of strong PPIs due to technical difficulties. Weak PPIs are often short-lived, which may result in more dynamic signals with important biological roles within and/or between cells. For example, the characteristics of PSD-95/Dlg/ZO-1 (PDZ) domain binding to internal sequences, which are primarily weak interactions, have not yet been systematically explored. In the present study, we constructed a nearly random octapeptide yeast two-hybrid library. A total of 24 PDZ domains were used as baits for screening the library. Fourteen of these domains were able to bind internal PDZ-domain binding motifs (PBMs), and PBMs screened for nine PDZ domains exhibited strong preferences. Among 11 PDZ domains that have not been reported their internal PBM binding ability, six were confirmed to bind internal PBMs. The first PDZ domain of LNX2, which has not been reported to bind C-terminal PBMs, was found to bind internal PBMs. These results suggest that the internal PBMs binding ability of PDZ domains may have been underestimated. The data provided diverse internal binding properties for several PDZ domains that may help identify their novel binding partners.

Detailed regulatory mechanism of the interaction between ZO-1 PDZ2 and connexin43 revealed by MD simulations.

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Fei Xiao

Full Text Available The gap junction protein connexin43 (Cx43 binds to the second PDZ domain of Zonula occludens-1 (ZO-1 through its C-terminal tail, mediating the regulation of gap junction plaque size and dynamics. Biochemical study demonstrated that the very C-terminal 12 residues of Cx43 are necessary and sufficient for ZO-1 PDZ2 binding and phosphorylation at residues Ser (-9 and Ser (-10 of the peptide can disrupt the association. However, only a crystal structure of ZO-1 PDZ2 in complex with a shorter 9 aa peptide of connexin43 was solved experimentally. Here, the interactions between ZO-1 PDZ2 and the short, long and phosphorylated Cx43 peptides were studied using molecular dynamics (MD simulations and free energy calculation. The short peptide bound to PDZ2 exhibits large structural variations, while the extension of three upstream residues stabilizes the peptide conformation and enhanced the interaction. Phosphorylation at Ser(-9 significantly weakens the binding and results in conformational flexibility of the peptide. Glu210 of ZO-1 PDZ2 was found to be a key regulatory point in Cx43 binding and phosphorylation induced dissociation.

Common features in the unfolding and misfolding of PDZ domains and beyond: the modulatory effect of domain swapping and extra-elements.

Science.gov (United States)

Murciano-Calles, Javier; Güell-Bosch, Jofre; Villegas, Sandra; Martinez, Jose C

2016-01-12

PDZ domains are protein-protein interaction modules sharing the same structural arrangement. To discern whether they display common features in their unfolding/misfolding behaviour we have analyzed in this work the unfolding thermodynamics, together with the misfolding kinetics, of the PDZ fold using three archetypical examples: the second and third PDZ domains of the PSD95 protein and the Erbin PDZ domain. Results showed that all domains passed through a common intermediate, which populated upon unfolding, and that this in turn drove the misfolding towards worm-like fibrillar structures. Thus, the unfolding/misfolding behaviour appears to be shared within these domains. We have also analyzed how this landscape can be modified upon the inclusion of extra-elements, as it is in the nNOS PDZ domain, or the organization of swapped species, as happens in the second PDZ domain of the ZO2 protein. Although the intermediates still formed upon thermal unfolding, the misfolding was prevented to varying degrees.

Insights into the molecular evolution of the PDZ/LIM family and identification of a novel conserved protein motif.

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Aartjan J W Te Velthuis

Full Text Available The PDZ and LIM domain-containing protein family is encoded by a diverse group of genes whose phylogeny has currently not been analyzed. In mammals, ten genes are found that encode both a PDZ- and one or several LIM-domains. These genes are: ALP, RIL, Elfin (CLP36, Mystique, Enigma (LMP-1, Enigma homologue (ENH, ZASP (Cypher, Oracle, LMO7 and the two LIM domain kinases (LIMK1 and LIMK2. As conventional alignment and phylogenetic procedures of full-length sequences fell short of elucidating the evolutionary history of these genes, we started to analyze the PDZ and LIM domain sequences themselves. Using information from most sequenced eukaryotic lineages, our phylogenetic analysis is based on full-length cDNA-, EST-derived- and genomic- PDZ and LIM domain sequences of over 25 species, ranging from yeast to humans. Plant and protozoan homologs were not found. Our phylogenetic analysis identifies a number of domain duplication and rearrangement events, and shows a single convergent event during evolution of the PDZ/LIM family. Further, we describe the separation of the ALP and Enigma subfamilies in lower vertebrates and identify a novel consensus motif, which we call 'ALP-like motif' (AM. This motif is highly-conserved between ALP subfamily proteins of diverse organisms. We used here a combinatorial approach to define the relation of the PDZ and LIM domain encoding genes and to reconstruct their phylogeny. This analysis allowed us to classify the PDZ/LIM family and to suggest a meaningful model for the molecular evolution of the diverse gene architectures found in this multi-domain family.

Computational design of selective peptides to discriminate between similar PDZ domains in an oncogenic pathway.

Science.gov (United States)

Zheng, Fan; Jewell, Heather; Fitzpatrick, Jeremy; Zhang, Jian; Mierke, Dale F; Grigoryan, Gevorg

2015-01-30

Reagents that target protein-protein interactions to rewire signaling are of great relevance in biological research. Computational protein design may offer a means of creating such reagents on demand, but methods for encoding targeting selectivity are sorely needed. This is especially challenging when targeting interactions with ubiquitous recognition modules--for example, PDZ domains, which bind C-terminal sequences of partner proteins. Here we consider the problem of designing selective PDZ inhibitor peptides in the context of an oncogenic signaling pathway, in which two PDZ domains (NHERF-2 PDZ2-N2P2 and MAGI-3 PDZ6-M3P6) compete for a receptor C-terminus to differentially modulate oncogenic activities. Because N2P2 has been shown to increase tumorigenicity and M3P6 to decreases it, we sought to design peptides that inhibit N2P2 without affecting M3P6. We developed a structure-based computational design framework that models peptide flexibility in binding yet is efficient enough to rapidly analyze tradeoffs between affinity and selectivity. Designed peptides showed low-micromolar inhibition constants for N2P2 and no detectable M3P6 binding. Peptides designed for reverse discrimination bound M3P6 tighter than N2P2, further testing our technology. Experimental and computational analysis of selectivity determinants revealed significant indirect energetic coupling in the binding site. Successful discrimination between N2P2 and M3P6, despite their overlapping binding preferences, is highly encouraging for computational approaches to selective PDZ targeting, especially because design relied on a homology model of M3P6. Still, we demonstrate specific deficiencies of structural modeling that must be addressed to enable truly robust design. The presented framework is general and can be applied in many scenarios to engineer selective targeting. Copyright © 2014 Elsevier Ltd. All rights reserved.

The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses

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Garcia, Rolando A. G.; Vasudevan, Kuzhalini; Buonanno, Andres

2000-01-01

Neuregulins regulate the expression of ligand- and voltage-gated channels in neurons and skeletal muscle by the activation of their cognate tyrosine kinase receptors, ErbB 1–4. The subcellular distribution and mechanisms that regulate the localization of ErbB receptors are unknown. We have found that ErbB receptors are present in brain subcellular fractions enriched for postsynaptic densities (PSD). The ErbB-4 receptor is unique among the ErbB proteins because its C-terminal tail (T-V-V) conforms to a sequence that binds to a protein motif known as the PDZ domain. Using the yeast two-hybrid system, we found that the C-terminal region of ErbB-4 interacts with the three related membrane-associated guanylate kinases (MAGUKs) PSD-95/SAP90, PSD-93/chapsyn-110, and SAP 102, which harbor three PDZ domains, as well as with β2-syntrophin, which has a single PDZ domain. As with N-methyl-d-aspartate (NMDA) receptors, ErbB4 interacts with the first two PDZ domains of PSD-95. Using coimmunoprecipitation assays, we confirmed the direct interactions between ErbB-4 and PSD-95 in transfected heterologous cells, as well as in vivo, where both proteins are coimmunoprecipitated from brain lysates. Moreover, evidence for colocalization of these proteins was also observed by immunofluorescence in cultured hippocampal neurons. ErbB-4 colocalizes with PSD-95 and NMDA receptors at a subset of excitatory synapses apposed to synaptophysin-positive presynaptic terminals. The capacity of ErbB receptors to interact with PDZ-domain proteins at cell junctions is conserved from invertebrates to mammals. As discussed, the interactions found between receptor tyrosine kinases and MAGUKs at neuronal synapses may have important implications for activity-dependent plasticity. PMID:10725395

A fluorescence polarization based screening assay for identification of small molecule inhibitors of the PICK1 PDZ domain

DEFF Research Database (Denmark)

Thorsen, Thor S; Madsen, Kenneth L; Dyhring, Tino

2011-01-01

PDZ (PSD-95/Discs-large/ZO-1 homology) domains represent putative targets in several diseases including cancer, stroke, addiction and neuropathic pain. Here we describe the application of a simple and fast screening assay based on fluorescence polarization (FP) to identify inhibitors of the PDZ...

Oracle, a novel PDZ-LIM domain protein expressed in heart and skeletal muscle.

Science.gov (United States)

Passier, R; Richardson, J A; Olson, E N

2000-04-01

In order to identify novel genes enriched in adult heart, we performed a subtractive hybridization for genes expressed in mouse heart but not in skeletal muscle. We identified two alternative splicing variants of a novel PDZ-LIM domain protein, which we named Oracle. Both variants contain a PDZ domain at the amino-terminus and three LIM domains at the carboxy-terminus. Highest homology of Oracle was found with the human and rat enigma proteins in the PDZ domain (62 and 61%, respectively) and in the LIM domains (60 and 69%, respectively). By Northern hybridization analysis, we showed that expression is highest in adult mouse heart, low in skeletal muscle and undetectable in other adult mouse tissues. In situ hybridization in mouse embryos confirmed and extended these data by showing high expression of Oracle mRNA in atrial and ventricular myocardial cells from E8.5. From E9.5 low expression of Oracle mRNA was detectable in myotomes. These data suggest a role for Oracle in the early development and function of heart and skeletal muscle.

The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity

International Nuclear Information System (INIS)

Shimomura, Tadanori; Miyamura, Norio; Hata, Shoji; Miura, Ryota; Hirayama, Jun; Nishina, Hiroshi

2014-01-01

Highlights: •Loss of the PDZ-binding motif inhibits constitutively active YAP (5SA)-induced oncogenic cell transformation. •The PDZ-binding motif of YAP promotes its nuclear localization in cultured cells and mouse liver. •Loss of the PDZ-binding motif inhibits YAP (5SA)-induced CTGF transcription in cultured cells and mouse liver. -- Abstract: YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains a highly conserved PDZ-binding motif that regulates YAP’s functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP’s co-activation of TEAD-mediated CTGF transcription

The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity

Energy Technology Data Exchange (ETDEWEB)

Shimomura, Tadanori; Miyamura, Norio; Hata, Shoji; Miura, Ryota; Hirayama, Jun, E-mail: hirayama.dbio@mri.tmd.ac.jp; Nishina, Hiroshi, E-mail: nishina.dbio@mri.tmd.ac.jp

2014-01-17

Highlights: •Loss of the PDZ-binding motif inhibits constitutively active YAP (5SA)-induced oncogenic cell transformation. •The PDZ-binding motif of YAP promotes its nuclear localization in cultured cells and mouse liver. •Loss of the PDZ-binding motif inhibits YAP (5SA)-induced CTGF transcription in cultured cells and mouse liver. -- Abstract: YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains a highly conserved PDZ-binding motif that regulates YAP’s functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP’s co-activation of TEAD-mediated CTGF transcription.

Corticotropin-Releasing Hormone Receptor Type 1 (CRHR1 Clustering with MAGUKs Is Mediated via Its C-Terminal PDZ Binding Motif.

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Julia Bender

Full Text Available The corticotropin-releasing hormone receptor type 1 (CRHR1 plays an important role in orchestrating neuroendocrine, behavioral, and autonomic responses to stress. To identify molecules capable of directly modulating CRHR1 signaling, we performed a yeast-two-hybrid screen using the C-terminal intracellular tail of the receptor as bait. We identified several members of the membrane-associated guanylate kinase (MAGUK family: postsynaptic density protein 95 (PSD95, synapse-associated protein 97 (SAP97, SAP102 and membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2. CRHR1 is co-expressed with the identified MAGUKs and with the additionally investigated PSD93 in neurons of the adult mouse brain and in primary hippocampal neurons, supporting the probability of a physiological interaction in vivo. The C-terminal PDZ (PSD-95, discs large, zona occludens 1 binding motif of CRHR1 is essential for its physical interaction with MAGUKs, as revealed by the CRHR1-STAVA mutant, which harbors a functionally impaired PDZ binding motif. The imitation of a phosphorylation at Thr413 within the PDZ binding motif also disrupted the interaction with MAGUKs. In contrast, distinct PDZ domains within the identified MAGUKs are involved in the interactions. Expression of CRHR1 in primary neurons demonstrated its localization throughout the neuronal plasma membrane, including the excitatory post synapse, where the receptor co-localized with PSD95 and SAP97. The co-expression of CRHR1 and respective interacting MAGUKs in HEK293 cells resulted in a clustered subcellular co-localization which required an intact PDZ binding motif. In conclusion, our study characterized the PDZ binding motif-mediated interaction of CRHR1 with multiple MAGUKs, which directly affects receptor function.

Surface targeting of the dopamine transporter involves discrete epitopes in the distal C terminus but does not require canonical PDZ domain interactions.

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Bjerggaard, Christian; Fog, Jacob U; Hastrup, Hanne; Madsen, Kenneth; Loland, Claus J; Javitch, Jonathan A; Gether, Ulrik

2004-08-04

The human dopamine transporter (hDAT) contains a C-terminal type 2 PDZ (postsynaptic density 95/Discs large/zona occludens 1) domain-binding motif (LKV) known to interact with PDZ domain proteins such as PICK1 (protein interacting with C-kinase 1). As reported previously, we found that, after deletion of this motif, hDAT was retained in the endoplasmic reticulum (ER) of human embryonic kidney (HEK) 293 and Neuro2A cells, suggesting that PDZ domain interactions might be critical for hDAT targeting. Nonetheless, substitution of LKV with SLL, the type 1 PDZ-binding sequence from the beta2-adrenergic receptor, did not disrupt plasma membrane targeting. Moreover, the addition of an alanine to the hDAT C terminus (+Ala), resulting in an LKVA termination sequence, or substitution of LKV with alanines (3xAla_618-620) prevented neither plasma membrane targeting nor targeting into sprouting neurites of differentiated N2A cells. The inability of +Ala and 3xAla_618-620 to bind PDZ domains was confirmed by lack of colocalization with PICK1 in cotransfected HEK293 cells and by the inability of corresponding C-terminal fusion proteins to pull down purified PICK1. Thus, although residues in the hDAT C terminus are indispensable for proper targeting, PDZ domain interactions are not required. By progressive substitutions with beta2-adrenergic receptor sequence, and by triple-alanine substitutions in the hDAT C terminus, we examined the importance of epitopes preceding the LKV motif. Substitution of RHW(615-617) with alanines caused retention of the transporter in the ER despite preserved ability of this mutant to bind PICK1. We propose dual roles of the hDAT C terminus: a role independent of PDZ interactions for ER export and surface targeting, and a not fully clarified role involving PDZ interactions with proteins such as PICK1.

Contribution of buried aspartic acid to the stability of the PDZ2 protein

International Nuclear Information System (INIS)

Jayasimha, Pruthvi; Shanmuganathan, Aranganathan; Suladze, Saba; Makhatadze, George I.

2012-01-01

Highlights: ► Buried Asp residues on average form 2.5 to 3 hydrogen bonds and/or 0.8 salt bridges. ► Contribution of buried Asp to stability was estimated using model protein PDZ2. ► The energetic contribution of Asp56 to PDZ2 stability estimated to be 18 kJ · mol −1 . ► Findings are discussed in terms of contribution of Asp residues to protein stability. - Abstract: Statistical analysis of protein structures shows that buried aspartic acid residues on average form 2.5 to 3 hydrogen bonds and/or 0.8 potential ionic interactions with other protein groups. To estimate the energetic contribution of such buried groups to the Gibbs free energy of proteins, we measured the effects of amino acid substitutions of D56 in a model protein PDZ2 on its stability. We used temperature-induced unfolding monitored by DSC and denaturant-induced unfolding monitored by the changes in fluorescence intensity. We find that all substitutions of D56 lead to protein unfolding, thus suggesting that this buried hydrogen bonded aspartic acid has a significant contribution to the stability. To quantify the changes in the Gibbs free energy, one of the variants, D56N was stabilized by addition of the protective osmolyte TMAO. Comparison of the stability of the D56N variant with the wild-type PDZ2 in the presence and absence of TMAO allowed us to estimate the contribution of D56 to the protein stability to be 18 kJ · mol −1 . These findings are discussed in terms of contribution of buried ionizable groups to protein stability.

An expanded view of the protein folding landscape of PDZ domains

DEFF Research Database (Denmark)

Hultqvist, Greta; Pedersen, Søren W; Chi, Celestine N.

2012-01-01

state. In light of these results, we have re-analyzed previous folding data on PDZ domains and present a unified folding mechanism with three distinct transition states separated by two high-energy intermediates. Our data show that sequence composition tunes the relative stabilities of folding...

PDZ-containing proteins: alternative splicing as a source of functional diversity.

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Sierralta, Jimena; Mendoza, Carolina

2004-12-01

Scaffold proteins allow specific protein complexes to be assembled in particular regions of the cell at which they organize subcellular structures and signal transduction complexes. This characteristic is especially important for neurons, which are highly polarized cells. Among the domains contained by scaffold proteins, the PSD-95, Discs-large, ZO-1 (PDZ) domains are of particular relevance in signal transduction processes and maintenance of neuronal and epithelial polarity. These domains are specialized in the binding of the carboxyl termini of proteins allowing membrane proteins to be localized by the anchoring to the cytoskeleton mediated by PDZ-containing scaffold proteins. In vivo studies carried out in Drosophila have taught that the role of many scaffold proteins is not limited to a single process; thus, in many cases the same genes are expressed in different tissues and participate in apparently very diverse processes. In addition to the differential expression of interactors of scaffold proteins, the expression of variants of these molecular scaffolds as the result of the alternative processing of the genes that encode them is proving to be a very important source of variability and complexity on a main theme. Alternative splicing in the nervous system is well documented, where specific isoforms play roles in neurotransmission, ion channel function, neuronal cell recognition, and are developmentally regulated making it a major mechanism of functional diversity. Here we review the current state of knowledge about the diversity and the known function of PDZ-containing proteins in Drosophila with emphasis in the role played by alternatively processed forms in the diversity of functions attributed to this family of proteins.

G protein-coupled estrogen receptor 1 (GPER1)/GPR30 increases ERK1/2 activity through PDZ motif-dependent and -independent mechanisms.

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Gonzalez de Valdivia, Ernesto; Broselid, Stefan; Kahn, Robin; Olde, Björn; Leeb-Lundberg, L M Fredrik

2017-06-16

G protein-coupled receptor 30 (GPR30), also called G protein-coupled estrogen receptor 1 (GPER1), is thought to play important roles in breast cancer and cardiometabolic regulation, but many questions remain about ligand activation, effector coupling, and subcellular localization. We showed recently that GPR30 interacts through the C-terminal type I PDZ motif with SAP97 and protein kinase A (PKA)-anchoring protein (AKAP) 5, which anchor the receptor in the plasma membrane and mediate an apparently constitutive decrease in cAMP production independently of G i/o Here, we show that GPR30 also constitutively increases ERK1/2 activity. Removing the receptor PDZ motif or knocking down specifically AKAP5 inhibited the increase, showing that this increase also requires the PDZ interaction. However, the increase was inhibited by pertussis toxin as well as by wortmannin but not by AG1478, indicating that G i/o and phosphoinositide 3-kinase (PI3K) mediate the increase independently of epidermal growth factor receptor transactivation. FK506 and okadaic acid also inhibited the increase, implying that a protein phosphatase is involved. The proposed GPR30 agonist G-1 also increased ERK1/2 activity, but this increase was only observed at a level of receptor expression below that required for the constitutive increase. Furthermore, deleting the PDZ motif did not inhibit the G-1-stimulated increase. Based on these results, we propose that GPR30 increases ERK1/2 activity via two G i/o -mediated mechanisms, a PDZ-dependent, apparently constitutive mechanism and a PDZ-independent G-1-stimulated mechanism. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The PDZ motif of the α1C subunit is not required for surface trafficking and adrenergic modulation of CaV1.2 channel in the heart.

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Yang, Lin; Katchman, Alexander; Weinberg, Richard L; Abrams, Jeffrey; Samad, Tahmina; Wan, Elaine; Pitt, Geoffrey S; Marx, Steven O

2015-01-23

Voltage-gated Ca(2+) channels play a key role in initiating muscle excitation-contraction coupling, neurotransmitter release, gene expression, and hormone secretion. The association of CaV1.2 with a supramolecular complex impacts trafficking, localization, turnover, and, most importantly, multifaceted regulation of its function in the heart. Several studies hint at an important role for the C terminus of the α1C subunit as a hub for multidimensional regulation of CaV1.2 channel trafficking and function. Recent studies have demonstrated an important role for the four-residue PDZ binding motif at the C terminus of α1C in interacting with scaffold proteins containing PDZ domains, in the subcellular localization of CaV1.2 in neurons, and in the efficient signaling to cAMP-response element-binding protein in neurons. However, the role of the α1C PDZ ligand domain in the heart is not known. To determine whether the α1C PDZ motif is critical for CaV1.2 trafficking and function in cardiomyocytes, we generated transgenic mice with inducible expression of an N-terminal FLAG epitope-tagged dihydropyridine-resistant α1C with the PDZ motif deleted (ΔPDZ). These mice were crossed with α-myosin heavy chain reverse transcriptional transactivator transgenic mice, and the double-transgenic mice were fed doxycycline. The ΔPDZ channels expressed, trafficked to the membrane, and supported robust excitation-contraction coupling in the presence of nisoldipine, a dihydropyridine Ca(2+) channel blocker, providing functional evidence that they appropriately target to dyads. The ΔPDZ Ca(2+) channels were appropriately regulated by isoproterenol and forskolin. These data indicate that the α1C PDZ motif is not required for surface trafficking, localization to the dyad, or adrenergic stimulation of CaV1.2 in adult cardiomyocytes. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Change in Allosteric Network Affects Binding Affinities of PDZ Domains: Analysis through Perturbation Response Scanning

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Gerek, Z. Nevin; Ozkan, S. Banu

2011-01-01

The allosteric mechanism plays a key role in cellular functions of several PDZ domain proteins (PDZs) and is directly linked to pharmaceutical applications; however, it is a challenge to elaborate the nature and extent of these allosteric interactions. One solution to this problem is to explore the dynamics of PDZs, which may provide insights about how intramolecular communication occurs within a single domain. Here, we develop an advancement of perturbation response scanning (PRS) that couples elastic network models with linear response theory (LRT) to predict key residues in allosteric transitions of the two most studied PDZs (PSD-95 PDZ3 domain and hPTP1E PDZ2 domain). With PRS, we first identify the residues that give the highest mean square fluctuation response upon perturbing the binding sites. Strikingly, we observe that the residues with the highest mean square fluctuation response agree with experimentally determined residues involved in allosteric transitions. Second, we construct the allosteric pathways by linking the residues giving the same directional response upon perturbation of the binding sites. The predicted intramolecular communication pathways reveal that PSD-95 and hPTP1E have different pathways through the dynamic coupling of different residue pairs. Moreover, our analysis provides a molecular understanding of experimentally observed hidden allostery of PSD-95. We show that removing the distal third alpha helix from the binding site alters the allosteric pathway and decreases the binding affinity. Overall, these results indicate that (i) dynamics plays a key role in allosteric regulations of PDZs, (ii) the local changes in the residue interactions can lead to significant changes in the dynamics of allosteric regulations, and (iii) this might be the mechanism that each PDZ uses to tailor their binding specificities regulation. PMID:21998559

The PDZ domain of the guanine nucleotide exchange factor PDZGEF directs binding to phosphatidic acid during brush border formation.

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Sarah V Consonni

Full Text Available PDZGEF is a guanine nucleotide exchange factor for the small G protein Rap. It was recently found that PDZGEF contributes to establishment of intestinal epithelial polarity downstream of the kinase Lkb1. By binding to phosphatidic acid enriched at the apical membrane, PDZGEF locally activates Rap2a resulting in induction of brush border formation via a pathway that includes the polarity players TNIK, Mst4 and Ezrin. Here we show that the PDZ domain of PDZGEF is essential and sufficient for targeting PDZGEF to the apical membrane of polarized intestinal epithelial cells. Inhibition of PLD and consequently production of phosphatidic acid inhibitis targeting of PDZGEF to the plasma membrane. Furthermore, localization requires specific positively charged residues within the PDZ domain. We conclude that local accumulation of PDZGEF at the apical membrane during establishment of epithelial polarity is mediated by electrostatic interactions between positively charged side chains in the PDZ domain and negatively charged phosphatidic acid.

The Role of Backbone Hydrogen Bonds in the Transition State for Protein Folding of a PDZ Domain.

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Søren W. Pedersen

Full Text Available Backbone hydrogen bonds are important for the structure and stability of proteins. However, since conventional site-directed mutagenesis cannot be applied to perturb the backbone, the contribution of these hydrogen bonds in protein folding and stability has been assessed only for a very limited set of small proteins. We have here investigated effects of five amide-to-ester mutations in the backbone of a PDZ domain, a 90-residue globular protein domain, to probe the influence of hydrogen bonds in a β-sheet for folding and stability. The amide-to-ester mutation removes NH-mediated hydrogen bonds and destabilizes hydrogen bonds formed by the carbonyl oxygen. The overall stability of the PDZ domain generally decreased for all amide-to-ester mutants due to an increase in the unfolding rate constant. For this particular region of the PDZ domain, it is therefore clear that native hydrogen bonds are formed after crossing of the rate-limiting barrier for folding. Moreover, three of the five amide-to-ester mutants displayed an increase in the folding rate constant suggesting that the hydrogen bonds are involved in non-native interactions in the transition state for folding.

ER EXPORT AND SURFACE TARGETING OF THE DOPAMINE TRANSPORTER ARE DEPENDENT ON THE DISTAL C-TERMINUS BUT OCCURS INDEPENDENTLY OF PDZ DOMAIN INTERACTIONS

DEFF Research Database (Denmark)

Bjerggaard(Vægter), Christian; Loland, Claus; Hastrup, Hanne

. Neuron 2001, 30:121-34). As expected, we find that deletion of the PDZ binding sequence (LKV) or substitution with three histidines resulted in retention of hDAT in the ER in both HEK293 and N2A neuroblastoma cells. However, substitution of LKV with the type 2 PDZ binding sequence SLL of the beta2...

The Human Papillomavirus E6 PDZ Binding Motif: From Life Cycle to Malignancy

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Ketaki Ganti

2015-07-01

Full Text Available Cancer-causing HPV E6 oncoproteins are characterized by the presence of a PDZ binding motif (PBM at their extreme carboxy terminus. It was long thought that this region of E6 had a sole function to confer interaction with a defined set of cellular substrates. However, more recent studies have shown that the E6 PBM has a complex pattern of regulation, whereby phosphorylation within the PBM can regulate interaction with two classes of cellular proteins: those containing PDZ domains and the members of the 14-3-3 family of proteins. In this review, we explore the roles that the PBM and its ligands play in the virus life cycle, and subsequently how these can inadvertently contribute towards the development of malignancy. We also explore how subtle alterations in cellular signal transduction pathways might result in aberrant E6 phosphorylation, which in turn might contribute towards disease progression.

PDZ domain-mediated interactions of G protein-coupled receptors with postsynaptic density protein 95

DEFF Research Database (Denmark)

Møller, Thor C; Wirth, Volker F; Roberts, Nina Ingerslev

2013-01-01

G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome. Their signaling is regulated by scaffold proteins containing PDZ domains, but although these interactions are important for GPCR function, they are still poorly understood. We here present...

A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter

DEFF Research Database (Denmark)

Rickhag, Karl Mattias; Hansen, Freja Herborg; Sørensen, Gunnar

2013-01-01

believed to bind synaptic scaffolding proteins, but its functional significance is uncertain. Here we demonstrate that two different dopamine transporter knock-in mice with disrupted PDZ-binding motifs (dopamine transporter-AAA and dopamine transporter+Ala) are characterized by dramatic loss of dopamine......The dopamine transporter mediates reuptake of dopamine from the synaptic cleft. The cellular mechanisms controlling dopamine transporter levels in striatal nerve terminals remain poorly understood. The dopamine transporters contain a C-terminal PDZ (PSD-95/Discs-large/ZO-1) domain-binding sequence...... transporter expression in the striatum, causing hyperlocomotion and attenuated response to amphetamine. In cultured dopaminergic neurons and striatal slices from dopamine transporter-AAA mice, we find markedly reduced dopamine transporter surface levels and evidence for enhanced constitutive internalization...

The PDZ Ligand Domain of the Human Papillomavirus Type 16 E6 Protein Is Required for E6's Induction of Epithelial Hyperplasia In Vivo

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Nguyen, Marie L.; Nguyen, Minh M.; Lee, Denis; Griep, Anne E.; Lambert, Paul F.

2003-01-01

Human papillomaviruses (HPVs) are the causative agent of warts. Infections with high-risk HPVs are associated with anogenital and head and neck cancers. One of the viral genes responsible for HPV's oncogenic activity is E6. Mice expressing the HPV-16 E6 protein in their epidermis (K14E6WT) develop epithelial hyperplasia and squamous carcinomas. Numerous cellular proteins interact with E6, some of which can be grouped based on common amino acid motifs in their E6-binding domains. One such group, the PDZ partners, including hDLG, hSCRIBBLE, MUPP1, and MAGI, bind to the carboxy-terminal four amino acids of E6 through their PDZ domains. E6's interaction with the PDZ partners leads to their degradation. Additionally, E6's binding to PDZ proteins has been correlated with its ability to transform baby rat kidney cells in tissue culture and to confer tumorigenicity onto cells in xenograft experiments. To address whether the ability of E6 to bind PDZ domain partners is necessary for E6 to confer epithelial hyperproliferation in vivo, we generated transgenic mice that express in stratified squamous epithelia a mutant of E6 lacking the last six amino acids at its carboxyl terminus, E6Δ146-151, from the human keratin 14 (K14) promoter. The K14E6Δ146-151 mice exhibit a radiation response similar to that of the K14E6WT mice, demonstrating that this protein, as predicted, retains an ability to inactivate p53. However, the K14E6Δ146-151 mice fail to display epithelial hyperplasia. These results indicate that an interaction of E6 with PDZ partners is necessary for its induction of epithelial hyperplasia. PMID:12768014

Analysis of the PDZ binding specificities of Influenza A Virus NS1 proteins

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Nagasaka Kazunori

2011-01-01

Full Text Available Abstract The Influenza A virus non-structural protein 1 (NS1 is a multifunctional virulence factor with several protein-protein interaction domains, involved in preventing apoptosis of the infected cell and in evading the interferon response. In addition, the majority of influenza A virus NS1 proteins have a class I PDZ-binding motif at the C-terminus, and this itself has been shown to be a virulence determinant. In the majority of human influenza NS1 proteins the consensus motif is RSxV: in avian NS1 it is ESxV. Of the few human strains that have the avian motif, all were from very high mortality outbreaks of the disease. Previous work has shown that minor differences in PDZ-binding motifs can have major effects on the spectrum of cellular proteins targeted. In this study we analyse the effect of these differences upon the binding of Influenza A virus NS1 protein to a range of cellular proteins involved in polarity and signal transduction.

A PDZ-Like Motif in the Biliary Transporter ABCB4 Interacts with the Scaffold Protein EBP50 and Regulates ABCB4 Cell Surface Expression.

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Quitterie Venot

Full Text Available ABCB4/MDR3, a member of the ABC superfamily, is an ATP-dependent phosphatidylcholine translocator expressed at the canalicular membrane of hepatocytes. Defects in the ABCB4 gene are associated with rare biliary diseases. It is essential to understand the mechanisms of its canalicular membrane expression in particular for the development of new therapies. The stability of several ABC transporters is regulated through their binding to PDZ (PSD95/DglA/ZO-1 domain-containing proteins. ABCB4 protein ends by the sequence glutamine-asparagine-leucine (QNL, which shows some similarity to PDZ-binding motifs. The aim of our study was to assess the potential role of the QNL motif on the surface expression of ABCB4 and to determine if PDZ domain-containing proteins are involved. We found that truncation of the QNL motif decreased the stability of ABCB4 in HepG2-transfected cells. The deleted mutant ABCB4-ΔQNL also displayed accelerated endocytosis. EBP50, a PDZ protein highly expressed in the liver, strongly colocalized and coimmunoprecipitated with ABCB4, and this interaction required the QNL motif. Down-regulation of EBP50 by siRNA or by expression of an EBP50 dominant-negative mutant caused a significant decrease in the level of ABCB4 protein expression, and in the amount of ABCB4 localized at the canalicular membrane. Interaction of ABCB4 with EBP50 through its PDZ-like motif plays a critical role in the regulation of ABCB4 expression and stability at the canalicular plasma membrane.

Discovery of novel interacting partners of PSMD9, a proteasomal chaperone: Role of an Atypical and versatile PDZ-domain motif interaction and identification of putative functional modules

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Nikhil Sangith

2014-01-01

Full Text Available PSMD9 (Proteasome Macropain non-ATPase subunit 9, a proteasomal assembly chaperone, harbors an uncharacterized PDZ-like domain. Here we report the identification of five novel interacting partners of PSMD9 and provide the first glimpse at the structure of the PDZ-domain, including the molecular details of the interaction. We based our strategy on two propositions: (a proteins with conserved C-termini may share common functions and (b PDZ domains interact with C-terminal residues of proteins. Screening of C-terminal peptides followed by interactions using full-length recombinant proteins, we discovered hnRNPA1 (an RNA binding protein, S14 (a ribosomal protein, CSH1 (a growth hormone, E12 (a transcription factor and IL6 receptor as novel PSMD9-interacting partners. Through multiple techniques and structural insights, we clearly demonstrate for the first time that human PDZ domain interacts with the predicted Short Linear Sequence Motif (SLIM at the C-termini of the client proteins. These interactions are also recapitulated in mammalian cells. Together, these results are suggestive of the role of PSMD9 in transcriptional regulation, mRNA processing and editing, hormone and receptor activity and protein translation. Our proof-of-principle experiments endorse a novel and quick method for the identification of putative interacting partners of similar PDZ-domain proteins from the proteome and for discovering novel functions.

Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ/PSD-95-PDZ interactions

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Bach, Anders

2015-01-01

ZL006 and IC87201 have been presented as efficient inhibitors of the nNOS/PSD-95 protein-protein interaction and shown great promise in cellular experiments and animal models of ischemic stroke and pain. Here, we investigate the proposed mechanism of action of ZL006 and IC87201 using biochemical...... by interacting with the β-finger of nNOS-PDZ. Our findings have implications for further medicinal chemistry efforts of ZL006, IC87201 and analogues, and challenge the general and widespread view on their mechanism of action....

Site-Specific Phosphorylation of PSD-95 PDZ Domains Reveals Fine-Tuned Regulation of Protein-Protein Interactions

DEFF Research Database (Denmark)

Pedersen, Søren W; Albertsen, Louise; Moran, Griffin E

2017-01-01

The postsynaptic density protein of 95 kDa (PSD-95) is a key scaffolding protein that controls signaling at synapses in the brain through interactions of its PDZ domains with the C-termini of receptors, ion channels, and enzymes. PSD-95 is highly regulated by phosphorylation. To explore the effec...

The PDZ protein GIPC regulates trafficking of the LPA1 receptor from APPL signaling endosomes and attenuates the cell's response to LPA.

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Tal Varsano

Full Text Available Lysophosphatidic acid (LPA mediates diverse cellular responses through the activation of at least six LPA receptors--LPA(1-6, but the interacting proteins and signaling pathways that mediate the specificity of these receptors are largely unknown. We noticed that LPA(1 contains a PDZ binding motif (SVV identical to that present in two other proteins that interact with the PDZ protein GIPC. GIPC is involved in endocytic trafficking of several receptors including TrkA, VEGFR2, lutropin and dopamine D2 receptors. Here we show that GIPC binds directly to the PDZ binding motif of LPA(1 but not that of other LPA receptors. LPA(1 colocalizes and coimmunoprecipitates with GIPC and its binding partner APPL, an activator of Akt signaling found on APPL signaling endosomes. GIPC depletion by siRNA disturbed trafficking of LPA(1 to EEA1 early endosomes and promoted LPA(1 mediated Akt signaling, cell proliferation, and cell motility. We propose that GIPC binds LPA(1 and promotes its trafficking from APPL-containing signaling endosomes to EEA1 early endosomes and thus attenuates LPA-mediated Akt signaling from APPL endosomes.

PDZ domain-binding motif of Tax sustains T-cell proliferation in HTLV-1-infected humanized mice

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Artesi, Maria; Jalinot, Pierre

2018-01-01

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive malignant proliferation of activated CD4+ T lymphocytes. The viral Tax oncoprotein is critically involved in both HTLV-1-replication and T-cell proliferation, a prerequisite to the development of ATLL. In this study, we investigated the in vivo contribution of the Tax PDZ domain-binding motif (PBM) to the lymphoproliferative process. To that aim, we examined T-cell proliferation in humanized mice (hu-mice) carrying a human hemato-lymphoid system infected with either a wild type (WT) or a Tax PBM-deleted (ΔPBM) provirus. We observed that the frequency of CD4+ activated T-cells in the peripheral blood and in the spleen was significantly higher in WT than in ΔPBM hu-mice. Likewise, human T-cells collected from WT hu-mice and cultivated in vitro in presence of interleukin-2 were proliferating at a higher level than those from ΔPBM animals. We next examined the association of Tax with the Scribble PDZ protein, a prominent regulator of T-cell polarity, in human T-cells analyzed either after ex vivo isolation or after in vitro culture. We confirmed the interaction of Tax with Scribble only in T-cells from the WT hu-mice. This association correlated with the presence of both proteins in aggregates at the leading edge of the cells and with the formation of long actin filopods. Finally, data from a comparative genome-wide transcriptomic analysis suggested that the PBM-PDZ association is implicated in the expression of genes regulating proliferation, apoptosis and cytoskeletal organization. Collectively, our findings suggest that the Tax PBM is an auxiliary motif that contributes to the sustained growth of HTLV-1 infected T-cells in vivo and in vitro and is essential to T-cell immortalization. PMID:29566098

PDZ domain-binding motif of Tax sustains T-cell proliferation in HTLV-1-infected humanized mice.

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Pérès, Eléonore; Blin, Juliana; Ricci, Emiliano P; Artesi, Maria; Hahaut, Vincent; Van den Broeke, Anne; Corbin, Antoine; Gazzolo, Louis; Ratner, Lee; Jalinot, Pierre; Duc Dodon, Madeleine

2018-03-01

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive malignant proliferation of activated CD4+ T lymphocytes. The viral Tax oncoprotein is critically involved in both HTLV-1-replication and T-cell proliferation, a prerequisite to the development of ATLL. In this study, we investigated the in vivo contribution of the Tax PDZ domain-binding motif (PBM) to the lymphoproliferative process. To that aim, we examined T-cell proliferation in humanized mice (hu-mice) carrying a human hemato-lymphoid system infected with either a wild type (WT) or a Tax PBM-deleted (ΔPBM) provirus. We observed that the frequency of CD4+ activated T-cells in the peripheral blood and in the spleen was significantly higher in WT than in ΔPBM hu-mice. Likewise, human T-cells collected from WT hu-mice and cultivated in vitro in presence of interleukin-2 were proliferating at a higher level than those from ΔPBM animals. We next examined the association of Tax with the Scribble PDZ protein, a prominent regulator of T-cell polarity, in human T-cells analyzed either after ex vivo isolation or after in vitro culture. We confirmed the interaction of Tax with Scribble only in T-cells from the WT hu-mice. This association correlated with the presence of both proteins in aggregates at the leading edge of the cells and with the formation of long actin filopods. Finally, data from a comparative genome-wide transcriptomic analysis suggested that the PBM-PDZ association is implicated in the expression of genes regulating proliferation, apoptosis and cytoskeletal organization. Collectively, our findings suggest that the Tax PBM is an auxiliary motif that contributes to the sustained growth of HTLV-1 infected T-cells in vivo and in vitro and is essential to T-cell immortalization.

A Simple PB/LIE Free Energy Function Accurately Predicts the Peptide Binding Specificity of the Tiam1 PDZ Domain.

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Panel, Nicolas; Sun, Young Joo; Fuentes, Ernesto J; Simonson, Thomas

2017-01-01

PDZ domains generally bind short amino acid sequences at the C-terminus of target proteins, and short peptides can be used as inhibitors or model ligands. Here, we used experimental binding assays and molecular dynamics simulations to characterize 51 complexes involving the Tiam1 PDZ domain and to test the performance of a semi-empirical free energy function. The free energy function combined a Poisson-Boltzmann (PB) continuum electrostatic term, a van der Waals interaction energy, and a surface area term. Each term was empirically weighted, giving a Linear Interaction Energy or "PB/LIE" free energy. The model yielded a mean unsigned deviation of 0.43 kcal/mol and a Pearson correlation of 0.64 between experimental and computed free energies, which was superior to a Null model that assumes all complexes have the same affinity. Analyses of the models support several experimental observations that indicate the orientation of the α 2 helix is a critical determinant for peptide specificity. The models were also used to predict binding free energies for nine new variants, corresponding to point mutants of the Syndecan1 and Caspr4 peptides. The predictions did not reveal improved binding; however, they suggest that an unnatural amino acid could be used to increase protease resistance and peptide lifetimes in vivo . The overall performance of the model should allow its use in the design of new PDZ ligands in the future.

PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo.

Science.gov (United States)

Xie, Li; Yamamoto, Brenda; Haoudi, Abdelali; Semmes, O John; Green, Patrick L

2006-03-01

HTLV-1 cellular transformation and disease induction is dependent on expression of the viral Tax oncoprotein. PDZ is a modular protein interaction domain used in organizing signaling complexes in eukaryotic cells through recognition of a specific binding motif in partner proteins. Tax-1, but not Tax-2, contains a PDZ-binding domain motif (PBM) that promotes the interaction with several cellular PDZ proteins. Herein, we investigate the contribution of the Tax-1 PBM in HTLV-induced proliferation and immortalization of primary T cells in vitro and viral survival in an infectious rabbit animal model. We generated several HTLV-1 and HTLV-2 Tax viral mutants, including HTLV-1deltaPBM, HTLV-2+C22(+PBM), and HTLV-2+ C18(deltaPBM). All Tax mutants maintained the ability to significantly activate the CREB/ATF or NFkappaB signaling pathways. Microtiter proliferation assays revealed that the Tax-1 PBM significantly increases both HTLV-1- and HTLV-2-induced primary T-cell proliferation. In addition, Tax-1 PBM was responsible for the micronuclei induction activity of Tax-1 relative to that of Tax-2. Viral infection and persistence were severely attenuated in rabbits inoculated with HTLV-1deltaPBM. Our results provide the first direct evidence suggesting that PBM-mediated associations between Tax-1 and cellular proteins play a key role in HTLV-induced cell proliferation and genetic instability in vitro and facilitate viral persistence in vivo.

A Simple PB/LIE Free Energy Function Accurately Predicts the Peptide Binding Specificity of the Tiam1 PDZ Domain

Directory of Open Access Journals (Sweden)

Nicolas Panel

2017-09-01

Full Text Available PDZ domains generally bind short amino acid sequences at the C-terminus of target proteins, and short peptides can be used as inhibitors or model ligands. Here, we used experimental binding assays and molecular dynamics simulations to characterize 51 complexes involving the Tiam1 PDZ domain and to test the performance of a semi-empirical free energy function. The free energy function combined a Poisson-Boltzmann (PB continuum electrostatic term, a van der Waals interaction energy, and a surface area term. Each term was empirically weighted, giving a Linear Interaction Energy or “PB/LIE” free energy. The model yielded a mean unsigned deviation of 0.43 kcal/mol and a Pearson correlation of 0.64 between experimental and computed free energies, which was superior to a Null model that assumes all complexes have the same affinity. Analyses of the models support several experimental observations that indicate the orientation of the α2 helix is a critical determinant for peptide specificity. The models were also used to predict binding free energies for nine new variants, corresponding to point mutants of the Syndecan1 and Caspr4 peptides. The predictions did not reveal improved binding; however, they suggest that an unnatural amino acid could be used to increase protease resistance and peptide lifetimes in vivo. The overall performance of the model should allow its use in the design of new PDZ ligands in the future.

Characterization of big bang, a novel gene encoding for PDZ domain-containing proteins that are dynamically expressed throughout Drosophila development.

Science.gov (United States)

Kim, Sabrina Y; Renihan, Maia K; Boulianne, Gabrielle L

2006-06-01

PDZ (PSD-95, Discs-large, ZO-1) domain proteins often function as scaffolding proteins and have been shown to play important roles in diverse cellular processes such as the establishment and maintenance of cell polarity, and signal transduction. Here, we report the identification and cloning of a novel Drosophila melanogaster gene that is predicted to produce several different PDZ domain-containing proteins through alternative promoter usage and alternative splicing. This gene, that we have named big bang (bbg), was first identified as C96-GAL4, a GAL4 enhancer trap line that was generated in our lab. To further characterize bbg, its expression pattern was examined in ovaries, embryos, and late third instar larvae using UAS reporter gene constructs, in situ hybridization, or immunocytochemistry. In addition, the expression of alternatively spliced transcripts was examined in more detail using in situ hybridization. We find that during embryogenesis bbg is predominantly expressed in the developing gut, but it is also expressed in external sensory organs found in the epidermis. In the late third instar larva, bbg is expressed along the presumptive wing margin in the wing disc, broadly in the eye disc, and in other imaginal discs as well as in the brain. The expression patterns observed are dynamic and specific during development, suggesting that like other genes that encode for several different PDZ domain protein isoforms, bbg likely plays important roles in multiple developmental processes.

Computational design of a PDZ domain peptide inhibitor that rescues CFTR activity.

Directory of Open Access Journals (Sweden)

Kyle E Roberts

Full Text Available The cystic fibrosis transmembrane conductance regulator (CFTR is an epithelial chloride channel mutated in patients with cystic fibrosis (CF. The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators ("potentiators" and "correctors", but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL, which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called "stabilizers" that rescue ΔF508-CFTR activity. To design the "stabilizers", we extended our structural ensemble-based computational protein redesign algorithm K* to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01 binds six-fold more tightly than the previous best hexamer (iCAL35, and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods.

An intact PDZ motif is essential for correct P2Y12 purinoceptor traffic in human platelets.

Science.gov (United States)

Nisar, Shaista; Daly, Martina E; Federici, Augusto B; Artoni, Andrea; Mumford, Andrew D; Watson, Stephen P; Mundell, Stuart J

2011-11-17

The platelet P2Y(12) purinoceptor (P2Y(12)R), which plays a crucial role in hemostasis, undergoes internalization and subsequent recycling to maintain receptor responsiveness, processes that are essential for normal platelet function. Here, we observe that P2Y(12)R function is compromised after deletion or mutation of the 4 amino acids at the extreme C-terminus of this receptor (ETPM), a putative postsynaptic density 95/disc large/zonula occludens-1 (PDZ)-binding motif. In cell line models, removal of this sequence or mutation of one of its core residues (P341A), attenuates receptor internalization and receptor recycling back to the membrane, thereby blocking receptor resensitization. The physiologic significance of these findings in the regulation of platelet function is shown by identification of a patient with a heterozygous mutation in the PDZ binding sequence of their P2Y(12)R (P341A) that is associated with reduced expression of the P2Y(12)R on the cell surface. Importantly, platelets from this subject showed significantly compromised P2Y(12)R recycling, emphasizing the importance of the extreme C-terminus of this receptor to ensure correct receptor traffic.

Artificial proteins as allosteric modulators of PDZ3 and SH3 in two-domain constructs: A computational characterization of novel chimeric proteins

Czech Academy of Sciences Publication Activity Database

Palani, Kirubakaran; Pfeiferová, Lucie; Boušová, Kristýna; Bednárová, Lucie; Obšilová, V.; Vondrášek, Jiří

2016-01-01

Roč. 84, č. 10 (2016), s. 1358-1374 ISSN 0887-3585 Institutional support: RVO:61388963 Keywords : protein design * fusion proteins * PDZ3 * SH3 * Trp-cage * two domain proteins Subject RIV: CE - Biochemistry Impact factor: 2.289, year: 2016

PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein augments the transforming activity in a rat fibroblast cell line

International Nuclear Information System (INIS)

Hirata, Akira; Higuchi, Masaya; Niinuma, Akiko; Ohashi, Minako; Fukushi, Masaya; Oie, Masayasu; Akiyama, Tetsu; Tanaka, Yuetsu; Gejyo, Fumitake; Fujii, Masahiro

2004-01-01

While human T-cell leukemia virus type 1 (HTLV-1) is associated with the development of adult T-cell leukemia (ATL), HTLV-2 has not been reported to be associated with such malignant leukemias. HTLV-1 Tax1 oncoprotein transforms a rat fibroblast cell line (Rat-1) to form multiple large colonies in soft agar, and this activity is much greater than that of HTLV-2 Tax2. We have demonstrated here that the increased number of transformed colonies induced by Tax1 relative to Tax2 was mediated by a PDZ domain-binding motif (PBM) in Tax1, which is absent in Tax2. Tax1 PBM mediated the interaction of Tax1 with the discs large (Dlg) tumor suppressor containing PDZ domains, and the interaction correlated well with the transforming activities of Tax1 and the mutants. Through this interaction, Tax1 altered the subcellular localization of Dlg from the detergent-soluble to the detergent-insoluble fraction in a fibroblast cell line as well as in HTLV-1-infected T-cell lines. These results suggest that the interaction of Tax1 with PDZ domain protein(s) is critically involved in the transforming activity of Tax1, the activity of which may be a crucial factor in malignant transformation of HTLV-1-infected cells in vivo

Two barcodes encoded by the type-1 PDZ and by phospho-Ser312 regulate retromer/WASH-mediated sorting of the ß1-adrenergic receptor from endosomes to the plasma membrane.

Science.gov (United States)

Nooh, Mohammed M; Bahouth, Suleiman W

2017-01-01

Recycling of the majority of agonist-internalized GPCR is dependent on a type I-PDZ "barcode" in their C-tail. The recycling of wild-type (WT) ß 1 -AR is also dependent on its default "type-1 PDZ barcode", but trafficking of the ß 1 -AR is inhibited when PKA or its substrate serine at position 312 (Ser 312 ) are inactivated. We tested the hypothesis that phospho-Ser 312 provided a second barcode for ß 1 -AR sorting from endosomes to the plasma membrane by determining the role of retromer/WASH complexes in ß 1 -AR trafficking. Recycling of WT ß 1 -AR or WT ß 2 -AR was dependent on targeting the retromer to endosomal membranes via SNX3 and rab7a, and on complexing the retromer to the WASH pentamer via the C-tail of FAM21 (FAM21 C ). These maneuvers however, did not inhibit the recycling of a phospho-Ser 312 ß 1 -AR mimic ((S312D) ß 1 -AR). Knockdown of the trans-acting PDZ protein sorting nexin27 (SNX27) inhibited the recycling of WT ß 1 -AR and WT ß 2 -AR, but had no effect on (S312D) ß 1 -AR∆PDZ or on phosphorylation of WT ß 1 -AR by PKA at Ser 312 . However, depletion of FKBP15, a FAM21 C -binding endosomal protein, selectively inhibited WT ß 1 -AR but not ß 2 -AR recycling, suggesting divergence might exist in GPCR trafficking roadmaps. These results indicate that two barcodes are involved in sorting WT ß 1 -AR out of early endosomes. The first and antecedent "barcode" was the "type-1 PDZ", followed by a second reversible "phospho-Ser 312 " verification "barcode". This organization allows tight regulation of ß 1 -AR density to signaling intensity in conditions associated with aberrant ß 1 -AR signaling such as in hypertension and heart failure. Copyright © 2016 Elsevier Inc. All rights reserved.

Artificial proteins as allosteric modulators of PDZ3 and SH3 in two-domain constructs: A computational characterization of novel chimeric proteins

Czech Academy of Sciences Publication Activity Database

Palani, K.; Pfeiferová, L.; Boušová, Kristýna; Bednárová, L.; Obšilová, Veronika; Vondrášek, J.

2016-01-01

Roč. 84, č. 10 (2016), s. 1358-1374 ISSN 0887-3585 Institutional support: RVO:67985823 Keywords : protein design * fusion proteins * PDZ3 * SH3 * Trp-cage * two domain proteins * molecular dynamics simulation * circular dichroism Subject RIV: BO - Biophysics Impact factor: 2.289, year: 2016

In vitro and in vivo Analysis of the Binding of the C Terminus of the HDL Receptor Scavenger Receptor Class B type I (SR-BI) to the PDZ1 Domain of its Cytoplasmic Adaptor Protein PDZK1

Energy Technology Data Exchange (ETDEWEB)

O Kocher; G Birrane; K Tsukamoto; S Fenske; A Yesilaltay; R Pal; K Daniels; J Ladias; M Krieger

2011-12-31

The PDZ1 domain of the four PDZ domain-containing protein PDZK1 has been reported to bind the C terminus of the HDL receptor scavenger receptor class B, type I (SR-BI), and to control hepatic SR-BI expression and function. We generated wild-type (WT) and mutant murine PDZ1 domains, the mutants bearing single amino acid substitutions in their carboxylate binding loop (Lys(14)-Xaa(4)-Asn(19)-Tyr-Gly-Phe-Phe-Leu(24)), and measured their binding affinity for a 7-residue peptide corresponding to the C terminus of SR-BI ((503)VLQEAKL(509)). The Y20A and G21Y substitutions abrogated all binding activity. Surprisingly, binding affinities (K(d)) of the K14A and F22A mutants were 3.2 and 4.0 ?M, respectively, similar to 2.6 ?M measured for the WT PDZ1. To understand these findings, we determined the high resolution structure of WT PDZ1 bound to a 5-residue sequence from the C-terminal SR-BI ((505)QEAKL(509)) using x-ray crystallography. In addition, we incorporated the K14A and Y20A substitutions into full-length PDZK1 liver-specific transgenes and expressed them in WT and PDZK1 knock-out mice. In WT mice, the transgenes did not alter endogenous hepatic SR-BI protein expression (intracellular distribution or amount) or lipoprotein metabolism (total plasma cholesterol, lipoprotein size distribution). In PDZK1 knock-out mice, as expected, the K14A mutant behaved like wild-type PDZK1 and completely corrected their hepatic SR-BI and plasma lipoprotein abnormalities. Unexpectedly, the 10-20-fold overexpressed Y20A mutant also substantially, but not completely, corrected these abnormalities. The results suggest that there may be an additional site(s) within PDZK1 that bind(s) SR-BI and mediate(s) productive SR-BI-PDZK1 interaction previously attributed exclusively to the canonical binding of the C-terminal SR-BI to PDZ1.

Crystallization and Preliminary Diffraction Analysis of the CAL PDZ Domain in Complex with a Selective Peptide Inhibitor

Energy Technology Data Exchange (ETDEWEB)

J Amacher; P Cushing; J Weiner; D Madden

2011-12-31

Cystic fibrosis (CF) is associated with loss-of-function mutations in the CF transmembrane conductance regulator (CFTR), which regulates epithelial fluid and ion homeostasis. The CFTR cytoplasmic C-terminus interacts with a number of PDZ (PSD-95/Dlg/ZO-1) proteins that modulate its intracellular trafficking and chloride-channel activity. Among these, the CFTR-associated ligand (CAL) has a negative effect on apical-membrane expression levels of the most common disease-associated mutant {Delta}F508-CFTR, making CAL a candidate target for the treatment of CF. A selective peptide inhibitor of the CAL PDZ domain (iCAL36) has recently been developed and shown to stabilize apical expression of {Delta}F508-CFTR, enhancing net chloride-channel activity, both alone and in combination with the folding corrector corr-4a. As a basis for structural studies of the CAL-iCAL36 interaction, a purification protocol has been developed that increases the oligomeric homogeneity of the protein. Here, the cocrystallization of the complex in space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 35.9, b = 47.7, c = 97.3 {angstrom}, is reported. The crystals diffracted to 1.4 {angstrom} resolution. Based on the calculated Matthews coefficient (1.96 {angstrom}{sup 3} Da{sup -1}), it appears that the asymmetric unit contains two complexes.

Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development.

Science.gov (United States)

Etheridge, S Leah; Ray, Saugata; Li, Shuangding; Hamblet, Natasha S; Lijam, Nardos; Tsang, Michael; Greer, Joy; Kardos, Natalie; Wang, Jianbo; Sussman, Daniel J; Chen, Ping; Wynshaw-Boris, Anthony

2008-11-01

Dishevelled (Dvl) proteins are important signaling components of both the canonical beta-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE) movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provide evidence of functional redundancy among the three murine Dvls. Dvl3(-/-) mice died perinatally with cardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncus arteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotype that was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap (LtapLp/+). Although neurulation appeared normal in both Dvl3(-/-) and LtapLp/+ mutants, Dvl3(+/-);LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we show that many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observed in Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvl transgenes demonstrated the ability of Dvls to compensate for each other to enable normal development. Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants, suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, we demonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance in the PCP pathway during neurulation and cochlea development. Finally, we establish several developmental processes in which the three Dvls are functionally redundant.

Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development.

Directory of Open Access Journals (Sweden)

S Leah Etheridge

2008-11-01

Full Text Available Dishevelled (Dvl proteins are important signaling components of both the canonical beta-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provide evidence of functional redundancy among the three murine Dvls. Dvl3(-/- mice died perinatally with cardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncus arteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotype that was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap (LtapLp/+. Although neurulation appeared normal in both Dvl3(-/- and LtapLp/+ mutants, Dvl3(+/-;LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we show that many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observed in Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvl transgenes demonstrated the ability of Dvls to compensate for each other to enable normal development. Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants, suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, we demonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance in the PCP pathway during neurulation and cochlea development. Finally, we establish several developmental processes in which the three Dvls are functionally redundant.

Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure.

Science.gov (United States)

Hamblet, Natasha S; Lijam, Nardos; Ruiz-Lozano, Pilar; Wang, Jianbo; Yang, Yasheng; Luo, Zhenge; Mei, Lin; Chien, Kenneth R; Sussman, Daniel J; Wynshaw-Boris, Anthony

2002-12-01

The murine dishevelled 2 (Dvl2) gene is an ortholog of the Drosophila segment polarity gene Dishevelled, a member of the highly conserved Wingless/Wnt developmental pathway. Dvl2-deficient mice were produced to determine the role of Dvl2 in mammalian development. Mice containing null mutations in Dvl2 present with 50% lethality in both inbred 129S6 and in a hybrid 129S6-NIH Black Swiss background because of severe cardiovascular outflow tract defects, including double outlet right ventricle, transposition of the great arteries and persistent truncus arteriosis. The majority of the surviving Dvl2(-/-) mice were female, suggesting that penetrance was influenced by sex. Expression of Pitx2 and plexin A2 was attenuated in Dvl2 null mutants, suggesting a defect in cardiac neural crest development during outflow tract formation. In addition, approximately 90% of Dvl2(-/-) mice have vertebral and rib malformations that affect the proximal as well as the distal parts of the ribs. These skeletal abnormalities were more pronounced in mice deficient for both Dvl1 and Dvl2. Somite differentiation markers used to analyze Dvl2(-/-) and Dvl1(-/-);Dvl2(-/-) mutant embryos revealed mildly aberrant expression of Uncx4.1, delta 1 and myogenin, suggesting defects in somite segmentation. Finally, 2-3% of Dvl2(-/-) embryos displayed thoracic spina bifida, while virtually all Dvl1/2 double mutant embryos displayed craniorachishisis, a completely open neural tube from the midbrain to the tail. Thus, Dvl2 is essential for normal cardiac morphogenesis, somite segmentation and neural tube closure, and there is functional redundancy between Dvl1 and Dvl2 in some phenotypes.

Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling

Energy Technology Data Exchange (ETDEWEB)

Luo, Ke; Gu, Xiuhui [School of Basic Medical Sciences, Chengdu Medical College, Chengdu (China); Liu, Jing; Zeng, Guodan; Peng, Liaotian; Huang, Houyi; Jiang, Mengju [School of Biomedical Sciences, Chengdu Medical College, Chengdu (China); Yang, Ping; Li, Minhui [School of Basic Medical Sciences, Chengdu Medical College, Chengdu (China); Yang, Yuhan; Wang, Yuanyuan [School of Biomedical Sciences, Chengdu Medical College, Chengdu (China); Peng, Quekun, E-mail: pengquekun@163.com [School of Biomedical Sciences, Chengdu Medical College, Chengdu (China); Zhu, Li, E-mail: 1968403299@qq.com [Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital, Chengdu Medical College, Chengdu (China); Zhang, Kun, E-mail: zhangkunyyo@163.com [School of Biomedical Sciences, Chengdu Medical College, Chengdu (China)

2016-09-10

Cisplatin (CDDP) is currently recommended as the front-line chemotherapeutic agent for lung cancer. However, the resistance to cisplatin is widespread in patients with advanced lung cancer, and the molecular mechanism of such resistance remains incompletely understood. Disheveled (DVL), a key mediator of Wnt/β-catenin, has been linked to cancer progression, while the role of DVL in cancer drug resistance is not clear. Here, we found that DVL2 was over-expressed in cisplatin-resistant human lung cancer cells A549/CDDP compared to the parental A549 cells. Inhibition of DVL2 by its inhibitor (3289-8625) or shDVL2 resensitized A549/CDDP cells to cisplatin. In addition, over-expression of DVL2 in A549 cells increased the protein levels of BCRP, MRP4, and Survivin, which are known to be associated with chemoresistance, while inhibition of DVL2 in A549/CDDP cells decreased these protein levels, and reduced the accumulation and nuclear translocation of β-catenin. In addition, shβ-catenin abolished the DVL2-induced the expression of BCRP, MRP4, and Survivin. Furthermore, our data showed that GSK3β/β-catenin signals were aberrantly activated by DVL2, and inactivation of GSK3β reversed the shDVL2-induced down-regulation of β-catenin. Taken together, these results suggested that inhibition of DVL2 can sensitize cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling and inhibiting BCRP, MRP4, and Survivin expression. It promises a new strategy to chemosensitize cisplatin-induced cytotoxicity in lung cancer. - Highlights: • Inhibition of DVL2 chemosensitizes resistant lung cancer to cisplatin. • DVL2 positively regulated the expression of BCRP, MRP4 and Survivin. • β-catenin mediated the DVL2-induced expression. • DVL2 increased the accumulation and nuclear translocation of β-catenin. • DVL2 up-regulated β-catenin via inhibiting GSK3β.

Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling

International Nuclear Information System (INIS)

Luo, Ke; Gu, Xiuhui; Liu, Jing; Zeng, Guodan; Peng, Liaotian; Huang, Houyi; Jiang, Mengju; Yang, Ping; Li, Minhui; Yang, Yuhan; Wang, Yuanyuan; Peng, Quekun; Zhu, Li; Zhang, Kun

2016-01-01

Cisplatin (CDDP) is currently recommended as the front-line chemotherapeutic agent for lung cancer. However, the resistance to cisplatin is widespread in patients with advanced lung cancer, and the molecular mechanism of such resistance remains incompletely understood. Disheveled (DVL), a key mediator of Wnt/β-catenin, has been linked to cancer progression, while the role of DVL in cancer drug resistance is not clear. Here, we found that DVL2 was over-expressed in cisplatin-resistant human lung cancer cells A549/CDDP compared to the parental A549 cells. Inhibition of DVL2 by its inhibitor (3289-8625) or shDVL2 resensitized A549/CDDP cells to cisplatin. In addition, over-expression of DVL2 in A549 cells increased the protein levels of BCRP, MRP4, and Survivin, which are known to be associated with chemoresistance, while inhibition of DVL2 in A549/CDDP cells decreased these protein levels, and reduced the accumulation and nuclear translocation of β-catenin. In addition, shβ-catenin abolished the DVL2-induced the expression of BCRP, MRP4, and Survivin. Furthermore, our data showed that GSK3β/β-catenin signals were aberrantly activated by DVL2, and inactivation of GSK3β reversed the shDVL2-induced down-regulation of β-catenin. Taken together, these results suggested that inhibition of DVL2 can sensitize cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling and inhibiting BCRP, MRP4, and Survivin expression. It promises a new strategy to chemosensitize cisplatin-induced cytotoxicity in lung cancer. - Highlights: • Inhibition of DVL2 chemosensitizes resistant lung cancer to cisplatin. • DVL2 positively regulated the expression of BCRP, MRP4 and Survivin. • β-catenin mediated the DVL2-induced expression. • DVL2 increased the accumulation and nuclear translocation of β-catenin. • DVL2 up-regulated β-catenin via inhibiting GSK3β.

Serine 77 in the PDZ domain of PICK1 is a protein kinase Cα phosphorylation site regulated by lipid membrane binding

DEFF Research Database (Denmark)

Ammendrup-Johnsen, Ina; Thorsen, Thor Seneca; Gether, Ulrik

2012-01-01

PICK1 (protein interacting with C kinase 1) contains an N-terminal protein binding PDZ domain and a C-terminal lipid binding BAR domain. PICK1 plays a key role in several physiological processes, including synaptic plasticity. However, little is known about the cellular mechanisms governing the a...... lipid binding and/or polymerization capacity. We propose that PICK1 is phosphorylated at Ser77 by PKCα preferentially when bound to membrane vesicles and that this phosphorylation in turn modulates its cellular distribution....

δ-Catenin Regulates Spine Architecture via Cadherin and PDZ-dependent Interactions*

Science.gov (United States)

Yuan, Li; Seong, Eunju; Beuscher, James L.; Arikkath, Jyothi

2015-01-01

The ability of neurons to maintain spine architecture and modulate it in response to synaptic activity is a crucial component of the cellular machinery that underlies information storage in pyramidal neurons of the hippocampus. Here we show a critical role for δ-catenin, a component of the cadherin-catenin cell adhesion complex, in regulating spine head width and length in pyramidal neurons of the hippocampus. The loss of Ctnnd2, the gene encoding δ-catenin, has been associated with the intellectual disability observed in the cri du chat syndrome, suggesting that the functional roles of δ-catenin are vital for neuronal integrity and higher order functions. We demonstrate that loss of δ-catenin in a mouse model or knockdown of δ-catenin in pyramidal neurons compromises spine head width and length, without altering spine dynamics. This is accompanied by a reduction in the levels of synaptic N-cadherin. The ability of δ-catenin to modulate spine architecture is critically dependent on its ability to interact with cadherin and PDZ domain-containing proteins. We propose that loss of δ-catenin during development perturbs synaptic architecture leading to developmental aberrations in neural circuit formation that contribute to the learning disabilities in a mouse model and humans with cri du chat syndrome. PMID:25724647

A novel family of small proteins that affect plant development

Energy Technology Data Exchange (ETDEWEB)

John Charles Walker

2011-04-29

The DVL genes represent a new group of plant proteins that influence plant growth and development. Overexpression of DVL1, and other members of the DVL family, causes striking phenotypic changes. The DVL proteins share sequence homology in their C-terminal half. Point mutations in the C-terminal domain show it is necessary and deletion studies demonstrate the C-terminal domain is sufficient to confer the overexpression phenotypes. The phenotypes observed, and the conservation of the protein sequence in the plant kingdom, does suggest the DVL proteins have a role in modulating plant growth and development. Our working hypothesis is the DVL proteins function as regulators of cellular signaling pathways that control growth and development.

Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling.

Science.gov (United States)

Luo, Ke; Gu, Xiuhui; Liu, Jing; Zeng, Guodan; Peng, Liaotian; Huang, Houyi; Jiang, Mengju; Yang, Ping; Li, Minhui; Yang, Yuhan; Wang, Yuanyuan; Peng, Quekun; Zhu, Li; Zhang, Kun

2016-09-10

Cisplatin (CDDP) is currently recommended as the front-line chemotherapeutic agent for lung cancer. However, the resistance to cisplatin is widespread in patients with advanced lung cancer, and the molecular mechanism of such resistance remains incompletely understood. Disheveled (DVL), a key mediator of Wnt/β-catenin, has been linked to cancer progression, while the role of DVL in cancer drug resistance is not clear. Here, we found that DVL2 was over-expressed in cisplatin-resistant human lung cancer cells A549/CDDP compared to the parental A549 cells. Inhibition of DVL2 by its inhibitor (3289-8625) or shDVL2 resensitized A549/CDDP cells to cisplatin. In addition, over-expression of DVL2 in A549 cells increased the protein levels of BCRP, MRP4, and Survivin, which are known to be associated with chemoresistance, while inhibition of DVL2 in A549/CDDP cells decreased these protein levels, and reduced the accumulation and nuclear translocation of β-catenin. In addition, shβ-catenin abolished the DVL2-induced the expression of BCRP, MRP4, and Survivin. Furthermore, our data showed that GSK3β/β-catenin signals were aberrantly activated by DVL2, and inactivation of GSK3β reversed the shDVL2-induced down-regulation of β-catenin. Taken together, these results suggested that inhibition of DVL2 can sensitize cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling and inhibiting BCRP, MRP4, and Survivin expression. It promises a new strategy to chemosensitize cisplatin-induced cytotoxicity in lung cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Side-chain interactions form late and cooperatively in the binding reaction between disordered peptides and PDZ domains

DEFF Research Database (Denmark)

Haq, S Raza; Chi, Celestine N; Bach, Anders

2012-01-01

Intrinsically disordered proteins are very common and mediate numerous protein-protein and protein-DNA interactions. While it is clear that these interactions are instrumental for the life of the mammalian cell, there is a paucity of data regarding their molecular binding mechanisms. We have here...... used short peptides as a model system for intrinsically disordered proteins. Linear free-energy relationships based on rate and equilibrium constants for the binding of these peptides to ordered target proteins, PDZ domains, demonstrate that native side-chain interactions form mainly after the rate......-limiting barrier for binding, in a cooperative fashion. This finding suggests that these disordered peptides first form a weak encounter complex with non-native interactions. The data do not support the recent notion that the affinities of intrinsically disordered proteins towards their targets are generally...

δ-Catenin Regulates Spine Architecture via Cadherin and PDZ-dependent Interactions.

Science.gov (United States)

Yuan, Li; Seong, Eunju; Beuscher, James L; Arikkath, Jyothi

2015-04-24

The ability of neurons to maintain spine architecture and modulate it in response to synaptic activity is a crucial component of the cellular machinery that underlies information storage in pyramidal neurons of the hippocampus. Here we show a critical role for δ-catenin, a component of the cadherin-catenin cell adhesion complex, in regulating spine head width and length in pyramidal neurons of the hippocampus. The loss of Ctnnd2, the gene encoding δ-catenin, has been associated with the intellectual disability observed in the cri du chat syndrome, suggesting that the functional roles of δ-catenin are vital for neuronal integrity and higher order functions. We demonstrate that loss of δ-catenin in a mouse model or knockdown of δ-catenin in pyramidal neurons compromises spine head width and length, without altering spine dynamics. This is accompanied by a reduction in the levels of synaptic N-cadherin. The ability of δ-catenin to modulate spine architecture is critically dependent on its ability to interact with cadherin and PDZ domain-containing proteins. We propose that loss of δ-catenin during development perturbs synaptic architecture leading to developmental aberrations in neural circuit formation that contribute to the learning disabilities in a mouse model and humans with cri du chat syndrome. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Machine learning approaches to evaluate correlation patterns in allosteric signaling: A case study of the PDZ2 domain

Science.gov (United States)

Botlani, Mohsen; Siddiqui, Ahnaf; Varma, Sameer

2018-06-01

Many proteins are regulated by dynamic allostery wherein regulator-induced changes in structure are comparable with thermal fluctuations. Consequently, understanding their mechanisms requires assessment of relationships between and within conformational ensembles of different states. Here we show how machine learning based approaches can be used to simplify this high-dimensional data mining task and also obtain mechanistic insight. In particular, we use these approaches to investigate two fundamental questions in dynamic allostery. First, how do regulators modify inter-site correlations in conformational fluctuations (Cij)? Second, how are regulator-induced shifts in conformational ensembles at two different sites in a protein related to each other? We address these questions in the context of the human protein tyrosine phosphatase 1E's PDZ2 domain, which is a model protein for studying dynamic allostery. We use molecular dynamics to generate conformational ensembles of the PDZ2 domain in both the regulator-bound and regulator-free states. The employed protocol reproduces methyl deuterium order parameters from NMR. Results from unsupervised clustering of Cij combined with flow analyses of weighted graphs of Cij show that regulator binding significantly alters the global signaling network in the protein; however, not by altering the spatial arrangement of strongly interacting amino acid clusters but by modifying the connectivity between clusters. Additionally, we find that regulator-induced shifts in conformational ensembles, which we evaluate by repartitioning ensembles using supervised learning, are, in fact, correlated. This correlation Δij is less extensive compared to Cij, but in contrast to Cij, Δij depends inversely on the distance from the regulator binding site. Assuming that Δij is an indicator of the transduction of the regulatory signal leads to the conclusion that the regulatory signal weakens with distance from the regulatory site. Overall, this

Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development.

OpenAIRE

S Leah Etheridge; Saugata Ray; Shuangding Li; Natasha S Hamblet; Nardos Lijam; Michael Tsang; Michael Tsang; Joy Greer; Natalie Kardos; Jianbo Wang; Daniel J Sussman; Ping Chen; Anthony Wynshaw-Boris

2008-01-01

Dishevelled (Dvl) proteins are important signaling components of both the canonical beta-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE) movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, ...

Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein

Science.gov (United States)

Marsh, Elizabeth K.; Delury, Craig P.; Davies, Nicholas J.; Weston, Christopher J.; Miah, Mohammed A.L.; Banks, Lawrence; Parish, Joanna L.

2017-01-01

The function of a conserved PDS95/DLG1/ZO1 (PDZ) binding motif (E6 PBM) at the C-termini of E6 oncoproteins of high-risk human papillomavirus (HPV) types contributes to the development of HPV-associated malignancies. Here, using a primary human keratinocyte-based model of the high-risk HPV18 life cycle, we identify a novel link between the E6 PBM and mitotic stability. In cultures containing a mutant genome in which the E6 PBM was deleted there was an increase in the frequency of abnormal mitoses, including multinucleation, compared to cells harboring the wild type HPV18 genome. The loss of the E6 PBM was associated with a significant increase in the frequency of mitotic spindle defects associated with anaphase and telophase. Furthermore, cells carrying this mutant genome had increased chromosome segregation defects and they also exhibited greater levels of genomic instability, as shown by an elevated level of centromere-positive micronuclei. In wild type HPV18 genome-containing organotypic cultures, the majority of mitotic cells reside in the suprabasal layers, in keeping with the hyperplastic morphology of the structures. However, in mutant genome-containing structures a greater proportion of mitotic cells were retained in the basal layer, which were often of undefined polarity, thus correlating with their reduced thickness. We conclude that the ability of E6 to target cellular PDZ proteins plays a critical role in maintaining mitotic stability of HPV infected cells, ensuring stable episome persistence and vegetative amplification. PMID:28061478

Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein.

Science.gov (United States)

Marsh, Elizabeth K; Delury, Craig P; Davies, Nicholas J; Weston, Christopher J; Miah, Mohammed A L; Banks, Lawrence; Parish, Joanna L; Higgs, Martin R; Roberts, Sally

2017-03-21

The function of a conserved PDS95/DLG1/ZO1 (PDZ) binding motif (E6 PBM) at the C-termini of E6 oncoproteins of high-risk human papillomavirus (HPV) types contributes to the development of HPV-associated malignancies. Here, using a primary human keratinocyte-based model of the high-risk HPV18 life cycle, we identify a novel link between the E6 PBM and mitotic stability. In cultures containing a mutant genome in which the E6 PBM was deleted there was an increase in the frequency of abnormal mitoses, including multinucleation, compared to cells harboring the wild type HPV18 genome. The loss of the E6 PBM was associated with a significant increase in the frequency of mitotic spindle defects associated with anaphase and telophase. Furthermore, cells carrying this mutant genome had increased chromosome segregation defects and they also exhibited greater levels of genomic instability, as shown by an elevated level of centromere-positive micronuclei. In wild type HPV18 genome-containing organotypic cultures, the majority of mitotic cells reside in the suprabasal layers, in keeping with the hyperplastic morphology of the structures. However, in mutant genome-containing structures a greater proportion of mitotic cells were retained in the basal layer, which were often of undefined polarity, thus correlating with their reduced thickness. We conclude that the ability of E6 to target cellular PDZ proteins plays a critical role in maintaining mitotic stability of HPV infected cells, ensuring stable episome persistence and vegetative amplification.

Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.

Science.gov (United States)

Sancho, Rosa M; Law, Bernard M H; Harvey, Kirsten

2009-10-15

Mutations in PARK8, encoding LRRK2, are the most common known cause of Parkinson's disease. The LRRK2 Roc-COR tandem domain exhibits GTPase activity controlling LRRK2 kinase activity via an intramolecular process. We report the interaction of LRRK2 with the dishevelled family of phosphoproteins (DVL1-3), key regulators of Wnt (Wingless/Int) signalling pathways important for axon guidance, synapse formation and neuronal maintenance. Interestingly, DVLs can interact with and mediate the activation of small GTPases with structural similarity to the LRRK2 Roc domain. The LRRK2 Roc-COR domain and the DVL1 DEP domain were necessary and sufficient for LRRK2-DVL1 interaction. Co-expression of DVL1 increased LRRK2 steady-state protein levels, an effect that was dependent on the DEP domain. Strikingly, LRRK2-DVL1-3 interactions were disrupted by the familial PARK8 mutation Y1699C, whereas pathogenic mutations at residues R1441 and R1728 strengthened LRRK2-DVL1 interactions. Co-expression of DVL1 with LRRK2 in mammalian cells resulted in the redistribution of LRRK2 to typical cytoplasmic DVL1 aggregates in HEK293 and SH-SY5Y cells and co-localization in neurites and growth cones of differentiated dopaminergic SH-SY5Y cells. This is the first report of the modulation of a key LRRK2-accessory protein interaction by PARK8 Roc-COR domain mutations segregating with Parkinson's disease. Since the DVL1 DEP domain is known to be involved in the regulation of small GTPases, we propose that: (i) DVLs may influence LRRK2 GTPase activity, and (ii) Roc-COR domain mutations modulating LRRK2-DVL interactions indirectly influence kinase activity. Our findings also link LRRK2 to Wnt signalling pathways, suggesting novel pathogenic mechanisms and new targets for genetic analysis in Parkinson's disease.

A novel D458V mutation in the SANS PDZ binding motif causes atypical Usher syndrome.

Science.gov (United States)

Kalay, E; de Brouwer, A P M; Caylan, R; Nabuurs, S B; Wollnik, B; Karaguzel, A; Heister, J G A M; Erdol, H; Cremers, F P M; Cremers, C W R J; Brunner, H G; Kremer, H

2005-12-01

Homozygosity mapping and linkage analysis in a Turkish family with autosomal recessive prelingual sensorineural hearing loss revealed a 15-cM critical region at 17q25.1-25.3 flanked by the polymorphic markers D17S1807 and D17S1806. The maximum two-point lod score was 4.07 at theta=0.0 for the marker D17S801. The linkage interval contains the Usher syndrome 1G gene (USH1G) that is mutated in patients with Usher syndrome (USH) type 1g and encodes the SANS protein. Mutation analysis of USH1G led to the identification of a homozygous missense mutation D458V at the -3 position of the PDZ binding motif of SANS. This mutation was also present homozygously in one out of 64 additional families from Turkey with autosomal recessive nonsyndromic hearing loss and heterozygously in one out of 498 control chromosomes. By molecular modeling, we provide evidence that this mutation impairs the interaction of SANS with harmonin. Ophthalmologic examination and vestibular evaluation of patients from both families revealed mild retinitis pigmentosa and normal vestibular function. These results suggest that these patients suffer from atypical USH.

Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development.

Science.gov (United States)

Chang, Baojun; Tessneer, Kandice L; McManus, John; Liu, Xiaolei; Hahn, Scott; Pasula, Satish; Wu, Hao; Song, Hoogeun; Chen, Yiyuan; Cai, Xiaofeng; Dong, Yunzhou; Brophy, Megan L; Rahman, Ruby; Ma, Jian-Xing; Xia, Lijun; Chen, Hong

2015-03-16

Uncontrolled canonical Wnt signalling supports colon epithelial tumour expansion and malignant transformation. Understanding the regulatory mechanisms involved is crucial for elucidating the pathogenesis of and will provide new therapeutic targets for colon cancer. Epsins are ubiquitin-binding adaptor proteins upregulated in several human cancers; however, the involvement of epsins in colon cancer is unknown. Here we show that loss of intestinal epithelial epsins protects against colon cancer by significantly reducing the stability of the crucial Wnt signalling effector, dishevelled (Dvl2), and impairing Wnt signalling. Consistently, epsins and Dvl2 are correspondingly upregulated in colon cancer. Mechanistically, epsin binds Dvl2 via its epsin N-terminal homology domain and ubiquitin-interacting motifs and prohibits Dvl2 polyubiquitination and degradation. Our findings reveal an unconventional role for epsins in stabilizing Dvl2 and potentiating Wnt signalling in colon cancer cells to ensure robust colon cancer progression. The pro-carcinogenic role of Epsins suggests that they are potential therapeutic targets to combat colon cancer.

New Methods for Estimating Water Current Velocity Fields from Autonomous Underwater Vehicles

Science.gov (United States)

Kinsey, J. C.; Medagoda, L.

2016-02-01

Water current velocities are a crucial component of understanding oceanographic processes and underwater robots, such as autonomous underwater vehicles (AUVs), provide a mobile platform for obtaining these observations. Estimating water current velocities requires both measurements of the water velocity, often obtained with an Acoustic Doppler Current Profiler (ADCP), as well as estimates of the vehicle velocity. Presently, vehicle velocities are supplied on the sea surface with velocity from GPS, or near the seafloor where Doppler Velocity Log (DVL) in bottom-lock is available; however, this capability is unavailable in the mid-water column where DVL bottom-lock and GPS are unavailable. Here we present a method which calculates vehicle velocities using consecutive ADCP measurements in the mid-water using an extended Kalman filter (EKF). The correlation of the spatially changing water current states, along with mass transport and shear constraints on the water current field, is formulated using least square constraints. Results from the Sentry AUV from a mid-water surveying mission at Deepwater Horizon and a small-scale hydrothermal vent flux estimation mission suggest the method is suitable for real-time use. DVL data is denied to simulate mid-water missions and the results compared to ground truth water velocity measurements estimated using DVL velocities. Results show quantifiable uncertainties in the water current velocities, along with similar performance, for the DVL and no-DVL case in the mid-water. This method has the potential to provide geo-referenced water velocity measurements from mobile ocean robots in the absence of GPS and DVL as well as estimate the uncertainty associated with the measurements.

The tyrosine Y2502.39 in Frizzled 4 defines a conserved motif important for structural integrity of the receptor and recruitment of Disheveled.

Science.gov (United States)

Strakova, Katerina; Matricon, Pierre; Yokota, Chika; Arthofer, Elisa; Bernatik, Ondrej; Rodriguez, David; Arenas, Ernest; Carlsson, Jens; Bryja, Vitezslav; Schulte, Gunnar

2017-10-01

Frizzleds (FZDs) are unconventional G protein-coupled receptors, which activate diverse intracellular signaling pathways via the phosphoprotein Disheveled (DVL) and heterotrimeric G proteins. The interaction interplay of FZDs with DVL and G proteins is complex, involves different regions of FZD and the potential dynamics are poorly understood. In the present study, we aimed to characterize the function of a highly conserved tyrosine (Y250 2.39 ) in the intracellular loop 1 (IL1) of human FZD 4 . We have found Y250 2.39 to be crucial for DVL2 interaction and DVL2 translocation to the plasma membrane. Mutant FZD 4 -Y250 2.39 F, impaired in DVL2 binding, was defective in both β-catenin-dependent and β-catenin-independent WNT signaling induced in Xenopus laevis embryos. The same mutant maintained interaction with the heterotrimeric G proteins Gα 12 and Gα 13 and was able to mediate WNT-induced G protein dissociation and G protein-dependent YAP/TAZ signaling. We conclude from modeling and dynamics simulation efforts that Y250 2.39 is important for the structural integrity of the FZD-DVL, but not for the FZD-G protein interface and hypothesize that the interaction network of Y250 2.39 and H348 4.46 plays a role in specifying downstream signaling pathways induced by the receptor. Copyright © 2017. Published by Elsevier Inc.

The PDZ domain binding motif (PBM) of human T-cell leukemia virus type 1 Tax can be substituted by heterologous PBMs from viral oncoproteins during T-cell transformation.

Science.gov (United States)

Aoyagi, Tomoya; Takahashi, Masahiko; Higuchi, Masaya; Oie, Masayasu; Tanaka, Yuetsu; Kiyono, Tohru; Aoyagi, Yutaka; Fujii, Masahiro

2010-04-01

Several tumor viruses, such as human T-cell leukemia virus (HTLV), human papilloma virus (HPV), human adenovirus, have high-oncogenic and low-oncogenic subtypes, and such subtype-specific oncogenesis is associated with the PDZ-domain binding motif (PBM) in their transforming proteins. HTLV-1, the causative agent of adult T-cell leukemia, encodes Tax1 with PBM as a transforming protein. The Tax1 PBM was substituted with those from other oncoviruses, and the transforming activity was examined. Tax1 mutants with PBM from either HPV-16 E6 or adenovirus type 9 E4ORF1 are fully active in the transformation of a mouse T-cell line from interleukin-2-dependent growth into independent growth. Interestingly, one such Tax1 PBM mutant had an extra amino acid insertion derived from E6 between PBM and the rest of Tax1, thus suggesting that the amino acid sequences of the peptides between PBM and the rest of Tax1 and the numbers only slightly affect the function of PBM in the transformation. Tax1 and Tax1 PBM mutants interacted with tumor suppressors Dlg1 and Scribble with PDZ-domains. Unlike E6, Tax1 PBM mutants as well as Tax1 did not or minimally induced the degradations of Dlg1 and Scribble, but instead induced their subcellular translocation from the detergent-soluble fraction into the insoluble fraction, thus suggesting that the inactivation mechanism of these tumor suppressor proteins is distinct. The present results suggest that PBMs of high-risk oncoviruses have a common function(s) required for these three tumor viruses to transform cells, which is likely associated with the subtype-specific oncogenesis of these tumor viruses.

Confinement of β1- and β2-adrenergic receptors in the plasma membrane of cardiomyocyte-like H9c2 cells is mediated by selective interactions with PDZ domain and A-kinase anchoring proteins but not caveolae

Science.gov (United States)

Valentine, Cathleen D.; Haggie, Peter M.

2011-01-01

The sympathetic nervous system regulates cardiac output by activating adrenergic receptors (ARs) in cardiac myocytes. The predominant cardiac ARs, β1- and β2AR, are structurally similar but mediate distinct signaling responses. Scaffold protein–mediated compartmentalization of ARs into discrete, multiprotein complexes has been proposed to dictate differential signaling responses. To test the hypothesis that βARs integrate into complexes in live cells, we measured receptor diffusion and interactions by single-particle tracking. Unstimulated β1- and β2AR were highly confined in the membrane of H9c2 cardiomyocyte-like cells, indicating that receptors are tethered and presumably integrated into protein complexes. Selective disruption of interactions with postsynaptic density protein 95/disks large/zonula occludens-1 (PDZ)–domain proteins and A-kinase anchoring proteins (AKAPs) increased receptor diffusion, indicating that these scaffold proteins participate in receptor confinement. In contrast, modulation of interactions between the putative scaffold caveolae and β2AR did not alter receptor dynamics, suggesting that these membrane domains are not involved in β2AR confinement. For both β1- and β2AR, the receptor carboxy-terminus was uniquely responsible for scaffold interactions. Our data formally demonstrate that distinct and stable protein complexes containing β1- or β2AR are formed in the plasma membrane of cardiomyocyte-like cells and that selective PDZ and AKAP interactions are responsible for the integration of receptors into complexes. PMID:21680711

Confinement of β(1)- and β(2)-adrenergic receptors in the plasma membrane of cardiomyocyte-like H9c2 cells is mediated by selective interactions with PDZ domain and A-kinase anchoring proteins but not caveolae.

Science.gov (United States)

Valentine, Cathleen D; Haggie, Peter M

2011-08-15

The sympathetic nervous system regulates cardiac output by activating adrenergic receptors (ARs) in cardiac myocytes. The predominant cardiac ARs, β(1)- and β(2)AR, are structurally similar but mediate distinct signaling responses. Scaffold protein-mediated compartmentalization of ARs into discrete, multiprotein complexes has been proposed to dictate differential signaling responses. To test the hypothesis that βARs integrate into complexes in live cells, we measured receptor diffusion and interactions by single-particle tracking. Unstimulated β(1)- and β(2)AR were highly confined in the membrane of H9c2 cardiomyocyte-like cells, indicating that receptors are tethered and presumably integrated into protein complexes. Selective disruption of interactions with postsynaptic density protein 95/disks large/zonula occludens-1 (PDZ)-domain proteins and A-kinase anchoring proteins (AKAPs) increased receptor diffusion, indicating that these scaffold proteins participate in receptor confinement. In contrast, modulation of interactions between the putative scaffold caveolae and β(2)AR did not alter receptor dynamics, suggesting that these membrane domains are not involved in β(2)AR confinement. For both β(1)- and β(2)AR, the receptor carboxy-terminus was uniquely responsible for scaffold interactions. Our data formally demonstrate that distinct and stable protein complexes containing β(1)- or β(2)AR are formed in the plasma membrane of cardiomyocyte-like cells and that selective PDZ and AKAP interactions are responsible for the integration of receptors into complexes.

Casein kinase 1-epsilon or 1-delta required for Wnt-mediated intestinal stem cell maintenance.

Science.gov (United States)

Morgenstern, Yael; Das Adhikari, Upasana; Ayyash, Muneef; Elyada, Ela; Tóth, Beáta; Moor, Andreas; Itzkovitz, Shalev; Ben-Neriah, Yinon

2017-10-16

The intestinal epithelium holds an immense regenerative capacity mobilized by intestinal stem cells (ISCs), much of it supported by Wnt pathway activation. Several unique regulatory mechanisms ensuring optimal levels of Wnt signaling have been recognized in ISCs. Here, we identify another Wnt signaling amplifier, CKIε, which is specifically upregulated in ISCs and is essential for ISC maintenance, especially in the absence of its close isoform CKIδ. Co-ablation of CKIδ/ε in the mouse gut epithelium results in rapid ISC elimination, with subsequent growth arrest, crypt-villous shrinking, and rapid mouse death. Unexpectedly, Wnt activation is preserved in all CKIδ/ε-deficient enterocyte populations, with the exception of Lgr5 + ISCs, which exhibit Dvl2-dependent Wnt signaling attenuation. CKIδ/ε-depleted gut organoids cease proliferating and die rapidly, yet survive and resume self-renewal upon reconstitution of Dvl2 expression. Our study underscores a unique regulation mode of the Wnt pathway in ISCs, possibly providing new means of stem cell enrichment for regenerative medicine. © 2017 The Authors.

Three-dimensional structure of lectin from Dioclea violacea and comparative vasorelaxant effects with Dioclea rostrata

Energy Technology Data Exchange (ETDEWEB)

Rocha, B.A.M.; Bezerra, M.J.B.; Bezerra, G.A.; Alencar, K.L.L.; Nascimento, K.S.; Naganao, C.S.; Sampaio, A.H.; Cavada, B.S. [Universidade Federal do Ceara (UFC), Fortaleza, CE (Brazil); Delatorre, P. [Universidade Federal da Paraiba (UFPB), Joao Pessoa, PB (Brazil); Rodrigues, N.V.; Pires, A.F.; Assreuy, A.M.S. [Universidade Estadual do Ceara (UECE), Fortaleza, CE (Brazil); Marins, J.L. [Universidade Federal de Pelotas (UFPel), Pelotas, RS (Brazil)

2012-07-01

Full text: Lectins are a structural heterogeneous group of proteins possessing at least one non-catalytic domain that binds reversibly to a specific mono or oligosaccharide. Diocleinae lectins exhibit glucose/mannose monosaccharide binding specificity and studies of their chemical and physicochemical properties revealed a high degree of identity in their amino acid sequences and three dimensional structures. This study investigated structural/functional relationships between lectins obtained from Dioclea violacea (DVL) and Dioclea rostrata (DRL). The purified lectin (DVL) was solubilized in 20 mM Tris-HCl pH 7.6 with 5 mM CaCl{sub 2} and MnCl{sub 2} buffer and incubated during one hour before the crystallization experiments with the ligand X-Man (5-bromo-4-chloro-3-indolyl-{alpha}-D-mannose) at 3 mM. Crystals of DVL grew in condition 33 of Crystal Screen I (4M Sodium formate) and belong to the orthorhombic space group I222. The structure of DVL at 2.6 resolution was obtained by molecular replacement using the coordinates of DRL (PDB code 2ZBJ), after the last refinement the structure presented R factor of 0.23 and R free of 0.27. The crystal structures reveal differences between them and could be related to relaxant activity. The conformation of residues HIS51, HIS131 and GLU205 and others positioned at CRD lead to different lectin binding activities. In fact, the pocket in DVL is small and deep and promotes weak interaction with carbohydrates, while DRL pocket is large and shallow, allowing strong interaction between CRD and sugars. This can explain why DVL and DRL elicited different degrees of aorta relaxation showing maximal effects of 43 % and 96 %, respectively. (author)

The PDZ protein tax-interacting protein-1 inhibits beta-catenin transcriptional activity and growth of colorectal cancer cells.

Science.gov (United States)

Kanamori, Mutsumi; Sandy, Peter; Marzinotto, Stefania; Benetti, Roberta; Kai, Chikatoshi; Hayashizaki, Yoshihide; Schneider, Claudio; Suzuki, Harukazu

2003-10-03

Wnt signaling is essential during development while deregulation of this pathway frequently leads to the formation of various tumors including colorectal carcinomas. A key component of the pathway is beta-catenin that, in association with TCF-4, directly regulates the expression of Wnt-responsive genes. To identify novel binding partners of beta-catenin that may control its transcriptional activity, we performed a mammalian two-hybrid screen and isolated the Tax-interacting protein (TIP-1). The in vivo complex formation between beta-catenin and TIP-1 was verified by coimmunoprecipitation, and a direct physical association was revealed by glutathione S-transferase pull-down experiments in vitro. By using a panel of deletion mutants of both proteins, we demonstrate that the interaction is mediated by the PDZ (PSD-95/DLG/ZO-1 homology) domain of TIP-1 and requires primarily the last four amino acids of beta-catenin. TIP-1 overexpression resulted in a dose-dependent decrease in the transcriptional activity of beta-catenin when tested on the TOP/FOPFLASH reporter system. Conversely, siRNA-mediated knock-down of endogenous TIP-1 slightly increased endogenous beta-catenin transactivation function. Moreover, we show that overexpression of TIP-1 reduced the proliferation and anchorage-independent growth of colorectal cancer cells. These data suggest that TIP-1 may represent a novel regulatory element in the Wnt/beta-catenin signaling pathway.

IQ-domain GTPase-activating protein 1 promotes the malignant phenotype of invasive ductal breast carcinoma via canonical Wnt pathway.

Science.gov (United States)

Zhao, Huan-Yu; Han, Yang; Wang, Jian; Yang, Lian-He; Zheng, Xiao-Ying; Du, Jiang; Wu, Guang-Ping; Wang, En-Hua

2017-06-01

IQ-domain GTPase-activating protein 1 is a scaffolding protein with multidomain which plays a role in modulating dishevelled (Dvl) nuclear translocation in canonical Wnt pathway. However, the biological function and mechanism of IQ-domain GTPase-activating protein 1 in invasive ductal carcinoma (IDC) remain unknown. In this study, we found that IQ-domain GTPase-activating protein 1 expression was elevated in invasive ductal carcinoma, which was positively correlated with tumor grade, lymphatic metastasis, and poor prognosis. Coexpression of IQ-domain GTPase-activating protein 1 and Dvl in the nucleus and cytoplasm of invasive ductal carcinoma was significantly correlated but not in the membrane. Postoperative survival in the patients with their coexpression in the nucleus and cytoplasm was obviously lower than that without coexpression. The positive expression rates of c-myc and cyclin D1 were significantly higher in the patients with nuclear coexpression of Dvl and IQ-domain GTPase-activating protein 1 than that with cytoplasmic coexpression, correlating with poor prognosis. IQ-domain GTPase-activating protein 1 significantly enhanced cell proliferation and invasion in invasive ductal carcinoma cell lines by interacting with Dvl in cytoplasm to promote Dvl nuclear translocation so as to upregulate the expression of c-myc and cyclin D1. Collectively, our data suggest that IQ-domain GTPase-activating protein 1 may promote the malignant phenotype of invasive ductal carcinoma via canonical Wnt signaling, and it could be used as a potential prognostic biomarker for breast cancer patients.

Crystallographic analysis of NHERF1–PLCβ3 interaction provides structural basis for CXCR2 signaling in pancreatic cancer

International Nuclear Information System (INIS)

Jiang, Yuanyuan; Wang, Shuo; Holcomb, Joshua; Trescott, Laura; Guan, Xiaoqing; Hou, Yuning; Brunzelle, Joseph; Sirinupong, Nualpun; Li, Chunying; Yang, Zhe

2014-01-01

Highlights: • CXCR2–NHERF1–PLCβ3 complex regulates CXCR2 signaling in pancreatic cancer. • The crystal structure of the NHERF1 PDZ1 domain in complex with PLCβ3. • The structure reveals specificity determinants of PDZ1–PLCβ3 interaction. • Endogenous PLCβ3 in pancreatic cancer cells interacts with both PDZ1 and PDZ2. • Structural basis of the PDZ1–PLCβ3 interaction is valuable in selective drug design. - Abstract: The formation of CXCR2–NHERF1–PLCβ3 macromolecular complex in pancreatic cancer cells regulates CXCR2 signaling activity and plays an important role in tumor proliferation and invasion. We previously have shown that disruption of the NHERF1-mediated CXCR2–PLCβ3 interaction abolishes the CXCR2 signaling cascade and inhibits pancreatic tumor growth in vitro and in vivo. Here we report the crystal structure of the NHERF1 PDZ1 domain in complex with the C-terminal PLCβ3 sequence. The structure reveals that the PDZ1–PLCβ3 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four PLCβ3 residues contributing to specific interactions. We also show that PLCβ3 can bind both NHERF1 PDZ1 and PDZ2 in pancreatic cancer cells, consistent with the observation that the peptide binding pockets of these PDZ domains are highly structurally conserved. This study provides an understanding of the structural basis for the PDZ-mediated NHERF1–PLCβ3 interaction that could prove valuable in selective drug design against CXCR2-related cancers

Crystallographic analysis of NHERF1–PLCβ3 interaction provides structural basis for CXCR2 signaling in pancreatic cancer

Energy Technology Data Exchange (ETDEWEB)

Jiang, Yuanyuan; Wang, Shuo; Holcomb, Joshua; Trescott, Laura; Guan, Xiaoqing; Hou, Yuning [Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI (United States); Brunzelle, Joseph [Advanced Photon Source, Argonne National Lab, Argonne, IL (United States); Sirinupong, Nualpun [Nutraceuticals and Functional Food Research and Development Center, Prince of Songkla University, Hat-Yai, Songkhla (Thailand); Li, Chunying, E-mail: cl@med.wayne.edu [Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI (United States); Yang, Zhe, E-mail: zyang@med.wayne.edu [Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI (United States)

2014-04-04

Highlights: • CXCR2–NHERF1–PLCβ3 complex regulates CXCR2 signaling in pancreatic cancer. • The crystal structure of the NHERF1 PDZ1 domain in complex with PLCβ3. • The structure reveals specificity determinants of PDZ1–PLCβ3 interaction. • Endogenous PLCβ3 in pancreatic cancer cells interacts with both PDZ1 and PDZ2. • Structural basis of the PDZ1–PLCβ3 interaction is valuable in selective drug design. - Abstract: The formation of CXCR2–NHERF1–PLCβ3 macromolecular complex in pancreatic cancer cells regulates CXCR2 signaling activity and plays an important role in tumor proliferation and invasion. We previously have shown that disruption of the NHERF1-mediated CXCR2–PLCβ3 interaction abolishes the CXCR2 signaling cascade and inhibits pancreatic tumor growth in vitro and in vivo. Here we report the crystal structure of the NHERF1 PDZ1 domain in complex with the C-terminal PLCβ3 sequence. The structure reveals that the PDZ1–PLCβ3 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four PLCβ3 residues contributing to specific interactions. We also show that PLCβ3 can bind both NHERF1 PDZ1 and PDZ2 in pancreatic cancer cells, consistent with the observation that the peptide binding pockets of these PDZ domains are highly structurally conserved. This study provides an understanding of the structural basis for the PDZ-mediated NHERF1–PLCβ3 interaction that could prove valuable in selective drug design against CXCR2-related cancers.

Loss of Dishevelleds disrupts planar polarity in ependymal motile cilia and results in hydrocephalus

Science.gov (United States)

Ohata, Shinya; Nakatani, Jin; Herranz-Pérez, Vicente; Cheng, JrGang; Belinson, Haim; Inubushi, Toshiro; Snider, William D.; García-Verdugo, Jose Manuel; Wynshaw-Boris, Anthony; Álvarez-Buylla, Arturo

2014-01-01

SUMMARY Defects in ependymal (E) cells, which line the ventricle and generate cerebrospinal fluid flow through ciliary beating, can cause hydrocephalus. Dishevelled genes (Dvls) are essential for Wnt signaling and Dvl2 has been shown to localize to the rootlet of motile cilia. Using the hGFAP-Cre;Dvl1−/−;2flox/flox;3+/− mouse, we show that compound genetic ablation of Dvls causes hydrocephalus. In hGFAP-Cre;Dvl1−/−;2flox/flox;3+/− mutants, E cells differentiated normally, but the intracellular and intercellular rotational alignments of ependymal motile cilia were disrupted. As a consequence, the fluid flow generated by the hGFAP-Cre;Dvl1−/−;2flox/flox;3+/− E cells was significantly slower than that observed in control mice. Dvls were also required for the proper positioning of motile cilia on the apical surface. Tamoxifen-induced conditional removal of Dvls in adult mice also resulted in defects in intracellular rotational alignment and positioning of ependymal motile cilia. These results suggest that Dvls are continuously required for E cell planar polarity and may prevent hydrocephalus. PMID:25043421

The expression of the new epididymal luminal protein of PDZ domain containing 1 is decreased in asthenozoospermia

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A-Juan Liang

2018-01-01

Full Text Available Spermatozoa are not mature until they transit the epididymis where they acquire motility and the ability to fertilize an egg through sequential modifications. The epididymis has three functional regions, caput, corpus, and cauda, and the luminal proteins of the epididymis play important roles in the above modifications. However, the proteins with differential enrichment between the caput and cauda are still largely unknown. To reveal the functions of the caput and cauda during sperm maturation, luminal proteins from caput and cauda of mice were analyzed by isobaric tag for relative and absolute quantitation (iTRAQ. Overall, 128 differentially enriched proteins were found, of which 46 were caput enriched and 82 were cauda enriched. Bioinformatic analysis showed that lipid metabolism was active in the caput; while anion- and cation-binding activity and phosphorus and organophosphate metabolism were active in the cauda. A new epididymal luminal protein, the caput-enriched PDZ domain containing 1 (Pdzk1, also named Na+/H+ exchange regulatory cofactor 3 (NHERF3, which plays a critical role in cholesterol metabolism and carnitine transport, was found in the lipid metabolism. Western blotting and immunofluorescence analyses showed that Pdzk1 was expressed in the epididymis but not in the testis, and localized at the middle piece of the sperm tail. Pdzk1 protein level was also reduced in the spermatozoa in case of asthenozoospermic patients compared with that in normozoospermic men, suggesting that Pdzk1 may participate in sperm maturation regulation and may be associated with male infertility. These results may provide new insights into the mechanisms of sperm maturation and male infertility.

Mechanism underlying selective regulation of G protein-gated inwardly rectifying potassium channels by the psychostimulant-sensitive sorting nexin 27

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Balana, Bartosz; Maslennikov, Innokentiy; Kwiatkowski, Witek; Stern, Kalyn M.; Bahima, Laia; Choe, Senyon; Slesinger, Paul A.

2011-01-01

G protein-gated inwardly rectifying potassium (GIRK) channels are important gatekeepers of neuronal excitability. The surface expression of neuronal GIRK channels is regulated by the psychostimulant-sensitive sorting nexin 27 (SNX27) protein through a class I (-X-Ser/Thr-X-Φ, where X is any residue and Φ is a hydrophobic amino acid) PDZ-binding interaction. The G protein-insensitive inward rectifier channel (IRK1) contains the same class I PDZ-binding motif but associates with a different synaptic PDZ protein, postsynaptic density protein 95 (PSD95). The mechanism by which SNX27 and PSD95 discriminate these channels was previously unclear. Using high-resolution structures coupled with biochemical and functional analyses, we identified key amino acids upstream of the channel's canonical PDZ-binding motif that associate electrostatically with a unique structural pocket in the SNX27-PDZ domain. Changing specific charged residues in the channel's carboxyl terminus or in the PDZ domain converts the selective association and functional regulation by SNX27. Elucidation of this unique interaction site between ion channels and PDZ-containing proteins could provide a therapeutic target for treating brain diseases. PMID:21422294

Allostery Is an Intrinsic Property of the Protease Domain of DegS Implications for Enzyme Function and Evolution

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Sohn, Jungsan; Grant, Robert A.; Sauer, Robert T. (MIT)

2010-12-02

DegS is a periplasmic Escherichia coli protease, which functions as a trimer to catalyze the initial rate-limiting step in a proteolytic cascade that ultimately activates transcription of stress response genes in the cytoplasm. Each DegS subunit consists of a protease domain and a PDZ domain. During protein folding stress, DegS is allosterically activated by peptides exposed in misfolded outer membrane porins, which bind to the PDZ domain and stabilize the active protease. It is not known whether allostery is conferred by the PDZ domains or is an intrinsic feature of the trimeric protease domain. Here, we demonstrate that free DegS{sup {Delta}PDZ} equilibrates between active and inactive trimers with the latter species predominating. Substrate binding stabilizes active DegS{sup {Delta}PDZ} in a positively cooperative fashion. Mutations can also stabilize active DegS{sup {Delta}PDZ} and produce an enzyme that displays hyperbolic kinetics and degrades substrate with a maximal velocity within error of that for fully activated, intact DegS. Crystal structures of multiple DegS{sup {Delta}PDZ} variants, in functional and non-functional conformations, support a two-state model in which allosteric switching is mediated by changes in specific elements of tertiary structure in the context of an invariant trimeric base. Overall, our results indicate that protein substrates must bind sufficiently tightly and specifically to the functional conformation of DegS{sup {Delta}PDZ} to assist their own degradation. Thus, substrate binding alone may have regulated the activities of ancestral DegS trimers with subsequent fusion of the protease domain to a PDZ domain, resulting in ligand-mediated regulation.

Nup358 interacts with Dishevelled and aPKC to regulate neuronal polarity

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Pankhuri Vyas

2013-10-01

Par polarity complex, consisting of Par3, Par6, and aPKC, plays a conserved role in the establishment and maintenance of polarization in diverse cellular contexts. Recent reports suggest that Dishevelled (Dvl, a cytoplasmic mediator of Wnt signalling, interacts with atypical protein kinase C and regulates its activity during neuronal differentiation and directed cell migration. Here we show that Nup358 (also called RanBP2, a nucleoporin previously implicated in polarity during directed cell migration, interacts with Dishevelled and aPKC through its N-terminal region (BPN and regulates axon–dendrite differentiation of cultured hippocampal neurons. Depletion of endogenous Nup358 leads to generation of multiple axons, whereas overexpression of BPN abrogates the process of axon formation. Moreover, siRNA-mediated knockdown of Dvl or inhibition of aPKC by a pseudosubstrate inhibitor significantly reverses the multiple axon phenotype produced by Nup358 depletion. Collectively, these data suggest that Nup358 plays an important role in regulating neuronal polarization upstream to Dvl and aPKC.

Biophysical characterization of the complex between human papillomavirus E6 protein and synapse-associated protein 97

DEFF Research Database (Denmark)

Chi, Celestine Ngang; Bach, Anders; Engström, Åke

2011-01-01

The E6 protein of human papillomavirus exhibits complex interaction patterns with several host proteins and their roles in HPV mediated oncogenesis have proved challenging to study. Here we use several biophysical techniques to explore the binding of E6 to the three PDZ domains of the tumor......, this quaternary complex has the same apparent hydrodynamic volume as the unliganded PDZ region, suggesting that a conformational change occurs in the PDZ region upon binding, a conclusion supported by kinetic experiments. Using NMR, we discovered a new mode of interaction between E6 and PDZ: a subset of residues...

Human T-Cell Leukemia Virus Type I-Mediated Repression of PDZ-LIM Domain-Containing Protein 2 Involves DNA Methylation But Independent of the Viral Oncoprotein Tax

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Pengrong Yan

2009-10-01

Full Text Available Human T-cell leukemia virus type I (HTLV-I is the etiological agent of adult T-cell leukemia (ATL. Our recent studies have shown that one important mechanism of HTLV-I-Mediated tumorigenesis is through PDZ-LIM domain-containing protein 2 (PDLIM2 repression, although the involved mechanism remains unknown. Here, we further report that HTLV-I-Mediated PDLIM2 repression was a pathophysiological event and the PDLIM2 repression involved DNA methylation. Whereas DNA methyltransferases 1 and 3b but not 3a were upregulated in HTLV-I-transformed T cells, the hypomethylating agent 5-aza-2′-deoxycytidine (5-aza-dC restored PDLIM2 expression and induced death of these malignant cells. Notably, the PDLIM2 repression was independent of the viral regulatory protein Tax because neither short-term induction nor long-term stable expression of Tax could downregulate PDLIM2 expression. These studies provide important insights into PDLIM2 regulation, HTLV-I leukemogenicity, long latency, and cancer health disparities. Given the efficient antitumor activity with no obvious toxicity of 5-aza-dC, these studies also suggest potential therapeutic strategies for ATL.

Membrane Localization is Critical for Activation of the PICK1 BAR Domain

Science.gov (United States)

Madsen, Kenneth L.; Eriksen, Jacob; Milan-Lobo, Laura; Han, Daniel S.; Niv, Masha Y.; Ammendrup-Johnsen, Ina; Henriksen, Ulla; Bhatia, Vikram K.; Stamou, Dimitrios; Sitte, Harald H.; McMahon, Harvey T.; Weinstein, Harel; Gether, Ulrik

2013-01-01

The PSD-95/Discs-large/ZO-1 homology (PDZ) domain protein, protein interacting with C kinase 1 (PICK1) contains a C-terminal Bin/amphiphysin/Rvs (BAR) domain mediating recognition of curved membranes; however, the molecular mechanisms controlling the activity of this domain are poorly understood. In agreement with negative regulation of the BAR domain by the N-terminal PDZ domain, PICK1 distributed evenly in the cytoplasm, whereas truncation of the PDZ domain caused BAR domain-dependent redistribution to clusters colocalizing with markers of recycling endosomal compartments. A similar clustering was observed both upon truncation of a short putative α-helical segment in the linker between the PDZ and the BAR domains and upon coexpression of PICK1 with a transmembrane PDZ ligand, including the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR2 subunit, the GluR2 C-terminus transferred to the single transmembrane protein Tac or the dopamine transporter C-terminus transferred to Tac. In contrast, transfer of the GluR2 C-terminus to cyan fluorescent protein, a cytosolic protein, did not elicit BAR domain-dependent clustering. Instead, localizing PICK1 to the membrane by introducing an N-terminal myristoylation site produced BAR domain-dependent, but ligand-independent, PICK1 clustering. The data support that in the absence of PDZ ligand, the PICK1 BAR domain is inhibited through a PDZ domain-dependent and linker-dependent mechanism. Moreover, they suggest that unmasking of the BAR domain’s membrane-binding capacity is not a consequence of ligand binding to the PDZ domain per se but results from, and coincides with, recruitment of PICK1 to a membrane compartment. PMID:18466293

Structural and Functional Analysis of Human HtrA3 Protease and Its Subdomains.

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Przemyslaw Glaza

Full Text Available Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (ΔN-HtrA3, showing that the protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The ΔN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. ΔN-HtrA3 with the PDZ removed (ΔN-HtrA3-ΔPDZ and an N-terminally truncated HtrA3S (ΔN-HtrA3S were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensable for HtrA3 activity. As determined by size exclusion chromatography, ΔN-HtrA3 formed stable trimers while both ΔN-HtrA3-ΔPDZ and ΔN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of ΔN-HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of ΔN-HtrA3. Results reported in this paper provide new insights into the structure and function of ΔN-HtrA3, which seems to have a unique combination of features among human HtrA proteases.

Structural and Functional Analysis of Human HtrA3 Protease and Its Subdomains.

Science.gov (United States)

Glaza, Przemyslaw; Osipiuk, Jerzy; Wenta, Tomasz; Zurawa-Janicka, Dorota; Jarzab, Miroslaw; Lesner, Adam; Banecki, Bogdan; Skorko-Glonek, Joanna; Joachimiak, Andrzej; Lipinska, Barbara

2015-01-01

Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (ΔN-HtrA3), showing that the protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The ΔN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. ΔN-HtrA3 with the PDZ removed (ΔN-HtrA3-ΔPDZ) and an N-terminally truncated HtrA3S (ΔN-HtrA3S) were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensable for HtrA3 activity. As determined by size exclusion chromatography, ΔN-HtrA3 formed stable trimers while both ΔN-HtrA3-ΔPDZ and ΔN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of ΔN-HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of ΔN-HtrA3. Results reported in this paper provide new insights into the structure and function of ΔN-HtrA3, which seems to have a unique combination of features among human HtrA proteases.

The phosphomimetic mutation of syndecan-4 binds and inhibits Tiam1 modulating Rac1 activity in PDZ interaction-dependent manner.

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Aniko Keller-Pinter

Full Text Available The small GTPases of the Rho family comprising RhoA, Rac1 and Cdc42 function as molecular switches controlling several essential biochemical pathways in eukaryotic cells. Their activity is cycling between an active GTP-bound and an inactive GDP-bound conformation. The exchange of GDP to GTP is catalyzed by guanine nucleotide exchange factors (GEFs. Here we report a novel regulatory mechanism of Rac1 activity, which is controlled by a phosphomimetic (Ser179Glu mutant of syndecan-4 (SDC4. SDC4 is a ubiquitously expressed transmembrane, heparan sulfate proteoglycan. In this study we show that the Ser179Glu mutant binds strongly Tiam1, a Rac1-GEF reducing Rac1-GTP by 3-fold in MCF-7 breast adenocarcinoma cells. Mutational analysis unravels the PDZ interaction between SDC4 and Tiam1 is indispensable for the suppression of the Rac1 activity. Neither of the SDC4 interactions is effective alone to block the Rac1 activity, on the contrary, lack of either of interactions can increase the activity of Rac1, therefore the Rac1 activity is the resultant of the inhibitory and stimulatory effects. In addition, SDC4 can bind and tether RhoGDI1 (GDP-dissociation inhibitor 1 to the membrane. Expression of the phosphomimetic SDC4 results in the accumulation of the Rac1-RhoGDI1 complex. Co-immunoprecipitation assays (co-IP-s reveal that SDC4 can form complexes with RhoGDI1. Together, the regulation of the basal activity of Rac1 is fine tuned and SDC4 is implicated in multiple ways.

The phosphomimetic mutation of syndecan-4 binds and inhibits Tiam1 modulating Rac1 activity in PDZ interaction–dependent manner

Science.gov (United States)

Keller-Pinter, Aniko; Ughy, Bettina; Domoki, Monika; Pettko-Szandtner, Aladar; Letoha, Tamas; Tovari, Jozsef; Timar, Jozsef

2017-01-01

The small GTPases of the Rho family comprising RhoA, Rac1 and Cdc42 function as molecular switches controlling several essential biochemical pathways in eukaryotic cells. Their activity is cycling between an active GTP-bound and an inactive GDP-bound conformation. The exchange of GDP to GTP is catalyzed by guanine nucleotide exchange factors (GEFs). Here we report a novel regulatory mechanism of Rac1 activity, which is controlled by a phosphomimetic (Ser179Glu) mutant of syndecan-4 (SDC4). SDC4 is a ubiquitously expressed transmembrane, heparan sulfate proteoglycan. In this study we show that the Ser179Glu mutant binds strongly Tiam1, a Rac1-GEF reducing Rac1-GTP by 3-fold in MCF-7 breast adenocarcinoma cells. Mutational analysis unravels the PDZ interaction between SDC4 and Tiam1 is indispensable for the suppression of the Rac1 activity. Neither of the SDC4 interactions is effective alone to block the Rac1 activity, on the contrary, lack of either of interactions can increase the activity of Rac1, therefore the Rac1 activity is the resultant of the inhibitory and stimulatory effects. In addition, SDC4 can bind and tether RhoGDI1 (GDP-dissociation inhibitor 1) to the membrane. Expression of the phosphomimetic SDC4 results in the accumulation of the Rac1–RhoGDI1 complex. Co-immunoprecipitation assays (co-IP-s) reveal that SDC4 can form complexes with RhoGDI1. Together, the regulation of the basal activity of Rac1 is fine tuned and SDC4 is implicated in multiple ways. PMID:29121646

The phosphomimetic mutation of syndecan-4 binds and inhibits Tiam1 modulating Rac1 activity in PDZ interaction-dependent manner.

Science.gov (United States)

Keller-Pinter, Aniko; Ughy, Bettina; Domoki, Monika; Pettko-Szandtner, Aladar; Letoha, Tamas; Tovari, Jozsef; Timar, Jozsef; Szilak, Laszlo

2017-01-01

The small GTPases of the Rho family comprising RhoA, Rac1 and Cdc42 function as molecular switches controlling several essential biochemical pathways in eukaryotic cells. Their activity is cycling between an active GTP-bound and an inactive GDP-bound conformation. The exchange of GDP to GTP is catalyzed by guanine nucleotide exchange factors (GEFs). Here we report a novel regulatory mechanism of Rac1 activity, which is controlled by a phosphomimetic (Ser179Glu) mutant of syndecan-4 (SDC4). SDC4 is a ubiquitously expressed transmembrane, heparan sulfate proteoglycan. In this study we show that the Ser179Glu mutant binds strongly Tiam1, a Rac1-GEF reducing Rac1-GTP by 3-fold in MCF-7 breast adenocarcinoma cells. Mutational analysis unravels the PDZ interaction between SDC4 and Tiam1 is indispensable for the suppression of the Rac1 activity. Neither of the SDC4 interactions is effective alone to block the Rac1 activity, on the contrary, lack of either of interactions can increase the activity of Rac1, therefore the Rac1 activity is the resultant of the inhibitory and stimulatory effects. In addition, SDC4 can bind and tether RhoGDI1 (GDP-dissociation inhibitor 1) to the membrane. Expression of the phosphomimetic SDC4 results in the accumulation of the Rac1-RhoGDI1 complex. Co-immunoprecipitation assays (co-IP-s) reveal that SDC4 can form complexes with RhoGDI1. Together, the regulation of the basal activity of Rac1 is fine tuned and SDC4 is implicated in multiple ways.

Membrane Localization is Critical for Activation of the PICK1 BAR Domain

OpenAIRE

Madsen, Kenneth L.; Eriksen, Jacob; Milan-Lobo, Laura; Han, Daniel S.; Niv, Masha Y.; Ammendrup-Johnsen, Ina; Henriksen, Ulla; Bhatia, Vikram K.; Stamou, Dimitrios; Sitte, Harald H.; McMahon, Harvey T.; Weinstein, Harel; Gether, Ulrik

2008-01-01

The PSD-95/Discs-large/ZO-1 homology (PDZ) domain protein, protein interacting with C kinase 1 (PICK1) contains a C-terminal Bin/amphiphysin/Rvs (BAR) domain mediating recognition of curved membranes; however, the molecular mechanisms controlling the activity of this domain are poorly understood. In agreement with negative regulation of the BAR domain by the N-terminal PDZ domain, PICK1 distributed evenly in the cytoplasm, whereas truncation of the PDZ domain caused BAR domain-dependent redis...

Distribution dynamics and functional importance of NHERF1 in regulation of Mrp-2 trafficking in hepatocytes.

Science.gov (United States)

Karvar, Serhan; Suda, Jo; Zhu, Lixin; Rockey, Don C

2014-10-15

Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) is a multifunctional scaffolding protein that interacts with receptors and ion transporters in its PDZ domains and with the ezrin-radixin-moesin (ERM) family of proteins in its COOH terminus. The role of NHERF1 in hepatocyte function remains largely unknown. We examine the distribution and physiological significance of NHERF1 and multidrug resistance-associated protein 2 (Mrp-2) in hepatocytes. A WT radixin binding site mutant (F355R) and NHERF1 PDZ1 and PDZ2 domain adenoviral mutant constructs were tagged with yellow fluorescent protein and expressed in polarized hepatocytes to study localization and function of NHERF1. Cellular distribution of NHERF1 and radixin was visualized by fluorescence microscopy. A 5-chloromethylfluorescein diacetate (CMFDA) assay was used to characterize Mrp-2 function. Similar to Mrp-2, WT NHERF1 and the NHERF1 PDZ2 deletion mutant were localized to the canalicular membrane. In contrast, the radixin binding site mutant (F355R) and the NHERF1 PDZ1 deletion mutant, which interacts poorly with Mrp-2, were rarely associated with the canalicular membrane. Knockdown of NHERF1 led to dramatically impaired CMFDA secretory response. Use of CMFDA showed that the NHERF1 PDZ1 and F355R mutants were devoid of a secretory response, while WT NHERF1-infected cells exhibited increased secretion of glutathione-methylfluorescein. The data indicate that NHERF1 interacts with Mrp-2 via the PDZ1 domain of NHERF1 and, furthermore, that NHERF1 is essential for maintaining the localization and function of Mrp-2. Copyright © 2014 the American Physiological Society.

Actin-Sorting Nexin 27 (SNX27)-Retromer Complex Mediates Rapid Parathyroid Hormone Receptor Recycling*

Science.gov (United States)

McGarvey, Jennifer C.; Xiao, Kunhong; Bowman, Shanna L.; Mamonova, Tatyana; Zhang, Qiangmin; Bisello, Alessandro; Sneddon, W. Bruce; Ardura, Juan A.; Jean-Alphonse, Frederic; Vilardaga, Jean-Pierre; Puthenveedu, Manojkumar A.; Friedman, Peter A.

2016-01-01

The G protein-coupled parathyroid hormone receptor (PTHR) regulates mineral-ion homeostasis and bone remodeling. Upon parathyroid hormone (PTH) stimulation, the PTHR internalizes into early endosomes and subsequently traffics to the retromer complex, a sorting platform on early endosomes that promotes recycling of surface receptors. The C terminus of the PTHR contains a type I PDZ ligand that binds PDZ domain-containing proteins. Mass spectrometry identified sorting nexin 27 (SNX27) in isolated endosomes as a PTHR binding partner. PTH treatment enriched endosomal PTHR. SNX27 contains a PDZ domain and serves as a cargo selector for the retromer complex. VPS26, VPS29, and VPS35 retromer subunits were isolated with PTHR in endosomes from cells stimulated with PTH. Molecular dynamics and protein binding studies establish that PTHR and SNX27 interactions depend on the PDZ recognition motif in PTHR and the PDZ domain of SNX27. Depletion of either SNX27 or VPS35 or actin depolymerization decreased the rate of PTHR recycling following agonist stimulation. Mutating the PDZ ligand of PTHR abolished the interaction with SNX27 but did not affect the overall rate of recycling, suggesting that PTHR may directly engage the retromer complex. Coimmunoprecipitation and overlay experiments show that both intact and mutated PTHR bind retromer through the VPS26 protomer and sequentially assemble a ternary complex with PTHR and SNX27. SNX27-independent recycling may involve N-ethylmaleimide-sensitive factor, which binds both PDZ intact and mutant PTHRs. We conclude that PTHR recycles rapidly through at least two pathways, one involving the ASRT complex of actin, SNX27, and retromer and another possibly involving N-ethylmaleimide-sensitive factor. PMID:27008860

Wnt Signalling Promotes Actin Dynamics during Axon Remodelling through the Actin-Binding Protein Eps8.

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Eleanna Stamatakou

Full Text Available Upon arrival at their synaptic targets, axons slow down their growth and extensively remodel before the assembly of presynaptic boutons. Wnt proteins are target-derived secreted factors that promote axonal remodelling and synaptic assembly. In the developing spinal cord, Wnts secreted by motor neurons promote axonal remodelling of NT-3 responsive dorsal root ganglia neurons. Axon remodelling induced by Wnts is characterised by growth cone pausing and enlargement, processes that depend on the re-organisation of microtubules. However, the contribution of the actin cytoskeleton has remained unexplored. Here, we demonstrate that Wnt3a regulates the actin cytoskeleton by rapidly inducing F-actin accumulation in growth cones from rodent DRG neurons through the scaffold protein Dishevelled-1 (Dvl1 and the serine-threonine kinase Gsk3β. Importantly, these changes in actin cytoskeleton occurs before enlargement of the growth cones is evident. Time-lapse imaging shows that Wnt3a increases lamellar protrusion and filopodia velocity. In addition, pharmacological inhibition of actin assembly demonstrates that Wnt3a increases actin dynamics. Through a yeast-two hybrid screen, we identified the actin-binding protein Eps8 as a direct interactor of Dvl1, a scaffold protein crucial for the Wnt signalling pathway. Gain of function of Eps8 mimics Wnt-mediated axon remodelling, whereas Eps8 silencing blocks the axon remodelling activity of Wnt3a. Importantly, blockade of the Dvl1-Eps8 interaction completely abolishes Wnt3a-mediated axonal remodelling. These findings demonstrate a novel role for Wnt-Dvl1 signalling through Eps8 in the regulation of axonal remodeling.

Microstructural and analytical analysis of plasma dissociated zircon

International Nuclear Information System (INIS)

Minnaar, E G; Neethling, J H; Lee, M E; Snyders, E

2012-01-01

The investigation of the microstructure and distribution of impurities was carried out on plasma dissociated zircon (PDZ). The morphology of the PDZ and crystalline nature of the zirconia was determined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) while energy dispersive X-ray spectrometry (EDS) provided compositional information. The SEM and TEM results indicate that the morphology and crystalline nature of the zirconia varies as a result of the existence of a thermal gradient. The EDS results show that the majority of the impurities segregates to the silica phase of the PDZ.

The roles of USH1 proteins and PDZ domain-containing USH proteins in USH2 complex integrity in cochlear hair cells.

Science.gov (United States)

Zou, Junhuang; Chen, Qian; Almishaal, Ali; Mathur, Pranav Dinesh; Zheng, Tihua; Tian, Cong; Zheng, Qing Y; Yang, Jun

2017-02-01

Usher syndrome (USH) is the most common cause of inherited deaf-blindness, manifested as USH1, USH2 and USH3 clinical types. The protein products of USH2 causative and modifier genes, USH2A, ADGRV1, WHRN and PDZD7, interact to assemble a multiprotein complex at the ankle link region of the mechanosensitive stereociliary bundle in hair cells. Defects in this complex cause stereociliary bundle disorganization and hearing loss. The four USH2 proteins also interact in vitro with USH1 proteins including myosin VIIa, USH1G (SANS), CIB2 and harmonin. However, it is unclear whether the interactions between USH1 and USH2 proteins occur in vivo and whether USH1 proteins play a role in USH2 complex assembly in hair cells. In this study, we identified a novel interaction between myosin VIIa and PDZD7 by FLAG pull-down assay. We further investigated the role of the above-mentioned four USH1 proteins in the cochlear USH2 complex assembly using USH1 mutant mice. We showed that only myosin VIIa is indispensable for USH2 complex assembly at ankle links, indicating the potential transport and/or anchoring role of myosin VIIa for USH2 proteins in hair cells. However, myosin VIIa is not required for USH2 complex assembly in photoreceptors. We further showed that, while PDZ protein harmonin is not involved, its paralogous USH2 proteins, PDZD7 and whirlin, function synergistically in USH2 complex assembly in cochlear hair cells. In summary, our studies provide novel insight into the functional relationship between USH1 and USH2 proteins in the cochlea and the retina as well as the disease mechanisms underlying USH1 and USH2. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Probing the role of backbone hydrogen bonds in protein-peptide interactions by amide-to-ester mutations

DEFF Research Database (Denmark)

Eildal, Jonas N N; Hultqvist, Greta; Balle, Thomas

2013-01-01

-protein interactions, those of the PDZ domain family involve formation of intermolecular hydrogen bonds: C-termini or internal linear motifs of proteins bind as β-strands to form an extended antiparallel β-sheet with the PDZ domain. Whereas extensive work has focused on the importance of the amino acid side chains...... of the protein ligand, the role of the backbone hydrogen bonds in the binding reaction is not known. Using amide-to-ester substitutions to perturb the backbone hydrogen-bonding pattern, we have systematically probed putative backbone hydrogen bonds between four different PDZ domains and peptides corresponding...... to natural protein ligands. Amide-to-ester mutations of the three C-terminal amides of the peptide ligand severely affected the affinity with the PDZ domain, demonstrating that hydrogen bonds contribute significantly to ligand binding (apparent changes in binding energy, ΔΔG = 1.3 to >3.8 kcal mol(-1...

Dynamics based alignment of proteins: an alternative approach to quantify dynamic similarity

Directory of Open Access Journals (Sweden)

Lyngsø Rune

2010-04-01

Full Text Available Abstract Background The dynamic motions of many proteins are central to their function. It therefore follows that the dynamic requirements of a protein are evolutionary constrained. In order to assess and quantify this, one needs to compare the dynamic motions of different proteins. Comparing the dynamics of distinct proteins may also provide insight into how protein motions are modified by variations in sequence and, consequently, by structure. The optimal way of comparing complex molecular motions is, however, far from trivial. The majority of comparative molecular dynamics studies performed to date relied upon prior sequence or structural alignment to define which residues were equivalent in 3-dimensional space. Results Here we discuss an alternative methodology for comparative molecular dynamics that does not require any prior alignment information. We show it is possible to align proteins based solely on their dynamics and that we can use these dynamics-based alignments to quantify the dynamic similarity of proteins. Our method was tested on 10 representative members of the PDZ domain family. Conclusions As a result of creating pair-wise dynamics-based alignments of PDZ domains, we have found evolutionarily conserved patterns in their backbone dynamics. The dynamic similarity of PDZ domains is highly correlated with their structural similarity as calculated with Dali. However, significant differences in their dynamics can be detected indicating that sequence has a more refined role to play in protein dynamics than just dictating the overall fold. We suggest that the method should be generally applicable.

Genetic changes of MLH1 and MSH2 genes could explain constant findings on microsatellite instability in intracranial meningioma.

Science.gov (United States)

Pećina-Šlaus, Nives; Kafka, Anja; Bukovac, Anja; Vladušić, Tomislav; Tomas, Davor; Hrašćan, Reno

2017-07-01

Postreplicative mismatch repair safeguards the stability of our genome. The defects in its functioning will give rise to microsatellite instability. In this study, 50 meningiomas were investigated for microsatellite instability. Two major mismatch repair genes, MLH1 and MSH2, were analyzed using microsatellite markers D1S1611 and BAT26 amplified by polymerase chain reaction and visualized by gel electrophoresis on high-resolution gels. Furthermore, genes DVL3 (D3S1262), AXIN1 (D16S3399), and CDH1 (D16S752) were also investigated for microsatellite instability. Our study revealed constant presence of microsatellite instability in meningioma patients when compared to their autologous blood DNA. Altogether 38% of meningiomas showed microsatellite instability at one microsatellite locus, 16% on two, and 13.3% on three loci. The percent of detected microsatellite instability for MSH2 gene was 14%, and for MLH1, it was 26%, for DVL3 22.9%, for AXIN1 17.8%, and for CDH1 8.3%. Since markers also allowed for the detection of loss of heterozygosity, gross deletions of MLH1 gene were found in 24% of meningiomas. Genetic changes between MLH1 and MSH2 were significantly positively correlated (p = 0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p = 0.034). No significant associations were observed when MLH1 or MSH2 was tested against specific histopathological meningioma subtype or World Health Organization grade. However, genetic changes in DVL3 were strongly associated with anaplastic histology of meningioma (χ 2  = 9.14; p = 0.01). Our study contributes to better understanding of the genetic profile of human intracranial meningiomas and suggests that meningiomas harbor defective cellular DNA mismatch repair mechanisms.

The GRIP1/14-3-3 pathway coordinates cargo trafficking and dendrite development

NARCIS (Netherlands)

Geiger, J.C.; Lipka, Joanna; Hoyer, S.; Schlager, M.A.; Wulf, Phebe; Weinges, S.; Demmers, J.; Hoogenraad, Casper

2014-01-01

Regulation of cargo transport via adaptor molecules is essential for neuronal development. However, the role of PDZ scaffolding proteins as adaptors in neuronal cargo trafficking is still poorly understood. Here, we show by genetic deletion in mice that the multi-PDZ domain scaffolding protein

Protein interacting with C kinase 1 (PICK1) reduces reinsertion rates of interaction partners sorted to Rab11-dependent slow recycling pathway

DEFF Research Database (Denmark)

Madsen, Kenneth Lindegaard; Thorsen, Thor Seneca; Rahbek-Clemmensen, Troels

2012-01-01

The scaffolding protein PICK1 (protein interacting with C kinase 1) contains an N-terminal PSD-95/Discs large/ZO-1 (PDZ) domain and a central lipid-binding Bin/amphiphysin/Rvs (BAR) domain. PICK1 is thought to regulate trafficking of its PDZ binding partners but different and even opposing...... functions have been suggested. Here, we apply ELISA-based assays and confocal microscopy in HEK293 cells with inducible PICK1 expression to assess in an isolated system the ability of PICK1 to regulate trafficking of natural and engineered PDZ binding partners. The dopamine transporter (DAT), which...

Association of whirlin with Cav1.3 (alpha1D) channels in photoreceptors, defining a novel member of the usher protein network.

NARCIS (Netherlands)

Kersten, F.F.J.; Wijk, E. van; Reeuwijk, J. van; Zwaag, B. van der; Marker, T.; Peters, T.A.; Katsanis, N.; Wolfrum, U.; Keunen, J.E.E.; Roepman, R.; Kremer, J.M.J.

2010-01-01

PURPOSE: Usher syndrome is the most common form of hereditary deaf-blindness. It is both clinically and genetically heterogeneous. The USH2D protein whirlin interacts via its PDZ domains with other Usher-associated proteins containing a C-terminal type I PDZ-binding motif. These proteins co-localize

Distinct 3D Architecture and Dynamics of the Human HtrA2(Omi Protease and Its Mutated Variants.

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Artur Gieldon

Full Text Available HtrA2(Omi protease controls protein quality in mitochondria and plays a major role in apoptosis. Its HtrA2S306A mutant (with the catalytic serine routinely disabled for an X-ray study to avoid self-degradation is a homotrimer whose subunits contain the serine protease domain (PD and the regulatory PDZ domain. In the inactive state, a tight interdomain interface limits penetration of both PDZ-activating ligands and PD substrates into their respective target sites. We successfully crystalized HtrA2V226K/S306A, whose active counterpart HtrA2V226K has had higher proteolytic activity, suggesting higher propensity to opening the PD-PDZ interface than that of the wild type HtrA2. Yet, the crystal structure revealed the HtrA2V226K/S306A architecture typical of the inactive protein. To get a consistent interpretation of crystallographic data in the light of kinetic results, we employed molecular dynamics (MD. V325D inactivating mutant was used as a reference. Our simulations demonstrated that upon binding of a specific peptide ligand NH2-GWTMFWV-COOH, the PDZ domains open more dynamically in the wild type protease compared to the V226K mutant, whereas the movement is not observed in the V325D mutant. The movement relies on a PDZ vs. PD rotation which opens the PD-PDZ interface in a lid-like (budding flower-like in trimer fashion. The noncovalent hinges A and B are provided by two clusters of interfacing residues, harboring V325D and V226K in the C- and N-terminal PD barrels, respectively. The opening of the subunit interfaces progresses in a sequential manner during the 50 ns MD simulation. In the systems without the ligand only minor PDZ shifts relative to PD are observed, but the interface does not open. Further activation-associated events, e.g. PDZ-L3 positional swap seen in any active HtrA protein (vs. HtrA2, were not observed. In summary, this study provides hints on the mechanism of activation of wtHtrA2, the dynamics of the inactive HtrA2V325D

A Lectin from Dioclea violacea Interacts with Midgut Surface of Lutzomyia migonei, Unlike Its Homologues, Cratylia floribunda Lectin and Canavalia gladiata Lectin

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Juliana Montezuma Barbosa Monteiro Tínel

2014-01-01

Full Text Available Leishmaniasis is a vector-borne disease transmitted by phlebotomine sand fly. Susceptibility and refractoriness to Leishmania depend on the outcome of multiple interactions that take place within the sand fly gut. Promastigote attachment to sand fly midgut epithelium is essential to avoid being excreted together with the digested blood meal. Promastigote and gut sand fly surface glycans are important ligands in this attachment. The purpose of the present study was to evaluate the interaction of three lectins isolated from leguminous seeds (Diocleinae subtribe, D-glucose and D-mannose-binding, with glycans on Lutzomyia migonei midgut. To study this interaction the lectins were labeled with FITC and a fluorescence assay was performed. The results showed that only Dioclea violacea lectin (DVL was able to interact with midgut glycans, unlike Cratylia floribunda lectin (CFL and Canavalia gladiata lectin (CGL. Furthermore, when DVL was blocked with D-mannose the interaction was inhibited. Differences of spatial arrangement of residues and volume of carbohydrate recognition domain (CRD may be the cause of the fine specificity of DVL for glycans in the surface on Lu. migonei midgut. The findings in this study showed the presence of glycans in the midgut with glucose/mannose residues in its composition and these residues may be important in interaction between Lu. migonei midgut and Leishmania.

Down-regulation of LRP1B in colon cancer promoted the growth and migration of cancer cells.

Science.gov (United States)

Wang, Zhiqiang; Sun, Peng; Gao, Chun; Chen, Ji; Li, Jun; Chen, Zhonghao; Xu, Ming; Shao, Jun; Zhang, Yunpeng; Xie, Jiang

2017-08-01

Aberrant activation of beta-catenin/TCF signaling is one of the hallmarks of colon cancer. It is of great interest to study the mechanism for the regulation of beta-catenin/TCF signaling. In this study, it was found that LRP1B was down-regulated in colon cancer tissues and inhibited the growth, migration and metastasis of colon cancer cells. The molecular mechanism study revealed that LRP1B interacted with DVL2, inhibited the interaction between DVL2 and Axin, and negatively regulated beta-catenin/TCF signaling. Taken together, our study demonstrated the suppressive roles of LRP1B in the progression of colon cancer, implicating that restoring the function of LRP1B would be a promising strategy for the treatment of colon cancer. Copyright © 2017. Published by Elsevier Inc.

Aripiprazole and Haloperidol Activate GSK3β-Dependent Signalling Pathway Differentially in Various Brain Regions of Rats.

Science.gov (United States)

Pan, Bo; Huang, Xu-Feng; Deng, Chao

2016-03-28

Aripiprazole, a dopamine D₂ receptor (D₂R) partial agonist, possesses a unique clinical profile. Glycogen synthase kinase 3β (GSK3β)-dependent signalling pathways have been implicated in the pathophysiology of schizophrenia and antipsychotic drug actions. The present study examined whether aripiprazole differentially affects the GSK3β-dependent signalling pathways in the prefrontal cortex (PFC), nucleus accumbens (NAc), and caudate putamen (CPu), in comparison with haloperidol (a D₂R antagonist) and bifeprunox (a D₂R partial agonist). Rats were orally administrated aripiprazole (0.75 mg/kg), bifeprunox (0.8 mg/kg), haloperidol (0.1 mg/kg) or vehicle three times per day for one week. The levels of protein kinase B (Akt), p-Akt, GSK3β, p-GSK3β, dishevelled (Dvl)-3, and β-catenin were measured by Western Blots. Aripiprazole increased GSK3β phosphorylation in the PFC and NAc, respectively, while haloperidol elevated it in the NAc only. However, Akt activity was not changed by any of these drugs. Additionally, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3 and β-catenin in the NAc. The present study suggests that activation of GSK3β phosphorylation in the PFC and NAc may be involved in the clinical profile of aripiprazole; additionally, aripiprazole can increase GSK3β phosphorylation via the Dvl-GSK3β-β-catenin signalling pathway in the NAc, probably due to its relatively low intrinsic activity at D₂Rs.

Evaluation of performance of Son Tek Argonaut acoustic doppler velocity log in tow tank and sea

Digital Repository Service at National Institute of Oceanography (India)

Joseph, A; Madhan, R.; Mascarenhas, A.A; Desai, R.G.P.; VijayKumar, K.; Dias, M.; Tengali, S.; Methar, A

Performance of a 500-kHz, 3-beam downward-looking Sontex Argonaut acoustic Doppler velocity log (DVL) based on measurements at tow-tank and sea is addressed. Its accuracy and linearity under tow-tank measurements were largely scattered...

The detection of annual hypoxia in a low latitude freshwater reservoir in Kerala, India, using the small AUV Maya

Digital Repository Service at National Institute of Oceanography (India)

Desa, E.S.; Madhan, R.; Maurya, P.K.; Navelkar, G.S.; Mascarenhas, A.A.M.Q.; Prabhudesai, S.; Afzulpurkar, S.; Desa, E.; Pascoal, A.M.; Nambiar, M.

dead reckoning methods that involve the integration of the DVL velocities in an inertial frame of reference. The underwater Z coordinate is not estimated but set equal to the pressure transducer output in meters. Simple Line of Sight (LOS) way...

PIST regulates the intracellular trafficking and plasma membrane expression of Cadherin 23

Directory of Open Access Journals (Sweden)

Oshima Kazuo

2010-10-01

Full Text Available Abstract Background The atypical cadherin protein cadherin 23 (CDH23 is crucial for proper function of retinal photoreceptors and inner ear hair cells. As we obtain more and more information about the specific roles of cadherin 23 in photoreceptors and hair cells, the regulatory mechanisms responsible for the transport of this protein to the plasma membrane are largely unknown. Results PIST, a Golgi-associated, PDZ domain-containing protein, interacted with cadherin 23 via the PDZ domain of PIST and the C-terminal PDZ domain-binding interface (PBI of cadherin 23. By binding to cadherin 23, PIST retained cadherin 23 in the trans-Golgi network of cultured cells. The retention was released when either of the two known cadherin 23-binding proteins MAGI-1 and harmonin was co-expressed. Similar to MAGI-1 and harmonin, PIST was detected in mouse inner ear sensory hair cells. Conclusions PIST binds cadherin 23 via its PDZ domain and retains cadherin 23 in trans-Golgi network. MAGI-1 and harmonin can compete with PIST for binding cadherin 23 and release cadherin 23 from PIST's retention. Our finding suggests that PIST, MAGI-1 and harmonin collaborate in intracellular trafficking of cadherin 23 and regulate the plasma membrane expression of cadherin 23.

Handbook for Greenhouse Rose Production Ethiopia

NARCIS (Netherlands)

Maden, van der E.; Hoogerwerf, F.; Marrewijk, van J.; Kerklaan, E.; Posthumus, J.; Boven, van A.; Elings, A.; Garcia Victoria, N.; Rikken, M.; Humphries, G.

2012-01-01

This practical handbook is prepared by DLV Plant, in collaboration with Wageningen UR, CBI and EHPEA, under assignment of the Ethiopia Netherlands Horticulture Partnership (ENHP). The following persons have contributed to this handbook: DVL Plant: Edwin van der Maden, Francis Hoogerwerf, Jeroen van

Detecting protein-protein interactions in living cells

DEFF Research Database (Denmark)

Gottschalk, Marie; Bach, Anders; Hansen, Jakob Lerche

2009-01-01

to the endogenous C-terminal peptide of the NMDA receptor, as evaluated by a cell-free protein-protein interaction assay. However, it is important to address both membrane permeability and effect in living cells. Therefore a bioluminescence resonance energy transfer (BRET) assay was established, where the C......-terminal of the NMDA receptor and PDZ2 of PSD-95 were fused to green fluorescent protein (GFP) and Renilla luciferase (Rluc) and expressed in COS7 cells. A robust and specific BRET signal was obtained by expression of the appropriate partner proteins and subsequently, the assay was used to evaluate a Tat......The PDZ domain mediated interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treatment of ischemic brain diseases. We have recently developed a number of peptide analogues with improved affinity for the PDZ domains of PSD-95 compared...

Mortality in farmed mink: Systematic collection versus arbitrary submissions for diagnostic investigation

DEFF Research Database (Denmark)

Rattenborg, Erik; Dietz, Hans-Henrik; Andersen, T.H.

1999-01-01

The distribution of diagnoses of mortality in mink submitted to the Danish Veterinary Laboratory (DVL) for diagnostic investigation in the calendar year 1997 was compared with the diagnoses of mortality in all dead mink collected at 4 selected farms (project farms) during the same period. A total...

Wnt3a regulates proliferation and migration of HUVEC via canonical and non-canonical Wnt signaling pathways

International Nuclear Information System (INIS)

Samarzija, Ivana; Sini, Patrizia; Schlange, Thomas; MacDonald, Gwen; Hynes, Nancy E.

2009-01-01

Untangling the signaling pathways involved in endothelial cell biology is of central interest for the development of antiangiogenesis based therapies. Here we report that Wnt3a induces the proliferation and migration of HUVECs, but does not affect their survival. Wnt3a-induced proliferation was VEGFR signaling independent, but reduced upon CamKII inhibition. In a search for the downstream mediators of Wnt3a's effects on HUVEC biology, we found that Wnt3a treatment leads to phosphorylation of DVL3 and stabilization of β-catenin. Moreover, under the same conditions we observed an upregulation in c-MYC, TIE-2 and GJA1 mRNA transcripts. Although treatment of HUVECs with Wnt5a induced DVL3 phosphorylation, we did not observe any of the other effects seen upon Wnt3a stimulation. Taken together, our data indicate that Wnt3a induces canonical and non-canonical Wnt signaling in HUVECs, and stimulates their proliferation and migration.

Wavelengths of the Ni-like 4d to 4p X-ray laser lines

International Nuclear Information System (INIS)

Utsumi, Takayuki; Sasaki, Akira

2000-01-01

The wavelengths of the Ni-like 4d to 4p X-ray laser lines for elements ranging from Pd(Z=46) to U(Z=92) calculated using the relativistic multi-configuration Dirac-Fock code, i.e. grasp92, are presented. These optimal level calculations agree well with measurements and previous calculations. To obtain accurate lasing wavelengths is important to grasp the energy level structure of the complicated Ni-like ions, and especially for the development of collisionally pumped X-ray lasers. The lasing wavelengths are also essential to identify the lines and when the X-ray laser is utilized for imaging and interferometry. (author)

Plasma Membrane Targeting of Protocadherin 15 Is Regulated by the Golgi-Associated Chaperone Protein PIST

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Hongyun Nie

2016-01-01

Full Text Available Protocadherin 15 (PCDH15 is a core component of hair cell tip-links and crucial for proper function of inner ear hair cells. Mutations of PCDH15 gene cause syndromic and nonsyndromic hearing loss. At present, the regulatory mechanisms responsible for the intracellular transportation of PCDH15 largely remain unknown. Here we show that PIST, a Golgi-associated, PDZ domain-containing protein, interacts with PCDH15. The interaction is mediated by the PDZ domain of PIST and the C-terminal PDZ domain-binding interface (PBI of PCDH15. Through this interaction, PIST retains PCDH15 in the trans-Golgi network (TGN and reduces the membrane expression of PCDH15. We have previously showed that PIST regulates the membrane expression of another tip-link component, cadherin 23 (CDH23. Taken together, our finding suggests that PIST regulates the intracellular trafficking and membrane targeting of the tip-link proteins CDH23 and PCDH15.

Regulation of Akt and Wnt signaling by the group II metabotropic glutamate receptor antagonist LY341495 and agonist LY379268.

Science.gov (United States)

Sutton, Laurie P; Rushlow, Walter J

2011-06-01

Metabotropic glutamate receptors 2/3 (mGlu(2/3)) have been implicated in schizophrenia and as a novel treatment target for schizophrenia. The current study examined whether mGlu(2/3) regulates Akt (protein kinase B) and Wnt (Wingless/Int-1) signaling, two cascades associated with schizophrenia and modified by antipsychotics. Western blotting revealed increases in phosphorylated Akt (pAkt) and phosphorylated glycogen synthase kinase-3 (pGSK-3) following acute and repeated treatment of LY379268 (mGlu(2/3) agonist), whereas increases in dishevelled-2 (Dvl-2), dishevelled-3 (Dvl-3), GSK-3 and β-catenin were only observed following repeated treatment. LY341495 (mGlu(2/3) antagonist) induced the opposite response compared with LY379268. Co-immunoprecipitation experiments showed an association between the mGlu(2/3) complex and Dvl-2 providing a possible mechanism to explain how the mGlu(2/3) can mediate changes in Wnt signaling. However, there was no association between the mGlu(2/3) complex and Akt suggesting that changes in Akt signaling following LY341495 and LY379268 treatments may not be directly mediated by the mGlu(2/3) . Finally, an increase in locomotor activity induced by LY341495 treatment correlated with increased pAkt and pGSK-3 levels and was attenuated by the administration of the GSK-3 inhibitor, SB216763. Overall, the results suggest that mGlu(2/3) regulates Akt and Wnt signaling and LY379268 treatment has overlapping effects with D(2) dopamine receptor antagonists (antipsychotic drugs). © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

A New Crucial Protein Interaction Element That Targets the Adenovirus E4-ORF1 Oncoprotein to Membrane Vesicles▿

OpenAIRE

Chung, Sang-Hyuk; Frese, Kristopher K.; Weiss, Robert S.; Prasad, B. V. Venkataram; Javier, Ronald T.

2007-01-01

Human adenovirus type 9 exclusively elicits mammary tumors in experimental animals, and the primary oncogenic determinant of this virus is the E4-ORF1 oncogene, as opposed to the well-known E1A and E1B oncogenes. The tumorigenic potential of E4-ORF1, as well as its ability to oncogenically stimulate phosphatidylinositol 3-kinase (PI3K), depends on a carboxyl-terminal PDZ domain-binding motif (PBM) that mediates interactions with several different membrane-associated cellular PDZ proteins, inc...

Optimally Stopped Optimization

Science.gov (United States)

Vinci, Walter; Lidar, Daniel

We combine the fields of heuristic optimization and optimal stopping. We propose a strategy for benchmarking randomized optimization algorithms that minimizes the expected total cost for obtaining a good solution with an optimal number of calls to the solver. To do so, rather than letting the objective function alone define a cost to be minimized, we introduce a further cost-per-call of the algorithm. We show that this problem can be formulated using optimal stopping theory. The expected cost is a flexible figure of merit for benchmarking probabilistic solvers that can be computed when the optimal solution is not known, and that avoids the biases and arbitrariness that affect other measures. The optimal stopping formulation of benchmarking directly leads to a real-time, optimal-utilization strategy for probabilistic optimizers with practical impact. We apply our formulation to benchmark the performance of a D-Wave 2X quantum annealer and the HFS solver, a specialized classical heuristic algorithm designed for low tree-width graphs. On a set of frustrated-loop instances with planted solutions defined on up to N = 1098 variables, the D-Wave device is between one to two orders of magnitude faster than the HFS solver.

Overexpression of cypin alters dendrite morphology, single neuron activity, and network properties via distinct mechanisms

Science.gov (United States)

Rodríguez, Ana R.; O'Neill, Kate M.; Swiatkowski, Przemyslaw; Patel, Mihir V.; Firestein, Bonnie L.

2018-02-01

Objective. This study investigates the effect that overexpression of cytosolic PSD-95 interactor (cypin), a regulator of synaptic PSD-95 protein localization and a core regulator of dendrite branching, exerts on the electrical activity of rat hippocampal neurons and networks. Approach. We cultured rat hippocampal neurons and used lipid-mediated transfection and lentiviral gene transfer to achieve high levels of cypin or cypin mutant (cypinΔPDZ PSD-95 non-binding) expression cellularly and network-wide, respectively. Main results. Our analysis revealed that although overexpression of cypin and cypinΔPDZ increase dendrite numbers and decrease spine density, cypin and cypinΔPDZ distinctly regulate neuronal activity. At the single cell level, cypin promotes decreases in bursting activity while cypinΔPDZ reduces sEPSC frequency and further decreases bursting compared to cypin. At the network level, by using the Fano factor as a measure of spike count variability, cypin overexpression results in an increase in variability of spike count, and this effect is abolished when cypin cannot bind PSD-95. This variability is also dependent on baseline activity levels and on mean spike rate over time. Finally, our spike sorting data show that overexpression of cypin results in a more complex distribution of spike waveforms and that binding to PSD-95 is essential for this complexity. Significance. Our data suggest that dendrite morphology does not play a major role in cypin action on electrical activity.

Mechanical properties and microstructures of 1100 aluminum subjected to dry machining

International Nuclear Information System (INIS)

Ni, H.; Elmadagli, M.; Alpas, A.T.

2004-01-01

Commercial purity 1100 aluminum samples with an initial grain size of 4.6 μm were subjected to dry orthogonal cutting, i.e., without using cutting fluid. The strain distributions in the deformed material ahead of the cutting tool tip were estimated using a metallographic method based on the observation of shear angles. Local flow stress values were estimated using microhardness measurements. Deformation structures developed in the material ahead of the tool tip were investigated at four different locations using transmission electron microscopy (TEM). The microstructure in the primary deformation zone (PDZ) was characterized by elongated subgrains, extending in the direction of the strain gradient. The average thickness of the subgrains was 380 nm and their width was 730 nm. The hardness of the PDZ was 80 kg/mm 2 , which represented an increase of 80% from the initial hardness. The strains in the machined chips (MC) reached a high value of 2.3. The corresponding microstructure consisted of a mixture of elongated subgrains with dimensions similar to those observed in the PDZ, and recrystallized equiaxed grains with diameters ranging between 25 and 75 nm. This was accompanied with an 8% decrease in the hardness of the MC compared to that of the PDZ. Grain growth occurred in the secondary deformation zone (SDZ) resulting in large equiaxed grains of 1.2 μm in diameter. The use of cooling fluid during machining restricted grain growth in the SDZ by limiting the grain size to 360 nm

Arrestin scaffolds NHERF1 to the P2Y12 receptor to regulate receptor internalization.

Science.gov (United States)

Nisar, Shaista P; Cunningham, Margaret; Saxena, Kunal; Pope, Robert J; Kelly, Eamonn; Mundell, Stuart J

2012-07-13

We have recently shown in a patient with mild bleeding that the PDZ-binding motif of the platelet G protein-coupled P2Y(12) receptor (P2Y(12)R) is required for effective receptor traffic in human platelets. In this study we show for the first time that the PDZ motif-binding protein NHERF1 exerts a major role in potentiating G protein-coupled receptor (GPCR) internalization. NHERF1 interacts with the C-tail of the P2Y(12)R and unlike many other GPCRs, NHERF1 interaction is required for effective P2Y(12)R internalization. In vitro and prior to agonist stimulation P2Y(12)R/NHERF1 interaction requires the intact PDZ binding motif of this receptor. Interestingly on receptor stimulation NHERF1 no longer interacts directly with the receptor but instead binds to the receptor via the endocytic scaffolding protein arrestin. These findings suggest a novel model by which arrestin can serve as an adaptor to promote NHERF1 interaction with a GPCR to facilitate effective NHERF1-dependent receptor internalization.

The PDZ and band 4.1 containing protein Frmpd1 regulates the subcellular location of activator of G-protein signaling 3 and its interaction with G-proteins.

Science.gov (United States)

An, Ningfei; Blumer, Joe B; Bernard, Michael L; Lanier, Stephen M

2008-09-05

Activator of G-protein signaling 3 (AGS3) is one of nine mammalian proteins containing one or more G-protein regulatory (GPR) motifs that stabilize the GDP-bound conformation of Galphai. Such proteins have revealed unexpected functional diversity for the "G-switch" in the control of events within the cell independent of the role of heterotrimeric G-proteins as transducers for G-protein-coupled receptors at the cell surface. A key question regarding this class of proteins is what controls their subcellular positioning and interaction with G-proteins. We conducted a series of yeast two-hybrid screens to identify proteins interacting with the tetratricopeptide repeat (TPR) of AGS3, which plays an important role in subcellular positioning of the protein. We report the identification of Frmpd1 (FERM and PDZ domain containing 1) as a regulatory binding partner of AGS3. Frmpd1 binds to the TPR domain of AGS3 and coimmunoprecipitates with AGS3 from cell lysates. Cell fractionation indicated that Frmpd1 stabilizes AGS3 in a membrane fraction. Upon cotransfection of COS7 cells with Frmpd1-GFP and AGS3-mRFP, AGS3-mRFP is observed in regions of the cell cortex and also in membrane extensions or processes where it appears to be colocalized with Frmpd1-GFP based upon the merged fluorescent signals. Frmpd1 knockdown (siRNA) in Cath.a-differentiated neuronal cells decreased the level of endogenous AGS3 in membrane fractions by approximately 50% and enhanced the alpha2-adrenergic receptor-mediated inhibition of forskolin-induced increases in cAMP. The coimmunoprecipitation of Frmpd1 with AGS3 is lost as the amount of Galphai3 in the cell is increased and AGS3 apparently switches its binding partner from Frmpd1 to Galphai3 indicating that the interaction of AGS3 with Frmpd1 and Galphai3 is mutually exclusive. Mechanistically, Frmpd1 may position AGS3 in a membrane environment where it then interacts with Galphai in a regulated manner.

Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.

Science.gov (United States)

Osada, Takuya; Chen, Minyong; Yang, Xiao Yi; Spasojevic, Ivan; Vandeusen, Jeffrey B; Hsu, David; Clary, Bryan M; Clay, Timothy M; Chen, Wei; Morse, Michael A; Lyerly, H Kim

2011-06-15

Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC.

Cftr Modulates Wnt/β-Catenin Signaling and Stem Cell Proliferation in Murine Intestine

Directory of Open Access Journals (Sweden)

Ashlee M. Strubberg

2018-01-01

Conclusions: CF intestine shows increased ISC proliferation and Wnt/β-catenin signaling. Loss of Cftr increases pHi in ISCs, which stabilizes the plasma membrane association of the Wnt transducer Dvl, likely facilitating Wnt/β-catenin signaling. Absence of Cftr-dependent suppression of ISC proliferation in the CF intestine may contribute to increased risk for intestinal tumors.

Cooperative Navigation for Low-bandwidth Mobile Acoustic Networks

Science.gov (United States)

2015-01-01

travel-time TXCO temperature compensated crystal oscillator UKF unscented Kalman filter UMBS University of Michigan Biological Station USBL ultra...access CEKF centralized extended Kalman filter CEIF centralized extended information filter CI covariance intersection CNA cooperative navigation aid DCCL...programming DEIF decentralized extended information filter DVL Doppler velocity log EIF extended information filter EKF extended Kalman filter FDMA

Ascorbic acid alters cell fate commitment of human neural progenitors in a WNT/β-catenin/ROS signaling dependent manner.

Science.gov (United States)

Rharass, Tareck; Lantow, Margareta; Gbankoto, Adam; Weiss, Dieter G; Panáková, Daniela; Lucas, Stéphanie

2017-10-16

Improving the neuronal yield from in vitro cultivated neural progenitor cells (NPCs) is an essential challenge in transplantation therapy in neurological disorders. In this regard, Ascorbic acid (AA) is widely used to expand neurogenesis from NPCs in cultures although the mechanisms of its action remain unclear. Neurogenesis from NPCs is regulated by the redox-sensitive WNT/β-catenin signaling pathway. We therefore aimed to investigate how AA interacts with this pathway and potentiates neurogenesis. Effects of 200 μM AA were compared with the pro-neurogenic reagent and WNT/β-catenin signaling agonist lithium chloride (LiCl), and molecules with antioxidant activities i.e. N-acetyl-L-cysteine (NAC) and ruthenium red (RuR), in differentiating neural progenitor ReNcell VM cells. Cells were supplemented with reagents for two periods of treatment: a full period encompassing the whole differentiation process versus an early short period that is restricted to the cell fate commitment stage. Intracellular redox balance and reactive oxygen species (ROS) metabolism were examined by flow cytometry using redox and ROS sensors. Confocal microscopy was performed to assess cell viability, neuronal yield, and levels of two proteins: Nucleoredoxin (NXN) and the WNT/β-catenin signaling component Dishevelled 2 (DVL2). TUBB3 and MYC gene responses were evaluated by quantitative real-time PCR. DVL2-NXN complex dissociation was measured by fluorescence resonance energy transfer (FRET). In contrast to NAC which predictably exhibited an antioxidant effect, AA treatment enhanced ROS metabolism with no cytotoxic induction. Both drugs altered ROS levels only at the early stage of the differentiation as no changes were held beyond the neuronal fate commitment stage. FRET studies showed that AA treatment accelerated the redox-dependent release of the initial pool of DVL2 from its sequestration by NXN, while RuR treatment hampered the dissociation of the two proteins. Accordingly, AA

MicroRNA-24 Attenuates Neointimal Hyperplasia in the Diabetic Rat Carotid Artery Injury Model by Inhibiting Wnt4 Signaling Pathway

Directory of Open Access Journals (Sweden)

Jian Yang

2016-05-01

Full Text Available The long-term stimulation of hyperglycemia greatly increases the incidence of vascular restenosis (RS after angioplasty. Neointimal hyperplasia after vascular injury is the pathological cause of RS, but its mechanism has not been elucidated. MicroRNA-24 (miR-24 has low expression in the injured carotid arteries of diabetic rats. However, the role of miR-24 in the vascular system is unknown. In this study, we explore whether over-expression of miR-24 could attenuate neointimal formation in streptozotocin (STZ-induced diabetic rats. Adenovirus (Ad-miR-24-GFP was used to deliver the miR-24 gene to injured carotid arteries in diabetic rats. The level of neointimal hyperplasia was examined by hematoxylin-eosin (HE staining. Vascular smooth muscle cell (VSMC proliferation in the neointima was evaluated by immunostaining for proliferating cell nuclear antigen (PCNA. The mRNA levels of miR-24, PCNA, wingless-type MMTV integration site family member 4 (Wnt4, disheveled-1 (Dvl-1, β-catenin and cell cycle-associated molecules (Cyclin D1, p21 were determined by Quantitative Real-Time PCR (qRT-PCR. PCNA, Wnt4, Dvl-1, β-catenin, Cyclin D1 and p21 protein levels were measured by Western blotting analysis. STZ administration decreased plasma insulin and increased fasting blood glucose in Sprague-Dawley (SD rats. The expression of miR-24 was decreased in the carotid artery after a balloon injury in diabetic rats, and adenoviral transfection (Ad-miR-24-GFP increased the expression of miR-24. Over-expression of miR-24 suppressed VSMC proliferation and neointimal hyperplasia in diabetic rats at 14 days. Furthermore, compared with Sham group, the mRNA and protein levels of PCNA, Wnt4, Dvl-1, β-catenin, and Cyclin D1 were strikingly up-regulated in the carotid arteries of diabetic rats after a balloon injury. Interestingly, up-regulation of miR-24 significantly reduced the mRNA and protein levels of these above molecules. In contrast, the change trend in p21 m

Interference of HTLV-1 Tax Protein with Cell Polarity Regulators: Defining the Subcellular Localization of the Tax-DLG1 Interaction

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Federico Marziali

2017-11-01

Full Text Available Human T cell leukemia virus (HTLV-1 Tax (Tax protein is very important in viral replication and cell transformation. Tax localizes in the nucleus and cytoplasm in association with organelles. Some activities of Tax depend on interactions with PDZ (PSD-95/Discs Large/Z0-1 domain–containing proteins such as Discs large protein 1 (DLG1 which is involved in cell polarity and proliferation. The DLG1 interaction results in a cytoplasmic co-localization pattern resembling vesicular aggregates, the nature of which is still unknown. To further explore the role of PDZ proteins in HTLV-1 cell transformation, we deeply investigated the Tax-DLG1 association. By fluorescence resonance energy transfer (FRET, we detected, for the first time, the direct binding of Tax to DLG1 within the cell. We showed that the interaction specifically affects the cellular distribution of not only DLG1, but also Tax. After studying different cell structures, we demonstrated that the aggregates distribute into the Golgi apparatus in spatial association with the microtubule-organizing center (MTOC. This study contributes to understand the biological significance of Tax-PDZ interactions.

Interference of HTLV-1 Tax Protein with Cell Polarity Regulators: Defining the Subcellular Localization of the Tax-DLG1 Interaction.

Science.gov (United States)

Marziali, Federico; Bugnon Valdano, Marina; Brunet Avalos, Clarisse; Moriena, Lucía; Cavatorta, Ana Laura; Gardiol, Daniela

2017-11-23

Human T cell leukemia virus (HTLV)-1 Tax (Tax) protein is very important in viral replication and cell transformation. Tax localizes in the nucleus and cytoplasm in association with organelles. Some activities of Tax depend on interactions with PDZ (PSD-95/Discs Large/Z0-1) domain-containing proteins such as Discs large protein 1 (DLG1) which is involved in cell polarity and proliferation. The DLG1 interaction results in a cytoplasmic co-localization pattern resembling vesicular aggregates, the nature of which is still unknown. To further explore the role of PDZ proteins in HTLV-1 cell transformation, we deeply investigated the Tax-DLG1 association. By fluorescence resonance energy transfer (FRET), we detected, for the first time, the direct binding of Tax to DLG1 within the cell. We showed that the interaction specifically affects the cellular distribution of not only DLG1, but also Tax. After studying different cell structures, we demonstrated that the aggregates distribute into the Golgi apparatus in spatial association with the microtubule-organizing center (MTOC). This study contributes to understand the biological significance of Tax-PDZ interactions.

Solving Optimization Problems via Vortex Optimization Algorithm and Cognitive Development Optimization Algorithm

Directory of Open Access Journals (Sweden)

Ahmet Demir

2017-01-01

Full Text Available In the fields which require finding the most appropriate value, optimization became a vital approach to employ effective solutions. With the use of optimization techniques, many different fields in the modern life have found solutions to their real-world based problems. In this context, classical optimization techniques have had an important popularity. But after a while, more advanced optimization problems required the use of more effective techniques. At this point, Computer Science took an important role on providing software related techniques to improve the associated literature. Today, intelligent optimization techniques based on Artificial Intelligence are widely used for optimization problems. The objective of this paper is to provide a comparative study on the employment of classical optimization solutions and Artificial Intelligence solutions for enabling readers to have idea about the potential of intelligent optimization techniques. At this point, two recently developed intelligent optimization algorithms, Vortex Optimization Algorithm (VOA and Cognitive Development Optimization Algorithm (CoDOA, have been used to solve some multidisciplinary optimization problems provided in the source book Thomas' Calculus 11th Edition and the obtained results have compared with classical optimization solutions. 

Tritium stripping in a nitrogen glove box using palladium/zeolite and SAES St 198 trademark

International Nuclear Information System (INIS)

Klien, J.E.; Wermer, J.R.

1995-01-01

Glove box clean-up experiments were conducted in a nitrogen glove box using palladium deposited on zeolite (Pd/z) and a SAES St 198 trademark getter as tritium stripping materials. Protium/deuterium samples spiked with tritium were released into a 620 liter glove box to simulate tritium releases in a 10,500 liter glove box. The Pd/z and the SAES St 198 trademark stripper beds produced a reduction in tritium activity of approximately two to three orders of magnitude and glove box clean-up was limited by a persistent background tritium activity level. Attempts to significantly reduce the glove box activity to lower levels without purging were unsuccessful

Optimization and Optimal Control

CERN Document Server

Chinchuluun, Altannar; Enkhbat, Rentsen; Tseveendorj, Ider

2010-01-01

During the last four decades there has been a remarkable development in optimization and optimal control. Due to its wide variety of applications, many scientists and researchers have paid attention to fields of optimization and optimal control. A huge number of new theoretical, algorithmic, and computational results have been observed in the last few years. This book gives the latest advances, and due to the rapid development of these fields, there are no other recent publications on the same topics. Key features: Provides a collection of selected contributions giving a state-of-the-art accou

Hypoxia inducible factor-1 is activated by transcriptional co-activator with PDZ-binding motif (TAZ) versus WWdomain-containing oxidoreductase (WWOX) in hypoxic microenvironment of bone metastasis from breast cancer.

Science.gov (United States)

Bendinelli, Paola; Maroni, Paola; Matteucci, Emanuela; Luzzati, Alessandro; Perrucchini, Giuseppe; Desiderio, Maria Alfonsina

2013-07-01

The hypoxic microenvironment of bone marrow favours the bone metastasis process. Hypoxia inducible factor (HIF)-1α is hallmark for hypoxia, correlating with poor prognosis and radio/chemotherapy resistance of primary-breast carcinoma. For bone metastasis, the molecular mechanisms involved in HIF-1α expression and HIF-1 (α/β heterodimer)-transcription factor activity are scarcely known. We studied the role played by HIF-1 in the cross-talk between neoplastic and supportive-microenvironmental cells. Also, WWdomain-containing oxidoreductase (Wwox) and transcriptional co-activator with PDZ-binding motif (TAZ) were taken into consideration evaluating whether these Hippo-pathway effectors affect bone-metastatic phenotype through HIF-1 activity. Considering bone-metastasis specimens, nuclear HIF-1α-TAZ co-localisation occurred in neoplastic and supportive cells, such as fibroblasts and endotheliocytes. Based on these data, the functional importance was verified using 1833-bone metastatic clone under hypoxia: nuclear HIF-1α and TAZ expression increased and co-immunoprecipitated, activating HIF-1-DNA binding and transactivation. In contrast, Wwox localised at perinuclear level in neoplastic cells of bone metastasis, being almost absent in supportive cells, and Wwox-protein expression diminished in hypoxic-1833 cells. Thus, TAZ regulation of HIF-1 activity might be important for bone-secondary growth, participating in metastasis-stroma cross-talk. Further, TAZ and HIF-1α-protein levels seemed correlated. In fact, blocking cyclooxygenase-2 with NS398 in hypoxic-1833 cells, not only HIF-1α decreased but also molecular-mechanism(s) upstream of the Hippo pathway were triggered: LATS-dependent TAZ phosphorylation seemed responsible for TAZ nucleus/cytoplasm translocation and degradation. In the 1833-xenograft model, NS398 largely prevented the outgrowth of bone-metastatic cells, probably related to remarkable-extracellular matrix assembly. We gained clinical insight into

Anti-helminth compound niclosamide downregulates Wnt Signaling and elicits antitumor responses in tumors with activating APC mutations

Science.gov (United States)

Osada, Takuya; Chen, Minyong; Yang, Xiao Yi; Spasojevic, Ivan; Vandeusen, Jeffrey B.; Hsu, David; Clary, Bryan M.; Clay, Timothy M.; Chen, Wei; Morse, Michael A.; Lyerly, H. Kim

2011-01-01

Wnt/β-catenin pathway activation caused by APC mutations occurs in approximately 80% of sporadic colorectal cancers. The anti-helminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined if niclosamide could inhibit the Wnt/ β-catenin pathway in human colorectal cancers and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/ β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling and exerted anti-proliferative effects in human colon cancer cell lines and colorectal cancer cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar anti-proliferative effects in these colorectal cancer model systems. In mice implanted with human colorectal cancer xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity and led to tumor control. Our findings support clinical explorations to reposition niclosamide for treatment of colorectal cancer. PMID:21531761

Identification of new binding partners of the chemosensory signalling protein Gγ13 expressed in taste and olfactory sensory cells.

Directory of Open Access Journals (Sweden)

Zhenhui eLiu

2012-06-01

Full Text Available Tastant detection in the oral cavity involves selective receptors localized at the apical extremity of a subset of specialized taste bud cells called taste receptor cells (TRCs. The identification of the genes coding for the taste receptors involved in this process have greatly improved our understanding of the molecular mechanisms underlying detection. However, how these receptors signal in TRCs, and whether the components of the signaling cascades interact with each other or are organized in complexes is mostly unexplored. Here we report on the identification of three new binding partners for the mouse G protein gamma 13 subunit (Gγ13, a component of the bitter taste receptors signalling cascade. For two of these Gγ13 associated proteins, namely GOPC and MPDZ, we describe the expression in taste bud cells for the first time. Furthermore, we demonstrate by means of a yeast two-hybrid interaction assay that the C terminal PDZ binding motif of Gγ13 interacts with selected PDZ domains in these proteins. In the case of the PDZ domain-containing protein zona occludens-1 (ZO-1, a major component of the tight junction defining the boundary between the apical and baso-lateral region of TRCs, we identified the first PDZ domain as the site of strong interaction with Gγ13. This association was further confirmed by co-immunoprecipitation experiments in HEK 293 cells. In addition, we present immunohistological data supporting partial co-localization of GOPC, MPDZ or ZO-1 and Gγ13 in taste buds cells. Finally, we extend this observation to olfactory sensory neurons, another type of chemosensory cells known to express both ZO-1 and Gγ13. Taken together our results implicate these new interaction partners in the sub-cellular distribution of Gγ13 in olfactory and gustatory primary sensory cells.

Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment.

Science.gov (United States)

Schneider, Eberhard; Märker, Tina; Daser, Angelika; Frey-Mahn, Gabriele; Beyer, Vera; Farcas, Ruxandra; Schneider-Rätzke, Brigitte; Kohlschmidt, Nicolai; Grossmann, Bärbel; Bauss, Katharina; Napiontek, Ulrike; Keilmann, Annerose; Bartsch, Oliver; Zechner, Ulrich; Wolfrum, Uwe; Haaf, Thomas

2009-02-15

A homozygous reciprocal translocation, 46,XY,t(10;11),t(10;11), was detected in a boy with non-syndromic congenital sensorineural hearing impairment. Both parents and their four other children were heterozygous translocation carriers, 46,XX,t(10;11) and 46,XY,t(10;11), respectively. Fluorescence in situ hybridization of region-specific clones to patient chromosomes was used to localize the breakpoints within bacterial artificial chromosome (BAC) RP11-108L7 on chromosome 10q24.3 and within BAC CTD-2527F12 on chromosome 11q23.3. Junction fragments were cloned by vector ligation and sequenced. The chromosome 10 breakpoint was identified within the PDZ domain containing 7 (PDZD7) gene, disrupting the open reading frame of transcript PDZD7-C (without PDZ domain) and the 5'-untranslated region of transcript PDZD7-D (with one PDZ and two prolin-rich domains). The chromosome 11 breakpoint was localized in an intergenic segment. Reverse transcriptase-polymerase chain reaction analysis revealed PDZD7 expression in the human inner ear. A murine Pdzd7 transcript that is most similar in structure to human PDZD7-D is known to be expressed in the adult inner ear and retina. PDZD7 shares sequence homology with the PDZ domain-containing genes, USH1C (harmonin) and DFNB31 (whirlin). Allelic mutations in harmonin and whirlin can cause both Usher syndrome (USH1C and USH2D, respectively) and congenital hearing impairment (DFNB18 and DFNB31, respectively). Protein-protein interaction assays revealed the integration of PDZD7 in the protein network related to the human Usher syndrome. Collectively, our data provide strong evidence that PDZD7 is a new autosomal-recessive deafness-causing gene and also a prime candidate gene for Usher syndrome.

Subcellular localization and photodynamic activity of Photodithazine (glucosamine salt of chlorin e6) in murine melanoma B16-F10: an in vitro and in vivo study

Science.gov (United States)

Ono, Bruno Andrade; Pires, Layla; Nogueira, Marcelo Saito; Kurachi, Cristina; Pratavieira, Sebastião.

2018-02-01

Photodynamic therapy (PDT) is already a good option for the clinical treatment of several lesions, including mainly nonmelanoma skin cancers. However, cutaneous melanoma treatment remains a challenge when using PDT. One of the reasons for its reduced efficacy is the high pigmentation of melanoma cells. The object of our study is to evaluate the feasibility of the Photodithazine as a photosensitizer for melanoma. Photodithazine is already used in some malignant tumors with satisfactory results and has significant absorption band around 660 nm where the absorption of melanin is low. In this study, we measured the subcellular localization and photodynamic activity of Photodithazine (PDZ) in murine melanoma B16-F10 cell culture. Additionally, a PDT procedure was applied in an animal melanoma model. This first result demonstrates that Photodithazine is more localized at mitochondria in B16F10 cell culture and the cell viability is reduced to less than 90% using 1 µg/mL (PDZ) and 2 J/cm2. We also noticed a rapid PDZ (less than one hour) accumulation in a murine melanoma model. The treatment of melanoma resulted in 20 % more animal survival after one session of PDT compared with the control group. More studies are required to evaluate the cytotoxic effects of Photodithazine at human melanoma.

Solving Optimization Problems via Vortex Optimization Algorithm and Cognitive Development Optimization Algorithm

OpenAIRE

Ahmet Demir; Utku kose

2017-01-01

In the fields which require finding the most appropriate value, optimization became a vital approach to employ effective solutions. With the use of optimization techniques, many different fields in the modern life have found solutions to their real-world based problems. In this context, classical optimization techniques have had an important popularity. But after a while, more advanced optimization problems required the use of more effective techniques. At this point, Computer Science took an...

The Human Dopamine Transporter: Investigating the Role of the C Terminus in Surface Targeting

DEFF Research Database (Denmark)

Vægter, Christian Bjerggaard

2005-01-01

Dopaminergic neurotransmission is involved in the modulation of locomotor activity, emotional behavior, memory and cognition. Hence, imbalances in the dopaminergic system in humans have been hypothesized to contribute to the pathogenesis of a number of illnesses, including Parkinson's disease......, schizophrenia, ADHD (attention deficit hyperactivity disorder) and addiction. The dopamine transporter (DAT) is a presynaptic protein of dopaminergic nerve terminals that terminate dopaminergic signaling by rapidly sequestering released dopamine from the synaptic cleft. The DAT therefore plays an important role....... New data suggest a potential role of the PDZ interaction in the regulation of DAT internalization and recycling: we found that iv disrupting the PDZ domain-binding sequence affected the regulation of constitutive internalization, degradation and potentially also recycling of DAT in Neuro2A cells. We...

Optimality Conditions in Vector Optimization

CERN Document Server

Jiménez, Manuel Arana; Lizana, Antonio Rufián

2011-01-01

Vector optimization is continuously needed in several science fields, particularly in economy, business, engineering, physics and mathematics. The evolution of these fields depends, in part, on the improvements in vector optimization in mathematical programming. The aim of this Ebook is to present the latest developments in vector optimization. The contributions have been written by some of the most eminent researchers in this field of mathematical programming. The Ebook is considered essential for researchers and students in this field.

Lifecycle-Based Swarm Optimization Method for Numerical Optimization

Directory of Open Access Journals (Sweden)

Hai Shen

2014-01-01

Full Text Available Bioinspired optimization algorithms have been widely used to solve various scientific and engineering problems. Inspired by biological lifecycle, this paper presents a novel optimization algorithm called lifecycle-based swarm optimization (LSO. Biological lifecycle includes four stages: birth, growth, reproduction, and death. With this process, even though individual organism died, the species will not perish. Furthermore, species will have stronger ability of adaptation to the environment and achieve perfect evolution. LSO simulates Biological lifecycle process through six optimization operators: chemotactic, assimilation, transposition, crossover, selection, and mutation. In addition, the spatial distribution of initialization population meets clumped distribution. Experiments were conducted on unconstrained benchmark optimization problems and mechanical design optimization problems. Unconstrained benchmark problems include both unimodal and multimodal cases the demonstration of the optimal performance and stability, and the mechanical design problem was tested for algorithm practicability. The results demonstrate remarkable performance of the LSO algorithm on all chosen benchmark functions when compared to several successful optimization techniques.

The Scaffolding Protein Synapse-Associated Protein 97 is Required for Enhanced Signaling Through Isotype-Switched IgG Memory B Cell Receptors

Science.gov (United States)

Liu, Wanli; Chen, Elizabeth; Zhao, Xing Wang; Wan, Zheng Peng; Gao, Yi Ren; Davey, Angel; Huang, Eric; Zhang, Lijia; Crocetti, Jillian; Sandoval, Gabriel; Joyce, M. Gordon; Miceli, Carrie; Lukszo, Jan; Aravind, L.; Swat, Wojciech; Brzostowski, Joseph; Pierce, Susan K.

2012-01-01

Memory B cells are generated during an individual's first encounter with a foreign antigen and respond to re-encounter with the same antigen through cell surface immunoglobulin G (IgG) B cell receptors (BCRs) resulting in rapid, high-titered IgG antibody responses. Despite a central role for IgG BCRs in B cell memory, our understanding of the molecular mechanism by which IgG BCRs enhance antibody responses is incomplete. Here, we showed that the conserved cytoplasmic tail of the IgG BCR, which contains a putative PDZ-binding motif, associated with synapse-associated protein 97 (SAP97), a member of the PDZ domain–containing, membrane-associated guanylate-kinase family of scaffolding molecules that play key roles in controlling receptor density and signal strength at neuronal synapses. We showed that SAP97 accumulated and bound to IgG BCRs in the immune synapses that formed in response to engagement of the B cell with antigen. Knocking down SAP97 in IgG-expressing B cells or mutating the putative PDZ-binding motif in the tail impaired immune synapse formation, the initiation of IgG BCR signaling, and downstream activation of p38 mitogen-activated protein kinase. Thus, heightened B cell memory responses are encoded, in part, by a mechanism that involves SAP97 serving as a scaffolding protein in the IgG BCR immune synapse. PMID:22855505

Optimal Computing Budget Allocation for Particle Swarm Optimization in Stochastic Optimization.

Science.gov (United States)

Zhang, Si; Xu, Jie; Lee, Loo Hay; Chew, Ek Peng; Wong, Wai Peng; Chen, Chun-Hung

2017-04-01

Particle Swarm Optimization (PSO) is a popular metaheuristic for deterministic optimization. Originated in the interpretations of the movement of individuals in a bird flock or fish school, PSO introduces the concept of personal best and global best to simulate the pattern of searching for food by flocking and successfully translate the natural phenomena to the optimization of complex functions. Many real-life applications of PSO cope with stochastic problems. To solve a stochastic problem using PSO, a straightforward approach is to equally allocate computational effort among all particles and obtain the same number of samples of fitness values. This is not an efficient use of computational budget and leaves considerable room for improvement. This paper proposes a seamless integration of the concept of optimal computing budget allocation (OCBA) into PSO to improve the computational efficiency of PSO for stochastic optimization problems. We derive an asymptotically optimal allocation rule to intelligently determine the number of samples for all particles such that the PSO algorithm can efficiently select the personal best and global best when there is stochastic estimation noise in fitness values. We also propose an easy-to-implement sequential procedure. Numerical tests show that our new approach can obtain much better results using the same amount of computational effort.

A CLINICAL AND HISTOPATHOLOGICAL STUDY OF LICHEN PLANUS

OpenAIRE

Ch. Madhu Babu; P. Padmaja; M. Roopa Shree

2016-01-01

BACKGROUND Lichen planus is an idiopathic subacute or chronic inflammatory disease of the skin, mucous membranes, and nails. We studied the clinicopathological profile of 50 cases of Lichen planus in Osmania General Hospital from September 2010-April 2012. METHODS A total of 50 cases Lichen planus attending DVL OPD at OGH were studied. Clinical features like age, sex, type of Lichen planus, location were recorded in the case record form. Histological features of Lichen planus...

Oil Reservoir Production Optimization using Optimal Control

DEFF Research Database (Denmark)

Völcker, Carsten; Jørgensen, John Bagterp; Stenby, Erling Halfdan

2011-01-01

Practical oil reservoir management involves solution of large-scale constrained optimal control problems. In this paper we present a numerical method for solution of large-scale constrained optimal control problems. The method is a single-shooting method that computes the gradients using the adjo...... reservoir using water ooding and smart well technology. Compared to the uncontrolled case, the optimal operation increases the Net Present Value of the oil field by 10%.......Practical oil reservoir management involves solution of large-scale constrained optimal control problems. In this paper we present a numerical method for solution of large-scale constrained optimal control problems. The method is a single-shooting method that computes the gradients using...

A hybrid bird mating optimizer algorithm with teaching-learning-based optimization for global numerical optimization

Directory of Open Access Journals (Sweden)

Qingyang Zhang

2015-02-01

Full Text Available Bird Mating Optimizer (BMO is a novel meta-heuristic optimization algorithm inspired by intelligent mating behavior of birds. However, it is still insufficient in convergence of speed and quality of solution. To overcome these drawbacks, this paper proposes a hybrid algorithm (TLBMO, which is established by combining the advantages of Teaching-learning-based optimization (TLBO and Bird Mating Optimizer (BMO. The performance of TLBMO is evaluated on 23 benchmark functions, and compared with seven state-of-the-art approaches, namely BMO, TLBO, Artificial Bee Bolony (ABC, Particle Swarm Optimization (PSO, Fast Evolution Programming (FEP, Differential Evolution (DE, Group Search Optimization (GSO. Experimental results indicate that the proposed method performs better than other existing algorithms for global numerical optimization.

Optimal Pollution, Optimal Population, and Sustainability

OpenAIRE

Ulla Lehmijoki

2012-01-01

This paper develops a long-run consumer optimization model with endogenous pollution and endogenous population. The positive check increases mortality if pollution increases. The optimal path is sustainable if it provides non-decreasing consumption for a non-decreasing population. As usually, optimality and sustainability may conflict; with population endogenous to pollution, this conflict may ultimately lead the human species toward self-imposed extinction. Not even technical progress can wa...

Three-Dimensional Imaging of Lipids and Metabolites in Tissues by Nanospray Desorption Electrospray Ionization Mass Spectrometry

Energy Technology Data Exchange (ETDEWEB)

Lanekoff, Ingela T.; Burnum-Johnson, Kristin E.; Thomas, Mathew; Cha, Jeeyeon; Dey, Sudhansu K.; yang, Pengxiang; Prieto, Mari; Laskin, Julia

2015-03-01

Abstract Three-dimensional (3D) imaging of tissue sections is a new frontier in mass spectrometry imaging (MSI). Here we report on fast 3D imaging of lipids and metabolites associated with mouse uterine decidual cells and embryo at the implantation site on day 6 of pregnancy. 2D imaging of 16-20 serial tissue sections deposited on the same glass slide was performed using nanospray desorption electrospray ionization (nano-DESI) – an ambient ionization technique that enables sensitive localized analysis of analytes on surfaces without special sample pre-treatment. In this proof-of-principle study, nano-DESI was coupled to a high-resolution Q-Exactive instrument operated at high repetition rate of >5 Hz with moderate mass resolution of 35,000 (m/Δm at m/z 200), which enabled acquisition of the entire 3D image with a spatial resolution of ~150 μm in less than 4.5 hours. The results demonstrate localization of acetylcholine in the primary decidual zone (PDZ) of the implantation site throughout the depth of the tissue examined, indicating an important role of this signaling molecule in decidualization. Choline and phosphocholine – metabolites associated with cell growth – are enhanced in the PDZ and abundant in other cellular regions of the implantation site. Very different 3D distributions were obtained for fatty acids (FA), oleic acid and linoleic acid (FA 18:1 and FA 18:2), differing only by one double bond. Localization of FA 18:2 in the PDZ indicates its important role in decidualization while FA 18:1 is distributed more evenly throughout the tissue. In contrast, several lysophosphatidylcholines (LPC) observed in this study show donut-like distributions with localization around the PDZ. Complementary distributions with minimal overlap were observed for LPC 18:0 and FA 18:2 while the 3D image of the potential precursor phosphatidylcholine (PC 36:2) showed a significant overlap with both LPC 18:0 and FA 18:2.

SwissProt search result: AK120089 [KOME

Lifescience Database Archive (English)

Full Text Available kinase (EC 2.7.1.37) (T-LAK cell-originated protein kinase) (PDZ-binding kinase) (Spermatogenesis-related protein kinase) (SPK) (MAPKK-like protein kinase) (Nori-3) TOPK_HUMAN 6e-12 ...

SwissProt search result: AK112001 [KOME

Lifescience Database Archive (English)

Full Text Available kinase (EC 2.7.1.37) (T-LAK cell-originated protein kinase) (PDZ-binding kinase) (Spermatogenesis-related protein kinase) (SPK) (MAPKK-like protein kinase) (Nori-3) TOPK_HUMAN 5e-16 ...

SwissProt search result: AK072014 [KOME

Lifescience Database Archive (English)

Full Text Available kinase (EC 2.7.1.37) (T-LAK cell-originated protein kinase) (PDZ-binding kinase) (Spermatogenesis-related protein kinase) (SPK) (MAPKK-like protein kinase) (Nori-3) TOPK_HUMAN 2e-11 ...

SwissProt search result: AK061767 [KOME

Lifescience Database Archive (English)

Full Text Available kinase (EC 2.7.1.37) (T-LAK cell-originated protein kinase) (PDZ-binding kinase) (Spermatogenesis-related protein kinase) (SPK) (MAPKK-like protein kinase) (Nori-3) TOPK_HUMAN 4e-12 ...

SwissProt search result: AK066381 [KOME

Lifescience Database Archive (English)

Full Text Available kinase (EC 2.7.1.37) (T-LAK cell-originated protein kinase) (PDZ-binding kinase) (Spermatogenesis-related protein kinase) (SPK) (MAPKK-like protein kinase) (Nori-3) TOPK_HUMAN 6e-14 ...

SwissProt search result: AK058504 [KOME

Lifescience Database Archive (English)

Full Text Available kinase (EC 2.7.1.37) (T-LAK cell-originated protein kinase) (PDZ-binding kinase) (Spermatogenesis-related protein kinase) (SPK) (MAPKK-like protein kinase) (Nori-3) TOPK_HUMAN 3e-14 ...

SwissProt search result: AK101312 [KOME

Lifescience Database Archive (English)

Full Text Available kinase (EC 2.7.1.37) (T-LAK cell-originated protein kinase) (PDZ-binding kinase) (Spermatogenesis-related protein kinase) (SPK) (MAPKK-like protein kinase) (Nori-3) TOPK_HUMAN 1e-11 ...

SwissProt search result: AK120146 [KOME

Lifescience Database Archive (English)

Full Text Available kinase (EC 2.7.1.37) (T-LAK cell-originated protein kinase) (PDZ-binding kinase) (Spermatogenesis-related protein kinase) (SPK) (MAPKK-like protein kinase) (Nori-3) TOPK_HUMAN 3e-17 ...

SwissProt search result: AK120857 [KOME

Lifescience Database Archive (English)

Full Text Available kinase (EC 2.7.1.37) (T-LAK cell-originated protein kinase) (PDZ-binding kinase) (Spermatogenesis-related protein kinase) (SPK) (MAPKK-like protein kinase) (Nori-3) TOPK_HUMAN 8e-14 ...

SwissProt search result: AK105268 [KOME

Lifescience Database Archive (English)

Full Text Available kinase (EC 2.7.1.37) (T-LAK cell-originated protein kinase) (PDZ-binding kinase) (Spermatogenesis-related protein kinase) (SPK) (MAPKK-like protein kinase) (Nori-3) TOPK_HUMAN 2e-11 ...

Plio-Quaternary tectonic evolution off Al Hoceima, Moroccan Margin of the Alboran Basin.

Science.gov (United States)

Lafosse, Manfred; d'Acremont, Elia; Rabaute, Alain; Mercier de Lépinay, Bernard; Gorini, Christian; Ammar, Abdellah; Tahayt, Abdelilah

2015-04-01

We use data from a compilation of industrial and academic 2D surveys and recent data from MARLBORO-1 (2011), MARLBORO-2 (2012), and SARAS (2012) surveys, which provide high resolution bathymetry and 2D seismic reflexion data. We focus on the key area located south of the Alboran Ridge and the Tofiño Bank, and encompassing the Nekor and Boudinar onshore-offshore basins on the Moroccan side of the Alboran Sea. The Nekor basin is a present pull-apart basin in relay between inherited N050° sinistral strike-slip faults. We consider that these faults define the Principal Displacement Zones (PDZ). The northern PDZ marks the position of the crustal Bokkoya fault, which is connected to the Al-Idrisi Fault Zone en relais with the Adra and Carboneras Fault Zones. On the seabed, right-stepping non-coalescent faults characterize the sinistral kinematics of the northern PDZ and give a general N050° azimuth for the crustal discontinuity. The southern PDZ corresponds to the Nekor fault Zone, a Miocene sinistral strike-slip fault acting as the structural limit of the External Rif. On its eastern edge, the Nekor basin is bounded by the N-S onshore-offshore Trougout fault, connecting the northern and the southern PDZ. The western boundary of the Nekor basin is marked by the Rouadi and El-Hammam Quaternary active N-S normal faults. In the offshore Nekor basin, recent N155° conjugated normal faults affect the seabed. Further east, the Boudinar basin is a Plio-Quaternary uplifted Neogene basin. The northeastern segment of the Nekor fault bounds this basin to the south but is inactive in the Quaternary. Normal east-dipping N150° faults are visible offshore in the continuity of the Boudinar fault. From our perspective, the orientation of major tectonic structures (Bokkoya, Nekor and Carboneras faults and the Alboran ridge) under the present compressive regime due to the Europe/Africa convergence is not compatible with a strike-slip motion. The orientation of the most recent Plio

Application of Nontraditional Optimization Techniques for Airfoil Shape Optimization

Directory of Open Access Journals (Sweden)

R. Mukesh

2012-01-01

Full Text Available The method of optimization algorithms is one of the most important parameters which will strongly influence the fidelity of the solution during an aerodynamic shape optimization problem. Nowadays, various optimization methods, such as genetic algorithm (GA, simulated annealing (SA, and particle swarm optimization (PSO, are more widely employed to solve the aerodynamic shape optimization problems. In addition to the optimization method, the geometry parameterization becomes an important factor to be considered during the aerodynamic shape optimization process. The objective of this work is to introduce the knowledge of describing general airfoil geometry using twelve parameters by representing its shape as a polynomial function and coupling this approach with flow solution and optimization algorithms. An aerodynamic shape optimization problem is formulated for NACA 0012 airfoil and solved using the methods of simulated annealing and genetic algorithm for 5.0 deg angle of attack. The results show that the simulated annealing optimization scheme is more effective in finding the optimum solution among the various possible solutions. It is also found that the SA shows more exploitation characteristics as compared to the GA which is considered to be more effective explorer.

Binary Cockroach Swarm Optimization for Combinatorial Optimization Problem

Directory of Open Access Journals (Sweden)

Ibidun Christiana Obagbuwa

2016-09-01

Full Text Available The Cockroach Swarm Optimization (CSO algorithm is inspired by cockroach social behavior. It is a simple and efficient meta-heuristic algorithm and has been applied to solve global optimization problems successfully. The original CSO algorithm and its variants operate mainly in continuous search space and cannot solve binary-coded optimization problems directly. Many optimization problems have their decision variables in binary. Binary Cockroach Swarm Optimization (BCSO is proposed in this paper to tackle such problems and was evaluated on the popular Traveling Salesman Problem (TSP, which is considered to be an NP-hard Combinatorial Optimization Problem (COP. A transfer function was employed to map a continuous search space CSO to binary search space. The performance of the proposed algorithm was tested firstly on benchmark functions through simulation studies and compared with the performance of existing binary particle swarm optimization and continuous space versions of CSO. The proposed BCSO was adapted to TSP and applied to a set of benchmark instances of symmetric TSP from the TSP library. The results of the proposed Binary Cockroach Swarm Optimization (BCSO algorithm on TSP were compared to other meta-heuristic algorithms.

Simulation-based optimization parametric optimization techniques and reinforcement learning

CERN Document Server

Gosavi, Abhijit

2003-01-01

Simulation-Based Optimization: Parametric Optimization Techniques and Reinforcement Learning introduces the evolving area of simulation-based optimization. The book's objective is two-fold: (1) It examines the mathematical governing principles of simulation-based optimization, thereby providing the reader with the ability to model relevant real-life problems using these techniques. (2) It outlines the computational technology underlying these methods. Taken together these two aspects demonstrate that the mathematical and computational methods discussed in this book do work. Broadly speaking, the book has two parts: (1) parametric (static) optimization and (2) control (dynamic) optimization. Some of the book's special features are: *An accessible introduction to reinforcement learning and parametric-optimization techniques. *A step-by-step description of several algorithms of simulation-based optimization. *A clear and simple introduction to the methodology of neural networks. *A gentle introduction to converg...

Hybrid Optimization Algorithm of Particle Swarm Optimization and Cuckoo Search for Preventive Maintenance Period Optimization

Directory of Open Access Journals (Sweden)

Jianwen Guo

2016-01-01

Full Text Available All equipment must be maintained during its lifetime to ensure normal operation. Maintenance is one of the critical roles in the success of manufacturing enterprises. This paper proposed a preventive maintenance period optimization model (PMPOM to find an optimal preventive maintenance period. By making use of the advantages of particle swarm optimization (PSO and cuckoo search (CS algorithm, a hybrid optimization algorithm of PSO and CS is proposed to solve the PMPOM problem. The test functions show that the proposed algorithm exhibits more outstanding performance than particle swarm optimization and cuckoo search. Experiment results show that the proposed algorithm has advantages of strong optimization ability and fast convergence speed to solve the PMPOM problem.

BRAIN Journal - Solving Optimization Problems via Vortex Optimization Algorithm and Cognitive Development Optimization Algorithm

OpenAIRE

Ahmet Demir; Utku Kose

2016-01-01

ABSTRACT In the fields which require finding the most appropriate value, optimization became a vital approach to employ effective solutions. With the use of optimization techniques, many different fields in the modern life have found solutions to their real-world based problems. In this context, classical optimization techniques have had an important popularity. But after a while, more advanced optimization problems required the use of more effective techniques. At this point, Computer Sc...

Global Optimization using Interval Analysis : Interval Optimization for Aerospace Applications

NARCIS (Netherlands)

Van Kampen, E.

2010-01-01

Optimization is an important element in aerospace related research. It is encountered for example in trajectory optimization problems, such as: satellite formation flying, spacecraft re-entry optimization and airport approach and departure optimization; in control optimization, for example in

Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis

International Nuclear Information System (INIS)

Turashvili, Gulisa; Srovnal, Josef; Hajduch, Marian; Murray, Paul; Kolar, Zdenek; Bouchal, Jan; Baumforth, Karl; Wei, Wenbin; Dziechciarkova, Marta; Ehrmann, Jiri; Klein, Jiri; Fridman, Eduard; Skarda, Jozef

2007-01-01

Invasive ductal and lobular carcinomas (IDC and ILC) are the most common histological types of breast cancer. Clinical follow-up data and metastatic patterns suggest that the development and progression of these tumors are different. The aim of our study was to identify gene expression profiles of IDC and ILC in relation to normal breast epithelial cells. We examined 30 samples (normal ductal and lobular cells from 10 patients, IDC cells from 5 patients, ILC cells from 5 patients) microdissected from cryosections of ten mastectomy specimens from postmenopausal patients. Fifty nanograms of total RNA were amplified and labeled by PCR and in vitro transcription. Samples were analysed upon Affymetrix U133 Plus 2.0 Arrays. The expression of seven differentially expressed genes (CDH1, EMP1, DDR1, DVL1, KRT5, KRT6, KRT17) was verified by immunohistochemistry on tissue microarrays. Expression of ASPN mRNA was validated by in situ hybridization on frozen sections, and CTHRC1, ASPN and COL3A1 were tested by PCR. Using GCOS pairwise comparison algorithm and rank products we have identified 84 named genes common to ILC versus normal cell types, 74 named genes common to IDC versus normal cell types, 78 named genes differentially expressed between normal ductal and lobular cells, and 28 named genes between IDC and ILC. Genes distinguishing between IDC and ILC are involved in epithelial-mesenchymal transition, TGF-beta and Wnt signaling. These changes were present in both tumor types but appeared to be more prominent in ILC. Immunohistochemistry for several novel markers (EMP1, DVL1, DDR1) distinguished large sets of IDC from ILC. IDC and ILC can be differentiated both at the gene and protein levels. In this study we report two candidate genes, asporin (ASPN) and collagen triple helix repeat containing 1 (CTHRC1) which might be significant in breast carcinogenesis. Besides E-cadherin, the proteins validated on tissue microarrays (EMP1, DVL1, DDR1) may represent novel

Wnt, RSPO and Hippo Signalling in the Intestine and Intestinal Stem Cells.

Science.gov (United States)

Kriz, Vitezslav; Korinek, Vladimir

2018-01-08

In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers. In human colorectal cancer (CRC), aberrant Wnt signalling is the driving mechanism initiating this type of neoplasia. The signalling role of the RSPO-binding transmembrane proteins, the leucine-rich-repeat-containing G-protein-coupled receptors (LGRs), is possibly more pleiotropic and not only limited to the enhancement of Wnt signalling. There is growing evidence for multiple crosstalk between Hippo and Wnt/β-catenin signalling. In the ON state, Hippo signalling results in serine/threonine phosphorylation of Yes-associated protein (YAP1) and tafazzin (TAZ), promoting formation of the β-catenin destruction complex. In contrast, YAP1 or TAZ dephosphorylation (and YAP1 methylation) results in β-catenin destruction complex deactivation and β-catenin nuclear localization. In the Hippo OFF state, YAP1 and TAZ are engaged with the nuclear β-catenin and participate in the β-catenin-dependent transcription program. Interestingly, YAP1/TAZ are dispensable for intestinal homeostasis; however, upon Wnt pathway hyperactivation, the proteins together with TEA domain (TEAD) transcription factors drive the transcriptional program essential for intestinal cell transformation. In addition, in many CRC cells, YAP1 phosphorylation by YES proto-oncogene 1 tyrosine kinase (YES1) leads to the formation of a transcriptional complex that includes YAP1, β-catenin and T-box 5 (TBX5) DNA-binding protein. YAP1/β-catenin/T-box 5-mediated transcription is necessary for CRC cell proliferation and survival. Interestingly, dishevelled (DVL) appears to be an important mediator involved in both Wnt and Hippo (YAP1/TAZ) signalling and some of the DVL functions were assigned to the nuclear DVL

Optimization of Mangala Hydropower Station, Pakistan, using Optimization Techniques

Directory of Open Access Journals (Sweden)

Zaman Muhammad

2017-01-01

Full Text Available Hydropower generation is one of the key element in the economy of a country. The present study focusses on the optimal electricity generation from the Mangla reservoir in Pakistan. A mathematical model has been developed for the Mangla hydropower station and particle swarm and genetic algorithm optimization techniques were applied at this model for optimal electricity generation. Results revealed that electricity production increases with the application of optimization techniques at the proposed mathematical model. Genetic Algorithm can produce maximum electricity than Particle swarm optimization but the time of execution of particle swarm optimization is much lesser than the Genetic algorithm. Mangla hydropower station can produce up to 59*109 kWh electricity by using the flows optimally than 47*108 kWh production from traditional methods.

Mechanical Design Optimization Using Advanced Optimization Techniques

CERN Document Server

Rao, R Venkata

2012-01-01

Mechanical design includes an optimization process in which designers always consider objectives such as strength, deflection, weight, wear, corrosion, etc. depending on the requirements. However, design optimization for a complete mechanical assembly leads to a complicated objective function with a large number of design variables. It is a good practice to apply optimization techniques for individual components or intermediate assemblies than a complete assembly. Analytical or numerical methods for calculating the extreme values of a function may perform well in many practical cases, but may fail in more complex design situations. In real design problems, the number of design parameters can be very large and their influence on the value to be optimized (the goal function) can be very complicated, having nonlinear character. In these complex cases, advanced optimization algorithms offer solutions to the problems, because they find a solution near to the global optimum within reasonable time and computational ...

Molecular cloning and characterization of a novel human kinase ...

Indian Academy of Sciences (India)

Unknown

LINGCHEN GUO, CHAONENG JI, SHAOHUA GU, KANG YING, HAIPENG CHENG,. XIAOGHUA NI ... minal LIM domain proteins that cantain a PDZ domain at the amino terminal ..... Taira M., Evrard J. L., Steinmetz A. and Dawid I. B. 1995.

(Too) optimistic about optimism: the belief that optimism improves performance.

Science.gov (United States)

Tenney, Elizabeth R; Logg, Jennifer M; Moore, Don A

2015-03-01

A series of experiments investigated why people value optimism and whether they are right to do so. In Experiments 1A and 1B, participants prescribed more optimism for someone implementing decisions than for someone deliberating, indicating that people prescribe optimism selectively, when it can affect performance. Furthermore, participants believed optimism improved outcomes when a person's actions had considerable, rather than little, influence over the outcome (Experiment 2). Experiments 3 and 4 tested the accuracy of this belief; optimism improved persistence, but it did not improve performance as much as participants expected. Experiments 5A and 5B found that participants overestimated the relationship between optimism and performance even when their focus was not on optimism exclusively. In summary, people prescribe optimism when they believe it has the opportunity to improve the chance of success-unfortunately, people may be overly optimistic about just how much optimism can do. PsycINFO Database Record (c) 2015 APA, all rights reserved.

Logic-based methods for optimization combining optimization and constraint satisfaction

CERN Document Server

Hooker, John

2011-01-01

A pioneering look at the fundamental role of logic in optimization and constraint satisfaction While recent efforts to combine optimization and constraint satisfaction have received considerable attention, little has been said about using logic in optimization as the key to unifying the two fields. Logic-Based Methods for Optimization develops for the first time a comprehensive conceptual framework for integrating optimization and constraint satisfaction, then goes a step further and shows how extending logical inference to optimization allows for more powerful as well as flexible

Treatment of Oral Candidiasis Using Photodithazine®- Mediated Photodynamic Therapy In Vivo.

Science.gov (United States)

Carmello, Juliana Cabrini; Alves, Fernanda; G Basso, Fernanda; de Souza Costa, Carlos Alberto; Bagnato, Vanderlei Salvador; Mima, Ewerton Garcia de Oliveira; Pavarina, Ana Cláudia

2016-01-01

This study evaluated the effectiveness of antimicrobial photodynamic therapy (aPDT) in the treatment of oral candidiasis in a murine model using Photodithazine® (PDZ). This model of oral candidiasis was developed to allow the monitoring of the infection and the establishment of the aPDT treatment. Six-week-old female mice were immunosuppressed and inoculated with C. albicans to induce oral candidiasis. PDZ-mediated aPDT and nystatin treatment were carried out for 5 consecutive days with one application per day. The macroscopic evaluation of oral lesions was performed. After each treatment, the tongue was swabbed to recover C. albicans cells. Viable colonies were quantified and the number of CFU/ml determined. The animals were sacrificed 24 hours and 7 days after treatment and the tongues were surgically removed for histological analysis and analysis of inflammatory cytokines expression (IL-1, TNF-α and IL-6) by RT-qPCR. Data were analyzed by two-way ANOVA. PDZ-mediated aPDT was as effective as Nystatin (NYS group) in the inactivation of C. albicans, reducing 3 and 3.2 logs10 respectively, 24 h after treatment (poral lesions, while animals treated with NYS presented partial remission of oral lesions in both periods assessed. Histological evaluation revealed mild inflammatory infiltrate in the groups treated with aPDT and NYS in both periods assessed. The aPDT induced the TNF-α expression when compared with the control (P-L-) (poral candidiasis.

Optimal PMU Placement By Improved Particle Swarm Optimization

DEFF Research Database (Denmark)

Rather, Zakir Hussain; Liu, Leo; Chen, Zhe

2013-01-01

This paper presents an improved method of binary particle swarm optimization (IBPSO) technique for optimal phasor measurement unit (PMU) placement in a power network for complete system observability. Various effective improvements have been proposed to enhance the efficiency and convergence rate...... of conventional particle swarm optimization method. The proposed method of IBPSO ensures optimal PMU placement with and without consideration of zero injection measurements. The proposed method has been applied to standard test systems like 17 bus, IEEE 24-bus, IEEE 30-bus, New England 39-bus, IEEE 57-bus system...

Nonlinear optimization

CERN Document Server

Ruszczynski, Andrzej

2011-01-01

Optimization is one of the most important areas of modern applied mathematics, with applications in fields from engineering and economics to finance, statistics, management science, and medicine. While many books have addressed its various aspects, Nonlinear Optimization is the first comprehensive treatment that will allow graduate students and researchers to understand its modern ideas, principles, and methods within a reasonable time, but without sacrificing mathematical precision. Andrzej Ruszczynski, a leading expert in the optimization of nonlinear stochastic systems, integrates the theory and the methods of nonlinear optimization in a unified, clear, and mathematically rigorous fashion, with detailed and easy-to-follow proofs illustrated by numerous examples and figures. The book covers convex analysis, the theory of optimality conditions, duality theory, and numerical methods for solving unconstrained and constrained optimization problems. It addresses not only classical material but also modern top...

An X11alpha/FSBP complex represses transcription of the GSK3beta gene promoter.

LENUS (Irish Health Repository)

Lau, Kwok-Fai

2010-08-04

X11alpha is a neuronal adaptor protein that interacts with the amyloid precursor protein (APP) through a centrally located phosphotyrosine binding domain to inhibit the production of Abeta peptide that is deposited in Alzheimer\\'s disease brains. X11alpha also contains two C-terminal postsynaptic density-95, large discs, zona occludens 1 (PDZ) domains, and we show here that through its PDZ domains, X11alpha interacts with a novel transcription factor, fibrinogen silencer binding protein. Moreover, we show that an X11alpha\\/fibrinogen silencer binding protein complex signals to the nucleus to repress glycogen synthase kinase-3beta promoter activity. Glycogen synthase kinase-3beta is a favoured candidate kinase for phosphorylating tau in Alzheimer\\'s disease. Our findings show a new function for X11alpha that may impact on Alzheimer\\'s disease pathogenesis.

Optimization of mechanical structures using particle swarm optimization

International Nuclear Information System (INIS)

Leite, Victor C.; Schirru, Roberto

2015-01-01

Several optimization problems are dealed with the particle swarm optimization (PSO) algorithm, there is a wide kind of optimization problems, it may be applications related to logistics or the reload of nuclear reactors. This paper discusses the use of the PSO in the treatment of problems related to mechanical structure optimization. The geometry and material characteristics of mechanical components are important for the proper functioning and performance of the systems were they are applied, particularly to the nuclear field. Calculations related to mechanical aspects are all made using ANSYS, while the PSO is programed in MATLAB. (author)

Optimization of mechanical structures using particle swarm optimization

Energy Technology Data Exchange (ETDEWEB)

Leite, Victor C.; Schirru, Roberto, E-mail: victor.coppo.leite@lmp.ufrj.br [Coordenacao dos Programas de Pos-Graduacao em Engenharia (LMP/PEN/COPPE/UFRJ), Rio de Janeiro, RJ (Brazil). Lab. de Monitoracao de Processos

2015-07-01

Several optimization problems are dealed with the particle swarm optimization (PSO) algorithm, there is a wide kind of optimization problems, it may be applications related to logistics or the reload of nuclear reactors. This paper discusses the use of the PSO in the treatment of problems related to mechanical structure optimization. The geometry and material characteristics of mechanical components are important for the proper functioning and performance of the systems were they are applied, particularly to the nuclear field. Calculations related to mechanical aspects are all made using ANSYS, while the PSO is programed in MATLAB. (author)

Dispositional Optimism

Science.gov (United States)

Carver, Charles S.; Scheier, Michael F.

2014-01-01

Optimism is a cognitive construct (expectancies regarding future outcomes) that also relates to motivation: optimistic people exert effort, whereas pessimistic people disengage from effort. Study of optimism began largely in health contexts, finding positive associations between optimism and markers of better psychological and physical health. Physical health effects likely occur through differences in both health-promoting behaviors and physiological concomitants of coping. Recently, the scientific study of optimism has extended to the realm of social relations: new evidence indicates that optimists have better social connections, partly because they work harder at them. In this review, we examine the myriad ways this trait can benefit an individual, and our current understanding of the biological basis of optimism. PMID:24630971

Quality assurance for high dose rate brachytherapy treatment planning optimization: using a simple optimization to verify a complex optimization

International Nuclear Information System (INIS)

Deufel, Christopher L; Furutani, Keith M

2014-01-01

As dose optimization for high dose rate brachytherapy becomes more complex, it becomes increasingly important to have a means of verifying that optimization results are reasonable. A method is presented for using a simple optimization as quality assurance for the more complex optimization algorithms typically found in commercial brachytherapy treatment planning systems. Quality assurance tests may be performed during commissioning, at regular intervals, and/or on a patient specific basis. A simple optimization method is provided that optimizes conformal target coverage using an exact, variance-based, algebraic approach. Metrics such as dose volume histogram, conformality index, and total reference air kerma agree closely between simple and complex optimizations for breast, cervix, prostate, and planar applicators. The simple optimization is shown to be a sensitive measure for identifying failures in a commercial treatment planning system that are possibly due to operator error or weaknesses in planning system optimization algorithms. Results from the simple optimization are surprisingly similar to the results from a more complex, commercial optimization for several clinical applications. This suggests that there are only modest gains to be made from making brachytherapy optimization more complex. The improvements expected from sophisticated linear optimizations, such as PARETO methods, will largely be in making systems more user friendly and efficient, rather than in finding dramatically better source strength distributions. (paper)

A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway.

Science.gov (United States)

Salašová, Alena; Yokota, Chika; Potěšil, David; Zdráhal, Zbyněk; Bryja, Vítězslav; Arenas, Ernest

2017-07-11

Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/β-catenin signaling via its interaction with the β-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients. Co-immunoprecipitation and tandem mass spectrometry was performed in a mouse substantia nigra cell line (SN4741) and human HEK293T cell line in order to identify novel LRRK2 binding partners. Inhibition of the WNT/β-catenin reporter, TOPFlash, was used as a read-out of WNT/PCP pathway activation. The capacity of LRRK2 to regulate WNT/PCP signaling in vivo was tested in Xenopus laevis' early development. Our proteomic analysis identified that LRRK2 interacts with proteins involved in WNT/PCP signaling such as the PDZ domain-containing protein GIPC1 and Integrin-linked kinase (ILK) in dopaminergic cells in vitro and in the mouse ventral midbrain in vivo. Moreover, co-immunoprecipitation analysis revealed that LRRK2 binds to two core components of the WNT/PCP signaling pathway, PRICKLE1 and CELSR1, as well as to FLOTILLIN-2 and CULLIN-3, which regulate WNT secretion and inhibit WNT/β-catenin signaling, respectively. We also found that PRICKLE1 and LRRK2 localize in signalosomes and act as dual regulators of WNT/PCP and β-catenin signaling. Accordingly, analysis of the function of LRRK2 in vivo, in X. laevis revelaed that LRKK2 not only inhibits WNT/β-catenin pathway, but induces a classical WNT/PCP phenotype in vivo. Our study shows for the first time that LRRK2 activates the WNT

Dishevelled links basal body docking and orientation in ciliated epithelial cells

Science.gov (United States)

Vladar, Eszter K.; Axelrod, Jeffrey D.

2014-01-01

Some epithelia contain cells with multiple, motile cilia that beat in a concerted fashion. New tools and experimental systems have facilitated molecular studies of cilium biogenesis and of the coordinated planar polarization of cilia that leads to their concerted motility. Recent, elegant work by Park and colleagues, using embryonic frog epidermis, demonstrates that Dishevelled (Dvl), a key regulator of both the Wnt/β-catenin and Planar Cell Polarity (PCP) pathways, controls both the docking and planar polarization of ciliary basal bodies. PMID:18819800

Energy Optimal Path Planning: Integrating Coastal Ocean Modelling with Optimal Control

Science.gov (United States)

Subramani, D. N.; Haley, P. J., Jr.; Lermusiaux, P. F. J.

2016-02-01

A stochastic optimization methodology is formulated for computing energy-optimal paths from among time-optimal paths of autonomous vehicles navigating in a dynamic flow field. To set up the energy optimization, the relative vehicle speed and headings are considered to be stochastic, and new stochastic Dynamically Orthogonal (DO) level-set equations that govern their stochastic time-optimal reachability fronts are derived. Their solution provides the distribution of time-optimal reachability fronts and corresponding distribution of time-optimal paths. An optimization is then performed on the vehicle's energy-time joint distribution to select the energy-optimal paths for each arrival time, among all stochastic time-optimal paths for that arrival time. The accuracy and efficiency of the DO level-set equations for solving the governing stochastic level-set reachability fronts are quantitatively assessed, including comparisons with independent semi-analytical solutions. Energy-optimal missions are studied in wind-driven barotropic quasi-geostrophic double-gyre circulations, and in realistic data-assimilative re-analyses of multiscale coastal ocean flows. The latter re-analyses are obtained from multi-resolution 2-way nested primitive-equation simulations of tidal-to-mesoscale dynamics in the Middle Atlantic Bight and Shelbreak Front region. The effects of tidal currents, strong wind events, coastal jets, and shelfbreak fronts on the energy-optimal paths are illustrated and quantified. Results showcase the opportunities for longer-duration missions that intelligently utilize the ocean environment to save energy, rigorously integrating ocean forecasting with optimal control of autonomous vehicles.

Multidisciplinary Optimization of a Transport Aircraft Wing using Particle Swarm Optimization

Science.gov (United States)

Sobieszczanski-Sobieski, Jaroslaw; Venter, Gerhard

2002-01-01

The purpose of this paper is to demonstrate the application of particle swarm optimization to a realistic multidisciplinary optimization test problem. The paper's new contributions to multidisciplinary optimization is the application of a new algorithm for dealing with the unique challenges associated with multidisciplinary optimization problems, and recommendations as to the utility of the algorithm in future multidisciplinary optimization applications. The selected example is a bi-level optimization problem that demonstrates severe numerical noise and has a combination of continuous and truly discrete design variables. The use of traditional gradient-based optimization algorithms is thus not practical. The numerical results presented indicate that the particle swarm optimization algorithm is able to reliably find the optimum design for the problem presented here. The algorithm is capable of dealing with the unique challenges posed by multidisciplinary optimization as well as the numerical noise and truly discrete variables present in the current example problem.

Coarse Alignment Technology on Moving base for SINS Based on the Improved Quaternion Filter Algorithm.

Science.gov (United States)

Zhang, Tao; Zhu, Yongyun; Zhou, Feng; Yan, Yaxiong; Tong, Jinwu

2017-06-17

Initial alignment of the strapdown inertial navigation system (SINS) is intended to determine the initial attitude matrix in a short time with certain accuracy. The alignment accuracy of the quaternion filter algorithm is remarkable, but the convergence rate is slow. To solve this problem, this paper proposes an improved quaternion filter algorithm for faster initial alignment based on the error model of the quaternion filter algorithm. The improved quaternion filter algorithm constructs the K matrix based on the principle of optimal quaternion algorithm, and rebuilds the measurement model by containing acceleration and velocity errors to make the convergence rate faster. A doppler velocity log (DVL) provides the reference velocity for the improved quaternion filter alignment algorithm. In order to demonstrate the performance of the improved quaternion filter algorithm in the field, a turntable experiment and a vehicle test are carried out. The results of the experiments show that the convergence rate of the proposed improved quaternion filter is faster than that of the tradition quaternion filter algorithm. In addition, the improved quaternion filter algorithm also demonstrates advantages in terms of correctness, effectiveness, and practicability.

Ant colony search algorithm for optimal reactive power optimization

Directory of Open Access Journals (Sweden)

Lenin K.

2006-01-01

Full Text Available The paper presents an (ACSA Ant colony search Algorithm for Optimal Reactive Power Optimization and voltage control of power systems. ACSA is a new co-operative agents’ approach, which is inspired by the observation of the behavior of real ant colonies on the topic of ant trial formation and foraging methods. Hence, in the ACSA a set of co-operative agents called "Ants" co-operates to find good solution for Reactive Power Optimization problem. The ACSA is applied for optimal reactive power optimization is evaluated on standard IEEE, 30, 57, 191 (practical test bus system. The proposed approach is tested and compared to genetic algorithm (GA, Adaptive Genetic Algorithm (AGA.

Optimal Design and Related Areas in Optimization and Statistics

CERN Document Server

Pronzato, Luc

2009-01-01

This edited volume, dedicated to Henry P. Wynn, reflects his broad range of research interests, focusing in particular on the applications of optimal design theory in optimization and statistics. It covers algorithms for constructing optimal experimental designs, general gradient-type algorithms for convex optimization, majorization and stochastic ordering, algebraic statistics, Bayesian networks and nonlinear regression. Written by leading specialists in the field, each chapter contains a survey of the existing literature along with substantial new material. This work will appeal to both the

Optimal configuration of power grid sources based on optimal particle swarm algorithm

Science.gov (United States)

Wen, Yuanhua

2018-04-01

In order to optimize the distribution problem of power grid sources, an optimized particle swarm optimization algorithm is proposed. First, the concept of multi-objective optimization and the Pareto solution set are enumerated. Then, the performance of the classical genetic algorithm, the classical particle swarm optimization algorithm and the improved particle swarm optimization algorithm are analyzed. The three algorithms are simulated respectively. Compared with the test results of each algorithm, the superiority of the algorithm in convergence and optimization performance is proved, which lays the foundation for subsequent micro-grid power optimization configuration solution.

Website Optimization

CERN Document Server

King, Andrew

2008-01-01

Remember when an optimized website was one that merely didn't take all day to appear? Times have changed. Today, website optimization can spell the difference between enterprise success and failure, and it takes a lot more know-how to achieve success. This book is a comprehensive guide to the tips, techniques, secrets, standards, and methods of website optimization. From increasing site traffic to maximizing leads, from revving up responsiveness to increasing navigability, from prospect retention to closing more sales, the world of 21st century website optimization is explored, exemplified a

Optimal Control and Optimization of Stochastic Supply Chain Systems

CERN Document Server

Song, Dong-Ping

2013-01-01

Optimal Control and Optimization of Stochastic Supply Chain Systems examines its subject in the context of the presence of a variety of uncertainties. Numerous examples with intuitive illustrations and tables are provided, to demonstrate the structural characteristics of the optimal control policies in various stochastic supply chains and to show how to make use of these characteristics to construct easy-to-operate sub-optimal policies.                 In Part I, a general introduction to stochastic supply chain systems is provided. Analytical models for various stochastic supply chain systems are formulated and analysed in Part II. In Part III the structural knowledge of the optimal control policies obtained in Part II is utilized to construct easy-to-operate sub-optimal control policies for various stochastic supply chain systems accordingly. Finally, Part IV discusses the optimisation of threshold-type control policies and their robustness. A key feature of the book is its tying together of ...

A New Hybrid Whale Optimizer Algorithm with Mean Strategy of Grey Wolf Optimizer for Global Optimization

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Narinder Singh

2018-03-01

Full Text Available The quest for an efficient nature-inspired optimization technique has continued over the last few decades. In this paper, a hybrid nature-inspired optimization technique has been proposed. The hybrid algorithm has been constructed using Mean Grey Wolf Optimizer (MGWO and Whale Optimizer Algorithm (WOA. We have utilized the spiral equation of Whale Optimizer Algorithm for two procedures in the Hybrid Approach GWO (HAGWO algorithm: (i firstly, we used the spiral equation in Grey Wolf Optimizer algorithm for balance between the exploitation and the exploration process in the new hybrid approach; and (ii secondly, we also applied this equation in the whole population in order to refrain from the premature convergence and trapping in local minima. The feasibility and effectiveness of the hybrid algorithm have been tested by solving some standard benchmarks, XOR, Baloon, Iris, Breast Cancer, Welded Beam Design, Pressure Vessel Design problems and comparing the results with those obtained through other metaheuristics. The solutions prove that the newly existing hybrid variant has higher stronger stability, faster convergence rate and computational accuracy than other nature-inspired metaheuristics on the maximum number of problems and can successfully resolve the function of constrained nonlinear optimization in reality.

SOCIAL NETWORK OPTIMIZATION A NEW METHAHEURISTIC FOR GENERAL OPTIMIZATION PROBLEMS

Directory of Open Access Journals (Sweden)

Hassan Sherafat

2017-12-01

Full Text Available In the recent years metaheuristics were studied and developed as powerful technics for hard optimization problems. Some of well-known technics in this field are: Genetic Algorithms, Tabu Search, Simulated Annealing, Ant Colony Optimization, and Swarm Intelligence, which are applied successfully to many complex optimization problems. In this paper, we introduce a new metaheuristic for solving such problems based on social networks concept, named as Social Network Optimization – SNO. We show that a wide range of np-hard optimization problems may be solved by SNO.

Optimization and anti-optimization of structures under uncertainty

National Research Council Canada - National Science Library

Elishakoff, Isaac; Ohsaki, Makoto

2010-01-01

The volume presents a collaboration between internationally recognized experts on anti-optimization and structural optimization, and summarizes various novel ideas, methodologies and results studied over 20 years...

Optimization and optimal control in automotive systems

CERN Document Server

Kolmanovsky, Ilya; Steinbuch, Maarten; Re, Luigi

2014-01-01

This book demonstrates the use of the optimization techniques that are becoming essential to meet the increasing stringency and variety of requirements for automotive systems. It shows the reader how to move away from earlier  approaches, based on some degree of heuristics, to the use of  more and more common systematic methods. Even systematic methods can be developed and applied in a large number of forms so the text collects contributions from across the theory, methods and real-world automotive applications of optimization. Greater fuel economy, significant reductions in permissible emissions, new drivability requirements and the generally increasing complexity of automotive systems are among the criteria that the contributing authors set themselves to meet. In many cases multiple and often conflicting requirements give rise to multi-objective constrained optimization problems which are also considered. Some of these problems fall into the domain of the traditional multi-disciplinary optimization applie...

Constrained Optimization and Optimal Control for Partial Differential Equations

CERN Document Server

Leugering, Günter; Griewank, Andreas

2012-01-01

This special volume focuses on optimization and control of processes governed by partial differential equations. The contributors are mostly participants of the DFG-priority program 1253: Optimization with PDE-constraints which is active since 2006. The book is organized in sections which cover almost the entire spectrum of modern research in this emerging field. Indeed, even though the field of optimal control and optimization for PDE-constrained problems has undergone a dramatic increase of interest during the last four decades, a full theory for nonlinear problems is still lacking. The cont

Optimal perturbations for nonlinear systems using graph-based optimal transport

Science.gov (United States)

Grover, Piyush; Elamvazhuthi, Karthik

2018-06-01

We formulate and solve a class of finite-time transport and mixing problems in the set-oriented framework. The aim is to obtain optimal discrete-time perturbations in nonlinear dynamical systems to transport a specified initial measure on the phase space to a final measure in finite time. The measure is propagated under system dynamics in between the perturbations via the associated transfer operator. Each perturbation is described by a deterministic map in the measure space that implements a version of Monge-Kantorovich optimal transport with quadratic cost. Hence, the optimal solution minimizes a sum of quadratic costs on phase space transport due to the perturbations applied at specified times. The action of the transport map is approximated by a continuous pseudo-time flow on a graph, resulting in a tractable convex optimization problem. This problem is solved via state-of-the-art solvers to global optimality. We apply this algorithm to a problem of transport between measures supported on two disjoint almost-invariant sets in a chaotic fluid system, and to a finite-time optimal mixing problem by choosing the final measure to be uniform. In both cases, the optimal perturbations are found to exploit the phase space structures, such as lobe dynamics, leading to efficient global transport. As the time-horizon of the problem is increased, the optimal perturbations become increasingly localized. Hence, by combining the transfer operator approach with ideas from the theory of optimal mass transportation, we obtain a discrete-time graph-based algorithm for optimal transport and mixing in nonlinear systems.

Optimal management strategies in variable environments: Stochastic optimal control methods

Science.gov (United States)

Williams, B.K.

1985-01-01

Dynamic optimization was used to investigate the optimal defoliation of salt desert shrubs in north-western Utah. Management was formulated in the context of optimal stochastic control theory, with objective functions composed of discounted or time-averaged biomass yields. Climatic variability and community patterns of salt desert shrublands make the application of stochastic optimal control both feasible and necessary. A primary production model was used to simulate shrub responses and harvest yields under a variety of climatic regimes and defoliation patterns. The simulation results then were used in an optimization model to determine optimal defoliation strategies. The latter model encodes an algorithm for finite state, finite action, infinite discrete time horizon Markov decision processes. Three questions were addressed: (i) What effect do changes in weather patterns have on optimal management strategies? (ii) What effect does the discounting of future returns have? (iii) How do the optimal strategies perform relative to certain fixed defoliation strategies? An analysis was performed for the three shrub species, winterfat (Ceratoides lanata), shadscale (Atriplex confertifolia) and big sagebrush (Artemisia tridentata). In general, the results indicate substantial differences among species in optimal control strategies, which are associated with differences in physiological and morphological characteristics. Optimal policies for big sagebrush varied less with variation in climate, reserve levels and discount rates than did either shadscale or winterfat. This was attributed primarily to the overwintering of photosynthetically active tissue and to metabolic activity early in the growing season. Optimal defoliation of shadscale and winterfat generally was more responsive to differences in plant vigor and climate, reflecting the sensitivity of these species to utilization and replenishment of carbohydrate reserves. Similarities could be seen in the influence of both

Load flow optimization and optimal power flow

CERN Document Server

Das, J C

2017-01-01

This book discusses the major aspects of load flow, optimization, optimal load flow, and culminates in modern heuristic optimization techniques and evolutionary programming. In the deregulated environment, the economic provision of electrical power to consumers requires knowledge of maintaining a certain power quality and load flow. Many case studies and practical examples are included to emphasize real-world applications. The problems at the end of each chapter can be solved by hand calculations without having to use computer software. The appendices are devoted to calculations of line and cable constants, and solutions to the problems are included throughout the book.

Particle swarm optimization: an alternative in marine propeller optimization?

Science.gov (United States)

Vesting, F.; Bensow, R. E.

2018-01-01

This article deals with improving and evaluating the performance of two evolutionary algorithm approaches for automated engineering design optimization. Here a marine propeller design with constraints on cavitation nuisance is the intended application. For this purpose, the particle swarm optimization (PSO) algorithm is adapted for multi-objective optimization and constraint handling for use in propeller design. Three PSO algorithms are developed and tested for the optimization of four commercial propeller designs for different ship types. The results are evaluated by interrogating the generation medians and the Pareto front development. The same propellers are also optimized utilizing the well established NSGA-II genetic algorithm to provide benchmark results. The authors' PSO algorithms deliver comparable results to NSGA-II, but converge earlier and enhance the solution in terms of constraints violation.

Observability Analysis of DVL/PS Aided INS for a Maneuvering AUV

Directory of Open Access Journals (Sweden)

Itzik Klein

2015-10-01

Full Text Available Recently, ocean exploration has increased considerably through the use of autonomous underwater vehicles (AUV. A key enabling technology is the precision of the AUV navigation capability. In this paper, we focus on understanding the limitation of the AUV navigation system. That is, what are the observable error-states for different maneuvering types of the AUV? Since analyzing the performance of an underwater navigation system is highly complex, to answer the above question, current approaches use simulations. This, of course, limits the conclusions to the emulated type of vehicle used and to the simulation setup. For this reason, we take a different approach and analyze the system observability for different types of vehicle dynamics by finding the set of observable and unobservable states. To that end, we apply the observability Gramian approach, previously used only for terrestrial applications. We demonstrate our analysis for an underwater inertial navigation system aided by a Doppler velocity logger or by a pressure sensor. The result is a first prediction of the performance of an AUV standing, rotating at a position and turning at a constant speed. Our conclusions of the observable and unobservable navigation error states for different dynamics are supported by extensive numerical simulation.

Optimization and anti-optimization of structures under uncertainty

National Research Council Canada - National Science Library

Elishakoff, Isaac; Ohsaki, Makoto

2010-01-01

.... The necessity of anti-optimization approach is first demonstrated, then the anti-optimization techniques are applied to static, dynamic and buckling problems, thus covering the broadest possible set of applications...

Optimal protocols and optimal transport in stochastic thermodynamics.

Science.gov (United States)

Aurell, Erik; Mejía-Monasterio, Carlos; Muratore-Ginanneschi, Paolo

2011-06-24

Thermodynamics of small systems has become an important field of statistical physics. Such systems are driven out of equilibrium by a control, and the question is naturally posed how such a control can be optimized. We show that optimization problems in small system thermodynamics are solved by (deterministic) optimal transport, for which very efficient numerical methods have been developed, and of which there are applications in cosmology, fluid mechanics, logistics, and many other fields. We show, in particular, that minimizing expected heat released or work done during a nonequilibrium transition in finite time is solved by the Burgers equation and mass transport by the Burgers velocity field. Our contribution hence considerably extends the range of solvable optimization problems in small system thermodynamics.

Evolutionary constrained optimization

CERN Document Server

Deb, Kalyanmoy

2015-01-01

This book makes available a self-contained collection of modern research addressing the general constrained optimization problems using evolutionary algorithms. Broadly the topics covered include constraint handling for single and multi-objective optimizations; penalty function based methodology; multi-objective based methodology; new constraint handling mechanism; hybrid methodology; scaling issues in constrained optimization; design of scalable test problems; parameter adaptation in constrained optimization; handling of integer, discrete and mix variables in addition to continuous variables; application of constraint handling techniques to real-world problems; and constrained optimization in dynamic environment. There is also a separate chapter on hybrid optimization, which is gaining lots of popularity nowadays due to its capability of bridging the gap between evolutionary and classical optimization. The material in the book is useful to researchers, novice, and experts alike. The book will also be useful...

Extreme Learning Machine and Particle Swarm Optimization in optimizing CNC turning operation

Science.gov (United States)

Janahiraman, Tiagrajah V.; Ahmad, Nooraziah; Hani Nordin, Farah

2018-04-01

The CNC machine is controlled by manipulating cutting parameters that could directly influence the process performance. Many optimization methods has been applied to obtain the optimal cutting parameters for the desired performance function. Nonetheless, the industry still uses the traditional technique to obtain those values. Lack of knowledge on optimization techniques is the main reason for this issue to be prolonged. Therefore, the simple yet easy to implement, Optimal Cutting Parameters Selection System is introduced to help the manufacturer to easily understand and determine the best optimal parameters for their turning operation. This new system consists of two stages which are modelling and optimization. In modelling of input-output and in-process parameters, the hybrid of Extreme Learning Machine and Particle Swarm Optimization is applied. This modelling technique tend to converge faster than other artificial intelligent technique and give accurate result. For the optimization stage, again the Particle Swarm Optimization is used to get the optimal cutting parameters based on the performance function preferred by the manufacturer. Overall, the system can reduce the gap between academic world and the industry by introducing a simple yet easy to implement optimization technique. This novel optimization technique can give accurate result besides being the fastest technique.

Practical mathematical optimization basic optimization theory and gradient-based algorithms

CERN Document Server

Snyman, Jan A

2018-01-01

This textbook presents a wide range of tools for a course in mathematical optimization for upper undergraduate and graduate students in mathematics, engineering, computer science, and other applied sciences. Basic optimization principles are presented with emphasis on gradient-based numerical optimization strategies and algorithms for solving both smooth and noisy discontinuous optimization problems. Attention is also paid to the difficulties of expense of function evaluations and the existence of multiple minima that often unnecessarily inhibit the use of gradient-based methods. This second edition addresses further advancements of gradient-only optimization strategies to handle discontinuities in objective functions. New chapters discuss the construction of surrogate models as well as new gradient-only solution strategies and numerical optimization using Python. A special Python module is electronically available (via springerlink) that makes the new algorithms featured in the text easily accessible and dir...

Topology Optimization

DEFF Research Database (Denmark)

A. Kristensen, Anders Schmidt; Damkilde, Lars

2007-01-01

. A way to solve the initial design problem namely finding a form can be solved by so-called topology optimization. The idea is to define a design region and an amount of material. The loads and supports are also fidefined, and the algorithm finds the optimal material distribution. The objective function...... dictates the form, and the designer can choose e.g. maximum stiness, maximum allowable stresses or maximum lowest eigenfrequency. The result of the topology optimization is a relatively coarse map of material layout. This design can be transferred to a CAD system and given the necessary geometrically...... refinements, and then remeshed and reanalysed in other to secure that the design requirements are met correctly. The output of standard topology optimization has seldom well-defined, sharp contours leaving the designer with a tedious interpretation, which often results in less optimal structures. In the paper...

Interactive Topology Optimization

DEFF Research Database (Denmark)

Nobel-Jørgensen, Morten

Interactivity is the continuous interaction between the user and the application to solve a task. Topology optimization is the optimization of structures in order to improve stiffness or other objectives. The goal of the thesis is to explore how topology optimization can be used in applications...... on theory of from human-computer interaction which is described in Chapter 2. Followed by a description of the foundations of topology optimization in Chapter 3. Our applications for topology optimization in 2D and 3D are described in Chapter 4 and a game which trains the human intuition of topology...... optimization is presented in Chapter 5. Topology optimization can also be used as an interactive modeling tool with local control which is presented in Chapter 6. Finally, Chapter 7 contains a summary of the findings and concludes the dissertation. Most of the presented applications of the thesis are available...

Fundamentals of Electrical Propulsion Plant Design,

Science.gov (United States)

1982-04-06

contacts DVI and DV2 close the indicator light LS2 and L53 circuits. Electric Fan starter n. r. contacts DVl and DY2 close the red indicator light...forward rotation, /. corresponding tD vessel movement i///’,/iI X,, /;/forward; ’ are curves of GED -tJ ’ !’ i ’ " f \\ \\ ’ . . L---,torques after reversal...Calculation based on generator static characteristics, i. e., based on parameters Xd and Td , are linked with the most difficult GED operating conditions

Particle Filter Based Fault-tolerant ROV Navigation using Hydro-acoustic Position and Doppler Velocity Measurements

DEFF Research Database (Denmark)

Zhao, Bo; Blanke, Mogens; Skjetne, Roger

2012-01-01

This paper presents a fault tolerant navigation system for a remotely operated vehicle (ROV). The navigation system uses hydro-acoustic position reference (HPR) and Doppler velocity log (DVL) measurements to achieve an integrated navigation. The fault tolerant functionality is based on a modied...... particle lter. This particle lter is able to run in an asynchronous manner to accommodate the measurement drop out problem, and it overcomes the measurement outliers by switching observation models. Simulations with experimental data show that this fault tolerant navigation system can accurately estimate...

Euler's fluid equations: Optimal control vs optimization

International Nuclear Information System (INIS)

Holm, Darryl D.

2009-01-01

An optimization method used in image-processing (metamorphosis) is found to imply Euler's equations for incompressible flow of an inviscid fluid, without requiring that the Lagrangian particle labels exactly follow the flow lines of the Eulerian velocity vector field. Thus, an optimal control problem and an optimization problem for incompressible ideal fluid flow both yield the same Euler fluid equations, although their Lagrangian parcel dynamics are different. This is a result of the gauge freedom in the definition of the fluid pressure for an incompressible flow, in combination with the symmetry of fluid dynamics under relabeling of their Lagrangian coordinates. Similar ideas are also illustrated for SO(N) rigid body motion.

Transaction fees and optimal rebalancing in the growth-optimal portfolio

OpenAIRE

Yu Feng; Matus Medo; Liang Zhang; Yi-Cheng Zhang

2010-01-01

The growth-optimal portfolio optimization strategy pioneered by Kelly is based on constant portfolio rebalancing which makes it sensitive to transaction fees. We examine the effect of fees on an example of a risky asset with a binary return distribution and show that the fees may give rise to an optimal period of portfolio rebalancing. The optimal period is found analytically in the case of lognormal returns. This result is consequently generalized and numerically verified for broad return di...

Optimal trading quantity integration as a basis for optimal portfolio management

Directory of Open Access Journals (Sweden)

Saša Žiković

2005-06-01

Full Text Available The author in this paper points out the reason behind calculating and using optimal trading quantity in conjunction with Markowitz’s Modern portfolio theory. In the opening part the author presents an example of calculating optimal weights using Markowitz’s Mean-Variance approach, followed by an explanation of basic logic behind optimal trading quantity. The use of optimal trading quantity is not limited to systems with Bernoulli outcome, but can also be used when trading shares, futures, options etc. Optimal trading quantity points out two often-overlooked axioms: (1 a system with negative mathematical expectancy can never be transformed in a system with positive mathematical expectancy, (2 by missing the optimal trading quantity an investor can turn a system with positive expectancy into a negative one. Optimal trading quantity is that quantity which maximizes geometric mean (growth function of a particular system. To determine the optimal trading quantity for simpler systems, with a very limited number of outcomes, a set of Kelly’s formulas is appropriate. In the conclusion the summary of the paper is presented.

Transaction fees and optimal rebalancing in the growth-optimal portfolio

Science.gov (United States)

Feng, Yu; Medo, Matúš; Zhang, Liang; Zhang, Yi-Cheng

2011-05-01

The growth-optimal portfolio optimization strategy pioneered by Kelly is based on constant portfolio rebalancing which makes it sensitive to transaction fees. We examine the effect of fees on an example of a risky asset with a binary return distribution and show that the fees may give rise to an optimal period of portfolio rebalancing. The optimal period is found analytically in the case of lognormal returns. This result is consequently generalized and numerically verified for broad return distributions and returns generated by a GARCH process. Finally we study the case when investment is rebalanced only partially and show that this strategy can improve the investment long-term growth rate more than optimization of the rebalancing period.

On the efficiency of chaos optimization algorithms for global optimization

International Nuclear Information System (INIS)

Yang Dixiong; Li Gang; Cheng Gengdong

2007-01-01

Chaos optimization algorithms as a novel method of global optimization have attracted much attention, which were all based on Logistic map. However, we have noticed that the probability density function of the chaotic sequences derived from Logistic map is a Chebyshev-type one, which may affect the global searching capacity and computational efficiency of chaos optimization algorithms considerably. Considering the statistical property of the chaotic sequences of Logistic map and Kent map, the improved hybrid chaos-BFGS optimization algorithm and the Kent map based hybrid chaos-BFGS algorithm are proposed. Five typical nonlinear functions with multimodal characteristic are tested to compare the performance of five hybrid optimization algorithms, which are the conventional Logistic map based chaos-BFGS algorithm, improved Logistic map based chaos-BFGS algorithm, Kent map based chaos-BFGS algorithm, Monte Carlo-BFGS algorithm, mesh-BFGS algorithm. The computational performance of the five algorithms is compared, and the numerical results make us question the high efficiency of the chaos optimization algorithms claimed in some references. It is concluded that the efficiency of the hybrid optimization algorithms is influenced by the statistical property of chaotic/stochastic sequences generated from chaotic/stochastic algorithms, and the location of the global optimum of nonlinear functions. In addition, it is inappropriate to advocate the high efficiency of the global optimization algorithms only depending on several numerical examples of low-dimensional functions

Particle Swarm Optimization

Science.gov (United States)

Venter, Gerhard; Sobieszczanski-Sobieski Jaroslaw

2002-01-01

The purpose of this paper is to show how the search algorithm known as particle swarm optimization performs. Here, particle swarm optimization is applied to structural design problems, but the method has a much wider range of possible applications. The paper's new contributions are improvements to the particle swarm optimization algorithm and conclusions and recommendations as to the utility of the algorithm, Results of numerical experiments for both continuous and discrete applications are presented in the paper. The results indicate that the particle swarm optimization algorithm does locate the constrained minimum design in continuous applications with very good precision, albeit at a much higher computational cost than that of a typical gradient based optimizer. However, the true potential of particle swarm optimization is primarily in applications with discrete and/or discontinuous functions and variables. Additionally, particle swarm optimization has the potential of efficient computation with very large numbers of concurrently operating processors.

Optimal Design of Gravity Pipeline Systems Using Genetic Algorithm and Mathematical Optimization

Directory of Open Access Journals (Sweden)

maryam rohani

2015-03-01

Full Text Available In recent years, the optimal design of pipeline systems has become increasingly important in the water industry. In this study, the two methods of genetic algorithm and mathematical optimization were employed for the optimal design of pipeline systems with the objective of avoiding the water hammer effect caused by valve closure. The problem of optimal design of a pipeline system is a constrained one which should be converted to an unconstrained optimization problem using an external penalty function approach in the mathematical programming method. The quality of the optimal solution greatly depends on the value of the penalty factor that is calculated by the iterative method during the optimization procedure such that the computational effort is simultaneously minimized. The results obtained were used to compare the GA and mathematical optimization methods employed to determine their efficiency and capabilities for the problem under consideration. It was found that the mathematical optimization method exhibited a slightly better performance compared to the GA method.

Optimal truss and frame design from projected homogenization-based topology optimization

DEFF Research Database (Denmark)

Larsen, S. D.; Sigmund, O.; Groen, J. P.

2018-01-01

In this article, we propose a novel method to obtain a near-optimal frame structure, based on the solution of a homogenization-based topology optimization model. The presented approach exploits the equivalence between Michell’s problem of least-weight trusses and a compliance minimization problem...... using optimal rank-2 laminates in the low volume fraction limit. In a fully automated procedure, a discrete structure is extracted from the homogenization-based continuum model. This near-optimal structure is post-optimized as a frame, where the bending stiffness is continuously decreased, to allow...

Particle Swarm Optimization Toolbox

Science.gov (United States)

Grant, Michael J.

2010-01-01

The Particle Swarm Optimization Toolbox is a library of evolutionary optimization tools developed in the MATLAB environment. The algorithms contained in the library include a genetic algorithm (GA), a single-objective particle swarm optimizer (SOPSO), and a multi-objective particle swarm optimizer (MOPSO). Development focused on both the SOPSO and MOPSO. A GA was included mainly for comparison purposes, and the particle swarm optimizers appeared to perform better for a wide variety of optimization problems. All algorithms are capable of performing unconstrained and constrained optimization. The particle swarm optimizers are capable of performing single and multi-objective optimization. The SOPSO and MOPSO algorithms are based on swarming theory and bird-flocking patterns to search the trade space for the optimal solution or optimal trade in competing objectives. The MOPSO generates Pareto fronts for objectives that are in competition. A GA, based on Darwin evolutionary theory, is also included in the library. The GA consists of individuals that form a population in the design space. The population mates to form offspring at new locations in the design space. These offspring contain traits from both of the parents. The algorithm is based on this combination of traits from parents to hopefully provide an improved solution than either of the original parents. As the algorithm progresses, individuals that hold these optimal traits will emerge as the optimal solutions. Due to the generic design of all optimization algorithms, each algorithm interfaces with a user-supplied objective function. This function serves as a "black-box" to the optimizers in which the only purpose of this function is to evaluate solutions provided by the optimizers. Hence, the user-supplied function can be numerical simulations, analytical functions, etc., since the specific detail of this function is of no concern to the optimizer. These algorithms were originally developed to support entry

Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis

Directory of Open Access Journals (Sweden)

Srovnal Josef

2007-03-01

Full Text Available Abstract Background Invasive ductal and lobular carcinomas (IDC and ILC are the most common histological types of breast cancer. Clinical follow-up data and metastatic patterns suggest that the development and progression of these tumors are different. The aim of our study was to identify gene expression profiles of IDC and ILC in relation to normal breast epithelial cells. Methods We examined 30 samples (normal ductal and lobular cells from 10 patients, IDC cells from 5 patients, ILC cells from 5 patients microdissected from cryosections of ten mastectomy specimens from postmenopausal patients. Fifty nanograms of total RNA were amplified and labeled by PCR and in vitro transcription. Samples were analysed upon Affymetrix U133 Plus 2.0 Arrays. The expression of seven differentially expressed genes (CDH1, EMP1, DDR1, DVL1, KRT5, KRT6, KRT17 was verified by immunohistochemistry on tissue microarrays. Expression of ASPN mRNA was validated by in situ hybridization on frozen sections, and CTHRC1, ASPN and COL3A1 were tested by PCR. Results Using GCOS pairwise comparison algorithm and rank products we have identified 84 named genes common to ILC versus normal cell types, 74 named genes common to IDC versus normal cell types, 78 named genes differentially expressed between normal ductal and lobular cells, and 28 named genes between IDC and ILC. Genes distinguishing between IDC and ILC are involved in epithelial-mesenchymal transition, TGF-beta and Wnt signaling. These changes were present in both tumor types but appeared to be more prominent in ILC. Immunohistochemistry for several novel markers (EMP1, DVL1, DDR1 distinguished large sets of IDC from ILC. Conclusion IDC and ILC can be differentiated both at the gene and protein levels. In this study we report two candidate genes, asporin (ASPN and collagen triple helix repeat containing 1 (CTHRC1 which might be significant in breast carcinogenesis. Besides E-cadherin, the proteins validated on tissue

PRODUCT OPTIMIZATION METHOD BASED ON ANALYSIS OF OPTIMAL VALUES OF THEIR CHARACTERISTICS

Directory of Open Access Journals (Sweden)

Constantin D. STANESCU

2016-05-01

Full Text Available The paper presents an original method of optimizing products based on the analysis of optimal values of their characteristics . Optimization method comprises statistical model and analytical model . With this original method can easily and quickly obtain optimal product or material .

A surrogate based multistage-multilevel optimization procedure for multidisciplinary design optimization

OpenAIRE

Yao, W.; Chen, X.; Ouyang, Q.; Van Tooren, M.

2011-01-01

Optimization procedure is one of the key techniques to address the computational and organizational complexities of multidisciplinary design optimization (MDO). Motivated by the idea of synthetically exploiting the advantage of multiple existing optimization procedures and meanwhile complying with the general process of satellite system design optimization in conceptual design phase, a multistage-multilevel MDO procedure is proposed in this paper by integrating multiple-discipline-feasible (M...

Control parameter optimization for AP1000 reactor using Particle Swarm Optimization

International Nuclear Information System (INIS)

Wang, Pengfei; Wan, Jiashuang; Luo, Run; Zhao, Fuyu; Wei, Xinyu

2016-01-01

Highlights: • The PSO algorithm is applied for control parameter optimization of AP1000 reactor. • Key parameters of the MSHIM control system are optimized. • Optimization results are evaluated though simulations and quantitative analysis. - Abstract: The advanced mechanical shim (MSHIM) core control strategy is implemented in the AP1000 reactor for core reactivity and axial power distribution control simultaneously. The MSHIM core control system can provide superior reactor control capabilities via automatic rod control only. This enables the AP1000 to perform power change operations automatically without the soluble boron concentration adjustments. In this paper, the Particle Swarm Optimization (PSO) algorithm has been applied for the parameter optimization of the MSHIM control system to acquire better reactor control performance for AP1000. System requirements such as power control performance, control bank movement and AO control constraints are reflected in the objective function. Dynamic simulations are performed based on an AP1000 reactor simulation platform in each iteration of the optimization process to calculate the fitness values of particles in the swarm. The simulation platform is developed in Matlab/Simulink environment with implementation of a nodal core model and the MSHIM control strategy. Based on the simulation platform, the typical 10% step load decrease transient from 100% to 90% full power is simulated and the objective function used for control parameter tuning is directly incorporated in the simulation results. With successful implementation of the PSO algorithm in the control parameter optimization of AP1000 reactor, four key parameters of the MSHIM control system are optimized. It has been demonstrated by the calculation results that the optimized MSHIM control system parameters can improve the reactor power control capability and reduce the control rod movement without compromising AO control. Therefore, the PSO based optimization

Investigation of tracking systems properties in CAVE-type virtual reality systems

Science.gov (United States)

Szymaniak, Magda; Mazikowski, Adam; Meironke, Michał

2017-08-01

In recent years, many scientific and industrial centers in the world developed a virtual reality systems or laboratories. One of the most advanced solutions are Immersive 3D Visualization Lab (I3DVL), a CAVE-type (Cave Automatic Virtual Environment) laboratory. It contains two CAVE-type installations: six-screen installation arranged in a form of a cube, and four-screen installation, a simplified version of the previous one. The user feeling of "immersion" and interaction with virtual world depend on many factors, in particular on the accuracy of the tracking system of the user. In this paper properties of the tracking systems applied in I3DVL was investigated. For analysis two parameters were selected: the accuracy of the tracking system and the range of detection of markers by the tracking system in space of the CAVE. Measurements of system accuracy were performed for six-screen installation, equipped with four tracking cameras for three axes: X, Y, Z. Rotation around the Y axis was also analyzed. Measured tracking system shows good linear and rotating accuracy. The biggest issue was the range of the monitoring of markers inside the CAVE. It turned out, that the tracking system lose sight of the markers in the corners of the installation. For comparison, for a simplified version of CAVE (four-screen installation), equipped with eight tracking cameras, this problem was not occur. Obtained results will allow for improvement of cave quality.

Neural Differentiation of Human Adipose Tissue-Derived Stem Cells Involves Activation of the Wnt5a/JNK Signalling

Directory of Open Access Journals (Sweden)

Sujeong Jang

2015-01-01

Full Text Available Stem cells are a powerful resource for cell-based transplantation therapies, but understanding of stem cell differentiation at the molecular level is not clear yet. We hypothesized that the Wnt pathway controls stem cell maintenance and neural differentiation. We have characterized the transcriptional expression of Wnt during the neural differentiation of hADSCs. After neural induction, the expressions of Wnt2, Wnt4, and Wnt11 were decreased, but the expression of Wnt5a was increased compared with primary hADSCs in RT-PCR analysis. In addition, the expression levels of most Fzds and LRP5/6 ligand were decreased, but not Fzd3 and Fzd5. Furthermore, Dvl1 and RYK expression levels were downregulated in NI-hADSCs. There were no changes in the expression of ß-catenin and GSK3ß. Interestingly, Wnt5a expression was highly increased in NI-hADSCs by real time RT-PCR analysis and western blot. Wnt5a level was upregulated after neural differentiation and Wnt3, Dvl2, and Naked1 levels were downregulated. Finally, we found that the JNK expression was increased after neural induction and ERK level was decreased. Thus, this study shows for the first time how a single Wnt5a ligand can activate the neural differentiation pathway through the activation of Wnt5a/JNK pathway by binding Fzd3 and Fzd5 and directing Axin/GSK-3ß in hADSCs.

Aircraft technology portfolio optimization using ant colony optimization

Science.gov (United States)

Villeneuve, Frederic J.; Mavris, Dimitri N.

2012-11-01

Technology portfolio selection is a combinatorial optimization problem often faced with a large number of combinations and technology incompatibilities. The main research question addressed in this article is to determine if Ant Colony Optimization (ACO) is better suited than Genetic Algorithms (GAs) and Simulated Annealing (SA) for technology portfolio optimization when incompatibility constraints between technologies are present. Convergence rate, capability to find optima, and efficiency in handling of incompatibilities are the three criteria of comparison. The application problem consists of finding the best technology portfolio from 29 aircraft technologies. The results show that ACO and GAs converge faster and find optima more easily than SA, and that ACO can optimize portfolios with technology incompatibilities without using penalty functions. This latter finding paves the way for more use of ACO when the number of constraints increases, such as in the technology and concept selection for complex engineering systems.

Optimization modeling with spreadsheets

CERN Document Server

Baker, Kenneth R

2015-01-01

An accessible introduction to optimization analysis using spreadsheets Updated and revised, Optimization Modeling with Spreadsheets, Third Edition emphasizes model building skills in optimization analysis. By emphasizing both spreadsheet modeling and optimization tools in the freely available Microsoft® Office Excel® Solver, the book illustrates how to find solutions to real-world optimization problems without needing additional specialized software. The Third Edition includes many practical applications of optimization models as well as a systematic framework that il

[SIAM conference on optimization

Energy Technology Data Exchange (ETDEWEB)

1992-05-10

Abstracts are presented of 63 papers on the following topics: large-scale optimization, interior-point methods, algorithms for optimization, problems in control, network optimization methods, and parallel algorithms for optimization problems.

Membrane localization is critical for activation of the PICK1 BAR domain

DEFF Research Database (Denmark)

Madsen, Kenneth L; Eriksen, Jacob; Milan-Lobo, Laura

2008-01-01

The PSD-95/Discs-large/ZO-1 homology (PDZ) domain protein, protein interacting with C kinase 1 (PICK1) contains a C-terminal Bin/amphiphysin/Rvs (BAR) domain mediating recognition of curved membranes; however, the molecular mechanisms controlling the activity of this domain are poorly understood....

A surrogate based multistage-multilevel optimization procedure for multidisciplinary design optimization

NARCIS (Netherlands)

Yao, W.; Chen, X.; Ouyang, Q.; Van Tooren, M.

2011-01-01

Optimization procedure is one of the key techniques to address the computational and organizational complexities of multidisciplinary design optimization (MDO). Motivated by the idea of synthetically exploiting the advantage of multiple existing optimization procedures and meanwhile complying with

A solution to the optimal power flow using multi-verse optimizer

Directory of Open Access Journals (Sweden)

Bachir Bentouati

2016-12-01

Full Text Available In this work, the most common problem of the modern power system named optimal power flow (OPF is optimized using the novel meta-heuristic optimization Multi-verse Optimizer(MVO algorithm. In order to solve the optimal power flow problem, the IEEE 30-bus and IEEE 57-bus systems are used. MVO is applied to solve the proposed problem. The problems considered in the OPF problem are fuel cost reduction, voltage profile improvement, voltage stability enhancement. The obtained results are compared with recently published meta-heuristics. Simulation results clearly reveal the effectiveness and the rapidity of the proposed algorithm for solving the OPF problem.

PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking.

Science.gov (United States)

Lu, Wei; Ziff, Edward B

2005-08-04

PICK1 and ABP/GRIP bind to the AMPA receptor (AMPAR) GluR2 subunit C terminus. Transfer of the receptor from ABP/GRIP to PICK1, facilitated by GluR2 S880 phosphorylation, may initiate receptor trafficking. Here we report protein interactions that regulate these steps. The PICK1 BAR domain interacts intermolecularly with the ABP/GRIP linker II region and intramolecularly with the PICK1 PDZ domain. Binding of PKCalpha or GluR2 to the PICK1 PDZ domain disrupts the intramolecular interaction and facilitates the PICK1 BAR domain association with ABP/GRIP. Interference with the PICK1-ABP/GRIP interaction impairs S880 phosphorylation of GluR2 by PKC and decreases the constitutive surface expression of GluR2, the NMDA-induced endocytosis of GluR2, and recycling of internalized GluR2. We suggest that the PICK1 interaction with ABP/GRIP is a critical step in controlling GluR2 trafficking.

The Gpn3 Q279* cancer-associated mutant inhibits Gpn1 nuclear export and is deficient in RNA polymerase II nuclear targeting.

Science.gov (United States)

Barbosa-Camacho, Angel A; Méndez-Hernández, Lucía E; Lara-Chacón, Bárbara; Peña-Gómez, Sonia G; Romero, Violeta; González-González, Rogelio; Guerra-Moreno, José A; Robledo-Rivera, Angélica Y; Sánchez-Olea, Roberto; Calera, Mónica R

2017-11-01

Gpn3 is required for RNA polymerase II (RNAPII) nuclear targeting. Here, we investigated the effect of a cancer-associated Q279* nonsense mutation in Gpn3 cellular function. Employing RNAi, we replaced endogenous Gpn3 by wt or Q279* RNAi-resistant Gpn3R in epithelial model cells. RNAPII nuclear accumulation and transcriptional activity were markedly decreased in cells expressing only Gpn3R Q279*. Wild-type Gpn3R localized to the cytoplasm but a fraction of Gpn3R Q279* entered the cell nucleus and inhibited Gpn1-EYFP nuclear export. This property and the transcriptional deficit in Gpn3R Q279*-expressing cells required a PDZ-binding motif generated by the Q279* mutation. We conclude that an acquired PDZ-binding motif in Gpn3 Q279* caused Gpn3 nuclear entry, and inhibited Gpn1 nuclear export and Gpn3-mediated RNAPII nuclear targeting. © 2017 Federation of European Biochemical Societies.

Machine Learning meets Mathematical Optimization to predict the optimal production of offshore wind parks

DEFF Research Database (Denmark)

Fischetti, Martina; Fraccaro, Marco

2018-01-01

In this paper we propose a combination of Mathematical Optimization and Machine Learning to estimate the value of optimized solutions. In particular, we investigate if a machine, trained on a large number of optimized solutions, could accurately estimate the value of the optimized solution for new...... in production between optimized/non optimized solutions, it is not trivial to understand the potential value of a new site without running a complete optimization. This could be too time consuming if a lot of sites need to be evaluated, therefore we propose to use Machine Learning to quickly estimate...... the potential of new sites (i.e., to estimate the optimized production of a site without explicitly running the optimization). To do so, we trained and tested different Machine Learning models on a dataset of 3000+ optimized layouts found by the optimizer. Thanks to the close collaboration with a leading...

Security constrained optimal power flow by modern optimization tools

African Journals Online (AJOL)

Security constrained optimal power flow by modern optimization tools. ... International Journal of Engineering, Science and Technology ... If you would like more information about how to print, save, and work with PDFs, Highwire Press ...

A Novel Particle Swarm Optimization Algorithm for Global Optimization.

Science.gov (United States)

Wang, Chun-Feng; Liu, Kui

2016-01-01

Particle Swarm Optimization (PSO) is a recently developed optimization method, which has attracted interest of researchers in various areas due to its simplicity and effectiveness, and many variants have been proposed. In this paper, a novel Particle Swarm Optimization algorithm is presented, in which the information of the best neighbor of each particle and the best particle of the entire population in the current iteration is considered. Meanwhile, to avoid premature, an abandoned mechanism is used. Furthermore, for improving the global convergence speed of our algorithm, a chaotic search is adopted in the best solution of the current iteration. To verify the performance of our algorithm, standard test functions have been employed. The experimental results show that the algorithm is much more robust and efficient than some existing Particle Swarm Optimization algorithms.

A Comparative Theoretical and Computational Study on Robust Counterpart Optimization: I. Robust Linear Optimization and Robust Mixed Integer Linear Optimization

Science.gov (United States)

Li, Zukui; Ding, Ran; Floudas, Christodoulos A.

2011-01-01

Robust counterpart optimization techniques for linear optimization and mixed integer linear optimization problems are studied in this paper. Different uncertainty sets, including those studied in literature (i.e., interval set; combined interval and ellipsoidal set; combined interval and polyhedral set) and new ones (i.e., adjustable box; pure ellipsoidal; pure polyhedral; combined interval, ellipsoidal, and polyhedral set) are studied in this work and their geometric relationship is discussed. For uncertainty in the left hand side, right hand side, and objective function of the optimization problems, robust counterpart optimization formulations induced by those different uncertainty sets are derived. Numerical studies are performed to compare the solutions of the robust counterpart optimization models and applications in refinery production planning and batch process scheduling problem are presented. PMID:21935263

Sequential stochastic optimization

CERN Document Server

Cairoli, Renzo

1996-01-01

Sequential Stochastic Optimization provides mathematicians and applied researchers with a well-developed framework in which stochastic optimization problems can be formulated and solved. Offering much material that is either new or has never before appeared in book form, it lucidly presents a unified theory of optimal stopping and optimal sequential control of stochastic processes. This book has been carefully organized so that little prior knowledge of the subject is assumed; its only prerequisites are a standard graduate course in probability theory and some familiarity with discrete-paramet

Optimal Power Flow by Interior Point and Non Interior Point Modern Optimization Algorithms

Directory of Open Access Journals (Sweden)

Marcin Połomski

2013-03-01

Full Text Available The idea of optimal power flow (OPF is to determine the optimal settings for control variables while respecting various constraints, and in general it is related to power system operational and planning optimization problems. A vast number of optimization methods have been applied to solve the OPF problem, but their performance is highly dependent on the size of a power system being optimized. The development of the OPF recently has tracked significant progress both in numerical optimization techniques and computer techniques application. In recent years, application of interior point methods to solve OPF problem has been paid great attention. This is due to the fact that IP methods are among the fastest algorithms, well suited to solve large-scale nonlinear optimization problems. This paper presents the primal-dual interior point method based optimal power flow algorithm and new variant of the non interior point method algorithm with application to optimal power flow problem. Described algorithms were implemented in custom software. The experiments show the usefulness of computational software and implemented algorithms for solving the optimal power flow problem, including the system model sizes comparable to the size of the National Power System.

A short numerical study on the optimization methods influence on topology optimization

DEFF Research Database (Denmark)

Rojas Labanda, Susana; Sigmund, Ole; Stolpe, Mathias

2017-01-01

Structural topology optimization problems are commonly defined using continuous design variables combined with material interpolation schemes. One of the challenges for density based topology optimization observed in the review article (Sigmund and Maute Struct Multidiscip Optim 48(6):1031–1055...... 2013) is the slow convergence that is often encountered in practice, when an almost solid-and-void design is found. The purpose of this forum article is to present some preliminary observations on how designs evolves during the optimization process for different choices of optimization methods...

Coupled Low-thrust Trajectory and System Optimization via Multi-Objective Hybrid Optimal Control

Science.gov (United States)

Vavrina, Matthew A.; Englander, Jacob Aldo; Ghosh, Alexander R.

2015-01-01

The optimization of low-thrust trajectories is tightly coupled with the spacecraft hardware. Trading trajectory characteristics with system parameters ton identify viable solutions and determine mission sensitivities across discrete hardware configurations is labor intensive. Local independent optimization runs can sample the design space, but a global exploration that resolves the relationships between the system variables across multiple objectives enables a full mapping of the optimal solution space. A multi-objective, hybrid optimal control algorithm is formulated using a multi-objective genetic algorithm as an outer loop systems optimizer around a global trajectory optimizer. The coupled problem is solved simultaneously to generate Pareto-optimal solutions in a single execution. The automated approach is demonstrated on two boulder return missions.

Optimization under Uncertainty

KAUST Repository

Lopez, Rafael H.

2016-01-06

The goal of this poster is to present the main approaches to optimization of engineering systems in the presence of uncertainties. We begin by giving an insight about robust optimization. Next, we detail how to deal with probabilistic constraints in optimization, the so called the reliability based design. Subsequently, we present the risk optimization approach, which includes the expected costs of failure in the objective function. After that the basic description of each approach is given, the projects developed by CORE are presented. Finally, the main current topic of research of CORE is described.

Journal of Biosciences | Indian Academy of Sciences

Indian Academy of Sciences (India)

Home; Journals; Journal of Biosciences. Kamalvishnu P Gottimukkala. Articles written in Journal of Biosciences. Volume 36 Issue 3 August 2011 pp 461-469 Articles. N-terminal PDZ-like domain of chromatin organizer SATB1 contributes towards its function as transcription regulator · Dimple Notani Praveena L Ramanujam ...

Flight plan optimization

Science.gov (United States)

Dharmaseelan, Anoop; Adistambha, Keyne D.

2015-05-01

Fuel cost accounts for 40 percent of the operating cost of an airline. Fuel cost can be minimized by planning a flight on optimized routes. The routes can be optimized by searching best connections based on the cost function defined by the airline. The most common algorithm that used to optimize route search is Dijkstra's. Dijkstra's algorithm produces a static result and the time taken for the search is relatively long. This paper experiments a new algorithm to optimize route search which combines the principle of simulated annealing and genetic algorithm. The experimental results of route search, presented are shown to be computationally fast and accurate compared with timings from generic algorithm. The new algorithm is optimal for random routing feature that is highly sought by many regional operators.

Optimal Water-Power Flow Problem: Formulation and Distributed Optimal Solution

Energy Technology Data Exchange (ETDEWEB)

Dall-Anese, Emiliano [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Zhao, Changhong [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Zamzam, Admed S. [University of Minnesota; Sidiropoulos, Nicholas D. [University of Minnesota; Taylor, Josh A. [University of Toronto

2018-01-12

This paper formalizes an optimal water-power flow (OWPF) problem to optimize the use of controllable assets across power and water systems while accounting for the couplings between the two infrastructures. Tanks and pumps are optimally managed to satisfy water demand while improving power grid operations; {for the power network, an AC optimal power flow formulation is augmented to accommodate the controllability of water pumps.} Unfortunately, the physics governing the operation of the two infrastructures and coupling constraints lead to a nonconvex (and, in fact, NP-hard) problem; however, after reformulating OWPF as a nonconvex, quadratically-constrained quadratic problem, a feasible point pursuit-successive convex approximation approach is used to identify feasible and optimal solutions. In addition, a distributed solver based on the alternating direction method of multipliers enables water and power operators to pursue individual objectives while respecting the couplings between the two networks. The merits of the proposed approach are demonstrated for the case of a distribution feeder coupled with a municipal water distribution network.

Security constrained optimal power flow by modern optimization tools

African Journals Online (AJOL)

The main objective of an optimal power flow (OPF) functions is to optimize .... It is characterized as propagation of plants and this happens by gametes union. ... ss and different variables, for example, wind, nearby fertilization can have a critic.

Deletion of the distal COOH-terminus of the A2B adenosine receptor switches internalization to an arrestin- and clathrin-independent pathway and inhibits recycling.

Science.gov (United States)

Mundell, S J; Matharu, A-L; Nisar, S; Palmer, T M; Benovic, J L; Kelly, E

2010-02-01

We have investigated the effect of deletions of a postsynaptic density, disc large and zo-1 protein (PDZ) motif at the end of the COOH-terminus of the rat A(2B) adenosine receptor on intracellular trafficking following long-term exposure to the agonist 5'-(N-ethylcarboxamido)-adenosine. The trafficking of the wild type A(2B) adenosine receptor and deletion mutants expressed in Chinese hamster ovary cells was studied using an enzyme-linked immunosorbent assay in combination with immunofluorescence microscopy. The wild type A(2B) adenosine receptor and deletion mutants were all extensively internalized following prolonged treatment with NECA. The intracellular compartment through which the Gln(325)-stop receptor mutant, which lacks the Type II PDZ motif found in the wild type receptor initially trafficked was not the same as the wild type receptor. Expression of dominant negative mutants of arrestin-2, dynamin or Eps-15 inhibited internalization of wild type and Leu(330)-stop receptors, whereas only dominant negative mutant dynamin inhibited agonist-induced internalization of Gln(325)-stop, Ser(326)-stop and Phe(328)-stop receptors. Following internalization, the wild type A(2B) adenosine receptor recycled rapidly to the cell surface, whereas the Gln(325)-stop receptor did not recycle. Deletion of the COOH-terminus of the A(2B) adenosine receptor beyond Leu(330) switches internalization from an arrestin- and clathrin-dependent pathway to one that is dynamin dependent but arrestin and clathrin independent. The presence of a Type II PDZ motif appears to be essential for arrestin- and clathrin-dependent internalization, as well as recycling of the A(2B) adenosine receptor following prolonged agonist addition.

Applications of combinatorial optimization

CERN Document Server

Paschos, Vangelis Th

2013-01-01

Combinatorial optimization is a multidisciplinary scientific area, lying in the interface of three major scientific domains: mathematics, theoretical computer science and management. The three volumes of the Combinatorial Optimization series aims to cover a wide range of topics in this area. These topics also deal with fundamental notions and approaches as with several classical applications of combinatorial optimization. "Applications of Combinatorial Optimization" is presenting a certain number among the most common and well-known applications of Combinatorial Optimization.

Concepts of combinatorial optimization

CERN Document Server

Paschos, Vangelis Th

2014-01-01

Combinatorial optimization is a multidisciplinary scientific area, lying in the interface of three major scientific domains: mathematics, theoretical computer science and management.  The three volumes of the Combinatorial Optimization series aim to cover a wide range  of topics in this area. These topics also deal with fundamental notions and approaches as with several classical applications of combinatorial optimization.Concepts of Combinatorial Optimization, is divided into three parts:- On the complexity of combinatorial optimization problems, presenting basics about worst-case and randomi

Structural optimization

CERN Document Server

MacBain, Keith M

2009-01-01

Intends to supplement the engineer's box of analysis and design tools making optimization as commonplace as the finite element method in the engineering workplace. This title introduces structural optimization and the methods of nonlinear programming such as Lagrange multipliers, Kuhn-Tucker conditions, and calculus of variations.

Robust buckling optimization of laminated composite structures using discrete material optimization considering “worst” shape imperfections

DEFF Research Database (Denmark)

Henrichsen, Søren Randrup; Lindgaard, Esben; Lund, Erik

2015-01-01

Robust buckling optimal design of laminated composite structures is conducted in this work. Optimal designs are obtained by considering geometric imperfections in the optimization procedure. Discrete Material Optimization is applied to obtain optimal laminate designs. The optimal geometric...... imperfection is represented by the “worst” shape imperfection. The two optimization problems are combined through the recurrence optimization. Hereby the imperfection sensitivity of the considered structures can be studied. The recurrence optimization is demonstrated through a U-profile and a cylindrical panel...... example. The imperfection sensitivity of the optimized structure decreases during the recurrence optimization for both examples, hence robust buckling optimal structures are designed....

Superfamily of G-protein coupled receptors (GPCRs – extraordinary and outstanding success of evolution

Directory of Open Access Journals (Sweden)

Kazimierz Kochman

2014-10-01

, via their C-terminal domain, with proteins containing PDZ domains, which are present in the PDZ proteins. These proteins organize the NMDA receptors and some K+ channels while their PDZ domains generally bind 3-4 amino-acid stretches of C-terminal sequences of target proteins. The -S/TXV motif was found in some PDZ target proteins. GPCRs can also interact with the Enabled/VASP homology (EVH-like domain which interacts directly with group 1 mGluR receptors. Every year brings new very important data in research of these proteins, which should be called “the most successful structures evolved during the whole of animal evolution”.

Optimization theory with applications

CERN Document Server

Pierre, Donald A

1987-01-01

Optimization principles are of undisputed importance in modern design and system operation. They can be used for many purposes: optimal design of systems, optimal operation of systems, determination of performance limitations of systems, or simply the solution of sets of equations. While most books on optimization are limited to essentially one approach, this volume offers a broad spectrum of approaches, with emphasis on basic techniques from both classical and modern work.After an introductory chapter introducing those system concepts that prevail throughout optimization problems of all typ

Application of a particle swarm optimization for shape optimization in hydraulic machinery

Science.gov (United States)

Moravec, Prokop; Rudolf, Pavel

A study of shape optimization has become increasingly popular in academia and industry. A typical problem is to find an optimal shape, which minimizes (or maximizes) a certain cost function and satisfies given constraints. Particle Swarm Optimization (PSO) has received a lot of attention in past years and is inspired by social behaviour of some animals such as flocking behaviour of birds. This paper focuses on a possibility of a diffuser shape optimization using particle swarm optimization (PSO), which is coupled with CFD simulation. Influence of main parameters of PSO-algorithm and later diffuser shapes obtained with this method are discussed and advantages/disadvantages summarized.

Application of a particle swarm optimization for shape optimization in hydraulic machinery

Directory of Open Access Journals (Sweden)

Moravec Prokop

2017-01-01

Full Text Available A study of shape optimization has become increasingly popular in academia and industry. A typical problem is to find an optimal shape, which minimizes (or maximizes a certain cost function and satisfies given constraints. Particle Swarm Optimization (PSO has received a lot of attention in past years and is inspired by social behaviour of some animals such as flocking behaviour of birds. This paper focuses on a possibility of a diffuser shape optimization using particle swarm optimization (PSO, which is coupled with CFD simulation. Influence of main parameters of PSO-algorithm and later diffuser shapes obtained with this method are discussed and advantages/disadvantages summarized.

Bayesian optimization for materials science

CERN Document Server

Packwood, Daniel

2017-01-01

This book provides a short and concise introduction to Bayesian optimization specifically for experimental and computational materials scientists. After explaining the basic idea behind Bayesian optimization and some applications to materials science in Chapter 1, the mathematical theory of Bayesian optimization is outlined in Chapter 2. Finally, Chapter 3 discusses an application of Bayesian optimization to a complicated structure optimization problem in computational surface science. Bayesian optimization is a promising global optimization technique that originates in the field of machine learning and is starting to gain attention in materials science. For the purpose of materials design, Bayesian optimization can be used to predict new materials with novel properties without extensive screening of candidate materials. For the purpose of computational materials science, Bayesian optimization can be incorporated into first-principles calculations to perform efficient, global structure optimizations. While re...

Methods of mathematical optimization

Science.gov (United States)

Vanderplaats, G. N.

The fundamental principles of numerical optimization methods are reviewed, with an emphasis on potential engineering applications. The basic optimization process is described; unconstrained and constrained minimization problems are defined; a general approach to the design of optimization software programs is outlined; and drawings and diagrams are shown for examples involving (1) the conceptual design of an aircraft, (2) the aerodynamic optimization of an airfoil, (3) the design of an automotive-engine connecting rod, and (4) the optimization of a 'ski-jump' to assist aircraft in taking off from a very short ship deck.

Introduction to Continuous Optimization

DEFF Research Database (Denmark)

Andreasson, Niclas; Evgrafov, Anton; Patriksson, Michael

optimal solutions for continuous optimization models. The main part of the mathematical material therefore concerns the analysis and linear algebra that underlie the workings of convexity and duality, and necessary/sufficient local/global optimality conditions for continuous optimization problems. Natural...... algorithms are then developed from these optimality conditions, and their most important convergence characteristics are analyzed. The book answers many more questions of the form “Why?” and “Why not?” than “How?”. We use only elementary mathematics in the development of the book, yet are rigorous throughout...

Distributed Cooperative Optimal Control for Multiagent Systems on Directed Graphs: An Inverse Optimal Approach.

Science.gov (United States)

Zhang, Huaguang; Feng, Tao; Yang, Guang-Hong; Liang, Hongjing

2015-07-01

In this paper, the inverse optimal approach is employed to design distributed consensus protocols that guarantee consensus and global optimality with respect to some quadratic performance indexes for identical linear systems on a directed graph. The inverse optimal theory is developed by introducing the notion of partial stability. As a result, the necessary and sufficient conditions for inverse optimality are proposed. By means of the developed inverse optimal theory, the necessary and sufficient conditions are established for globally optimal cooperative control problems on directed graphs. Basic optimal cooperative design procedures are given based on asymptotic properties of the resulting optimal distributed consensus protocols, and the multiagent systems can reach desired consensus performance (convergence rate and damping rate) asymptotically. Finally, two examples are given to illustrate the effectiveness of the proposed methods.

Optimization and approximation

CERN Document Server

Pedregal, Pablo

2017-01-01

This book provides a basic, initial resource, introducing science and engineering students to the field of optimization. It covers three main areas: mathematical programming, calculus of variations and optimal control, highlighting the ideas and concepts and offering insights into the importance of optimality conditions in each area. It also systematically presents affordable approximation methods. Exercises at various levels have been included to support the learning process.

Workshop on Computational Optimization

CERN Document Server

2015-01-01

Our everyday life is unthinkable without optimization. We try to minimize our effort and to maximize the achieved profit. Many real world and industrial problems arising in engineering, economics, medicine and other domains can be formulated as optimization tasks. This volume is a comprehensive collection of extended contributions from the Workshop on Computational Optimization 2013. It presents recent advances in computational optimization. The volume includes important real life problems like parameter settings for controlling processes in bioreactor, resource constrained project scheduling, problems arising in transport services, error correcting codes, optimal system performance and energy consumption and so on. It shows how to develop algorithms for them based on new metaheuristic methods like evolutionary computation, ant colony optimization, constrain programming and others.

An Improved Marriage in Honey Bees Optimization Algorithm for Single Objective Unconstrained Optimization

Directory of Open Access Journals (Sweden)

Yuksel Celik

2013-01-01

Full Text Available Marriage in honey bees optimization (MBO is a metaheuristic optimization algorithm developed by inspiration of the mating and fertilization process of honey bees and is a kind of swarm intelligence optimizations. In this study we propose improved marriage in honey bees optimization (IMBO by adding Levy flight algorithm for queen mating flight and neighboring for worker drone improving. The IMBO algorithm’s performance and its success are tested on the well-known six unconstrained test functions and compared with other metaheuristic optimization algorithms.

4th Optimization Day

CERN Document Server

Eberhard, Andrew; Ralph, Daniel; Glover, Barney M

1999-01-01

Although the monograph Progress in Optimization I: Contributions from Aus­ tralasia grew from the idea of publishing a proceedings of the Fourth Optimiza­ tion Day, held in July 1997 at the Royal Melbourne Institute of Technology, the focus soon changed to a refereed volume in optimization. The intention is to publish a similar book annually, following each Optimization Day. The idea of having an annual Optimization Day was conceived by Barney Glover; the first of these Optimization Days was held in 1994 at the University of Ballarat. Barney hoped that such a yearly event would bring together the many, but widely dispersed, researchers in Australia who were publishing in optimization and related areas such as control. The first Optimization Day event was followed by similar conferences at The University of New South Wales (1995), The University of Melbourne (1996), the Royal Melbourne Institute of Technology (1997), and The University of Western Australia (1998). The 1999 conference will return to Ballarat ...

Optimization strategies for discrete multi-material stiffness optimization

DEFF Research Database (Denmark)

Hvejsel, Christian Frier; Lund, Erik; Stolpe, Mathias

2011-01-01

Design of composite laminated lay-ups are formulated as discrete multi-material selection problems. The design problem can be modeled as a non-convex mixed-integer optimization problem. Such problems are in general only solvable to global optimality for small to moderate sized problems. To attack...... which numerically confirm the sought properties of the new scheme in terms of convergence to a discrete solution....

Evolution strategies for robust optimization

NARCIS (Netherlands)

Kruisselbrink, Johannes Willem

2012-01-01

Real-world (black-box) optimization problems often involve various types of uncertainties and noise emerging in different parts of the optimization problem. When this is not accounted for, optimization may fail or may yield solutions that are optimal in the classical strict notion of optimality, but

System performance optimization

International Nuclear Information System (INIS)

Bednarz, R.J.

1978-01-01

The System Performance Optimization has become an important and difficult field for large scientific computer centres. Important because the centres must satisfy increasing user demands at the lowest possible cost. Difficult because the System Performance Optimization requires a deep understanding of hardware, software and workload. The optimization is a dynamic process depending on the changes in hardware configuration, current level of the operating system and user generated workload. With the increasing complication of the computer system and software, the field for the optimization manoeuvres broadens. The hardware of two manufacturers IBM and CDC is discussed. Four IBM and two CDC operating systems are described. The description concentrates on the organization of the operating systems, the job scheduling and I/O handling. The performance definitions, workload specification and tools for the system stimulation are given. The measurement tools for the System Performance Optimization are described. The results of the measurement and various methods used for the operating system tuning are discussed. (Auth.)

Interior point algorithms: guaranteed optimality for fluence map optimization in IMRT

Energy Technology Data Exchange (ETDEWEB)

Aleman, Dionne M [Department of Mechanical and Industrial Engineering, University of Toronto, 5 King' s College Road, Toronto, ON M5S 3G8 (Canada); Glaser, Daniel [Division of Optimization and Systems Theory, Department of Mathematics, Royal Institute of Technology, Stockholm (Sweden); Romeijn, H Edwin [Department of Industrial and Operations Engineering, University of Michigan, Ann Arbor, MI 48109-2117 (United States); Dempsey, James F, E-mail: aleman@mie.utoronto.c, E-mail: romeijn@umich.ed, E-mail: jfdempsey@viewray.co [ViewRay, Inc. 2 Thermo Fisher Way, Village of Oakwood, OH 44146 (United States)

2010-09-21

One of the most widely studied problems of the intensity-modulated radiation therapy (IMRT) treatment planning problem is the fluence map optimization (FMO) problem, the problem of determining the amount of radiation intensity, or fluence, of each beamlet in each beam. For a given set of beams, the fluences of the beamlets can drastically affect the quality of the treatment plan, and thus it is critical to obtain good fluence maps for radiation delivery. Although several approaches have been shown to yield good solutions to the FMO problem, these solutions are not guaranteed to be optimal. This shortcoming can be attributed to either optimization model complexity or properties of the algorithms used to solve the optimization model. We present a convex FMO formulation and an interior point algorithm that yields an optimal treatment plan in seconds, making it a viable option for clinical applications.

Interior point algorithms: guaranteed optimality for fluence map optimization in IMRT

International Nuclear Information System (INIS)

Aleman, Dionne M; Glaser, Daniel; Romeijn, H Edwin; Dempsey, James F

2010-01-01

One of the most widely studied problems of the intensity-modulated radiation therapy (IMRT) treatment planning problem is the fluence map optimization (FMO) problem, the problem of determining the amount of radiation intensity, or fluence, of each beamlet in each beam. For a given set of beams, the fluences of the beamlets can drastically affect the quality of the treatment plan, and thus it is critical to obtain good fluence maps for radiation delivery. Although several approaches have been shown to yield good solutions to the FMO problem, these solutions are not guaranteed to be optimal. This shortcoming can be attributed to either optimization model complexity or properties of the algorithms used to solve the optimization model. We present a convex FMO formulation and an interior point algorithm that yields an optimal treatment plan in seconds, making it a viable option for clinical applications.

Finding Multiple Optimal Solutions to Optimal Load Distribution Problem in Hydropower Plant

Directory of Open Access Journals (Sweden)

Xinhao Jiang

2012-05-01

Full Text Available Optimal load distribution (OLD among generator units of a hydropower plant is a vital task for hydropower generation scheduling and management. Traditional optimization methods for solving this problem focus on finding a single optimal solution. However, many practical constraints on hydropower plant operation are very difficult, if not impossible, to be modeled, and the optimal solution found by those models might be of limited practical uses. This motivates us to find multiple optimal solutions to the OLD problem, which can provide more flexible choices for decision-making. Based on a special dynamic programming model, we use a modified shortest path algorithm to produce multiple solutions to the problem. It is shown that multiple optimal solutions exist for the case study of China’s Geheyan hydropower plant, and they are valuable for assessing the stability of generator units, showing the potential of reducing occurrence times of units across vibration areas.

Medicinsk Optimering

DEFF Research Database (Denmark)

Birkholm, Klavs

2010-01-01

En undersøgelse af anvendelsen af medicin til optimering af koncentration, hukommelse og følelsestonus. Efterfulgt af etiske overvejelser og anbefalinger til det politiske system......En undersøgelse af anvendelsen af medicin til optimering af koncentration, hukommelse og følelsestonus. Efterfulgt af etiske overvejelser og anbefalinger til det politiske system...

Optimal control and optimal trajectories of regional macroeconomic dynamics based on the Pontryagin maximum principle

Science.gov (United States)

Bulgakov, V. K.; Strigunov, V. V.

2009-05-01

The Pontryagin maximum principle is used to prove a theorem concerning optimal control in regional macroeconomics. A boundary value problem for optimal trajectories of the state and adjoint variables is formulated, and optimal curves are analyzed. An algorithm is proposed for solving the boundary value problem of optimal control. The performance of the algorithm is demonstrated by computing an optimal control and the corresponding optimal trajectories.

Regularizing portfolio optimization

International Nuclear Information System (INIS)

Still, Susanne; Kondor, Imre

2010-01-01

The optimization of large portfolios displays an inherent instability due to estimation error. This poses a fundamental problem, because solutions that are not stable under sample fluctuations may look optimal for a given sample, but are, in effect, very far from optimal with respect to the average risk. In this paper, we approach the problem from the point of view of statistical learning theory. The occurrence of the instability is intimately related to over-fitting, which can be avoided using known regularization methods. We show how regularized portfolio optimization with the expected shortfall as a risk measure is related to support vector regression. The budget constraint dictates a modification. We present the resulting optimization problem and discuss the solution. The L2 norm of the weight vector is used as a regularizer, which corresponds to a diversification 'pressure'. This means that diversification, besides counteracting downward fluctuations in some assets by upward fluctuations in others, is also crucial because it improves the stability of the solution. The approach we provide here allows for the simultaneous treatment of optimization and diversification in one framework that enables the investor to trade off between the two, depending on the size of the available dataset.

Optimizing countershading camouflage.

Science.gov (United States)

Cuthill, Innes C; Sanghera, N Simon; Penacchio, Olivier; Lovell, Paul George; Ruxton, Graeme D; Harris, Julie M

2016-11-15

Countershading, the widespread tendency of animals to be darker on the side that receives strongest illumination, has classically been explained as an adaptation for camouflage: obliterating cues to 3D shape and enhancing background matching. However, there have only been two quantitative tests of whether the patterns observed in different species match the optimal shading to obliterate 3D cues, and no tests of whether optimal countershading actually improves concealment or survival. We use a mathematical model of the light field to predict the optimal countershading for concealment that is specific to the light environment and then test this prediction with correspondingly patterned model "caterpillars" exposed to avian predation in the field. We show that the optimal countershading is strongly illumination-dependent. A relatively sharp transition in surface patterning from dark to light is only optimal under direct solar illumination; if there is diffuse illumination from cloudy skies or shade, the pattern provides no advantage over homogeneous background-matching coloration. Conversely, a smoother gradation between dark and light is optimal under cloudy skies or shade. The demonstration of these illumination-dependent effects of different countershading patterns on predation risk strongly supports the comparative evidence showing that the type of countershading varies with light environment.

Regularizing portfolio optimization

Science.gov (United States)

Still, Susanne; Kondor, Imre

2010-07-01

The optimization of large portfolios displays an inherent instability due to estimation error. This poses a fundamental problem, because solutions that are not stable under sample fluctuations may look optimal for a given sample, but are, in effect, very far from optimal with respect to the average risk. In this paper, we approach the problem from the point of view of statistical learning theory. The occurrence of the instability is intimately related to over-fitting, which can be avoided using known regularization methods. We show how regularized portfolio optimization with the expected shortfall as a risk measure is related to support vector regression. The budget constraint dictates a modification. We present the resulting optimization problem and discuss the solution. The L2 norm of the weight vector is used as a regularizer, which corresponds to a diversification 'pressure'. This means that diversification, besides counteracting downward fluctuations in some assets by upward fluctuations in others, is also crucial because it improves the stability of the solution. The approach we provide here allows for the simultaneous treatment of optimization and diversification in one framework that enables the investor to trade off between the two, depending on the size of the available dataset.

A novel comprehensive learning artificial bee colony optimizer for dynamic optimization biological problems.

Science.gov (United States)

Su, Weixing; Chen, Hanning; Liu, Fang; Lin, Na; Jing, Shikai; Liang, Xiaodan; Liu, Wei

2017-03-01

There are many dynamic optimization problems in the real world, whose convergence and searching ability is cautiously desired, obviously different from static optimization cases. This requires an optimization algorithm adaptively seek the changing optima over dynamic environments, instead of only finding the global optimal solution in the static environment. This paper proposes a novel comprehensive learning artificial bee colony optimizer (CLABC) for optimization in dynamic environments problems, which employs a pool of optimal foraging strategies to balance the exploration and exploitation tradeoff. The main motive of CLABC is to enrich artificial bee foraging behaviors in the ABC model by combining Powell's pattern search method, life-cycle, and crossover-based social learning strategy. The proposed CLABC is a more bee-colony-realistic model that the bee can reproduce and die dynamically throughout the foraging process and population size varies as the algorithm runs. The experiments for evaluating CLABC are conducted on the dynamic moving peak benchmarks. Furthermore, the proposed algorithm is applied to a real-world application of dynamic RFID network optimization. Statistical analysis of all these cases highlights the significant performance improvement due to the beneficial combination and demonstrates the performance superiority of the proposed algorithm.

Time-Space Topology Optimization

DEFF Research Database (Denmark)

Jensen, Jakob Søndergaard

2008-01-01

A method for space-time topology optimization is outlined. The space-time optimization strategy produces structures with optimized material distributions that vary in space and in time. The method is demonstrated for one-dimensional wave propagation in an elastic bar that has a time-dependent Young......’s modulus and is subjected to a transient load. In the example an optimized dynamic structure is demonstrated that compresses a propagating Gauss pulse....

Coevolutionary particle swarm optimization using Gaussian distribution for solving constrained optimization problems.

Science.gov (United States)

Krohling, Renato A; Coelho, Leandro dos Santos

2006-12-01

In this correspondence, an approach based on coevolutionary particle swarm optimization to solve constrained optimization problems formulated as min-max problems is presented. In standard or canonical particle swarm optimization (PSO), a uniform probability distribution is used to generate random numbers for the accelerating coefficients of the local and global terms. We propose a Gaussian probability distribution to generate the accelerating coefficients of PSO. Two populations of PSO using Gaussian distribution are used on the optimization algorithm that is tested on a suite of well-known benchmark constrained optimization problems. Results have been compared with the canonical PSO (constriction factor) and with a coevolutionary genetic algorithm. Simulation results show the suitability of the proposed algorithm in terms of effectiveness and robustness.

Optimal configuration of microstructure in ferroelectric materials by stochastic optimization

Science.gov (United States)

Jayachandran, K. P.; Guedes, J. M.; Rodrigues, H. C.

2010-07-01

An optimization procedure determining the ideal configuration at the microstructural level of ferroelectric (FE) materials is applied to maximize piezoelectricity. Piezoelectricity in ceramic FEs differs significantly from that of single crystals because of the presence of crystallites (grains) possessing crystallographic axes aligned imperfectly. The piezoelectric properties of a polycrystalline (ceramic) FE is inextricably related to the grain orientation distribution (texture). The set of combination of variables, known as solution space, which dictates the texture of a ceramic is unlimited and hence the choice of the optimal solution which maximizes the piezoelectricity is complicated. Thus, a stochastic global optimization combined with homogenization is employed for the identification of the optimal granular configuration of the FE ceramic microstructure with optimum piezoelectric properties. The macroscopic equilibrium piezoelectric properties of polycrystalline FE is calculated using mathematical homogenization at each iteration step. The configuration of grains characterized by its orientations at each iteration is generated using a randomly selected set of orientation distribution parameters. The optimization procedure applied to the single crystalline phase compares well with the experimental data. Apparent enhancement of piezoelectric coefficient d33 is observed in an optimally oriented BaTiO3 single crystal. Based on the good agreement of results with the published data in single crystals, we proceed to apply the methodology in polycrystals. A configuration of crystallites, simultaneously constraining the orientation distribution of the c-axis (polar axis) while incorporating ab-plane randomness, which would multiply the overall piezoelectricity in ceramic BaTiO3 is also identified. The orientation distribution of the c-axes is found to be a narrow Gaussian distribution centered around 45°. The piezoelectric coefficient in such a ceramic is found to

Journal of Genetics | Indian Academy of Sciences

Indian Academy of Sciences (India)

The PDZ and LIM domain 5 (PDLIM5) gene may play a role in cancer, bipolar disorder, major depression, alcohol dependence and schizophrenia; however, little is known about the interaction effect of steroid and PDLIM5 gene on cancer. This study examined 47 single-nucleotide polymorphisms (SNPs) within the PDLIM5 ...

A novel approach for optimal chiller loading using particle swarm optimization

Energy Technology Data Exchange (ETDEWEB)

Ardakani, A. Jahanbani; Ardakani, F. Fattahi; Hosseinian, S.H. [Department of Electrical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Hafez Avenue, Tehran 15875-4413 (Iran, Islamic Republic of)

2008-07-01

This study employs two new methods to solve optimal chiller loading (OCL) problem. These methods are continuous genetic algorithm (GA) and particle swarm optimization (PSO). Because of continuous nature of variables in OCL problem, continuous GA and PSO easily overcome deficiencies in other conventional optimization methods. Partial load ratio (PLR) of the chiller is chosen as the variable to be optimized and consumption power of the chiller is considered as fitness function. Both of these methods find the optimal solution while the equality constraint is exactly satisfied. Some of the major advantages of proposed approaches over other conventional methods can be mentioned as fast convergence, escaping from getting into local optima, simple implementation as well as independency of the solution from the problem. Abilities of proposed methods are examined with reference to an example system. To demonstrate these abilities, results are compared with binary genetic algorithm method. The proposed approaches can be perfectly applied to air-conditioning systems. (author)

Optimization of photonic crystal cavities

DEFF Research Database (Denmark)

Wang, Fengwen; Sigmund, Ole

2017-01-01

We present optimization of photonic crystal cavities. The optimization problem is formulated to maximize the Purcell factor of a photonic crystal cavity. Both topology optimization and air-hole-based shape optimization are utilized for the design process. Numerical results demonstrate...... that the Purcell factor of the photonic crystal cavity can be significantly improved through optimization....

Giga-Voxel Structural Optimization

DEFF Research Database (Denmark)

Aage, Niels; Andreassen, Erik; Lazarov, Boyan Stefanov

2017-01-01

The optimal topology of large structural systems has until now been concerned with the design of individual parts and not that of complete assemblies. However, due to recent advances in numerical algorithms tailored for large scale structural optimization this limitation can now be circumvented....... In this work we present several examplesdisplaying how high resolution topology optimization can be used to obtain new, as well as already known, insight within the field of structural optimization. To demonstrate the capabilities of the developed framework we apply it to the design of the supporting structure...... topology optimization provides new insight and possible weight savings forfuture aircraft designs....

Pseudolinear functions and optimization

CERN Document Server

Mishra, Shashi Kant

2015-01-01

Pseudolinear Functions and Optimization is the first book to focus exclusively on pseudolinear functions, a class of generalized convex functions. It discusses the properties, characterizations, and applications of pseudolinear functions in nonlinear optimization problems.The book describes the characterizations of solution sets of various optimization problems. It examines multiobjective pseudolinear, multiobjective fractional pseudolinear, static minmax pseudolinear, and static minmax fractional pseudolinear optimization problems and their results. The authors extend these results to locally

Optimization algorithms and applications

CERN Document Server

Arora, Rajesh Kumar

2015-01-01

Choose the Correct Solution Method for Your Optimization ProblemOptimization: Algorithms and Applications presents a variety of solution techniques for optimization problems, emphasizing concepts rather than rigorous mathematical details and proofs. The book covers both gradient and stochastic methods as solution techniques for unconstrained and constrained optimization problems. It discusses the conjugate gradient method, Broyden-Fletcher-Goldfarb-Shanno algorithm, Powell method, penalty function, augmented Lagrange multiplier method, sequential quadratic programming, method of feasible direc

Stochastic optimization methods

CERN Document Server

Marti, Kurt

2005-01-01

Optimization problems arising in practice involve random parameters. For the computation of robust optimal solutions, i.e., optimal solutions being insensitive with respect to random parameter variations, deterministic substitute problems are needed. Based on the distribution of the random data, and using decision theoretical concepts, optimization problems under stochastic uncertainty are converted into deterministic substitute problems. Due to the occurring probabilities and expectations, approximative solution techniques must be applied. Deterministic and stochastic approximation methods and their analytical properties are provided: Taylor expansion, regression and response surface methods, probability inequalities, First Order Reliability Methods, convex approximation/deterministic descent directions/efficient points, stochastic approximation methods, differentiation of probability and mean value functions. Convergence results of the resulting iterative solution procedures are given.

Euler's fluid equations: Optimal control vs optimization

Energy Technology Data Exchange (ETDEWEB)

Holm, Darryl D., E-mail: d.holm@ic.ac.u [Department of Mathematics, Imperial College London, SW7 2AZ (United Kingdom)

2009-11-23

An optimization method used in image-processing (metamorphosis) is found to imply Euler's equations for incompressible flow of an inviscid fluid, without requiring that the Lagrangian particle labels exactly follow the flow lines of the Eulerian velocity vector field. Thus, an optimal control problem and an optimization problem for incompressible ideal fluid flow both yield the same Euler fluid equations, although their Lagrangian parcel dynamics are different. This is a result of the gauge freedom in the definition of the fluid pressure for an incompressible flow, in combination with the symmetry of fluid dynamics under relabeling of their Lagrangian coordinates. Similar ideas are also illustrated for SO(N) rigid body motion.

Optimization of Inventory

OpenAIRE

PROKOPOVÁ, Nikola

2017-01-01

The subject of this thesis is optimization of inventory in selected organization. Inventory optimization is a very important topic in each organization because it reduces storage costs. At the beginning the inventory theory is presented. It shows the meaning and types of inventory, inventory control and also different methods and models of inventory control. Inventory optimization in the enterprise can be reached by using models of inventory control. In the second part the company on which is...

Search engine optimization

OpenAIRE

Marolt, Klemen

2013-01-01

Search engine optimization techniques, often shortened to “SEO,” should lead to first positions in organic search results. Some optimization techniques do not change over time, yet still form the basis for SEO. However, as the Internet and web design evolves dynamically, new optimization techniques flourish and flop. Thus, we looked at the most important factors that can help to improve positioning in search results. It is important to emphasize that none of the techniques can guarantee high ...

An optimal generic model for multi-parameters and big data optimizing: a laboratory experimental study

Science.gov (United States)

Utama, D. N.; Ani, N.; Iqbal, M. M.

2018-03-01

Optimization is a process for finding parameter (parameters) that is (are) able to deliver an optimal value for an objective function. Seeking an optimal generic model for optimizing is a computer science study that has been being practically conducted by numerous researchers. Generic model is a model that can be technically operated to solve any varieties of optimization problem. By using an object-oriented method, the generic model for optimizing was constructed. Moreover, two types of optimization method, simulated-annealing and hill-climbing, were functioned in constructing the model and compared to find the most optimal one then. The result said that both methods gave the same result for a value of objective function and the hill-climbing based model consumed the shortest running time.

Topology optimization under stochastic stiffness

Science.gov (United States)

Asadpoure, Alireza

Topology optimization is a systematic computational tool for optimizing the layout of materials within a domain for engineering design problems. It allows variation of structural boundaries and connectivities. This freedom in the design space often enables discovery of new, high performance designs. However, solutions obtained by performing the optimization in a deterministic setting may be impractical or suboptimal when considering real-world engineering conditions with inherent variabilities including (for example) variabilities in fabrication processes and operating conditions. The aim of this work is to provide a computational methodology for topology optimization in the presence of uncertainties associated with structural stiffness, such as uncertain material properties and/or structural geometry. Existing methods for topology optimization under deterministic conditions are first reviewed. Modifications are then proposed to improve the numerical performance of the so-called Heaviside Projection Method (HPM) in continuum domains. Next, two approaches, perturbation and Polynomial Chaos Expansion (PCE), are proposed to account for uncertainties in the optimization procedure. These approaches are intrusive, allowing tight and efficient coupling of the uncertainty quantification with the optimization sensitivity analysis. The work herein develops a robust topology optimization framework aimed at reducing the sensitivity of optimized solutions to uncertainties. The perturbation-based approach combines deterministic topology optimization with a perturbation method for the quantification of uncertainties. The use of perturbation transforms the problem of topology optimization under uncertainty to an augmented deterministic topology optimization problem. The PCE approach combines the spectral stochastic approach for the representation and propagation of uncertainties with an existing deterministic topology optimization technique. The resulting compact representations

Optimal control for chemical engineers

CERN Document Server

Upreti, Simant Ranjan

2013-01-01

Optimal Control for Chemical Engineers gives a detailed treatment of optimal control theory that enables readers to formulate and solve optimal control problems. With a strong emphasis on problem solving, the book provides all the necessary mathematical analyses and derivations of important results, including multiplier theorems and Pontryagin's principle.The text begins by introducing various examples of optimal control, such as batch distillation and chemotherapy, and the basic concepts of optimal control, including functionals and differentials. It then analyzes the notion of optimality, de

Optimization of externalities using DTM measures: a Pareto optimal multi objective optimization using the evolutionary algorithm SPEA2+

NARCIS (Netherlands)

Wismans, Luc Johannes Josephus; van Berkum, Eric C.; Bliemer, Michiel; Allkim, T.P.; van Arem, Bart

2010-01-01

Multi objective optimization of externalities of traffic is performed solving a network design problem in which Dynamic Traffic Management measures are used. The resulting Pareto optimal set is determined by employing the SPEA2+ evolutionary algorithm.

A novel comprehensive learning artificial bee colony optimizer for dynamic optimization biological problems

Directory of Open Access Journals (Sweden)

Weixing Su

2017-03-01

Full Text Available There are many dynamic optimization problems in the real world, whose convergence and searching ability is cautiously desired, obviously different from static optimization cases. This requires an optimization algorithm adaptively seek the changing optima over dynamic environments, instead of only finding the global optimal solution in the static environment. This paper proposes a novel comprehensive learning artificial bee colony optimizer (CLABC for optimization in dynamic environments problems, which employs a pool of optimal foraging strategies to balance the exploration and exploitation tradeoff. The main motive of CLABC is to enrich artificial bee foraging behaviors in the ABC model by combining Powell’s pattern search method, life-cycle, and crossover-based social learning strategy. The proposed CLABC is a more bee-colony-realistic model that the bee can reproduce and die dynamically throughout the foraging process and population size varies as the algorithm runs. The experiments for evaluating CLABC are conducted on the dynamic moving peak benchmarks. Furthermore, the proposed algorithm is applied to a real-world application of dynamic RFID network optimization. Statistical analysis of all these cases highlights the significant performance improvement due to the beneficial combination and demonstrates the performance superiority of the proposed algorithm.

Optimization of multi-objective micro-grid based on improved particle swarm optimization algorithm

Science.gov (United States)

Zhang, Jian; Gan, Yang

2018-04-01

The paper presents a multi-objective optimal configuration model for independent micro-grid with the aim of economy and environmental protection. The Pareto solution set can be obtained by solving the multi-objective optimization configuration model of micro-grid with the improved particle swarm algorithm. The feasibility of the improved particle swarm optimization algorithm for multi-objective model is verified, which provides an important reference for multi-objective optimization of independent micro-grid.

Optimal Alarm Systems

Data.gov (United States)

National Aeronautics and Space Administration — An optimal alarm system is simply an optimal level-crossing predictor that can be designed to elicit the fewest false alarms for a fixed detection probability. It...

Taking Stock of Unrealistic Optimism.

Science.gov (United States)

Shepperd, James A; Klein, William M P; Waters, Erika A; Weinstein, Neil D

2013-07-01

Researchers have used terms such as unrealistic optimism and optimistic bias to refer to concepts that are similar but not synonymous. Drawing from three decades of research, we critically discuss how researchers define unrealistic optimism and we identify four types that reflect different measurement approaches: unrealistic absolute optimism at the individual and group level and unrealistic comparative optimism at the individual and group level. In addition, we discuss methodological criticisms leveled against research on unrealistic optimism and note that the criticisms are primarily relevant to only one type-the group form of unrealistic comparative optimism. We further clarify how the criticisms are not nearly as problematic even for unrealistic comparative optimism as they might seem. Finally, we note boundary conditions on the different types of unrealistic optimism and reflect on five broad questions that deserve further attention.

Taking Stock of Unrealistic Optimism

Science.gov (United States)

Shepperd, James A.; Klein, William M. P.; Waters, Erika A.; Weinstein, Neil D.

2015-01-01

Researchers have used terms such as unrealistic optimism and optimistic bias to refer to concepts that are similar but not synonymous. Drawing from three decades of research, we critically discuss how researchers define unrealistic optimism and we identify four types that reflect different measurement approaches: unrealistic absolute optimism at the individual and group level and unrealistic comparative optimism at the individual and group level. In addition, we discuss methodological criticisms leveled against research on unrealistic optimism and note that the criticisms are primarily relevant to only one type—the group form of unrealistic comparative optimism. We further clarify how the criticisms are not nearly as problematic even for unrealistic comparative optimism as they might seem. Finally, we note boundary conditions on the different types of unrealistic optimism and reflect on five broad questions that deserve further attention. PMID:26045714

Optimal placement of capacito

Directory of Open Access Journals (Sweden)

N. Gnanasekaran

2016-06-01

Full Text Available Optimal size and location of shunt capacitors in the distribution system plays a significant role in minimizing the energy loss and the cost of reactive power compensation. This paper presents a new efficient technique to find optimal size and location of shunt capacitors with the objective of minimizing cost due to energy loss and reactive power compensation of distribution system. A new Shark Smell Optimization (SSO algorithm is proposed to solve the optimal capacitor placement problem satisfying the operating constraints. The SSO algorithm is a recently developed metaheuristic optimization algorithm conceptualized using the shark’s hunting ability. It uses a momentum incorporated gradient search and a rotational movement based local search for optimization. To demonstrate the applicability of proposed method, it is tested on IEEE 34-bus and 118-bus radial distribution systems. The simulation results obtained are compared with previous methods reported in the literature and found to be encouraging.

5th Optimization Day

CERN Document Server

Mees, Alistair; Fisher, Mike; Jennings, Les

2000-01-01

'Optimization Day' (OD) has been a series of annual mini-conferences in Australia since 1994. The purpose of this series of events is to gather researchers in optimization and its related areas from Australia and their collaborators, in order to exchange new developments of optimization theories, methods and their applications. The first four OD mini-conferences were held in The Uni­ versity of Ballarat (1994), The University of New South Wales (1995), The University of Melbourne (1996) and Royal Melbourne Institute of Technology (1997), respectively. They were all on the eastern coast of Australia. The fifth mini-conference Optimization Days was held at the Centre for Ap­ plied Dynamics and Optimization (CADO), Department of Mathematics and Statistics, The University of Western Australia, Perth, from 29 to 30 June 1998. This is the first time the OD mini-conference has been held at the west­ ern coast of Australia. This fifth OD preceded the International Conference on Optimization: Techniques and Applica...

Identification of brain-specific angiogenesis inhibitor 2 as an interaction partner of glutaminase interacting protein

International Nuclear Information System (INIS)

Zencir, Sevil; Ovee, Mohiuddin; Dobson, Melanie J.; Banerjee, Monimoy; Topcu, Zeki; Mohanty, Smita

2011-01-01

Highlights: → Brain-specific angiogenesis inhibitor 2 (BAI2) is a new partner protein for GIP. → BAI2 interaction with GIP was revealed by yeast two-hybrid assay. → Binding of BAI2 to GIP was characterized by NMR, CD and fluorescence. → BAI2 and GIP binding was mediated through the C-terminus of BAI2. -- Abstract: The vast majority of physiological processes in living cells are mediated by protein-protein interactions often specified by particular protein sequence motifs. PDZ domains, composed of 80-100 amino acid residues, are an important class of interaction motif. Among the PDZ-containing proteins, glutaminase interacting protein (GIP), also known as Tax Interacting Protein TIP-1, is unique in being composed almost exclusively of a single PDZ domain. GIP has important roles in cellular signaling, protein scaffolding and modulation of tumor growth and interacts with a number of physiological partner proteins, including Glutaminase L, β-Catenin, FAS, HTLV-1 Tax, HPV16 E6, Rhotekin and Kir 2.3. To identify the network of proteins that interact with GIP, a human fetal brain cDNA library was screened using a yeast two-hybrid assay with GIP as bait. We identified brain-specific angiogenesis inhibitor 2 (BAI2), a member of the adhesion-G protein-coupled receptors (GPCRs), as a new partner of GIP. BAI2 is expressed primarily in neurons, further expanding GIP cellular functions. The interaction between GIP and the carboxy-terminus of BAI2 was characterized using fluorescence, circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy assays. These biophysical analyses support the interaction identified in the yeast two-hybrid assay. This is the first study reporting BAI2 as an interaction partner of GIP.

Heterodimerization with the β1 subunit directs the α2 subunit of nitric oxide-sensitive guanylyl cyclase to calcium-insensitive cell-cell contacts in HEK293 cells: Interaction with Lin7a.

Science.gov (United States)

Hochheiser, Julia; Haase, Tobias; Busker, Mareike; Sömmer, Anne; Kreienkamp, Hans-Jürgen; Behrends, Sönke

2016-12-15

Nitric oxide-sensitive guanylyl cyclase is a heterodimeric enzyme consisting of an α and a β subunit. Two different α subunits (α 1 and α 2 ) give rise to two heterodimeric enzymes α 1 /β 1 and α 2 /β 1 . Both coexist in a wide range of tissues including blood vessels and the lung, but expression of the α 2 /β 1 form is generally much lower and approaches levels similar to the α 1 /β 1 form in the brain only. In the present paper, we show that the α 2 /β 1 form interacts with Lin7a in mouse brain synaptosomes based on co-precipitation analysis. In HEK293 cells, we found that the overexpressed α 2 /β 1 form, but not the α 1 /β 1 form is directed to calcium-insensitive cell-cell contacts. The isolated PDZ binding motif of an amino-terminally truncated α 2 subunit was sufficient for cell-cell contact localization. For the full length α 2 subunit with the PDZ binding motif this was only the case in the heterodimer configuration with the β 1 subunit, but not as isolated α 2 subunit. We conclude that the PDZ binding motif of the α 2 subunit is only accessible in the heterodimer conformation of the mature nitric oxide-sensitive enzyme. Interaction with Lin7a, a small scaffold protein important for synaptic function and cell polarity, can direct this complex to nectin based cell-cell contacts via MPP3 in HEK293 cells. We conclude that heterodimerization is a prerequisite for further protein-protein interactions that direct the α 2 /β 1 form to strategic sites of the cell membrane with adjacent neighbouring cells. Drugs increasing the nitric oxide-sensitivity of this specific form may be particularly effective. Copyright © 2016 Elsevier Inc. All rights reserved.

Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor: EFFECT ON PKA LOCALIZATION AND P-Rex1 SIGNALING.

Science.gov (United States)

Chávez-Vargas, Lydia; Adame-García, Sendi Rafael; Cervantes-Villagrana, Rodolfo Daniel; Castillo-Kauil, Alejandro; Bruystens, Jessica G H; Fukuhara, Shigetomo; Taylor, Susan S; Mochizuki, Naoki; Reyes-Cruz, Guadalupe; Vázquez-Prado, José

2016-03-18

Morphology of migrating cells is regulated by Rho GTPases and fine-tuned by protein interactions and phosphorylation. PKA affects cell migration potentially through spatiotemporal interactions with regulators of Rho GTPases. Here we show that the endogenous regulatory (R) subunit of type I PKA interacts with P-Rex1, a Rac guanine nucleotide exchange factor that integrates chemotactic signals. Type I PKA holoenzyme interacts with P-Rex1 PDZ domains via the CNB B domain of RIα, which when expressed by itself facilitates endothelial cell migration. P-Rex1 activation localizes PKA to the cell periphery, whereas stimulation of PKA phosphorylates P-Rex1 and prevents its activation in cells responding to SDF-1 (stromal cell-derived factor 1). The P-Rex1 DEP1 domain is phosphorylated at Ser-436, which inhibits the DH-PH catalytic cassette by direct interaction. In addition, the P-Rex1 C terminus is indirectly targeted by PKA, promoting inhibitory interactions independently of the DEP1-PDZ2 region. A P-Rex1 S436A mutant construct shows increased RacGEF activity and prevents the inhibitory effect of forskolin on sphingosine 1-phosphate-dependent endothelial cell migration. Altogether, these results support the idea that P-Rex1 contributes to the spatiotemporal localization of type I PKA, which tightly regulates this guanine exchange factor by a multistep mechanism, initiated by interaction with the PDZ domains of P-Rex1 followed by direct phosphorylation at the first DEP domain and putatively indirect regulation of the C terminus, thus promoting inhibitory intramolecular interactions. This reciprocal regulation between PKA and P-Rex1 might represent a key node of integration by which chemotactic signaling is fine-tuned by PKA. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor

Science.gov (United States)

Chávez-Vargas, Lydia; Adame-García, Sendi Rafael; Cervantes-Villagrana, Rodolfo Daniel; Castillo-Kauil, Alejandro; Bruystens, Jessica G. H.; Fukuhara, Shigetomo; Taylor, Susan S.; Mochizuki, Naoki; Reyes-Cruz, Guadalupe; Vázquez-Prado, José

2016-01-01

Morphology of migrating cells is regulated by Rho GTPases and fine-tuned by protein interactions and phosphorylation. PKA affects cell migration potentially through spatiotemporal interactions with regulators of Rho GTPases. Here we show that the endogenous regulatory (R) subunit of type I PKA interacts with P-Rex1, a Rac guanine nucleotide exchange factor that integrates chemotactic signals. Type I PKA holoenzyme interacts with P-Rex1 PDZ domains via the CNB B domain of RIα, which when expressed by itself facilitates endothelial cell migration. P-Rex1 activation localizes PKA to the cell periphery, whereas stimulation of PKA phosphorylates P-Rex1 and prevents its activation in cells responding to SDF-1 (stromal cell-derived factor 1). The P-Rex1 DEP1 domain is phosphorylated at Ser-436, which inhibits the DH-PH catalytic cassette by direct interaction. In addition, the P-Rex1 C terminus is indirectly targeted by PKA, promoting inhibitory interactions independently of the DEP1-PDZ2 region. A P-Rex1 S436A mutant construct shows increased RacGEF activity and prevents the inhibitory effect of forskolin on sphingosine 1-phosphate-dependent endothelial cell migration. Altogether, these results support the idea that P-Rex1 contributes to the spatiotemporal localization of type I PKA, which tightly regulates this guanine exchange factor by a multistep mechanism, initiated by interaction with the PDZ domains of P-Rex1 followed by direct phosphorylation at the first DEP domain and putatively indirect regulation of the C terminus, thus promoting inhibitory intramolecular interactions. This reciprocal regulation between PKA and P-Rex1 might represent a key node of integration by which chemotactic signaling is fine-tuned by PKA. PMID:26797121

Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery.

Directory of Open Access Journals (Sweden)

Robert Kalescky

2016-04-01

Full Text Available Intra-protein information is transmitted over distances via allosteric processes. This ubiquitous protein process allows for protein function changes due to ligand binding events. Understanding protein allostery is essential to understanding protein functions. In this study, allostery in the second PDZ domain (PDZ2 in the human PTP1E protein is examined as model system to advance a recently developed rigid residue scan method combining with configurational entropy calculation and principal component analysis. The contributions from individual residues to whole-protein dynamics and allostery were systematically assessed via rigid body simulations of both unbound and ligand-bound states of the protein. The entropic contributions of individual residues to whole-protein dynamics were evaluated based on covariance-based correlation analysis of all simulations. The changes of overall protein entropy when individual residues being held rigid support that the rigidity/flexibility equilibrium in protein structure is governed by the La Châtelier's principle of chemical equilibrium. Key residues of PDZ2 allostery were identified with good agreement with NMR studies of the same protein bound to the same peptide. On the other hand, the change of entropic contribution from each residue upon perturbation revealed intrinsic differences among all the residues. The quasi-harmonic and principal component analyses of simulations without rigid residue perturbation showed a coherent allosteric mode from unbound and bound states, respectively. The projection of simulations with rigid residue perturbation onto coherent allosteric modes demonstrated the intrinsic shifting of ensemble distributions supporting the population-shift theory of protein allostery. Overall, the study presented here provides a robust and systematic approach to estimate the contribution of individual residue internal motion to overall protein dynamics and allostery.

G protein-coupled receptor 30 (GPR30) forms a plasma membrane complex with membrane-associated guanylate kinases (MAGUKs) and protein kinase A-anchoring protein 5 (AKAP5) that constitutively inhibits cAMP production.

Science.gov (United States)

Broselid, Stefan; Berg, Kelly A; Chavera, Teresa A; Kahn, Robin; Clarke, William P; Olde, Björn; Leeb-Lundberg, L M Fredrik

2014-08-08

GPR30, or G protein-coupled estrogen receptor, is a G protein-coupled receptor reported to bind 17β-estradiol (E2), couple to the G proteins Gs and Gi/o, and mediate non-genomic estrogenic responses. However, controversies exist regarding the receptor pharmacological profile, effector coupling, and subcellular localization. We addressed the role of the type I PDZ motif at the receptor C terminus in receptor trafficking and coupling to cAMP production in HEK293 cells and CHO cells ectopically expressing the receptor and in Madin-Darby canine kidney cells expressing the native receptor. GPR30 was localized both intracellularly and in the plasma membrane and subject to limited basal endocytosis. E2 and G-1, reported GPR30 agonists, neither stimulated nor inhibited cAMP production through GPR30, nor did they influence receptor localization. Instead, GPR30 constitutively inhibited cAMP production stimulated by a heterologous agonist independently of Gi/o. Moreover, siRNA knockdown of native GPR30 increased cAMP production. Deletion of the receptor PDZ motif interfered with inhibition of cAMP production and increased basal receptor endocytosis. GPR30 interacted with membrane-associated guanylate kinases, including SAP97 and PSD-95, and protein kinase A-anchoring protein (AKAP) 5 in the plasma membrane in a PDZ-dependent manner. Knockdown of AKAP5 or St-Ht31 treatment, to disrupt AKAP interaction with the PKA RIIβ regulatory subunit, decreased inhibition of cAMP production, and St-Ht31 increased basal receptor endocytosis. Therefore, GPR30 forms a plasma membrane complex with a membrane-associated guanylate kinase and AKAP5, which constitutively attenuates cAMP production in response to heterologous agonists independently of Gi/o and retains receptors in the plasma membrane. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Hetero-oligomeric Complex between the G Protein-coupled Estrogen Receptor 1 and the Plasma Membrane Ca2+-ATPase 4b.

Science.gov (United States)

Tran, Quang-Kim; VerMeer, Mark; Burgard, Michelle A; Hassan, Ali B; Giles, Jennifer

2015-05-22

The new G protein-coupled estrogen receptor 1 (GPER/GPR30) plays important roles in many organ systems. The plasma membrane Ca(2+)-ATPase (PMCA) is essential for removal of cytoplasmic Ca(2+) and for shaping the time courses of Ca(2+)-dependent activities. Here, we show that PMCA and GPER/GPR30 physically interact and functionally influence each other. In primary endothelial cells, GPER/GPR30 agonist G-1 decreases PMCA-mediated Ca(2+) extrusion by promoting PMCA tyrosine phosphorylation. GPER/GPR30 overexpression decreases PMCA activity, and G-1 further potentiates this effect. GPER/GPR30 knockdown increases PMCA activity, whereas PMCA knockdown substantially reduces GPER/GPR30-mediated phosphorylation of the extracellular signal-related kinase (ERK1/2). GPER/GPR30 co-immunoprecipitates with PMCA with or without treatment with 17β-estradiol, thapsigargin, or G-1. Heterologously expressed GPER/GPR30 in HEK 293 cells co-localizes with PMCA4b, the main endothelial PMCA isoform. Endothelial cells robustly express the PDZ post-synaptic density protein (PSD)-95, whose knockdown reduces the association between GPER/GPR30 and PMCA. Additionally, the association between PMCA4b and GPER/GPR30 is substantially reduced by truncation of either or both of their C-terminal PDZ-binding motifs. Functionally, inhibition of PMCA activity is significantly reduced by truncation of GPER/GPR30's C-terminal PDZ-binding motif. These data strongly indicate that GPER/GPR30 and PMCA4b form a hetero-oligomeric complex in part via the anchoring action of PSD-95, in which they constitutively affect each other's function. Activation of GPER/GPR30 further inhibits PMCA activity through tyrosine phosphorylation of the pump. These interactions represent cross-talk between Ca(2+) signaling and GPER/GPR30-mediated activities. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Bedrock Hydrogeology-Groundwater flow modelling. Site investigation SFR

International Nuclear Information System (INIS)

Oehman, Johan; Follin, Sven; Oden, Magnus

2013-05-01

The hydrogeological model developed for the SFR extension project (PSU) consists of 40 geologically modelled deformation zones (DZ) and 8 sub-horizontal structural-hydraulic features, called SBAstructures, not defined in the geological model. However, some of the SBA-structures coincide with what is defined as unresolved possible deformation zones (Unresolved PDZ) in the geological modelling. In addition, the hydrogeological model consists of a stochastic discrete fracture network (DFN) model intended for the less fractured rock mass volumes (fracture domains) between the zones and the SBA-structures, and a stochastic fracture model intended to handle remaining Unresolved PDZs in the geological modelling not modelled as SBA-structures in the hydrogeological modelling. The four structural components of the bedrock in the hydrogeological model, i.e. DZ, SBA, Unresolved PDZ and DFN, are assigned hydraulic properties in the hydrogeological model based on the transmissivities interpreted from single-hole hydraulic tests. The main objective of the present work is to present the characteristics of the hydrogeological model with regard to the needs of the forthcoming safety assessment SR-PSU. In concrete words, simulated data are compared with measured data, i.e. hydraulic heads in boreholes and tunnel inflow to the existing repository (SFR). The calculations suggest that the available data for flow model calibration cannot be used to motivate a substantial adjustment of the initial hydraulic parameterisation (assignment of hydraulic properties) of the hydrogeological model. It is suggested that uncertainties in the hydrogeological model are studied in the safety assessment SR-PSU by means of a large number of calculation cases. These should address hydraulic heterogeneity of deterministic structures (DZ and SBA) and realisations of stochastic fractures/fracture networks (Unresolved PDZ and DFN) within the entire SFR Regional model domain

Bedrock Hydrogeology - Groundwater flow modelling. Site investigation SFR

Energy Technology Data Exchange (ETDEWEB)

Oehman, Johan [Geosigma AB, Uppsala (Sweden); Follin, Sven [SF GeoLogic AB, Taeby (Sweden); Oden, Magnus [SKB, Stockholm (Sweden)

2013-05-15

The hydrogeological model developed for the SFR extension project (PSU) consists of 40 geologically modelled deformation zones (DZ) and 8 sub-horizontal structural-hydraulic features, called SBAstructures, not defined in the geological model. However, some of the SBA-structures coincide with what is defined as unresolved possible deformation zones (Unresolved PDZ) in the geological modelling. In addition, the hydrogeological model consists of a stochastic discrete fracture network (DFN) model intended for the less fractured rock mass volumes (fracture domains) between the zones and the SBA-structures, and a stochastic fracture model intended to handle remaining Unresolved PDZs in the geological modelling not modelled as SBA-structures in the hydrogeological modelling. The four structural components of the bedrock in the hydrogeological model, i.e. DZ, SBA, Unresolved PDZ and DFN, are assigned hydraulic properties in the hydrogeological model based on the transmissivities interpreted from single-hole hydraulic tests. The main objective of the present work is to present the characteristics of the hydrogeological model with regard to the needs of the forthcoming safety assessment SR-PSU. In concrete words, simulated data are compared with measured data, i.e. hydraulic heads in boreholes and tunnel inflow to the existing repository (SFR). The calculations suggest that the available data for flow model calibration cannot be used to motivate a substantial adjustment of the initial hydraulic parameterisation (assignment of hydraulic properties) of the hydrogeological model. It is suggested that uncertainties in the hydrogeological model are studied in the safety assessment SR-PSU by means of a large number of calculation cases. These should address hydraulic heterogeneity of deterministic structures (DZ and SBA) and realisations of stochastic fractures/fracture networks (Unresolved PDZ and DFN) within the entire SFR Regional model domain.

Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss.

Directory of Open Access Journals (Sweden)

Jun Yang

2010-05-01

Full Text Available Mutations in whirlin cause either Usher syndrome type II (USH2, a deafness-blindness disorder, or nonsyndromic deafness. The molecular basis for the variable disease expression is unknown. We show here that only the whirlin long isoform, distinct from a short isoform by virtue of having two N-terminal PDZ domains, is expressed in the retina. Both long and short isoforms are expressed in the inner ear. The N-terminal PDZ domains of the long whirlin isoform mediates the formation of a multi-protein complex that includes usherin and VLGR1, both of which are also implicated in USH2. We localized this USH2 protein complex to the periciliary membrane complex (PMC in mouse photoreceptors that appears analogous to the frog periciliary ridge complex. The latter is proposed to play a role in photoreceptor protein trafficking through the connecting cilium. Mice carrying a targeted disruption near the N-terminus of whirlin manifest retinal and inner ear defects, reproducing the clinical features of human USH2 disease. This is in contrast to mice with mutations affecting the C-terminal portion of whirlin in which the phenotype is restricted to the inner ear. In mice lacking any one of the USH2 proteins, the normal localization of all USH2 proteins is disrupted, and there is evidence of protein destabilization. Taken together, our findings provide new insights into the pathogenic mechanism of Usher syndrome. First, the three USH2 proteins exist as an obligatory functional complex in vivo, and loss of one USH2 protein is functionally close to loss of all three. Second, defects in the three USH2 proteins share a common pathogenic process, i.e., disruption of the PMC. Third, whirlin mutations that ablate the N-terminal PDZ domains lead to Usher syndrome, but non-syndromic hearing loss will result if they are spared.

HEURISTIC APPROACHES FOR PORTFOLIO OPTIMIZATION

OpenAIRE

Manfred Gilli, Evis Kellezi

2000-01-01

The paper first compares the use of optimization heuristics to the classical optimization techniques for the selection of optimal portfolios. Second, the heuristic approach is applied to problems other than those in the standard mean-variance framework where the classical optimization fails.

Characterization of the association of connexins and ZO-1 in the lens

NARCIS (Netherlands)

Nielsen, P A; Baruch, A; Giepmans, B N; Kumar, Nalin M

2001-01-01

ZO-1 (Zona Occludens protein 1) has previously been shown to bind Cx43alpha1. This interaction involves the most C-terminal residues of Cx43alpha1 and the second PDZ-domain of ZO-1. The biological significance of this interaction is not well understood. The similarity of the C-terminal residues of

Optimal design of the heat pipe using TLBO (teaching–learning-based optimization) algorithm

International Nuclear Information System (INIS)

Rao, R.V.; More, K.C.

2015-01-01

Heat pipe is a highly efficient and reliable heat transfer component. It is a closed container designed to transfer a large amount of heat in system. Since the heat pipe operates on a closed two-phase cycle, the heat transfer capacity is greater than for solid conductors. Also, the thermal response time is less than with solid conductors. The three major elemental parts of the rotating heat pipe are: a cylindrical evaporator, a truncated cone condenser, and a fixed amount of working fluid. In this paper, a recently proposed new stochastic advanced optimization algorithm called TLBO (Teaching–Learning-Based Optimization) algorithm is used for single objective as well as multi-objective design optimization of heat pipe. It is easy to implement, does not make use of derivatives and it can be applied to unconstrained or constrained problems. Two examples of heat pipe are presented in this paper. The results of application of TLBO algorithm for the design optimization of heat pipe are compared with the NPGA (Niched Pareto Genetic Algorithm), GEM (Grenade Explosion Method) and GEO (Generalized External optimization). It is found that the TLBO algorithm has produced better results as compared to those obtained by using NPGA, GEM and GEO algorithms. - Highlights: • The TLBO (Teaching–Learning-Based Optimization) algorithm is used for the design and optimization of a heat pipe. • Two examples of heat pipe design and optimization are presented. • The TLBO algorithm is proved better than the other optimization algorithms in terms of results and the convergence

Optimism and Adaptation to Multiple Sclerosis: What Does Optimism Mean?

NARCIS (Netherlands)

Fournier, M.; Ridder, D.T.D. de; Bensing, J.

1999-01-01

The aim of the present study was to determine the meaning of optimism by explicating the dimensions underlying the notion and their links to adjusting to MS. Seventy-three patients responded to optimism questionnaire s (i.e., the LOT, Generalized Self-Efficacy Scale) and outcome questionnaires.

Optimism and adaptation to multiple sclerosis: what does optimism mean?

NARCIS (Netherlands)

Fournier, M.; Ridder, D. de; Bensing, J.

1999-01-01

The aim of the present study was to determine the meaning of optimism by explicating the dimensions underlying the notion and their links to adjusting to MS. Seventy-three patients responded to optimism questionnaires (i.e., the LOT, Generalized Self-Efficacy Scale) and outcome questionnaires. In

Optimal placement of FACTS devices using optimization techniques: A review

Science.gov (United States)

Gaur, Dipesh; Mathew, Lini

2018-03-01

Modern power system is dealt with overloading problem especially transmission network which works on their maximum limit. Today’s power system network tends to become unstable and prone to collapse due to disturbances. Flexible AC Transmission system (FACTS) provides solution to problems like line overloading, voltage stability, losses, power flow etc. FACTS can play important role in improving static and dynamic performance of power system. FACTS devices need high initial investment. Therefore, FACTS location, type and their rating are vital and should be optimized to place in the network for maximum benefit. In this paper, different optimization methods like Particle Swarm Optimization (PSO), Genetic Algorithm (GA) etc. are discussed and compared for optimal location, type and rating of devices. FACTS devices such as Thyristor Controlled Series Compensator (TCSC), Static Var Compensator (SVC) and Static Synchronous Compensator (STATCOM) are considered here. Mentioned FACTS controllers effects on different IEEE bus network parameters like generation cost, active power loss, voltage stability etc. have been analyzed and compared among the devices.

Integer and combinatorial optimization

CERN Document Server

Nemhauser, George L

1999-01-01

Rave reviews for INTEGER AND COMBINATORIAL OPTIMIZATION ""This book provides an excellent introduction and survey of traditional fields of combinatorial optimization . . . It is indeed one of the best and most complete texts on combinatorial optimization . . . available. [And] with more than 700 entries, [it] has quite an exhaustive reference list.""-Optima ""A unifying approach to optimization problems is to formulate them like linear programming problems, while restricting some or all of the variables to the integers. This book is an encyclopedic resource for such f

Bolt Thread Stress Optimization

DEFF Research Database (Denmark)

Pedersen, Niels Leergaard

2012-01-01

of threads and therefore indirectly the bolt fatigue life. The root shape is circular, and from shape optimization for minimum stress concentration it is well known that the circular shape is seldom optimal. An axisymmetric Finite Element (FE) formulation is used to analyze the bolted connection, and a study...... is performed to establish the need for contact modeling with regard to finding the correct stress concentration factor. Optimization is performed with a simple parameterization with two design variables. Stress reduction of up to 9% is found in the optimization process, and some similarities are found...... in the optimized designs leading to the proposal of a new standard. The reductions in the stress are achieved by rather simple changes made to the cutting tool....

Workshop on Computational Optimization

CERN Document Server

2016-01-01

This volume is a comprehensive collection of extended contributions from the Workshop on Computational Optimization 2014, held at Warsaw, Poland, September 7-10, 2014. The book presents recent advances in computational optimization. The volume includes important real problems like parameter settings for controlling processes in bioreactor and other processes, resource constrained project scheduling, infection distribution, molecule distance geometry, quantum computing, real-time management and optimal control, bin packing, medical image processing, localization the abrupt atmospheric contamination source and so on. It shows how to develop algorithms for them based on new metaheuristic methods like evolutionary computation, ant colony optimization, constrain programming and others. This research demonstrates how some real-world problems arising in engineering, economics, medicine and other domains can be formulated as optimization tasks.

Optimized manufacturable porous materials

DEFF Research Database (Denmark)

Andreassen, Erik; Andreasen, Casper Schousboe; Jensen, Jakob Søndergaard

Topology optimization has been used to design two-dimensional material structures with specific elastic properties, but optimized designs of three-dimensional material structures are more scarsely seen. Partly because it requires more computational power, and partly because it is a major challenge...... to include manufacturing constraints in the optimization. This work focuses on incorporating the manufacturability into the optimization procedure, allowing the resulting material structure to be manufactured directly using rapid manufacturing techniques, such as selective laser melting/sintering (SLM....../S). The available manufacturing methods are best suited for porous materials (one constituent and void), but the optimization procedure can easily include more constituents. The elasticity tensor is found from one unit cell using the homogenization method together with a standard finite element (FE) discretization...

Airfoil shape optimization using non-traditional optimization technique and its validation

Directory of Open Access Journals (Sweden)

R. Mukesh

2014-07-01

Full Text Available Computational fluid dynamics (CFD is one of the computer-based solution methods which is more widely employed in aerospace engineering. The computational power and time required to carry out the analysis increase as the fidelity of the analysis increases. Aerodynamic shape optimization has become a vital part of aircraft design in the recent years. Generally if we want to optimize an airfoil we have to describe the airfoil and for that, we need to have at least hundred points of x and y co-ordinates. It is really difficult to optimize airfoils with this large number of co-ordinates. Nowadays many different schemes of parameter sets are used to describe general airfoil such as B-spline, and PARSEC. The main goal of these parameterization schemes is to reduce the number of needed parameters as few as possible while controlling the important aerodynamic features effectively. Here the work has been done on the PARSEC geometry representation method. The objective of this work is to introduce the knowledge of describing general airfoil using twelve parameters by representing its shape as a polynomial function. And also we have introduced the concept of Genetic Algorithm to optimize the aerodynamic characteristics of a general airfoil for specific conditions. A MATLAB program has been developed to implement PARSEC, Panel Technique, and Genetic Algorithm. This program has been tested for a standard NACA 2411 airfoil and optimized to improve its coefficient of lift. Pressure distribution and co-efficient of lift for airfoil geometries have been calculated using the Panel method. The optimized airfoil has improved co-efficient of lift compared to the original one. The optimized airfoil is validated using wind tunnel data.

Optimizing detectability

International Nuclear Information System (INIS)

Anon.

1992-01-01

HPLC is useful for trace and ultratrace analyses of a variety of compounds. For most applications, HPLC is useful for determinations in the nanogram-to-microgram range; however, detection limits of a picogram or less have been demonstrated in certain cases. These determinations require state-of-the-art capability; several examples of such determinations are provided in this chapter. As mentioned before, to detect and/or analyze low quantities of a given analyte at submicrogram or ultratrace levels, it is necessary to optimize the whole separation system, including the quantity and type of sample, sample preparation, HPLC equipment, chromatographic conditions (including column), choice of detector, and quantitation techniques. A limited discussion is provided here for optimization based on theoretical considerations, chromatographic conditions, detector selection, and miscellaneous approaches to detectability optimization. 59 refs

In vivo subcellular localization of Mal de Rio Cuarto virus (MRCV) non-structural proteins in insect cells reveals their putative functions

Energy Technology Data Exchange (ETDEWEB)

Maroniche, Guillermo A.; Mongelli, Vanesa C.; Llauger, Gabriela; Alfonso, Victoria; Taboga, Oscar [Instituto de Biotecnologia, CICVyA, Instituto Nacional de Tecnologia Agropecuaria (IB-INTA), Las cabanas y Los Reseros s/n. Hurlingham Cp 1686, Buenos Aires (Argentina); Vas, Mariana del, E-mail: mdelvas@cnia.inta.gov.ar [Instituto de Biotecnologia, CICVyA, Instituto Nacional de Tecnologia Agropecuaria (IB-INTA), Las cabanas y Los Reseros s/n. Hurlingham Cp 1686, Buenos Aires (Argentina)

2012-09-01

The in vivo subcellular localization of Mal de Rio Cuarto virus (MRCV, Fijivirus, Reoviridae) non-structural proteins fused to GFP was analyzed by confocal microscopy. P5-1 showed a cytoplasmic vesicular-like distribution that was lost upon deleting its PDZ binding TKF motif, suggesting that P5-1 interacts with cellular PDZ proteins. P5-2 located at the nucleus and its nuclear import was affected by the deletion of its basic C-termini. P7-1 and P7-2 also entered the nucleus and therefore, along with P5-2, could function as regulators of host gene expression. P6 located in the cytoplasm and in perinuclear cloud-like inclusions, was driven to P9-1 viroplasm-like structures and co-localized with P7-2, P10 and {alpha}-tubulin, suggesting its involvement in viroplasm formation and viral intracellular movement. Finally, P9-2 was N-glycosylated and located at the plasma membrane in association with filopodia-like protrusions containing actin, suggesting a possible role in virus cell-to-cell movement and spread.

Origins of Allostery and Evolvability in Proteins: A Case Study.

Science.gov (United States)

Raman, Arjun S; White, K Ian; Ranganathan, Rama

2016-07-14

Proteins display the capacity for adaptation to new functions, a property critical for evolvability. But what structural principles underlie the capacity for adaptation? Here, we show that adaptation to a physiologically distinct class of ligand specificity in a PSD95, DLG1, ZO-1 (PDZ) domain preferentially occurs through class-bridging intermediate mutations located distant from the ligand-binding site. These mutations provide a functional link between ligand classes and demonstrate the principle of "conditional neutrality" in mediating evolutionary adaptation. Structures show that class-bridging mutations work allosterically to open up conformational plasticity at the active site, permitting novel functions while retaining existing function. More generally, the class-bridging phenotype arises from mutations in an evolutionarily conserved network of coevolving amino acids in the PDZ family (the sector) that connects the active site to distant surface sites. These findings introduce the concept that allostery in proteins could have its origins not in protein function but in the capacity to adapt. Copyright © 2016 Elsevier Inc. All rights reserved.

A Novel Consensus-Based Particle Swarm Optimization-Assisted Trust-Tech Methodology for Large-Scale Global Optimization.

Science.gov (United States)

Zhang, Yong-Feng; Chiang, Hsiao-Dong

2017-09-01

A novel three-stage methodology, termed the "consensus-based particle swarm optimization (PSO)-assisted Trust-Tech methodology," to find global optimal solutions for nonlinear optimization problems is presented. It is composed of Trust-Tech methods, consensus-based PSO, and local optimization methods that are integrated to compute a set of high-quality local optimal solutions that can contain the global optimal solution. The proposed methodology compares very favorably with several recently developed PSO algorithms based on a set of small-dimension benchmark optimization problems and 20 large-dimension test functions from the CEC 2010 competition. The analytical basis for the proposed methodology is also provided. Experimental results demonstrate that the proposed methodology can rapidly obtain high-quality optimal solutions that can contain the global optimal solution. The scalability of the proposed methodology is promising.

Optimization : insights and applications

CERN Document Server

Brinkhuis, Jan

2005-01-01

This self-contained textbook is an informal introduction to optimization through the use of numerous illustrations and applications. The focus is on analytically solving optimization problems with a finite number of continuous variables. In addition, the authors provide introductions to classical and modern numerical methods of optimization and to dynamic optimization. The book's overarching point is that most problems may be solved by the direct application of the theorems of Fermat, Lagrange, and Weierstrass. The authors show how the intuition for each of the theoretical results can be s

Portfolio Optimization

OpenAIRE

Issagali, Aizhan; Alshimbayeva, Damira; Zhalgas, Aidana

2015-01-01

In this paper Portfolio Optimization techniques were used to determine the most favorable investment portfolio. In particular, stock indices of three companies, namely Microsoft Corporation, Christian Dior Fashion House and Shevron Corporation were evaluated. Using this data the amounts invested in each asset when a portfolio is chosen on the efficient frontier were calculated. In addition, the Portfolio with minimum variance, tangency portfolio and optimal Markowitz portfolio are presented.

Optimally cloned binary coherent states

DEFF Research Database (Denmark)

Mueller, C. R.; Leuchs, G.; Marquardt, Ch

2017-01-01

their quantum-optimal clones. We analyze the Wigner function and the cumulants of the clones, and we conclude that optimal cloning of binary coherent states requires a nonlinearity above second order. We propose several practical and near-optimal cloning schemes and compare their cloning fidelity to the optimal...

Encyclopedia of optimization

CERN Document Server

Pardalos, Panos

2001-01-01

Optimization problems are widespread in the mathematical modeling of real world systems and their applications arise in all branches of science, applied science and engineering. The goal of the Encyclopedia of Optimization is to introduce the reader to a complete set of topics in order to show the spectrum of recent research activities and the richness of ideas in the development of theories, algorithms and the applications of optimization. It is directed to a diverse audience of students, scientists, engineers, decision makers and problem solvers in academia, business, industry, and government.

Optimization under Uncertainty

KAUST Repository

Lopez, Rafael H.

2016-01-01

in optimization, the so called the reliability based design. Subsequently, we present the risk optimization approach, which includes the expected costs of failure in the objective function. After that the basic description of each approach is given, the projects

A Novel Optimal Control Method for Impulsive-Correction Projectile Based on Particle Swarm Optimization

Directory of Open Access Journals (Sweden)

Ruisheng Sun

2016-01-01

Full Text Available This paper presents a new parametric optimization approach based on a modified particle swarm optimization (PSO to design a class of impulsive-correction projectiles with discrete, flexible-time interval, and finite-energy control. In terms of optimal control theory, the task is described as the formulation of minimum working number of impulses and minimum control error, which involves reference model linearization, boundary conditions, and discontinuous objective function. These result in difficulties in finding the global optimum solution by directly utilizing any other optimization approaches, for example, Hp-adaptive pseudospectral method. Consequently, PSO mechanism is employed for optimal setting of impulsive control by considering the time intervals between two neighboring lateral impulses as design variables, which makes the briefness of the optimization process. A modification on basic PSO algorithm is developed to improve the convergence speed of this optimization through linearly decreasing the inertial weight. In addition, a suboptimal control and guidance law based on PSO technique are put forward for the real-time consideration of the online design in practice. Finally, a simulation case coupled with a nonlinear flight dynamic model is applied to validate the modified PSO control algorithm. The results of comparative study illustrate that the proposed optimal control algorithm has a good performance in obtaining the optimal control efficiently and accurately and provides a reference approach to handling such impulsive-correction problem.

Design optimization of axial flow hydraulic turbine runner: Part II - multi-objective constrained optimization method

Science.gov (United States)

Peng, Guoyi; Cao, Shuliang; Ishizuka, Masaru; Hayama, Shinji

2002-06-01

This paper is concerned with the design optimization of axial flow hydraulic turbine runner blade geometry. In order to obtain a better design plan with good performance, a new comprehensive performance optimization procedure has been presented by combining a multi-variable multi-objective constrained optimization model with a Q3D inverse computation and a performance prediction procedure. With careful analysis of the inverse design of axial hydraulic turbine runner, the total hydraulic loss and the cavitation coefficient are taken as optimization objectives and a comprehensive objective function is defined using the weight factors. Parameters of a newly proposed blade bound circulation distribution function and parameters describing positions of blade leading and training edges in the meridional flow passage are taken as optimization variables.The optimization procedure has been applied to the design optimization of a Kaplan runner with specific speed of 440 kW. Numerical results show that the performance of designed runner is successfully improved through optimization computation. The optimization model is found to be validated and it has the feature of good convergence. With the multi-objective optimization model, it is possible to control the performance of designed runner by adjusting the value of weight factors defining the comprehensive objective function. Copyright

Topology optimized permanent magnet systems

Science.gov (United States)

Bjørk, R.; Bahl, C. R. H.; Insinga, A. R.

2017-09-01

Topology optimization of permanent magnet systems consisting of permanent magnets, high permeability iron and air is presented. An implementation of topology optimization for magnetostatics is discussed and three examples are considered. The Halbach cylinder is topology optimized with iron and an increase of 15% in magnetic efficiency is shown. A topology optimized structure to concentrate a homogeneous field is shown to increase the magnitude of the field by 111%. Finally, a permanent magnet with alternating high and low field regions is topology optimized and a Λcool figure of merit of 0.472 is reached, which is an increase of 100% compared to a previous optimized design.

Modern optimization with R

CERN Document Server

Cortez, Paulo

2014-01-01

The goal of this book is to gather in a single document the most relevant concepts related to modern optimization methods, showing how such concepts and methods can be addressed using the open source, multi-platform R tool. Modern optimization methods, also known as metaheuristics, are particularly useful for solving complex problems for which no specialized optimization algorithm has been developed. These methods often yield high quality solutions with a more reasonable use of computational resources (e.g. memory and processing effort). Examples of popular modern methods discussed in this book are: simulated annealing; tabu search; genetic algorithms; differential evolution; and particle swarm optimization. This book is suitable for undergraduate and graduate students in Computer Science, Information Technology, and related areas, as well as data analysts interested in exploring modern optimization methods using R.

Optimism and Well-Being

Science.gov (United States)

Reivich, Karen

2010-01-01

Dictionary definitions of optimism encompass two related concepts. The first of these is a hopeful disposition or a conviction that good will ultimately prevail. The second, broader conception of optimism refers to the belief, or the inclination to believe, that the world is the best of all possible worlds. In psychological research, optimism has…

Learning optimal embedded cascades.

Science.gov (United States)

Saberian, Mohammad Javad; Vasconcelos, Nuno

2012-10-01

The problem of automatic and optimal design of embedded object detector cascades is considered. Two main challenges are identified: optimization of the cascade configuration and optimization of individual cascade stages, so as to achieve the best tradeoff between classification accuracy and speed, under a detection rate constraint. Two novel boosting algorithms are proposed to address these problems. The first, RCBoost, formulates boosting as a constrained optimization problem which is solved with a barrier penalty method. The constraint is the target detection rate, which is met at all iterations of the boosting process. This enables the design of embedded cascades of known configuration without extensive cross validation or heuristics. The second, ECBoost, searches over cascade configurations to achieve the optimal tradeoff between classification risk and speed. The two algorithms are combined into an overall boosting procedure, RCECBoost, which optimizes both the cascade configuration and its stages under a detection rate constraint, in a fully automated manner. Extensive experiments in face, car, pedestrian, and panda detection show that the resulting detectors achieve an accuracy versus speed tradeoff superior to those of previous methods.

Totally optimal decision rules

KAUST Repository

Amin, Talha

2017-11-22

Optimality of decision rules (patterns) can be measured in many ways. One of these is referred to as length. Length signifies the number of terms in a decision rule and is optimally minimized. Another, coverage represents the width of a rule’s applicability and generality. As such, it is desirable to maximize coverage. A totally optimal decision rule is a decision rule that has the minimum possible length and the maximum possible coverage. This paper presents a method for determining the presence of totally optimal decision rules for “complete” decision tables (representations of total functions in which different variables can have domains of differing values). Depending on the cardinalities of the domains, we can either guarantee for each tuple of values of the function that totally optimal rules exist for each row of the table (as in the case of total Boolean functions where the cardinalities are equal to 2) or, for each row, we can find a tuple of values of the function for which totally optimal rules do not exist for this row.

Totally optimal decision rules

KAUST Repository

Amin, Talha M.; Moshkov, Mikhail

2017-01-01

Optimality of decision rules (patterns) can be measured in many ways. One of these is referred to as length. Length signifies the number of terms in a decision rule and is optimally minimized. Another, coverage represents the width of a rule’s applicability and generality. As such, it is desirable to maximize coverage. A totally optimal decision rule is a decision rule that has the minimum possible length and the maximum possible coverage. This paper presents a method for determining the presence of totally optimal decision rules for “complete” decision tables (representations of total functions in which different variables can have domains of differing values). Depending on the cardinalities of the domains, we can either guarantee for each tuple of values of the function that totally optimal rules exist for each row of the table (as in the case of total Boolean functions where the cardinalities are equal to 2) or, for each row, we can find a tuple of values of the function for which totally optimal rules do not exist for this row.

Optimal Design of Pumped Pipeline Systems Using Genetic Algorithm and Mathematical Optimization

Directory of Open Access Journals (Sweden)

Mohammadhadi Afshar

2007-12-01

Full Text Available In recent years, much attention has been paid to the optimal design of pipeline systems. In this study, the problem of pipeline system optimal design has been solved through genetic algorithm and mathematical optimization. Pipe diameters and their thicknesses are considered as decision variables to be designed in a manner that water column separation and excessive pressures are avoided in the event of pump failure. Capabilities of the genetic algorithm and the mathematical programming method are compared for the problem under consideration. For simulation of transient streams, explicit characteristic method is used in which devices such as pumps are defined as boundary conditions of the equations defining the hydraulic behavior of pipe segments. The problem of optimal design of pipeline systems is a constrained problem which is converted to an unconstrained optimization problem using an external penalty function approach. The efficiency of the proposed approaches is verified in one example and the results are presented.

AFRICAN BUFFALO OPTIMIZATION ico-pdf

Directory of Open Access Journals (Sweden)

Julius Beneoluchi Odili

2016-02-01

Full Text Available This is an introductory paper to the newly-designed African Buffalo Optimization (ABO algorithm for solving combinatorial and other optimization problems. The algorithm is inspired by the behavior of African buffalos, a species of wild cows known for their extensive migrant lifestyle. This paper presents an overview of major metaheuristic algorithms with the aim of providing a basis for the development of the African Buffalo Optimization algorithm which is a nature-inspired, population-based metaheuristic algorithm. Experimental results obtained from applying the novel ABO to solve a number of benchmark global optimization test functions as well as some symmetric and asymmetric Traveling Salesman’s Problems when compared to the results obtained from using other popular optimization methods show that the African Buffalo Optimization is a worthy addition to the growing number of swarm intelligence optimization techniques.

A Dynamic Multistage Hybrid Swarm Intelligence Optimization Algorithm for Function Optimization

Directory of Open Access Journals (Sweden)

Daqing Wu

2012-01-01

Full Text Available A novel dynamic multistage hybrid swarm intelligence optimization algorithm is introduced, which is abbreviated as DM-PSO-ABC. The DM-PSO-ABC combined the exploration capabilities of the dynamic multiswarm particle swarm optimizer (PSO and the stochastic exploitation of the cooperative artificial bee colony algorithm (CABC for solving the function optimization. In the proposed hybrid algorithm, the whole process is divided into three stages. In the first stage, a dynamic multiswarm PSO is constructed to maintain the population diversity. In the second stage, the parallel, positive feedback of CABC was implemented in each small swarm. In the third stage, we make use of the particle swarm optimization global model, which has a faster convergence speed to enhance the global convergence in solving the whole problem. To verify the effectiveness and efficiency of the proposed hybrid algorithm, various scale benchmark problems are tested to demonstrate the potential of the proposed multistage hybrid swarm intelligence optimization algorithm. The results show that DM-PSO-ABC is better in the search precision, and convergence property and has strong ability to escape from the local suboptima when compared with several other peer algorithms.

Optimization of Multipurpose Reservoir Operation with Application Particle Swarm Optimization Algorithm

Directory of Open Access Journals (Sweden)

Elahe Fallah Mehdipour

2012-12-01

Full Text Available Optimal operation of multipurpose reservoirs is one of the complex and sometimes nonlinear problems in the field of multi-objective optimization. Evolutionary algorithms are optimization tools that search decision space using simulation of natural biological evolution and present a set of points as the optimum solutions of problem. In this research, application of multi-objective particle swarm optimization (MOPSO in optimal operation of Bazoft reservoir with different objectives, including generating hydropower energy, supplying downstream demands (drinking, industry and agriculture, recreation and flood control have been considered. In this regard, solution sets of the MOPSO algorithm in bi-combination of objectives and compromise programming (CP using different weighting and power coefficients have been first compared that the MOPSO algorithm in all combinations of objectives is more capable than the CP to find solution with appropriate distribution and these solutions have dominated the CP solutions. Then, ending points of solution set from the MOPSO algorithm and nonlinear programming (NLP results have been compared. Results showed that the MOPSO algorithm with 0.3 percent difference from the NLP results has more capability to present optimum solutions in the ending points of solution set.

Parameter Optimization of MIMO Fuzzy Optimal Model Predictive Control By APSO

Directory of Open Access Journals (Sweden)

Adel Taieb

2017-01-01

Full Text Available This paper introduces a new development for designing a Multi-Input Multi-Output (MIMO Fuzzy Optimal Model Predictive Control (FOMPC using the Adaptive Particle Swarm Optimization (APSO algorithm. The aim of this proposed control, called FOMPC-APSO, is to develop an efficient algorithm that is able to have good performance by guaranteeing a minimal control. This is done by determining the optimal weights of the objective function. Our method is considered an optimization problem based on the APSO algorithm. The MIMO system to be controlled is modeled by a Takagi-Sugeno (TS fuzzy system whose parameters are identified using weighted recursive least squares method. The utility of the proposed controller is demonstrated by applying it to two nonlinear processes, Continuous Stirred Tank Reactor (CSTR and Tank system, where the proposed approach provides better performances compared with other methods.

Dynamic stochastic optimization

CERN Document Server

Ermoliev, Yuri; Pflug, Georg

2004-01-01

Uncertainties and changes are pervasive characteristics of modern systems involving interactions between humans, economics, nature and technology. These systems are often too complex to allow for precise evaluations and, as a result, the lack of proper management (control) may create significant risks. In order to develop robust strategies we need approaches which explic­ itly deal with uncertainties, risks and changing conditions. One rather general approach is to characterize (explicitly or implicitly) uncertainties by objec­ tive or subjective probabilities (measures of confidence or belief). This leads us to stochastic optimization problems which can rarely be solved by using the standard deterministic optimization and optimal control methods. In the stochastic optimization the accent is on problems with a large number of deci­ sion and random variables, and consequently the focus ofattention is directed to efficient solution procedures rather than to (analytical) closed-form solu­ tions. Objective an...

Optimal mixture experiments

CERN Document Server

Sinha, B K; Pal, Manisha; Das, P

2014-01-01

The book dwells mainly on the optimality aspects of mixture designs. As mixture models are a special case of regression models, a general discussion on regression designs has been presented, which includes topics like continuous designs, de la Garza phenomenon, Loewner order domination, Equivalence theorems for different optimality criteria and standard optimality results for single variable polynomial regression and multivariate linear and quadratic regression models. This is followed by a review of the available literature on estimation of parameters in mixture models. Based on recent research findings, the volume also introduces optimal mixture designs for estimation of optimum mixing proportions in different mixture models, which include Scheffé’s quadratic model, Darroch-Waller model, log- contrast model, mixture-amount models, random coefficient models and multi-response model.  Robust mixture designs and mixture designs in blocks have been also reviewed. Moreover, some applications of mixture desig...

Optimization with Extremal Dynamics

International Nuclear Information System (INIS)

Boettcher, Stefan; Percus, Allon G.

2001-01-01

We explore a new general-purpose heuristic for finding high-quality solutions to hard discrete optimization problems. The method, called extremal optimization, is inspired by self-organized criticality, a concept introduced to describe emergent complexity in physical systems. Extremal optimization successively updates extremely undesirable variables of a single suboptimal solution, assigning them new, random values. Large fluctuations ensue, efficiently exploring many local optima. We use extremal optimization to elucidate the phase transition in the 3-coloring problem, and we provide independent confirmation of previously reported extrapolations for the ground-state energy of ±J spin glasses in d=3 and 4

Maintenance optimization after RCM

International Nuclear Information System (INIS)

Doyle, E.K.; Lee, C.-G.; Cho, D.

2005-01-01

Variant forms of RCM (Reliability Centered Maintenance) have been the maintenance optimizing tools of choice in industry for the last 20 years. Several such optimization techniques have been implemented at the Bruce Nuclear Station. Further cost refinement of the Station preventive maintenance strategy whereby decisions are based on statistical analysis of historical failure data are now being evaluated. The evaluation includes a requirement to demonstrate that earlier optimization projects have long term positive impacts. This proved to be a significant challenge. Eventually a methodology was developed using Crowe/AMSAA (Army Materials Systems Analysis Activity) plots to justify expenditures on further optimization efforts. (authors)

Beam optimization: improving methodology

International Nuclear Information System (INIS)

Quinteiro, Guillermo F.

2004-01-01

Different optimization techniques commonly used in biology and food technology allow a systematic and complete analysis of response functions. In spite of the great interest in medical and nuclear physics in the problem of optimizing mixed beams, little attention has been given to sophisticate mathematical tools. Indeed, many techniques are perfectly suited to the typical problem of beam optimization. This article is intended as a guide to the use of two methods, namely Response Surface Methodology and Simplex, that are expected to fasten the optimization process and, meanwhile give more insight into the relationships among the dependent variables controlling the response

Pointwise second-order necessary optimality conditions and second-order sensitivity relations in optimal control

Science.gov (United States)

Frankowska, Hélène; Hoehener, Daniel

2017-06-01

This paper is devoted to pointwise second-order necessary optimality conditions for the Mayer problem arising in optimal control theory. We first show that with every optimal trajectory it is possible to associate a solution p (ṡ) of the adjoint system (as in the Pontryagin maximum principle) and a matrix solution W (ṡ) of an adjoint matrix differential equation that satisfy a second-order transversality condition and a second-order maximality condition. These conditions seem to be a natural second-order extension of the maximum principle. We then prove a Jacobson like necessary optimality condition for general control systems and measurable optimal controls that may be only ;partially singular; and may take values on the boundary of control constraints. Finally we investigate the second-order sensitivity relations along optimal trajectories involving both p (ṡ) and W (ṡ).

Design optimization of shell-and-tube heat exchangers using single objective and multiobjective particle swarm optimization

International Nuclear Information System (INIS)

Elsays, Mostafa A.; Naguib Aly, M; Badawi, Alya A.

2010-01-01

The Particle Swarm Optimization (PSO) algorithm is used to optimize the design of shell-and-tube heat exchangers and determine the optimal feasible solutions so as to eliminate trial-and-error during the design process. The design formulation takes into account the area and the total annual cost of heat exchangers as two objective functions together with operating as well as geometrical constraints. The Nonlinear Constrained Single Objective Particle Swarm Optimization (NCSOPSO) algorithm is used to minimize and find the optimal feasible solution for each of the nonlinear constrained objective functions alone, respectively. Then, a novel Nonlinear Constrained Mult-objective Particle Swarm Optimization (NCMOPSO) algorithm is used to minimize and find the Pareto optimal solutions for both of the nonlinear constrained objective functions together. The experimental results show that the two algorithms are very efficient, fast and can find the accurate optimal feasible solutions of the shell and tube heat exchangers design optimization problem. (orig.)

Design Optimization of Mechanical Components Using an Enhanced Teaching-Learning Based Optimization Algorithm with Differential Operator

Directory of Open Access Journals (Sweden)

B. Thamaraikannan

2014-01-01

Full Text Available This paper studies in detail the background and implementation of a teaching-learning based optimization (TLBO algorithm with differential operator for optimization task of a few mechanical components, which are essential for most of the mechanical engineering applications. Like most of the other heuristic techniques, TLBO is also a population-based method and uses a population of solutions to proceed to the global solution. A differential operator is incorporated into the TLBO for effective search of better solutions. To validate the effectiveness of the proposed method, three typical optimization problems are considered in this research: firstly, to optimize the weight in a belt-pulley drive, secondly, to optimize the volume in a closed coil helical spring, and finally to optimize the weight in a hollow shaft. have been demonstrated. Simulation result on the optimization (mechanical components problems reveals the ability of the proposed methodology to find better optimal solutions compared to other optimization algorithms.

An Indirect Simulation-Optimization Model for Determining Optimal TMDL Allocation under Uncertainty

Directory of Open Access Journals (Sweden)

Feng Zhou

2015-11-01

Full Text Available An indirect simulation-optimization model framework with enhanced computational efficiency and risk-based decision-making capability was developed to determine optimal total maximum daily load (TMDL allocation under uncertainty. To convert the traditional direct simulation-optimization model into our indirect equivalent model framework, we proposed a two-step strategy: (1 application of interval regression equations derived by a Bayesian recursive regression tree (BRRT v2 algorithm, which approximates the original hydrodynamic and water-quality simulation models and accurately quantifies the inherent nonlinear relationship between nutrient load reductions and the credible interval of algal biomass with a given confidence interval; and (2 incorporation of the calibrated interval regression equations into an uncertain optimization framework, which is further converted to our indirect equivalent framework by the enhanced-interval linear programming (EILP method and provides approximate-optimal solutions at various risk levels. The proposed strategy was applied to the Swift Creek Reservoir’s nutrient TMDL allocation (Chesterfield County, VA to identify the minimum nutrient load allocations required from eight sub-watersheds to ensure compliance with user-specified chlorophyll criteria. Our results indicated that the BRRT-EILP model could identify critical sub-watersheds faster than the traditional one and requires lower reduction of nutrient loadings compared to traditional stochastic simulation and trial-and-error (TAE approaches. This suggests that our proposed framework performs better in optimal TMDL development compared to the traditional simulation-optimization models and provides extreme and non-extreme tradeoff analysis under uncertainty for risk-based decision making.

Topology optimized permanent magnet systems

DEFF Research Database (Denmark)

Bjørk, Rasmus; Bahl, Christian; Insinga, Andrea Roberto

2017-01-01

Topology optimization of permanent magnet systems consisting of permanent magnets, high permeability iron and air is presented. An implementation of topology optimization for magnetostatics is discussed and three examples are considered. The Halbach cylinder is topology optimized with iron...... and an increase of 15% in magnetic efficiency is shown. A topology optimized structure to concentrate a homogeneous field is shown to increase the magnitude of the field by 111%. Finally, a permanent magnet with alternating high and low field regions is topology optimized and a ΛcoolΛcool figure of merit of 0...

The Theory of Optimal Taxation

DEFF Research Database (Denmark)

Sørensen, Peter Birch

The paper discusses the implications of optimal tax theory for the debates on uniform commodity taxation and neutral capital income taxation. While strong administrative and political economy arguments in favor of uniform and neutral taxation remain, recent advances in optimal tax theory suggest...... that the information needed to implement the differentiated taxation prescribed by optimal tax theory may be easier to obtain than previously believed. The paper also points to the strong similarity between optimal commodity tax rules and the rules for optimal source-based capital income taxation...

The theory of optimal taxation

DEFF Research Database (Denmark)

Sørensen, Peter Birch

2007-01-01

The paper discusses the implications of optimal tax theory for the debates on uniform commodity taxation and neutral capital income taxation. While strong administrative and political economy arguments in favor of uniform and neutral taxation remain, recent advances in optimal tax theory suggest...... that the information needed to implement the differentiated taxation prescribed by optimal tax theory may be easier to obtain than previously believed. The paper also points to the strong similarity between optimal commodity tax rules and the rules for optimal source-based capital income taxation...

Topology Optimization of Thermal Heat Sinks

DEFF Research Database (Denmark)

Klaas Haertel, Jan Hendrik; Engelbrecht, Kurt; Lazarov, Boyan Stefanov

2015-01-01

In this paper, topology optimization is applied to optimize the cooling performance of thermal heat sinks. The coupled two-dimensional thermofluid model of a heat sink cooled with forced convection and a density-based topology optimization including density filtering and projection are implemented...... in COMSOL Multiphysics. The optimization objective is to minimize the heat sink’s temperature for a prescribed pressure drop and fixed heat generation. To conduct the optimization, COMSOL’s Optimization Module with GCMMA as the optimization method is used. The implementation of this topology optimization...... approach in COMSOL Multiphysics is described in this paper and results for optimized two-dimensional heat sinks are presented. Furthermore, parameter studies regarding the effect of the prescribed pressure drop of the system on Reynolds number and realized heat sink temperature are presented and discussed....

Joint global optimization of tomographic data based on particle swarm optimization and decision theory

Science.gov (United States)

Paasche, H.; Tronicke, J.

2012-04-01

In many near surface geophysical applications multiple tomographic data sets are routinely acquired to explore subsurface structures and parameters. Linking the model generation process of multi-method geophysical data sets can significantly reduce ambiguities in geophysical data analysis and model interpretation. Most geophysical inversion approaches rely on local search optimization methods used to find an optimal model in the vicinity of a user-given starting model. The final solution may critically depend on the initial model. Alternatively, global optimization (GO) methods have been used to invert geophysical data. They explore the solution space in more detail and determine the optimal model independently from the starting model. Additionally, they can be used to find sets of optimal models allowing a further analysis of model parameter uncertainties. Here we employ particle swarm optimization (PSO) to realize the global optimization of tomographic data. PSO is an emergent methods based on swarm intelligence characterized by fast and robust convergence towards optimal solutions. The fundamental principle of PSO is inspired by nature, since the algorithm mimics the behavior of a flock of birds searching food in a search space. In PSO, a number of particles cruise a multi-dimensional solution space striving to find optimal model solutions explaining the acquired data. The particles communicate their positions and success and direct their movement according to the position of the currently most successful particle of the swarm. The success of a particle, i.e. the quality of the currently found model by a particle, must be uniquely quantifiable to identify the swarm leader. When jointly inverting disparate data sets, the optimization solution has to satisfy multiple optimization objectives, at least one for each data set. Unique determination of the most successful particle currently leading the swarm is not possible. Instead, only statements about the Pareto

Radiological optimization

International Nuclear Information System (INIS)

Zeevaert, T.

1998-01-01

Radiological optimization is one of the basic principles in each radiation-protection system and it is a basic requirement in the safety standards for radiation protection in the European Communities. The objectives of the research, performed in this field at the Belgian Nuclear Research Centre SCK-CEN, are: (1) to implement the ALARA principles in activities with radiological consequences; (2) to develop methodologies for optimization techniques in decision-aiding; (3) to optimize radiological assessment models by validation and intercomparison; (4) to improve methods to assess in real time the radiological hazards in the environment in case of an accident; (5) to develop methods and programmes to assist decision-makers during a nuclear emergency; (6) to support the policy of radioactive waste management authorities in the field of radiation protection; (7) to investigate existing software programmes in the domain of multi criteria analysis. The main achievements for 1997 are given

Stiffened Composite Fuselage Barrel Optimization

Science.gov (United States)

Movva, R. G.; Mittal, A.; Agrawal, K.; Upadhyay, C. S.

2012-07-01

In a typical commercial transport aircraft, Stiffened skin panels and frames contribute around 40% of the fuselage weight. In the current study a stiffened composite fuselage skin panel optimization engine is developed for optimization of the layups of composite panels and stringers using Genetic Algorithm (GA). The skin and stringers of the fuselage section are optimized for the strength and the stability requirements. The selection of the GA parameters considered for the optimization is arrived by performing case studies on selected problems. The optimization engine facilitates in carrying out trade studies for selection of the optimum ply layup and material combination for the configuration being analyzed. The optimization process is applied on a sample model and the results are presented.

Pareto-optimal alloys

DEFF Research Database (Denmark)

Bligaard, Thomas; Johannesson, Gisli Holmar; Ruban, Andrei

2003-01-01

Large databases that can be used in the search for new materials with specific properties remain an elusive goal in materials science. The problem is complicated by the fact that the optimal material for a given application is usually a compromise between a number of materials properties and the ......Large databases that can be used in the search for new materials with specific properties remain an elusive goal in materials science. The problem is complicated by the fact that the optimal material for a given application is usually a compromise between a number of materials properties...... and the cost. In this letter we present a database consisting of the lattice parameters, bulk moduli, and heats of formation for over 64 000 ordered metallic alloys, which has been established by direct first-principles density-functional-theory calculations. Furthermore, we use a concept from economic theory......, the Pareto-optimal set, to determine optimal alloy solutions for the compromise between low compressibility, high stability, and cost....

Well-posed optimization problems

CERN Document Server

Dontchev, Asen L

1993-01-01

This book presents in a unified way the mathematical theory of well-posedness in optimization. The basic concepts of well-posedness and the links among them are studied, in particular Hadamard and Tykhonov well-posedness. Abstract optimization problems as well as applications to optimal control, calculus of variations and mathematical programming are considered. Both the pure and applied side of these topics are presented. The main subject is often introduced by heuristics, particular cases and examples. Complete proofs are provided. The expected knowledge of the reader does not extend beyond textbook (real and functional) analysis, some topology and differential equations and basic optimization. References are provided for more advanced topics. The book is addressed to mathematicians interested in optimization and related topics, and also to engineers, control theorists, economists and applied scientists who can find here a mathematical justification of practical procedures they encounter.

Overall bolt stress optimization

DEFF Research Database (Denmark)

Pedersen, Niels Leergaard

2013-01-01

The state of stress in bolts and nuts with International Organization for Standardization metric thread design is examined and optimized. The assumed failure mode is fatigue, so the applied preload and the load amplitude together with the stress concentrations define the connection strength....... Maximum stress in the bolt is found at the fillet under the head, at the thread start, or at the thread root. To minimize the stress concentration, shape optimization is applied. Nut shape optimization also has a positive effect on the maximum stress. The optimization results show that designing a nut......, which results in a more evenly distribution of load along the engaged thread, has a limited influence on the maximum stress due to the stress concentration at the first thread root. To further reduce the maximum stress, the transition from bolt shank to the thread must be optimized. Stress reduction...

Initiating statistical maintenance optimization

International Nuclear Information System (INIS)

Doyle, E. Kevin; Tuomi, Vesa; Rowley, Ian

2007-01-01

Since the 1980 s maintenance optimization has been centered around various formulations of Reliability Centered Maintenance (RCM). Several such optimization techniques have been implemented at the Bruce Nuclear Station. Further cost refinement of the Station preventive maintenance strategy includes evaluation of statistical optimization techniques. A review of successful pilot efforts in this direction is provided as well as initial work with graphical analysis. The present situation reguarding data sourcing, the principle impediment to use of stochastic methods in previous years, is discussed. The use of Crowe/AMSAA (Army Materials Systems Analysis Activity) plots is demonstrated from the point of view of justifying expenditures in optimization efforts. (author)

Asymptotically Optimal Agents

OpenAIRE

Lattimore, Tor; Hutter, Marcus

2011-01-01

Artificial general intelligence aims to create agents capable of learning to solve arbitrary interesting problems. We define two versions of asymptotic optimality and prove that no agent can satisfy the strong version while in some cases, depending on discounting, there does exist a non-computable weak asymptotically optimal agent.

An Optimization Scheme for ProdMod

International Nuclear Information System (INIS)

Gregory, M.V.

1999-01-01

A general purpose dynamic optimization scheme has been devised in conjunction with the ProdMod simulator. The optimization scheme is suitable for the Savannah River Site (SRS) High Level Waste (HLW) complex operations, and able to handle different types of optimizations such as linear, nonlinear, etc. The optimization is performed in the stand-alone FORTRAN based optimization deliver, while the optimizer is interfaced with the ProdMod simulator for flow of information between the two

Stochastic optimization: beyond mathematical programming

CERN Multimedia

CERN. Geneva

2015-01-01

Stochastic optimization, among which bio-inspired algorithms, is gaining momentum in areas where more classical optimization algorithms fail to deliver satisfactory results, or simply cannot be directly applied. This presentation will introduce baseline stochastic optimization algorithms, and illustrate their efficiency in different domains, from continuous non-convex problems to combinatorial optimization problem, to problems for which a non-parametric formulation can help exploring unforeseen possible solution spaces.

OPTIMIZED PARTICLE SWARM OPTIMIZATION BASED DEADLINE CONSTRAINED TASK SCHEDULING IN HYBRID CLOUD

Directory of Open Access Journals (Sweden)

Dhananjay Kumar

2016-01-01

Full Text Available Cloud Computing is a dominant way of sharing of computing resources that can be configured and provisioned easily. Task scheduling in Hybrid cloud is a challenge as it suffers from producing the best QoS (Quality of Service when there is a high demand. In this paper a new resource allocation algorithm, to find the best External Cloud provider when the intermediate provider’s resources aren’t enough to satisfy the customer’s demand is proposed. The proposed algorithm called Optimized Particle Swarm Optimization (OPSO combines the two metaheuristic algorithms namely Particle Swarm Optimization and Ant Colony Optimization (ACO. These metaheuristic algorithms are used for the purpose of optimization in the search space of the required solution, to find the best resource from the pool of resources and to obtain maximum profit even when the number of tasks submitted for execution is very high. This optimization is performed to allocate job requests to internal and external cloud providers to obtain maximum profit. It helps to improve the system performance by improving the CPU utilization, and handle multiple requests at the same time. The simulation result shows that an OPSO yields 0.1% - 5% profit to the intermediate cloud provider compared with standard PSO and ACO algorithms and it also increases the CPU utilization by 0.1%.

Optimal taxation with household production

DEFF Research Database (Denmark)

Kleven, Henrik Jacobsen; Richter, Wolfram F.; Sørensen, Peter Birch

2000-01-01

on consumer services even if such services are complements to leisure. Second, we find that when services and other goods are equally substitutable for leisure, so that uniform commodity taxation would be optimal in the absence of home production, the optimal tax structure will certainly involve a relatively......This paper suggests that the optimal tax system should favour market-produced services which are close substitutes for home-produced services. First, we modify the classical Corlett-Hague rule for optimal commodity taxation by showing that it may be optimal to impose a relatively low tax rate...... low tax rate on consumer services...

Structural Optimization with Reliability Constraints

DEFF Research Database (Denmark)

Sørensen, John Dalsgaard; Thoft-Christensen, Palle

1986-01-01

During the last 25 years considerable progress has been made in the fields of structural optimization and structural reliability theory. In classical deterministic structural optimization all variables are assumed to be deterministic. Due to the unpredictability of loads and strengths of actual......]. In this paper we consider only structures which can be modelled as systems of elasto-plastic elements, e.g. frame and truss structures. In section 2 a method to evaluate the reliability of such structural systems is presented. Based on a probabilistic point of view a modern structural optimization problem...... is formulated in section 3. The formulation is a natural extension of the commonly used formulations in determinstic structural optimization. The mathematical form of the optimization problem is briefly discussed. In section 4 two new optimization procedures especially designed for the reliability...

Optimal patent policies: A survey

DEFF Research Database (Denmark)

Poulsen, Odile

2002-01-01

This paper surveys some of the patent literature, in particular, it focuses on optimal patent policies. We compare two situations. The first where the government only has a single policy tool to design the optimal patent policy, namely the optimal patent length. In the second situation......, the government uses two policy tools, the optimal breadth and length. We show that theoretical models give very different answers to what is the optimal patent policy. In particular, we show that the optimal patent policy depends among othet things on the price elasticity of demand, the intersectoral elasticity...... of research outputs as well as the degree of compettition in the R&D sector. The actual law on intellectual property, which advocates a unique patent length of 20 years is in general not supported by theoretical models....

Agent-Based Optimization

CERN Document Server

Jędrzejowicz, Piotr; Kacprzyk, Janusz

2013-01-01

This volume presents a collection of original research works by leading specialists focusing on novel and promising approaches in which the multi-agent system paradigm is used to support, enhance or replace traditional approaches to solving difficult optimization problems. The editors have invited several well-known specialists to present their solutions, tools, and models falling under the common denominator of the agent-based optimization. The book consists of eight chapters covering examples of application of the multi-agent paradigm and respective customized tools to solve  difficult optimization problems arising in different areas such as machine learning, scheduling, transportation and, more generally, distributed and cooperative problem solving.

Handbook of optimization in telecommunications

CERN Document Server

Pardalos, Panos M

2008-01-01

Covers the field of optimization in telecommunications, and the optimization developments that are frequently applied to telecommunications. This book aims to provide a reference tool for scientists and engineers in telecommunications who depend upon optimization.

Optimality conditions for the numerical solution of optimization problems with PDE constraints :

Energy Technology Data Exchange (ETDEWEB)

Aguilo Valentin, Miguel Alejandro; Ridzal, Denis

2014-03-01

A theoretical framework for the numerical solution of partial di erential equation (PDE) constrained optimization problems is presented in this report. This theoretical framework embodies the fundamental infrastructure required to e ciently implement and solve this class of problems. Detail derivations of the optimality conditions required to accurately solve several parameter identi cation and optimal control problems are also provided in this report. This will allow the reader to further understand how the theoretical abstraction presented in this report translates to the application.

Contingency Contractor Optimization Phase 3 Sustainment Software Design Document - Contingency Contractor Optimization Tool - Prototype

Energy Technology Data Exchange (ETDEWEB)

Durfee, Justin David; Frazier, Christopher Rawls; Bandlow, Alisa; Jones, Katherine A

2016-05-01

This document describes the final software design of the Contingency Contractor Optimization Tool - Prototype. Its purpose is to provide the overall architecture of the software and the logic behind this architecture. Documentation for the individual classes is provided in the application Javadoc. The Contingency Contractor Optimization project is intended to address Department of Defense mandates by delivering a centralized strategic planning tool that allows senior decision makers to quickly and accurately assess the impacts, risks, and mitigation strategies associated with utilizing contract support. The Contingency Contractor Optimization Tool - Prototype was developed in Phase 3 of the OSD ATL Contingency Contractor Optimization project to support strategic planning for contingency contractors. The planning tool uses a model to optimize the Total Force mix by minimizing the combined total costs for selected mission scenarios. The model optimizes the match of personnel types (military, DoD civilian, and contractors) and capabilities to meet mission requirements as effectively as possible, based on risk, cost, and other requirements.

Nature-inspired optimization algorithms

CERN Document Server

Yang, Xin-She

2014-01-01

Nature-Inspired Optimization Algorithms provides a systematic introduction to all major nature-inspired algorithms for optimization. The book's unified approach, balancing algorithm introduction, theoretical background and practical implementation, complements extensive literature with well-chosen case studies to illustrate how these algorithms work. Topics include particle swarm optimization, ant and bee algorithms, simulated annealing, cuckoo search, firefly algorithm, bat algorithm, flower algorithm, harmony search, algorithm analysis, constraint handling, hybrid methods, parameter tuning

LOGISTICS OPTIMIZATION USING ONTOLOGIES

OpenAIRE

Hendi , Hayder; Ahmad , Adeel; Bouneffa , Mourad; Fonlupt , Cyril

2014-01-01

International audience; Logistics processes involve complex physical flows and integration of different elements. It is widely observed that the uncontrolled processes can decline the state of logistics. The optimization of logistic processes can support the desired growth and consistent continuity of logistics. In this paper, we present a software framework for logistic processes optimization. It primarily defines logistic ontologies and then optimize them. It intends to assist the design of...

A New Hybrid Nelder-Mead Particle Swarm Optimization for Coordination Optimization of Directional Overcurrent Relays

Directory of Open Access Journals (Sweden)

An Liu

2012-01-01

Full Text Available Coordination optimization of directional overcurrent relays (DOCRs is an important part of an efficient distribution system. This optimization problem involves obtaining the time dial setting (TDS and pickup current (Ip values of each DOCR. The optimal results should have the shortest primary relay operating time for all fault lines. Recently, the particle swarm optimization (PSO algorithm has been considered an effective tool for linear/nonlinear optimization problems with application in the protection and coordination of power systems. With a limited runtime period, the conventional PSO considers the optimal solution as the final solution, and an early convergence of PSO results in decreased overall performance and an increase in the risk of mistaking local optima for global optima. Therefore, this study proposes a new hybrid Nelder-Mead simplex search method and particle swarm optimization (proposed NM-PSO algorithm to solve the DOCR coordination optimization problem. PSO is the main optimizer, and the Nelder-Mead simplex search method is used to improve the efficiency of PSO due to its potential for rapid convergence. To validate the proposal, this study compared the performance of the proposed algorithm with that of PSO and original NM-PSO. The findings demonstrate the outstanding performance of the proposed NM-PSO in terms of computation speed, rate of convergence, and feasibility.

The Improvement of Particle Swarm Optimization: a Case Study of Optimal Operation in Goupitan Reservoir

Science.gov (United States)

Li, Haichen; Qin, Tao; Wang, Weiping; Lei, Xiaohui; Wu, Wenhui

2018-02-01

Due to the weakness in holding diversity and reaching global optimum, the standard particle swarm optimization has not performed well in reservoir optimal operation. To solve this problem, this paper introduces downhill simplex method to work together with the standard particle swarm optimization. The application of this approach in Goupitan reservoir optimal operation proves that the improved method had better accuracy and higher reliability with small investment.

Evaluation of optimization strategies and the effect of initial conditions on IMAT optimization using a leaf position optimization algorithm

International Nuclear Information System (INIS)

Oliver, Mike; Jensen, Michael; Chen, Jeff; Wong, Eugene

2009-01-01

Intensity-modulated arc therapy (IMAT) is a rotational variant of intensity-modulated radiation therapy (IMRT) that can be implemented with or without angular dose rate variation. The purpose of this study is to assess optimization strategies and initial conditions using a leaf position optimization (LPO) algorithm altered for variable dose rate IMAT. A concave planning target volume (PTV) with a central cylindrical organ at risk (OAR) was used in this study. The initial IMAT arcs were approximated by multiple static beams at 5 deg. angular increments where multi-leaf collimator (MLC) leaf positions were determined from the beam's eye view to irradiate the PTV but avoid the OAR. For the optimization strategy, two arcs with arc ranges of 280 deg. and 150 deg. were employed and plans were created using LPO alone, variable dose rate optimization (VDRO) alone, simultaneous LPO and VDRO and sequential combinations of these strategies. To assess the MLC initialization effect, three single 360 deg. arc plans with different initial MLC configurations were generated using the simultaneous LPO and VDRO. The effect of changing optimization degrees of freedom was investigated by employing 3 deg., 5 deg. and 10 deg. angular sampling intervals for the two 280 deg., two 150 deg. and single arc plans using LPO and VDRO. The objective function value, a conformity index, a dose homogeneity index, mean dose to OAR and normal tissues were computed and used to evaluate the treatment plans. This study shows that the best optimization strategy for a concave target is to use simultaneous MLC LPO and VDRO. We found that the optimization result is sensitive to the choice of initial MLC aperture shapes suggesting that an LPO-based IMAT plan may not be able to overcome local minima for this geometry. In conclusion, simultaneous MLC leaf position and VDRO are needed with the most appropriate initial conditions (MLC positions, arc ranges and number of arcs) for IMAT.

Optimization of Gain, Impedance, and Bandwidth of Yagi-Uda Array Using Particle Swarm Optimization

Directory of Open Access Journals (Sweden)

Munish Rattan

2008-01-01

Full Text Available Particle swarm optimization (PSO is a new, high-performance evolutionary technique, which has recently been used for optimization problems in antennas and electromagnetics. It is a global optimization technique-like genetic algorithm (GA but has less computational cost compared to GA. In this paper, PSO has been used to optimize the gain, impedance, and bandwidth of Yagi-Uda array. To evaluate the performance of designs, a method of moments code NEC2 has been used. The results are comparable to those obtained using GA.

On the complexity of determining tolerances for ->e--optimal solutions to min-max combinatorial optimization problems

NARCIS (Netherlands)

Ghosh, D.; Sierksma, G.

2000-01-01

Sensitivity analysis of e-optimal solutions is the problem of calculating the range within which a problem parameter may lie so that the given solution re-mains e-optimal. In this paper we study the sensitivity analysis problem for e-optimal solutions tocombinatorial optimization problems with

Optimal planning of electric vehicle charging station at the distribution system using hybrid optimization algorithm

DEFF Research Database (Denmark)

Awasthi, Abhishek; Venkitusamy, Karthikeyan; Padmanaban, Sanjeevikumar

2017-01-01

India's ever increasing population has made it necessary to develop alternative modes of transportation with electric vehicles being the most preferred option. The major obstacle is the deteriorating impact on the utility distribution system brought about by improper setup of these charging...... stations. This paper deals with the optimal planning (siting and sizing) of charging station infrastructure in the city of Allahabad, India. This city is one of the upcoming smart cities, where electric vehicle transportation pilot project is going on under Government of India initiative. In this context......, a hybrid algorithm based on genetic algorithm and improved version of conventional particle swarm optimization is utilized for finding optimal placement of charging station in the Allahabad distribution system. The particle swarm optimization algorithm re-optimizes the received sub-optimal solution (site...

Adaptive Bacterial Foraging Optimization

Directory of Open Access Journals (Sweden)

Hanning Chen

2011-01-01

Full Text Available Bacterial Foraging Optimization (BFO is a recently developed nature-inspired optimization algorithm, which is based on the foraging behavior of E. coli bacteria. Up to now, BFO has been applied successfully to some engineering problems due to its simplicity and ease of implementation. However, BFO possesses a poor convergence behavior over complex optimization problems as compared to other nature-inspired optimization techniques. This paper first analyzes how the run-length unit parameter of BFO controls the exploration of the whole search space and the exploitation of the promising areas. Then it presents a variation on the original BFO, called the adaptive bacterial foraging optimization (ABFO, employing the adaptive foraging strategies to improve the performance of the original BFO. This improvement is achieved by enabling the bacterial foraging algorithm to adjust the run-length unit parameter dynamically during algorithm execution in order to balance the exploration/exploitation tradeoff. The experiments compare the performance of two versions of ABFO with the original BFO, the standard particle swarm optimization (PSO and a real-coded genetic algorithm (GA on four widely-used benchmark functions. The proposed ABFO shows a marked improvement in performance over the original BFO and appears to be comparable with the PSO and GA.

Non-convex multi-objective optimization

CERN Document Server

Pardalos, Panos M; Žilinskas, Julius

2017-01-01

Recent results on non-convex multi-objective optimization problems and methods are presented in this book, with particular attention to expensive black-box objective functions. Multi-objective optimization methods facilitate designers, engineers, and researchers to make decisions on appropriate trade-offs between various conflicting goals. A variety of deterministic and stochastic multi-objective optimization methods are developed in this book. Beginning with basic concepts and a review of non-convex single-objective optimization problems; this book moves on to cover multi-objective branch and bound algorithms, worst-case optimal algorithms (for Lipschitz functions and bi-objective problems), statistical models based algorithms, and probabilistic branch and bound approach. Detailed descriptions of new algorithms for non-convex multi-objective optimization, their theoretical substantiation, and examples for practical applications to the cell formation problem in manufacturing engineering, the process design in...

[Optimize preparation of compound licorice microemulsion with D-optimal design].

Science.gov (United States)

Ma, Shu-Wei; Wang, Yong-Jie; Chen, Cheng; Qiu, Yue; Wu, Qing

2018-03-01

In order to increase the solubility of essential oil in compound licorice microemulsion and improve the efficacy of the decoction for treating chronic eczema, this experiment intends to prepare the decoction into microemulsion. The essential oil was used as the oil phase of the microemulsion and the extract was used as the water phase. Then the microemulsion area and maximum ratio of water capacity was obtained by plotting pseudo-ternary phase diagram, to determine the appropriate types of surfactant and cosurfactant, and Km value-the mass ratio between surfactant and cosurfactant. With particle size and skin retention of active ingredients as the index, microemulsion prescription was optimized by D-optimal design method, to investigate the in vitro release behavior of the optimized prescription. The results showed that the microemulsion was optimal with tween-80 as the surfactant and anhydrous ethanol as the cosurfactant. When the Km value was 1, the area of the microemulsion region was largest while when the concentration of extract was 0.5 g·mL⁻¹, it had lowest effect on the particle size distribution of microemulsion. The final optimized formulation was as follows: 9.4% tween-80, 9.4% anhydrous ethanol, 1.0% peppermint oil and 80.2% 0.5 g·mL⁻¹ extract. The microemulsion prepared under these conditions had a small viscosity, good stability and high skin retention of drug; in vitro release experiment showed that microemulsion had a sustained-release effect on glycyrrhizic acid and liquiritin, basically achieving the expected purpose of the project. Copyright© by the Chinese Pharmaceutical Association.

Optimal Control of Mechanical Systems

Directory of Open Access Journals (Sweden)

Vadim Azhmyakov

2007-01-01

Full Text Available In the present work, we consider a class of nonlinear optimal control problems, which can be called “optimal control problems in mechanics.” We deal with control systems whose dynamics can be described by a system of Euler-Lagrange or Hamilton equations. Using the variational structure of the solution of the corresponding boundary-value problems, we reduce the initial optimal control problem to an auxiliary problem of multiobjective programming. This technique makes it possible to apply some consistent numerical approximations of a multiobjective optimization problem to the initial optimal control problem. For solving the auxiliary problem, we propose an implementable numerical algorithm.

Optimal recombination in genetic algorithms for combinatorial optimization problems: Part I

Directory of Open Access Journals (Sweden)

Eremeev Anton V.

2014-01-01

Full Text Available This paper surveys results on complexity of the optimal recombination problem (ORP, which consists in finding the best possible offspring as a result of a recombination operator in a genetic algorithm, given two parent solutions. We consider efficient reductions of the ORPs, allowing to establish polynomial solvability or NP-hardness of the ORPs, as well as direct proofs of hardness results. Part I presents the basic principles of optimal recombination with a survey of results on Boolean Linear Programming Problems. Part II (to appear in a subsequent issue is devoted to the ORPs for problems which are naturally formulated in terms of search for an optimal permutation.

Introduction to optimal control theory

International Nuclear Information System (INIS)

Agrachev, A.A.

2002-01-01

These are lecture notes of the introductory course in Optimal Control theory treated from the geometric point of view. Optimal Control Problem is reduced to the study of controls (and corresponding trajectories) leading to the boundary of attainable sets. We discuss Pontryagin Maximum Principle, basic existence results, and apply these tools to concrete simple optimal control problems. Special sections are devoted to the general theory of linear time-optimal problems and linear-quadratic problems. (author)

Fifth French-German Conference on Optimization

CERN Document Server

1989-01-01

The 2-yearly French-German Conferences on Optimization review the state-of-the-art and the trends in the field. The proceedings of the Fifth Conference include papers on projective methods in linear programming (special session at the conference), nonsmooth optimization, two-level optimization, multiobjective optimization, partial inverse method, variational convergence, Newton type algorithms and flows and on practical applications of optimization. A. Ioffe and J.-Ph. Vial have contributed survey papers on, respectively second order optimality conditions and projective methods in linear programming.

POSTDOC : THE HUMAN OPTIMIZATION

OpenAIRE

Satish Gajawada

2013-01-01

This paper is dedicated to everyone who is interested in the Artificial Intelligence. John Henry Holland proposed Genetic Algorithm in the early 1970s. Ant Colony Optimization was proposed by Marco Dorigo in 1992. Particle Swarm Optimization was introduced by Kennedy and Eberhart in 1995. Storn and Price introduced Differential Evolution in 1996. K.M. Passino introduced Bacterial Foraging Optimization Algorithm in 2002. In 2003, X.L. Li proposed Artificial Fish Swarm Algorithm....

A sequential binding mechanism in a PDZ domain

DEFF Research Database (Denmark)

Chi, Celestine N; Bach, Anders; Engström, Åke

2009-01-01

that ligand binding involves at least a two-step process. By using an ultrarapid continuous-flow mixer, we then detected a hyperbolic dependence of binding rate constants on peptide concentration, corroborating the two-step binding mechanism. Furthermore, we found a similar dependence of the rate constants...

Performance-based shape optimization of continuum structures

International Nuclear Information System (INIS)

Liang Qingquan

2010-01-01

This paper presents a performance-based optimization (PBO) method for optimal shape design of continuum structures with stiffness constraints. Performance-based design concepts are incorporated in the shape optimization theory to achieve optimal designs. In the PBO method, the traditional shape optimization problem of minimizing the weight of a continuum structure with displacement or mean compliance constraints is transformed to the problem of maximizing the performance of the structure. The optimal shape of a continuum structure is obtained by gradually eliminating inefficient finite elements from the structure until its performance is maximized. Performance indices are employed to monitor the performance of optimized shapes in an optimization process. Performance-based optimality criteria are incorporated in the PBO method to identify the optimum from the optimization process. The PBO method is used to produce optimal shapes of plane stress continuum structures and plates in bending. Benchmark numerical results are provided to demonstrate the effectiveness of the PBO method for generating the maximum stiffness shape design of continuum structures. It is shown that the PBO method developed overcomes the limitations of traditional shape optimization methods in optimal design of continuum structures. Performance-based optimality criteria presented can be incorporated in any shape and topology optimization methods to obtain optimal designs of continuum structures.

Modified Chaos Particle Swarm Optimization-Based Optimized Operation Model for Stand-Alone CCHP Microgrid

Directory of Open Access Journals (Sweden)

Fei Wang

2017-07-01

Full Text Available The optimized dispatch of different distributed generations (DGs in stand-alone microgrid (MG is of great significance to the operation’s reliability and economy, especially for energy crisis and environmental pollution. Based on controllable load (CL and combined cooling-heating-power (CCHP model of micro-gas turbine (MT, a multi-objective optimization model with relevant constraints to optimize the generation cost, load cut compensation and environmental benefit is proposed in this paper. The MG studied in this paper consists of photovoltaic (PV, wind turbine (WT, fuel cell (FC, diesel engine (DE, MT and energy storage (ES. Four typical scenarios were designed according to different day types (work day or weekend and weather conditions (sunny or rainy in view of the uncertainty of renewable energy in variable situations and load fluctuation. A modified dispatch strategy for CCHP is presented to further improve the operation economy without reducing the consumers’ comfort feeling. Chaotic optimization and elite retention strategy are introduced into basic particle swarm optimization (PSO to propose modified chaos particle swarm optimization (MCPSO whose search capability and convergence speed are improved greatly. Simulation results validate the correctness of the proposed model and the effectiveness of MCPSO algorithm in the optimized operation application of stand-alone MG.

Rotorcraft Optimization Tools: Incorporating Rotorcraft Design Codes into Multi-Disciplinary Design, Analysis, and Optimization

Science.gov (United States)

Meyn, Larry A.

2018-01-01

One of the goals of NASA's Revolutionary Vertical Lift Technology Project (RVLT) is to provide validated tools for multidisciplinary design, analysis and optimization (MDAO) of vertical lift vehicles. As part of this effort, the software package, RotorCraft Optimization Tools (RCOTOOLS), is being developed to facilitate incorporating key rotorcraft conceptual design codes into optimizations using the OpenMDAO multi-disciplinary optimization framework written in Python. RCOTOOLS, also written in Python, currently supports the incorporation of the NASA Design and Analysis of RotorCraft (NDARC) vehicle sizing tool and the Comprehensive Analytical Model of Rotorcraft Aerodynamics and Dynamics II (CAMRAD II) analysis tool into OpenMDAO-driven optimizations. Both of these tools use detailed, file-based inputs and outputs, so RCOTOOLS provides software wrappers to update input files with new design variable values, execute these codes and then extract specific response variable values from the file outputs. These wrappers are designed to be flexible and easy to use. RCOTOOLS also provides several utilities to aid in optimization model development, including Graphical User Interface (GUI) tools for browsing input and output files in order to identify text strings that are used to identify specific variables as optimization input and response variables. This paper provides an overview of RCOTOOLS and its use

Short-Term Wind Speed Forecasting Using Support Vector Regression Optimized by Cuckoo Optimization Algorithm

Directory of Open Access Journals (Sweden)

Jianzhou Wang

2015-01-01

Full Text Available This paper develops an effectively intelligent model to forecast short-term wind speed series. A hybrid forecasting technique is proposed based on recurrence plot (RP and optimized support vector regression (SVR. Wind caused by the interaction of meteorological systems makes itself extremely unsteady and difficult to forecast. To understand the wind system, the wind speed series is analyzed using RP. Then, the SVR model is employed to forecast wind speed, in which the input variables are selected by RP, and two crucial parameters, including the penalties factor and gamma of the kernel function RBF, are optimized by various optimization algorithms. Those optimized algorithms are genetic algorithm (GA, particle swarm optimization algorithm (PSO, and cuckoo optimization algorithm (COA. Finally, the optimized SVR models, including COA-SVR, PSO-SVR, and GA-SVR, are evaluated based on some criteria and a hypothesis test. The experimental results show that (1 analysis of RP reveals that wind speed has short-term predictability on a short-term time scale, (2 the performance of the COA-SVR model is superior to that of the PSO-SVR and GA-SVR methods, especially for the jumping samplings, and (3 the COA-SVR method is statistically robust in multi-step-ahead prediction and can be applied to practical wind farm applications.

A novel optimization method, Gravitational Search Algorithm (GSA), for PWR core optimization

International Nuclear Information System (INIS)

Mahmoudi, S.M.; Aghaie, M.; Bahonar, M.; Poursalehi, N.

2016-01-01

Highlights: • The Gravitational Search Algorithm (GSA) is introduced. • The advantage of GSA is verified in Shekel’s Foxholes. • Reload optimizing in WWER-1000 and WWER-440 cases are performed. • Maximizing K eff , minimizing PPFs and flattening power density is considered. - Abstract: In-core fuel management optimization (ICFMO) is one of the most challenging concepts of nuclear engineering. In recent decades several meta-heuristic algorithms or computational intelligence methods have been expanded to optimize reactor core loading pattern. This paper presents a new method of using Gravitational Search Algorithm (GSA) for in-core fuel management optimization. The GSA is constructed based on the law of gravity and the notion of mass interactions. It uses the theory of Newtonian physics and searcher agents are the collection of masses. In this work, at the first step, GSA method is compared with other meta-heuristic algorithms on Shekel’s Foxholes problem. In the second step for finding the best core, the GSA algorithm has been performed for three PWR test cases including WWER-1000 and WWER-440 reactors. In these cases, Multi objective optimizations with the following goals are considered, increment of multiplication factor (K eff ), decrement of power peaking factor (PPF) and power density flattening. It is notable that for neutronic calculation, PARCS (Purdue Advanced Reactor Core Simulator) code is used. The results demonstrate that GSA algorithm have promising performance and could be proposed for other optimization problems of nuclear engineering field.

Equipment cost optimization

International Nuclear Information System (INIS)

Ribeiro, E.M.; Farias, M.A.; Dreyer, S.R.B.

1995-01-01

Considering the importance of the cost of material and equipment in the overall cost profile of an oil company, which in the case of Petrobras, represents approximately 23% of the total operational cost or 10% of the sales, an organization for the optimization of such costs has been established within Petrobras. Programs are developed aiming at: optimization of life-cycle cost of material and equipment; optimization of industrial processes costs through material development. This paper describes the methodology used in the management of the development programs and presents some examples of concluded and ongoing programs, which are conducted in permanent cooperation with suppliers, technical laboratories and research institutions and have been showing relevant results

The Sizing and Optimization Language (SOL): A computer language to improve the user/optimizer interface

Science.gov (United States)

Lucas, S. H.; Scotti, S. J.

1989-01-01

The nonlinear mathematical programming method (formal optimization) has had many applications in engineering design. A figure illustrates the use of optimization techniques in the design process. The design process begins with the design problem, such as the classic example of the two-bar truss designed for minimum weight as seen in the leftmost part of the figure. If formal optimization is to be applied, the design problem must be recast in the form of an optimization problem consisting of an objective function, design variables, and constraint function relations. The middle part of the figure shows the two-bar truss design posed as an optimization problem. The total truss weight is the objective function, the tube diameter and truss height are design variables, with stress and Euler buckling considered as constraint function relations. Lastly, the designer develops or obtains analysis software containing a mathematical model of the object being optimized, and then interfaces the analysis routine with existing optimization software such as CONMIN, ADS, or NPSOL. This final state of software development can be both tedious and error-prone. The Sizing and Optimization Language (SOL), a special-purpose computer language whose goal is to make the software implementation phase of optimum design easier and less error-prone, is presented.

New advances of TMEM88 in cancer initiation and progression, with special emphasis on Wnt signaling pathway.

Science.gov (United States)

Ge, Yun-Xuan; Wang, Chang-Hui; Hu, Fu-Yong; Pan, Lin-Xin; Min, Jie; Niu, Kai-Yuan; Zhang, Lei; Li, Jun; Xu, Tao

2018-01-01

Transmembrane protein 88 (TMEM88), a newly discovered protein localized on the cell membrane. Recent studies showed that TMEM88 was involved in the regulation of several types of cancer. TMEM88 was expressed at significantly higher levels in breast cancer (BC) cell line than in normal breast cell line with co-localized with Dishevelled (DVL) in the cytoplasm of BC cell line. TMEM88 silencing in the ovarian cancer cell line CP70 resulted in significant upregulation of Wnt downstream genes (c-Myc, cyclin-D1) and other Wnt target genes including JUN, PTIX2, CTNNB1 (β-catenin), further supporting that TMEM88 inhibits canonical Wnt signaling pathway. Wnt signaling pathway has been known to play important roles in many diseases, especially in cancer. For instance, hepatocellular carcinoma (HCC) has become one of the most common tumors harboring mutations in the Wnt signaling pathway. As the inhibitor of Wnt signaling, TMEM88 has been considered to act as an oncogene or a tumor suppressor. Up-regulated TMEM88 or gene therapy approaches could be an effective therapeutic approach against tumor as TMEM88 inhibits Wnt signaling through direct interaction with DVL. Here, we review the current knowledge on the functional role and potential clinical application of TMEM88 in the control of various cancers. Highlights Wnt signaling displays an important role in several pathogenesis of cancer. Wnt signaling pathway is activated during cancer development. TMEM88 has an impact on cancer by inhibiting canonical Wnt signaling. We discuss the importance and new applications of TMEM88 in cancer therapy. © 2017 Wiley Periodicals, Inc.

Energy-economical optimization of industrial sites

International Nuclear Information System (INIS)

Berthold, A.; Saliba, S.; Franke, R.

2015-01-01

The holistic optimization of an industrial estate networks all electrical components of a location and combines energy trading, energy management and production processes. This allows to minimize the energy consumption from the supply network and to relieve the power grid and to maximize the profitability of the industrial self-generation. By analyzing the potential is detected and the cost of optimization solution is estimated. The generation-side optimization is supported through demand-side optimization (demand response). Through a real-time optimization the of Use of fuels is managed, controlled and optimized. [de

The Ontology of Knowledge Based Optimization

OpenAIRE

Nasution, Mahyuddin K. M.

2012-01-01

Optimization has been becoming a central of studies in mathematic and has many areas with different applications. However, many themes of optimization came from different area have not ties closing to origin concepts. This paper is to address some variants of optimization problems using ontology in order to building basic of knowledge about optimization, and then using it to enhance strategy to achieve knowledge based optimization.

Coil Optimization for HTS Machines

DEFF Research Database (Denmark)

Mijatovic, Nenad; Jensen, Bogi Bech; Abrahamsen, Asger Bech

An optimization approach of HTS coils in HTS synchronous machines (SM) is presented. The optimization is aimed at high power SM suitable for direct driven wind turbines applications. The optimization process was applied to a general radial flux machine with a peak air gap flux density of ~3T...... is suitable for which coil segment is presented. Thus, the performed study gives valuable input for the coil design of HTS machines ensuring optimal usage of HTS tapes....

Recent advances in computational optimization

CERN Document Server

2013-01-01

Optimization is part of our everyday life. We try to organize our work in a better way and optimization occurs in minimizing time and cost or the maximization of the profit, quality and efficiency. Also many real world problems arising in engineering, economics, medicine and other domains can be formulated as optimization tasks. This volume is a comprehensive collection of extended contributions from the Workshop on Computational Optimization. This book presents recent advances in computational optimization. The volume includes important real world problems like parameter settings for con- trolling processes in bioreactor, robot skin wiring, strip packing, project scheduling, tuning of PID controller and so on. Some of them can be solved by applying traditional numerical methods, but others need a huge amount of computational resources. For them it is shown that is appropriate to develop algorithms based on metaheuristic methods like evolutionary computation, ant colony optimization, constrain programming etc...

Bi-objective optimization for multi-modal transportation routing planning problem based on Pareto optimality

Directory of Open Access Journals (Sweden)

Yan Sun

2015-09-01

Full Text Available Purpose: The purpose of study is to solve the multi-modal transportation routing planning problem that aims to select an optimal route to move a consignment of goods from its origin to its destination through the multi-modal transportation network. And the optimization is from two viewpoints including cost and time. Design/methodology/approach: In this study, a bi-objective mixed integer linear programming model is proposed to optimize the multi-modal transportation routing planning problem. Minimizing the total transportation cost and the total transportation time are set as the optimization objectives of the model. In order to balance the benefit between the two objectives, Pareto optimality is utilized to solve the model by gaining its Pareto frontier. The Pareto frontier of the model can provide the multi-modal transportation operator (MTO and customers with better decision support and it is gained by the normalized normal constraint method. Then, an experimental case study is designed to verify the feasibility of the model and Pareto optimality by using the mathematical programming software Lingo. Finally, the sensitivity analysis of the demand and supply in the multi-modal transportation organization is performed based on the designed case. Findings: The calculation results indicate that the proposed model and Pareto optimality have good performance in dealing with the bi-objective optimization. The sensitivity analysis also shows the influence of the variation of the demand and supply on the multi-modal transportation organization clearly. Therefore, this method can be further promoted to the practice. Originality/value: A bi-objective mixed integer linear programming model is proposed to optimize the multi-modal transportation routing planning problem. The Pareto frontier based sensitivity analysis of the demand and supply in the multi-modal transportation organization is performed based on the designed case.

Design optimization applied in structural dynamics

NARCIS (Netherlands)

Akcay-Perdahcioglu, Didem; de Boer, Andries; van der Hoogt, Peter; Tiskarna, T

2007-01-01

This paper introduces the design optimization strategies, especially for structures which have dynamic constraints. Design optimization involves first the modeling and then the optimization of the problem. Utilizing the Finite Element (FE) model of a structure directly in an optimization process

Unconstrained Optimization

DEFF Research Database (Denmark)

Frandsen, P. E.; Jonasson, K.; Nielsen, Hans Bruun

1999-01-01

This lecture note is intended for use in the course 04212 Optimization and Data Fitting at the Technincal University of Denmark. It covers about 25% of the curriculum. Hopefully, the note may be useful also to interested persons not participating in that course. The aim of the note is to give...... an introduction to algorithms for unconstrained optimization. We present Conjugate Gradient, Damped Newton and Quasi Newton methods together with the relevant theoretical background. The reader is assumed to be familiar with algorithms for solving linear and nonlinear system of equations, at a level corresponding...

An Improved Real-Coded Population-Based Extremal Optimization Method for Continuous Unconstrained Optimization Problems

Directory of Open Access Journals (Sweden)

Guo-Qiang Zeng

2014-01-01

Full Text Available As a novel evolutionary optimization method, extremal optimization (EO has been successfully applied to a variety of combinatorial optimization problems. However, the applications of EO in continuous optimization problems are relatively rare. This paper proposes an improved real-coded population-based EO method (IRPEO for continuous unconstrained optimization problems. The key operations of IRPEO include generation of real-coded random initial population, evaluation of individual and population fitness, selection of bad elements according to power-law probability distribution, generation of new population based on uniform random mutation, and updating the population by accepting the new population unconditionally. The experimental results on 10 benchmark test functions with the dimension N=30 have shown that IRPEO is competitive or even better than the recently reported various genetic algorithm (GA versions with different mutation operations in terms of simplicity, effectiveness, and efficiency. Furthermore, the superiority of IRPEO to other evolutionary algorithms such as original population-based EO, particle swarm optimization (PSO, and the hybrid PSO-EO is also demonstrated by the experimental results on some benchmark functions.

Dictionary descent in optimization

OpenAIRE

Temlyakov, Vladimir

2015-01-01

The problem of convex optimization is studied. Usually in convex optimization the minimization is over a d-dimensional domain. Very often the convergence rate of an optimization algorithm depends on the dimension d. The algorithms studied in this paper utilize dictionaries instead of a canonical basis used in the coordinate descent algorithms. We show how this approach allows us to reduce dimensionality of the problem. Also, we investigate which properties of a dictionary are beneficial for t...

Potential and challenges in home care service process optimization : a route optimization approach

OpenAIRE

Nakari, Pentti J. E.

2016-01-01

Aging of the population is an increasing problem in many countries, including Finland, and it poses a challenge to public services such as home care. Vehicle routing optimization (VRP) type optimization solutions are one possible way to decrease the time required for planning home visits and driving to customer addresses, as well as decreasing transportation costs. Although VRP optimization is widely and succesfully applied to commercial and industrial logistics, the home care ...

Risk Based Optimal Fatigue Testing

DEFF Research Database (Denmark)

Sørensen, John Dalsgaard; Faber, M.H.; Kroon, I.B.

1992-01-01

Optimal fatigue life testing of materials is considered. Based on minimization of the total expected costs of a mechanical component a strategy is suggested to determine the optimal stress range levels for which additional experiments are to be performed together with an optimal value...

Thermodynamic optimization of power plants

NARCIS (Netherlands)

Haseli, Y.

2011-01-01

Thermodynamic Optimization of Power Plants aims to establish and illustrate comparative multi-criteria optimization of various models and configurations of power plants. It intends to show what optimization objectives one may define on the basis of the thermodynamic laws, and how they can be applied

Accelerating ROP detector layout optimization

International Nuclear Information System (INIS)

Kastanya, D.; Fodor, B.

2012-01-01

The ADORE (Alternating Detector layout Optimization for REgional overpower protection system) algorithm for performing the optimization of regional overpower protection (ROP) system for CANDU® reactors have been recently developed. The simulated annealing (SA) stochastic optimization technique is utilized to come up with a quasi optimized detector layout for the ROP systems. Within each simulated annealing history, the objective function is calculated as a function of the trip set point (TSP) corresponding to the detector layout for that particular history. The evaluation of the TSP is done probabilistically using the ROVER-F code. Since during each optimization execution thousands of candidate detector layouts are evaluated, the overall optimization process is time consuming. Since for each ROVER-F evaluation the number of fuelling ripples controls the execution time, reducing the number of fuelling ripples used during the calculation of TSP will reduce the overall optimization execution time. This approach has been investigated and the results are presented in this paper. The challenge is to construct a set of representative fuelling ripples which will significantly speedup the optimization process while guaranteeing that the resulting detector layout has similar quality to the ones produced when the complete set of fuelling ripples is employed. Results presented in this paper indicate that a speedup of up to around 40 times is attainable when this approach is utilized. (author)

Optimization of Metronidazole Emulgel

Directory of Open Access Journals (Sweden)

Monica Rao

2013-01-01

Full Text Available The purpose of the present study was to develop and optimize the emulgel system for MTZ (Metronidazole, a poorly water soluble drug. The pseudoternary phase diagrams were developed for various microemulsion formulations composed of Capmul 908 P, Acconon MC8-2, and propylene glycol. The emulgel was optimized using a three-factor, two-level factorial design, the independent variables selected were Capmul 908 P, and surfactant mixture (Acconon MC8-2 and gelling agent, and the dependent variables (responses were a cumulative amount of drug permeated across the dialysis membrane in 24 h ( and spreadability (. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equations were generated for responses and . The statistical validity of the polynomials was established, and optimized formulation factors were selected. Validation of the optimization study with 3 confirmatory runs indicated a high degree of prognostic ability of response surface methodology. Emulgel system of MTZ was developed and optimized using 23 factorial design and could provide an effective treatment against topical infections.

Optimization of entanglement witnesses

Science.gov (United States)

Lewenstein, M.; Kraus, B.; Cirac, J. I.; Horodecki, P.

2000-11-01

An entanglement witness (EW) is an operator that allows the detection of entangled states. We give necessary and sufficient conditions for such operators to be optimal, i.e., to detect entangled states in an optimal way. We show how to optimize general EW, and then we particularize our results to the nondecomposable ones; the latter are those that can detect positive partial transpose entangled states (PPTES's). We also present a method to systematically construct and optimize this last class of operators based on the existence of ``edge'' PPTES's, i.e., states that violate the range separability criterion [Phys. Lett. A 232, 333 (1997)] in an extreme manner. This method also permits a systematic construction of nondecomposable positive maps (PM's). Our results lead to a sufficient condition for entanglement in terms of nondecomposable EW's and PM's. Finally, we illustrate our results by constructing optimal EW acting on H=C2⊗C4. The corresponding PM's constitute examples of PM's with minimal ``qubit'' domains, or-equivalently-minimal Hermitian conjugate codomains.

Optimal Training Systems STTR

National Research Council Canada - National Science Library

Best, Brad; Lovett, Marsha

2005-01-01

.... Using an optimal model of task performance subject to human constraints may be a more efficient way to develop models of skilled human performance for use in training, especially since optimal models...

Frontiers in Optimization : Theory and Applications

CERN Document Server

Maulik, Ujjwal; Li, Xiang; FOTA 2016; Operations Research and Optimization

2018-01-01

This book discusses recent developments in the vast domain of optimization. Featuring papers presented at the 1st International Conference on Frontiers in Optimization: Theory and Applications (FOTA 2016), held at the Heritage Institute of Technology, Kolkata, on 24–26 December 2016, it opens new avenues of research in all topics related to optimization, such as linear and nonlinear optimization; combinatorial-, stochastic-, dynamic-, fuzzy-, and uncertain optimization; optimal control theory; as well as multi-objective, evolutionary and convex optimization and their applications in intelligent information and technology, systems science, knowledge management, information and communication, supply chain and inventory control, scheduling, networks, transportation and logistics and finance. The book is a valuable resource for researchers, scientists and engineers from both academia and industry.

Partisan optimism and political bargaining

DEFF Research Database (Denmark)

Jensen, Thomas; Madum, Andreas

2017-01-01

to explore the implications of partisan optimism for political bargaining. We show that increased optimism among a partisan group leads to a stronger bargaining position for their party, but may hurt its electoral prospects. Another main finding is that even high levels of partisan optimism do...

Optimization of lift gas allocation in a gas lifted oil field as non-linear optimization problem

Directory of Open Access Journals (Sweden)

Roshan Sharma

2012-01-01

Full Text Available Proper allocation and distribution of lift gas is necessary for maximizing total oil production from a field with gas lifted oil wells. When the supply of the lift gas is limited, the total available gas should be optimally distributed among the oil wells of the field such that the total production of oil from the field is maximized. This paper describes a non-linear optimization problem with constraints associated with the optimal distribution of the lift gas. A non-linear objective function is developed using a simple dynamic model of the oil field where the decision variables represent the lift gas flow rate set points of each oil well of the field. The lift gas optimization problem is solved using the emph'fmincon' solver found in MATLAB. As an alternative and for verification, hill climbing method is utilized for solving the optimization problem. Using both of these methods, it has been shown that after optimization, the total oil production is increased by about 4. For multiple oil wells sharing lift gas from a common source, a cascade control strategy along with a nonlinear steady state optimizer behaves as a self-optimizing control structure when the total supply of lift gas is assumed to be the only input disturbance present in the process. Simulation results show that repeated optimization performed after the first time optimization under the presence of the input disturbance has no effect in the total oil production.

An Improved Method for Reconfiguring and Optimizing Electrical Active Distribution Network Using Evolutionary Particle Swarm Optimization

Directory of Open Access Journals (Sweden)

Nur Faziera Napis

2018-05-01

Full Text Available The presence of optimized distributed generation (DG with suitable distribution network reconfiguration (DNR in the electrical distribution network has an advantage for voltage support, power losses reduction, deferment of new transmission line and distribution structure and system stability improvement. However, installation of a DG unit at non-optimal size with non-optimal DNR may lead to higher power losses, power quality problem, voltage instability and incremental of operational cost. Thus, an appropriate DG and DNR planning are essential and are considered as an objective of this research. An effective heuristic optimization technique named as improved evolutionary particle swarm optimization (IEPSO is proposed in this research. The objective function is formulated to minimize the total power losses (TPL and to improve the voltage stability index (VSI. The voltage stability index is determined for three load demand levels namely light load, nominal load, and heavy load with proper optimal DNR and DG sizing. The performance of the proposed technique is compared with other optimization techniques, namely particle swarm optimization (PSO and iteration particle swarm optimization (IPSO. Four case studies on IEEE 33-bus and IEEE 69-bus distribution systems have been conducted to validate the effectiveness of the proposed IEPSO. The optimization results show that, the best achievement is done by IEPSO technique with power losses reduction up to 79.26%, and 58.41% improvement in the voltage stability index. Moreover, IEPSO has the fastest computational time for all load conditions as compared to other algorithms.

Optimization of wind turbine rotors - using advanced aerodynamic and aeroelastic models and numerical optimization

DEFF Research Database (Denmark)

Døssing, Mads

of very large machines introduces new problems in the practical design, and optimization tools are necessary. These must combine the dynamic eects of both aerodynamics and structure in an integrated optimization environment. This is referred to as aeroelastic optimization. The Ris DTU optimization...... software HAWTOPT has been used in this project. The quasi-steady aerodynamic module have been improved with a corrected blade element momentum method. A structure module has also been developed which lays out the blade structural properties. This is done in a simplied way allowing fast conceptual design...... studies and with focus on the overall properties relevant for the aeroelastic properties. Aeroelastic simulations in the time domain were carried out using the aeroelastic code HAWC2. With these modules coupled to HAWTOPT, optimizations have been made. In parallel with the developments of the mentioned...

Cost-Optimal Analysis for Nearly Zero Energy Buildings Design and Optimization: A Critical Review

Directory of Open Access Journals (Sweden)

Maria Ferrara

2018-06-01

Full Text Available Since the introduction of the recast of the EPBD European Directive 2010/31/EU, many studies on the cost-effective feasibility of nearly zero-energy buildings (NZEBs were carried out either by academic research bodies and by national bodies. In particular, the introduction of the cost-optimal methodology has given a strong impulse to research in this field. This paper presents a comprehensive and significant review on scientific works based on the application of cost-optimal analysis applications in Europe since the EPBD recast entered into force, pointing out the differences in the analyzed studies and comparing their outcomes before the new recast of EPBD enters into force in 2018. The analysis is conducted with special regard to the methods used for the energy performance assessment, the global cost calculation, and for the selection of the energy efficiency measures leading to design optimization. A critical discussion about the assumptions on which the studies are based and the resulting gaps between the resulting cost-optimal performance and the zero energy target is provided together with a summary of the resulting cost-optimal set of technologies to be used for cost-optimal NZEB design in different contexts. It is shown that the cost-optimal approach results as an effective method for delineating the future of NZEB design throughout Europe while emerging criticalities and open research issues are presented.

Exergetic optimization of a thermoacoustic engine using the particle swarm optimization method

International Nuclear Information System (INIS)

Chaitou, Hussein; Nika, Philippe

2012-01-01

Highlights: ► Optimization of a thermoacoustic engine using the particle swarm optimization method. ► Exergetic efficiency, acoustic power and their product are the optimized functions. ► PSO method is used successfully for the first time in the TA research. ► The powerful PSO tool is advised to be more involved in the TA research and design. ► EE times AP optimized function is highly recommended to design any new TA devices. - Abstract: Thermoacoustic engines convert heat energy into acoustic energy. Then, the acoustic energy can be used to pump heat or to generate electricity. It is well-known that the acoustic energy and therefore the exergetic efficiency depend on parameters such as the stack’s hydraulic radius, the stack’s position in the resonator and the traveling–standing-wave ratio. In this paper, these three parameters are investigated in order to study and analyze the best value of the produced acoustic energy, the exergetic efficiency and the product of the acoustic energy by the exergetic efficiency of a thermoacoustic engine with a parallel-plate stack. The dimensionless expressions of the thermoacoustic equations are derived and calculated. Then, the Particle Swarm Optimization method (PSO) is introduced and used for the first time in the thermoacoustic research. The use of the PSO method and the optimization of the acoustic energy multiplied by the exergetic efficiency are novel contributions to this domain of research. This paper discusses some significant conclusions which are useful for the design of new thermoacoustic engines.

A Class-Specific Optimizing Compiler

Directory of Open Access Journals (Sweden)

Michael D. Sharp

1993-01-01

Full Text Available Class-specific optimizations are compiler optimizations specified by the class implementor to the compiler. They allow the compiler to take advantage of the semantics of the particular class so as to produce better code. Optimizations of interest include the strength reduction of class:: array address calculations, elimination of large temporaries, and the placement of asynchronous send/recv calls so as to achieve computation/communication overlap. We will outline our progress towards the implementation of a C++ compiler capable of incorporating class-specific optimizations.

Optimally segmented permanent magnet structures

DEFF Research Database (Denmark)

Insinga, Andrea Roberto; Bjørk, Rasmus; Smith, Anders

2016-01-01

We present an optimization approach which can be employed to calculate the globally optimal segmentation of a two-dimensional magnetic system into uniformly magnetized pieces. For each segment the algorithm calculates the optimal shape and the optimal direction of the remanent flux density vector......, with respect to a linear objective functional. We illustrate the approach with results for magnet design problems from different areas, such as a permanent magnet electric motor, a beam focusing quadrupole magnet for particle accelerators and a rotary device for magnetic refrigeration....

Optimization methods for logical inference

CERN Document Server

Chandru, Vijay

2011-01-01

Merging logic and mathematics in deductive inference-an innovative, cutting-edge approach. Optimization methods for logical inference? Absolutely, say Vijay Chandru and John Hooker, two major contributors to this rapidly expanding field. And even though ""solving logical inference problems with optimization methods may seem a bit like eating sauerkraut with chopsticks. . . it is the mathematical structure of a problem that determines whether an optimization model can help solve it, not the context in which the problem occurs."" Presenting powerful, proven optimization techniques for logic in

RF Gun Optimization Study

International Nuclear Information System (INIS)

Alicia Hofler; Pavel Evtushenko

2007-01-01

Injector gun design is an iterative process where the designer optimizes a few nonlinearly interdependent beam parameters to achieve the required beam quality for a particle accelerator. Few tools exist to automate the optimization process and thoroughly explore the parameter space. The challenging beam requirements of new accelerator applications such as light sources and electron cooling devices drive the development of RF and SRF photo injectors. A genetic algorithm (GA) has been successfully used to optimize DC photo injector designs at Cornell University [1] and Jefferson Lab [2]. We propose to apply GA techniques to the design of RF and SRF gun injectors. In this paper, we report on the initial phase of the study where we model and optimize a system that has been benchmarked with beam measurements and simulation

Setting value optimization method in integration for relay protection based on improved quantum particle swarm optimization algorithm

Science.gov (United States)

Yang, Guo Sheng; Wang, Xiao Yang; Li, Xue Dong

2018-03-01

With the establishment of the integrated model of relay protection and the scale of the power system expanding, the global setting and optimization of relay protection is an extremely difficult task. This paper presents a kind of application in relay protection of global optimization improved particle swarm optimization algorithm and the inverse time current protection as an example, selecting reliability of the relay protection, selectivity, quick action and flexibility as the four requires to establish the optimization targets, and optimizing protection setting values of the whole system. Finally, in the case of actual power system, the optimized setting value results of the proposed method in this paper are compared with the particle swarm algorithm. The results show that the improved quantum particle swarm optimization algorithm has strong search ability, good robustness, and it is suitable for optimizing setting value in the relay protection of the whole power system.

Optimal control in thermal engineering

CERN Document Server

Badescu, Viorel

2017-01-01

This book is the first major work covering applications in thermal engineering and offering a comprehensive introduction to optimal control theory, which has applications in mechanical engineering, particularly aircraft and missile trajectory optimization. The book is organized in three parts: The first part includes a brief presentation of function optimization and variational calculus, while the second part presents a summary of the optimal control theory. Lastly, the third part describes several applications of optimal control theory in solving various thermal engineering problems. These applications are grouped in four sections: heat transfer and thermal energy storage, solar thermal engineering, heat engines and lubrication.Clearly presented and easy-to-use, it is a valuable resource for thermal engineers and thermal-system designers as well as postgraduate students.

Optimizing the dynamic response of the H.B. Robinson nuclear plant using multiobjective particle swarm optimization

International Nuclear Information System (INIS)

Elsays, Mostafa A.; Naguib Aly, M.; Badawi, Alya A.

2009-01-01

In this paper, the Particle Swarm Optimization (PSO) algorithm is modified to deal with Multiobjective Optimization Problems (MOPs). A mathematical model for predicting the dynamic response of the H. B. Robinson nuclear power plant, which represents an Initial Value Problem (IVP) of Ordinary Differential Equations (ODEs), is solved using Runge-Kutta formula. The resulted data values are represented as a system of nonlinear algebraic equations by interpolation schemes for data fitting. This system of fitted nonlinear algebraic equations represents a nonlinear multiobjective optimization problem. A Multiobjective Particle Swarm Optimizer (MOPSO) which is based on the Pareto optimality concept is developed and applied to maximize the above mentioned problem. Results show that MOPSO efficiently cope with the problem and finds multiple Pareto optimal solutions. (orig.)

A PROCEDURE FOR DETERMINING OPTIMAL FACILITY LOCATION AND SUB-OPTIMAL POSITIONS

Directory of Open Access Journals (Sweden)

P.K. Dan

2012-01-01

Full Text Available

ENGLISH ABSTRACT: This research presents a methodology for determining the optimal location of a new facility, having physical flow interaction of various degrees with other existing facilities in the presence of barriers impeding the shortest flow-path as well as the sub-optimal iso-cost positions. It also determines sub-optimal iso-cost positions with additional cost or penalty for not being able to site it at the computed optimal point. The proposed methodology considers all types of quadrilateral barrier or forbidden region configurations to generalize and by-pass such impenetrable obstacles, and adopts a scheme of searching through the vertices of the quadrilaterals to determine the alternative shortest flow-path. This procedure of obstacle avoidance is novel. Software has been developed to facilitate computations for the search algorithm to determine the optimal and iso-cost co-ordinates. The test results are presented.

AFRIKAANSE OPSOMMING: Die navorsing behandel ‘n procedure vir die bepaling van optimum stigtingsposisie vir ‘n onderneming met vloei vanaf ander bestaande fasiliteite in die teenwoordigheid van ‘n verskeidenheid van randvoorwaardes. Die prodedure lewer as resultaat suboptimale isokoste-stigtingsplekke met bekendmaking van die koste wat onstaan a.g.v. afwyking van die randvoorwaardlose optimum oplossingskoste, die prosedure maak gebruik van ‘n vindingryke soekmetode wat toegepas word op niersydige meerkundige voorstellings vir die bepaling van korste roetes wat versperring omseil. Die prosedure word onderskei deur programmatuur. Toetsresultate word voorgehou.

Germinal Center Optimization Applied to Neural Inverse Optimal Control for an All-Terrain Tracked Robot

Directory of Open Access Journals (Sweden)

Carlos Villaseñor

2017-12-01

Full Text Available Nowadays, there are several meta-heuristics algorithms which offer solutions for multi-variate optimization problems. These algorithms use a population of candidate solutions which explore the search space, where the leadership plays a big role in the exploration-exploitation equilibrium. In this work, we propose to use a Germinal Center Optimization algorithm (GCO which implements temporal leadership through modeling a non-uniform competitive-based distribution for particle selection. GCO is used to find an optimal set of parameters for a neural inverse optimal control applied to all-terrain tracked robot. In the Neural Inverse Optimal Control (NIOC scheme, a neural identifier, based on Recurrent High Orden Neural Network (RHONN trained with an extended kalman filter algorithm, is used to obtain a model of the system, then, a control law is design using such model with the inverse optimal control approach. The RHONN identifier is developed without knowledge of the plant model or its parameters, on the other hand, the inverse optimal control is designed for tracking velocity references. Applicability of the proposed scheme is illustrated using simulations results as well as real-time experimental results with an all-terrain tracked robot.

Sequential ensemble-based optimal design for parameter estimation: SEQUENTIAL ENSEMBLE-BASED OPTIMAL DESIGN

Energy Technology Data Exchange (ETDEWEB)

Man, Jun [Zhejiang Provincial Key Laboratory of Agricultural Resources and Environment, Institute of Soil and Water Resources and Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou China; Zhang, Jiangjiang [Zhejiang Provincial Key Laboratory of Agricultural Resources and Environment, Institute of Soil and Water Resources and Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou China; Li, Weixuan [Pacific Northwest National Laboratory, Richland Washington USA; Zeng, Lingzao [Zhejiang Provincial Key Laboratory of Agricultural Resources and Environment, Institute of Soil and Water Resources and Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou China; Wu, Laosheng [Department of Environmental Sciences, University of California, Riverside California USA

2016-10-01

The ensemble Kalman filter (EnKF) has been widely used in parameter estimation for hydrological models. The focus of most previous studies was to develop more efficient analysis (estimation) algorithms. On the other hand, it is intuitively understandable that a well-designed sampling (data-collection) strategy should provide more informative measurements and subsequently improve the parameter estimation. In this work, a Sequential Ensemble-based Optimal Design (SEOD) method, coupled with EnKF, information theory and sequential optimal design, is proposed to improve the performance of parameter estimation. Based on the first-order and second-order statistics, different information metrics including the Shannon entropy difference (SD), degrees of freedom for signal (DFS) and relative entropy (RE) are used to design the optimal sampling strategy, respectively. The effectiveness of the proposed method is illustrated by synthetic one-dimensional and two-dimensional unsaturated flow case studies. It is shown that the designed sampling strategies can provide more accurate parameter estimation and state prediction compared with conventional sampling strategies. Optimal sampling designs based on various information metrics perform similarly in our cases. The effect of ensemble size on the optimal design is also investigated. Overall, larger ensemble size improves the parameter estimation and convergence of optimal sampling strategy. Although the proposed method is applied to unsaturated flow problems in this study, it can be equally applied in any other hydrological problems.

Optimal river monitoring network using optimal partition analysis: a case study of Hun River, Northeast China.

Science.gov (United States)

Wang, Hui; Liu, Chunyue; Rong, Luge; Wang, Xiaoxu; Sun, Lina; Luo, Qing; Wu, Hao

2018-01-09

River monitoring networks play an important role in water environmental management and assessment, and it is critical to develop an appropriate method to optimize the monitoring network. In this study, an effective method was proposed based on the attainment rate of National Grade III water quality, optimal partition analysis and Euclidean distance, and Hun River was taken as a method validation case. There were 7 sampling sites in the monitoring network of the Hun River, and 17 monitoring items were analyzed once a month during January 2009 to December 2010. The results showed that the main monitoring items in the surface water of Hun River were ammonia nitrogen (NH 4 + -N), chemical oxygen demand, and biochemical oxygen demand. After optimization, the required number of monitoring sites was reduced from seven to three, and 57% of the cost was saved. In addition, there were no significant differences between non-optimized and optimized monitoring networks, and the optimized monitoring networks could correctly represent the original monitoring network. The duplicate setting degree of monitoring sites decreased after optimization, and the rationality of the monitoring network was improved. Therefore, the optimal method was identified as feasible, efficient, and economic.

An Ameliorative Whale Optimization Algorithm for Multi-Objective Optimal Allocation of Water Resources in Handan, China

Directory of Open Access Journals (Sweden)

Zhihong Yan

2018-01-01

Full Text Available With the deepening discrepancy between water supply and demand caused by water shortages, alleviating water shortages by optimizing water resource allocation has received extensive attention. How to allocate water resources optimally, rapidly, and effectively has become a challenging problem. Thus, this study employs a meta-heuristic swarm-based algorithm, the whale optimization algorithm (WOA. To overcome drawbacks like relatively low convergence precision and convergence rates, when applying the WOA algorithm to complex optimization problems, logistic mapping is used to initialize swarm location, and inertia weighting is employed to improve the algorithm. The resulting ameliorative whale optimization algorithm (AWOA shows substantially enhanced convergence rates and precision than the WOA and particle swarm optimization algorithms, demonstrating relatively high reliability and applicability. A water resource allocation optimization model with optimal economic efficiency and least total water shortage volume is established for Handan, China, and solved by the AWOA. The allocation results better reflect actual water usage in Handan. In 2030, the p = 50% total water shortage is forecast as 404.34 × 106 m3 or 14.8%. The shortage is mainly in the primary agricultural sector. The allocation results provide a reference for regional water resources management.

Optimization of wind turbine rotors - using advanced aerodynamic and aeroelastic models and numerical optimization

Energy Technology Data Exchange (ETDEWEB)

Doessing, M.

2011-05-15

During the last decades the annual energy produced by wind turbines has increased dramatically and wind turbines are now available in the 5MW range. Turbines in this range are constantly being developed and it is also being investigated whether turbines as large as 10-20MW are feasible. The design of very large machines introduces new problems in the practical design, and optimization tools are necessary. These must combine the dynamic effects of both aerodynamics and structure in an integrated optimization environment. This is referred to as aeroelastic optimization. The Risoe DTU optimization software HAWTOPT has been used in this project. The quasi-steady aerodynamic module have been improved with a corrected blade element momentum method. A structure module has also been developed which lays out the blade structural properties. This is done in a simplified way allowing fast conceptual design studies and with focus on the overall properties relevant for the aeroelastic properties. Aeroelastic simulations in the time domain were carried out using the aeroelastic code HAWC2. With these modules coupled to HAWTOPT, optimizations have been made. In parallel with the developments of the mentioned numerical modules, focus has been on analysis and a fundamental understanding of the key parameters in wind turbine design. This has resulted in insight and an effective design methodology is presented. Using the optimization environment a 5MW wind turbine rotor has been optimized for reduced fatigue loads due to apwise bending moments. Among other things this has indicated that airfoils for wind turbine blades should have a high lift coefficient. The design methodology proved to be stable and a help in the otherwise challenging task of numerical aeroelastic optimization. (Author)

Dynamic optimization the calculus of variations and optimal control in economics and management

CERN Document Server

Kamien, Morton I

2012-01-01

Since its initial publication, this text has defined courses in dynamic optimization taught to economics and management science students. The two-part treatment covers the calculus of variations and optimal control. 1998 edition.

Global Optimization Based on the Hybridization of Harmony Search and Particle Swarm Optimization Methods

Directory of Open Access Journals (Sweden)

A. P. Karpenko

2014-01-01

Full Text Available We consider a class of stochastic search algorithms of global optimization which in various publications are called behavioural, intellectual, metaheuristic, inspired by the nature, swarm, multi-agent, population, etc. We use the last term.Experience in using the population algorithms to solve challenges of global optimization shows that application of one such algorithm may not always effective. Therefore now great attention is paid to hybridization of population algorithms of global optimization. Hybrid algorithms unite various algorithms or identical algorithms, but with various values of free parameters. Thus efficiency of one algorithm can compensate weakness of another.The purposes of the work are development of hybrid algorithm of global optimization based on known algorithms of harmony search (HS and swarm of particles (PSO, software implementation of algorithm, study of its efficiency using a number of known benchmark problems, and a problem of dimensional optimization of truss structure.We set a problem of global optimization, consider basic algorithms of HS and PSO, give a flow chart of the offered hybrid algorithm called PSO HS , present results of computing experiments with developed algorithm and software, formulate main results of work and prospects of its development.

Multi-Objective Optimization of Squeeze Casting Process using Genetic Algorithm and Particle Swarm Optimization

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Patel G.C.M.

2016-09-01

Full Text Available The near net shaped manufacturing ability of squeeze casting process requiresto set the process variable combinations at their optimal levels to obtain both aesthetic appearance and internal soundness of the cast parts. The aesthetic and internal soundness of cast parts deal with surface roughness and tensile strength those can readily put the part in service without the requirement of costly secondary manufacturing processes (like polishing, shot blasting, plating, hear treatment etc.. It is difficult to determine the levels of the process variable (that is, pressure duration, squeeze pressure, pouring temperature and die temperature combinations for extreme values of the responses (that is, surface roughness, yield strength and ultimate tensile strength due to conflicting requirements. In the present manuscript, three population based search and optimization methods, namely genetic algorithm (GA, particle swarm optimization (PSO and multi-objective particle swarm optimization based on crowding distance (MOPSO-CD methods have been used to optimize multiple outputs simultaneously. Further, validation test has been conducted for the optimal casting conditions suggested by GA, PSO and MOPSO-CD. The results showed that PSO outperformed GA with regard to computation time.

Optimization of Wind Turbine Airfoil Using Nondominated Sorting Genetic Algorithm and Pareto Optimal Front

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Ziaul Huque

2012-01-01

Full Text Available A Computational Fluid Dynamics (CFD and response surface-based multiobjective design optimization were performed for six different 2D airfoil profiles, and the Pareto optimal front of each airfoil is presented. FLUENT, which is a commercial CFD simulation code, was used to determine the relevant aerodynamic loads. The Lift Coefficient (CL and Drag Coefficient (CD data at a range of 0° to 12° angles of attack (α and at three different Reynolds numbers (Re=68,459, 479, 210, and 958, 422 for all the six airfoils were obtained. Realizable k-ε turbulence model with a second-order upwind solution method was used in the simulations. The standard least square method was used to generate response surface by the statistical code JMP. Elitist Non-dominated Sorting Genetic Algorithm (NSGA-II was used to determine the Pareto optimal set based on the response surfaces. Each Pareto optimal solution represents a different compromise between design objectives. This gives the designer a choice to select a design compromise that best suits the requirements from a set of optimal solutions. The Pareto solution set is presented in the form of a Pareto optimal front.

Nonlinear optimal control theory

CERN Document Server

Berkovitz, Leonard David

2012-01-01

Nonlinear Optimal Control Theory presents a deep, wide-ranging introduction to the mathematical theory of the optimal control of processes governed by ordinary differential equations and certain types of differential equations with memory. Many examples illustrate the mathematical issues that need to be addressed when using optimal control techniques in diverse areas. Drawing on classroom-tested material from Purdue University and North Carolina State University, the book gives a unified account of bounded state problems governed by ordinary, integrodifferential, and delay systems. It also dis

Optimization of Antivirus Software

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2007-01-01

Full Text Available The paper describes the main techniques used in development of computer antivirus software applications. For this particular category of software, are identified and defined optimum criteria that helps determine which solution is better and what are the objectives of the optimization process. From the general viewpoint of software optimization are presented methods and techniques that are applied at code development level. Regarding the particularities of antivirus software, the paper analyzes some of the optimization concepts applied to this category of applications

Optimal Design of Porous Materials

DEFF Research Database (Denmark)

Andreassen, Erik

The focus of this thesis is topology optimization of material microstructures. That is, creating new materials, with attractive properties, by combining classic materials in periodic patterns. First, large-scale topology optimization is used to design complicated three-dimensional materials......, throughout the thesis extra attention is given to obtain structures that can be manufactured. That is also the case in the final part, where a simple multiscale method for the optimization of structural damping is presented. The method can be used to obtain an optimized component with structural details...

Novelty-driven Particle Swarm Optimization