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Sample records for synthetic combinatorial library

  1. COMBINATORIAL LIBRARIES

    DEFF Research Database (Denmark)

    1997-01-01

    The invention provides a method for the production of a combinatorial library of compound of general formula (I) using solid phase methodologies. The cleavage of the array of immobilised compounds of the phthalimido type from the solid support matrix is accomplished by using an array of dinucleop......The invention provides a method for the production of a combinatorial library of compound of general formula (I) using solid phase methodologies. The cleavage of the array of immobilised compounds of the phthalimido type from the solid support matrix is accomplished by using an array...... of dinucleophiles, e.g. hydrazines (hydrazinolysis) or N-hydroxylamines, whereby a combinatorial dimension is introduced in the cleavage step. The invention also provides a compound library....

  2. Synthetic molecular evolution of pore–forming peptides by Iterative combinatorial library screening

    Science.gov (United States)

    Krauson, Aram J.; He, Jing; Wimley, Andrew W.; Hoffmann, Andrew R.; Wimley, William C

    2013-01-01

    We previously reported the de novo design of a combinatorial peptide library that was subjected to high–throughput screening to identify membrane permeabilizing antimicrobial peptides that have β–sheet–like secondary structure. Those peptides do not form discreet pores in membranes but instead partition into membrane interfaces and cause transient permeabilization by membrane disruption, but only when present at high concentration. In this work, we used a consensus sequence from that initial screen as a template to design an iterative, second generation library. In the 24–26–residue, 16,200 member second generation library we varied six residues. Two diad repeat motifs of alternating polar and nonpolar amino acids were preserved to maintain a propensity for non–helical secondary structure. We used a new high–throughput assay to identify members that self–assemble into equilibrium pores in synthetic lipid bilayers. This screen was done at a very stringent peptide to lipid ratio of 1:1000 where most known membrane permeabilizing peptides, including the template peptide, are not active. In a screen of 10,000 library members we identified 16 (~0.2%) that are equilibrium pore–formers at this high stringency. These rare and highly active peptides, which share a common sequence motif, are as potent as the most active pore–forming peptides known. Furthermore, they are not α–helical, which makes them unusual, as most of the highly potent pore–forming peptides are amphipathic α–helices. Here we demonstrate that this synthetic molecular evolution–based approach, taken together with the new high–throughput tools we have developed, enables the identification, refinement and optimization of unique membrane active peptides. PMID:23394375

  3. Synthetic molecular evolution of pore-forming peptides by iterative combinatorial library screening.

    Science.gov (United States)

    Krauson, Aram J; He, Jing; Wimley, Andrew W; Hoffmann, Andrew R; Wimley, William C

    2013-04-19

    We previously reported the de novo design of a combinatorial peptide library that was subjected to high-throughput screening to identify membrane-permeabilizing antimicrobial peptides that have β-sheet-like secondary structure. Those peptides do not form discrete pores in membranes but instead partition into membrane interfaces and cause transient permeabilization by membrane disruption, but only when present at high concentration. In this work, we used a consensus sequence from that initial screen as a template to design an iterative, second generation library. In the 24-26-residue, 16,200-member second generation library we varied six residues. Two diad repeat motifs of alternating polar and nonpolar amino acids were preserved to maintain a propensity for non-helical secondary structure. We used a new high-throughput assay to identify members that self-assemble into equilibrium pores in synthetic lipid bilayers. This screen was done at a very stringent peptide to lipid ratio of 1:1000 where most known membrane-permeabilizing peptides, including the template peptide, are not active. In a screen of 10,000 library members we identified 16 (~0.2%) that are equilibrium pore-formers at this high stringency. These rare and highly active peptides, which share a common sequence motif, are as potent as the most active pore-forming peptides known. Furthermore, they are not α-helical, which makes them unusual, as most of the highly potent pore-forming peptides are amphipathic α-helices. Here we demonstrate that this synthetic molecular evolution-based approach, taken together with the new high-throughput tools we have developed, enables the identification, refinement, and optimization of unique membrane active peptides.

  4. Multidisciplinary synthetic approach for rapid combinatorial library synthesis of triaza-fluorenes.

    Science.gov (United States)

    Hsiao, Ya-Shan; Yellol, Gorakh S; Chen, Li-Hsun; Sun, Chung-Ming

    2010-09-13

    A new multidisciplinary synthetic approach comprising polymer-support synthesis, microwave-assisted synthesis, and multicomponent condensation facilitates synthesis of triaza-fluorenes library with a set of advantages such as rapid process, simple purification, and structural diversity in one shot. Microwave-assisted multistep synthetic protocol was used to construct the benzimidazole ring on soluble polymer support using activated aryl-fluorides. The PEG anchored aryl fluoride was condensed with selective primary amines via an ipso-fluoro displacement reaction followed by reduction of nitro group. The subsequent cyclization with cyanogen bromide is used as a key step to furnish immobilized benzimidazoles. Finally multicomponent condensation of resulted polymer bound benzimidazoles with various aldehydes and 1,3-diones under microwave irradiations provides rapid access for triaza-fluorenes with high purity and excellent yields. Microwave irradiation greatly accelerates the rate of all reactions while polymer support facilitates purifications by simple precipitation technique. This strategy dramatically increases efficiency of overall multistep synthesis.

  5. Screening of a synthetic peptide combinatorial library to identify inhibitors of the appressorium formation in Magnaporthe oryzae.

    Science.gov (United States)

    Rebollar, Aarón; Marcos, Jose F; López-García, Belén

    2014-11-07

    The rice blast disease caused by Magnaporthe oryzae is one of the most devastating diseases of cultivated rice. One of the most important stages in the infective cycle of M. oryzae is the formation of the dome-shaped structure called appressorium. The purpose of the present study was to identify novel peptides to control the rice blast disease by blocking the appressorium formation through screening of a synthetic peptide combinatorial library. As result of the screening, a set of 29 putative bioactive peptides were identified, synthesized and assayed in comparison with the previously identified peptide PAF104. The peptides MgAPI24, MgAPI40 and MgAPI47 showed improved inhibitory activity on the M. oryzae appressorium formation. Our data show that these peptides have a differential effect on two developmental structures: appressoria and appressorium-like structures. Antimicrobial assays against M. oryzae and other non-target microorganisms showed a weak or no toxicity of these peptides, demonstrating their specific activity blocking the appressorium formation. Therefore, the outcome of this research would be useful in the development of novel target-oriented peptides to use in plant protection. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Identification of novel peptide ligands for the cancer-specific receptor mutation EFGRvIII using a mixture-based synthetic combinatorial library

    DEFF Research Database (Denmark)

    Denholt, Charlotte Lund; Hansen, Paul Robert; Pedersen, Nina

    2009-01-01

    . This study demonstrates the value of using mixture-based combinatorial positional scanning libraries for the identification of novel peptide ligands targeted against the cancer-specific EGFRvIII. Our best candidate H-FALGEA-NH(2) will be radioactively labeled and evaluated as an imaging agent for positron......We report here, the design and synthesis of a positional scanning synthetic combinatorial library for the identification of novel peptide ligands targeted against the cancer-specific epidermal growth factor tyrosine kinase receptor mutation variant III (EGFRvIII). This receptor is expressed...... in several kinds of cancer, in particular, ovarian, glioblastomas, and breast cancer, but not in normal tissue. The library consisted of six individual positional sublibraries in the format, H-O(1-6)XXXXX-NH(2), O being one of the 19 proteinogenic amino acids (cysteine omitted) and X an equimolar mixture...

  7. PIPERIDINE OLIGOMERS AND COMBINATORIAL LIBRARIES THEREOF

    DEFF Research Database (Denmark)

    1999-01-01

    The present invention relates to piperidine oligomers, methods for the preparation of piperidine oligomers and compound libraries thereof, and the use of piperidine oligomers as drug substances. The present invention also relates to the use of combinatorial libraries of piperidine oligomers...... in libraries (arrays) of compounds especially suitable for screening purposes....

  8. Toward Chemical Implementation of Encoded Combinatorial Libraries

    DEFF Research Database (Denmark)

    Nielsen, John; Janda, Kim D.

    1994-01-01

    The recent application of "combinatorial libraries" to supplement existing drug screening processes might simplify and accelerate the search for new lead compounds or drugs. Recently, a scheme for encoded combinatorial chemistry was put forward to surmount a number of the limitations possessed by...... by existing methodologies. Here we detail the synthesis of several matrices and the necessary chemistry to implement the conceptual scheme. In addition, we disclose how this novel technology permits a controlled ′dendritic" display of the chemical libraries....

  9. Rationally reduced libraries for combinatorial pathway optimization minimizing experimental effort.

    Science.gov (United States)

    Jeschek, Markus; Gerngross, Daniel; Panke, Sven

    2016-03-31

    Rational flux design in metabolic engineering approaches remains difficult since important pathway information is frequently not available. Therefore empirical methods are applied that randomly change absolute and relative pathway enzyme levels and subsequently screen for variants with improved performance. However, screening is often limited on the analytical side, generating a strong incentive to construct small but smart libraries. Here we introduce RedLibs (Reduced Libraries), an algorithm that allows for the rational design of smart combinatorial libraries for pathway optimization thereby minimizing the use of experimental resources. We demonstrate the utility of RedLibs for the design of ribosome-binding site libraries by in silico and in vivo screening with fluorescent proteins and perform a simple two-step optimization of the product selectivity in the branched multistep pathway for violacein biosynthesis, indicating a general applicability for the algorithm and the proposed heuristics. We expect that RedLibs will substantially simplify the refactoring of synthetic metabolic pathways.

  10. Structure-based library design: molecular modelling merges with combinatorial chemistry.

    Science.gov (United States)

    Böhm, H J; Stahl, M

    2000-06-01

    Recent advances in both computational and experimental techniques now allow a very fruitful interplay of computational and combinatorial chemistry in the structure-based design of combinatorial libraries.

  11. Chemoinformatic analysis of combinatorial libraries, drugs, natural products, and molecular libraries small molecule repository.

    Science.gov (United States)

    Singh, Narender; Guha, Rajarshi; Giulianotti, Marc A; Pinilla, Clemencia; Houghten, Richard A; Medina-Franco, Jose L

    2009-04-01

    A multiple criteria approach is presented, that is used to perform a comparative analysis of four recently developed combinatorial libraries to drugs, Molecular Libraries Small Molecule Repository (MLSMR) and natural products. The compound databases were assessed in terms of physicochemical properties, scaffolds, and fingerprints. The approach enables the analysis of property space coverage, degree of overlap between collections, scaffold and structural diversity, and overall structural novelty. The degree of overlap between combinatorial libraries and drugs was assessed using the R-NN curve methodology, which measures the density of chemical space around a query molecule embedded in the chemical space of a target collection. The combinatorial libraries studied in this work exhibit scaffolds that were not observed in the drug, MLSMR, and natural products databases. The fingerprint-based comparisons indicate that these combinatorial libraries are structurally different than current drugs. The R-NN curve methodology revealed that a proportion of molecules in the combinatorial libraries is located within the property space of the drugs. However, the R-NN analysis also showed that there are a significant number of molecules in several combinatorial libraries that are located in sparse regions of the drug space.

  12. Price-Focused Analysis of Commercially Available Building Blocks for Combinatorial Library Synthesis.

    Science.gov (United States)

    Kalliokoski, Tuomo

    2015-10-12

    Combinatorial libraries are synthesized by combining smaller reagents (building blocks), the price of which is an important component of the total costs associated with the synthetic exercise. A significant portion of commercially available reagents are too expensive for large scale work. In this study, 13 commonly used reagent classes in combinatorial library synthesis (primary and secondary amines, carboxylic acids, alcohols, ketones, aldehydes, boronic acids, acyl halides, sulfonyl chlorides, isocyanates, isothiocyanates, azides and chloroformates) were analyzed with respect to the cost, physicochemical properties (molecular weight and calculated logP), chemical diversity, and 3D-likeness using a large data set. The results define the chemical space accessible under a constraint of limited financial resources.

  13. Multi-line split DNA synthesis: a novel combinatorial method to make high quality peptide libraries

    Directory of Open Access Journals (Sweden)

    Ueno Shingo

    2004-09-01

    Full Text Available Abstract Background We developed a method to make a various high quality random peptide libraries for evolutionary protein engineering based on a combinatorial DNA synthesis. Results A split synthesis in codon units was performed with mixtures of bases optimally designed by using a Genetic Algorithm program. It required only standard DNA synthetic reagents and standard DNA synthesizers in three lines. This multi-line split DNA synthesis (MLSDS is simply realized by adding a mix-and-split process to normal DNA synthesis protocol. Superiority of MLSDS method over other methods was shown. We demonstrated the synthesis of oligonucleotide libraries with 1016 diversity, and the construction of a library with random sequence coding 120 amino acids containing few stop codons. Conclusions Owing to the flexibility of the MLSDS method, it will be able to design various "rational" libraries by using bioinformatics databases.

  14. Solid-Phase Synthesis of Small Molecule Libraries using Double Combinatorial Chemistry

    DEFF Research Database (Denmark)

    Nielsen, John; Jensen, Flemming R.

    1997-01-01

    The first synthesis of a combinatorial library using double combinatorial chemistry is presented. Coupling of unprotected Fmoc-tyrosine to the solid support was followed by Mitsunobu O-alkylation. Introduction of a diacid linker yields a system in which the double combinatorial step can be demons...

  15. Chemoinformatic Analysis of Combinatorial Libraries, Drugs, Natural Products and Molecular Libraries Small Molecule Repository

    OpenAIRE

    Singh, Narender; Guha, Rajarshi; Giulianotti, Marc; Pinilla, Clemencia; Houghten, Richard; Medina-Franco, Jose L.

    2009-01-01

    A multiple criteria approach is presented, that is used to perform a comparative analysis of four recently developed combinatorial libraries to drugs, Molecular Libraries Small Molecule Repository (MLSMR) and natural products. The compound databases were assessed in terms of physicochemical properties, scaffolds and fingerprints. The approach enables the analysis of property space coverage, degree of overlap between collections, scaffold and structural diversity and overall structural novelty...

  16. Identification of a hexapeptide inhibitor of the human immunodeficiency virus integrase protein by using a combinatorial chemical library.

    OpenAIRE

    Puras Lutzke, R A; Eppens, N A; Weber, P A; Houghten, R A; Plasterk, R H

    1995-01-01

    Integration of human immunodeficiency virus (HIV) DNA into the human genome requires the virus-encoded integrase (IN) protein, and therefore the IN protein is a suitable target for antiviral strategies. To find a potent HIV IN inhibitor, we screened a "synthetic peptide combinatorial library." We identified a hexapeptide with the sequence HCKFWW that inhibits IN-mediated 3'-processing and integration with an IC50 of 2 microM. The peptide is active on IN proteins from other retroviruses such a...

  17. Simultaneous Disulfide and Boronic Acid Ester Exchange in Dynamic Combinatorial Libraries

    Directory of Open Access Journals (Sweden)

    Sanna L. Diemer

    2015-09-01

    Full Text Available Dynamic combinatorial chemistry has emerged as a promising tool for the discovery of complex receptors in supramolecular chemistry. At the heart of dynamic combinatorial chemistry are the reversible reactions that enable the exchange of building blocks between library members in dynamic combinatorial libraries (DCLs ensuring thermodynamic control over the system. If more than one reversible reaction operates in a single dynamic combinatorial library, the complexity of the system increases dramatically, and so does its possible applications. One can imagine two reversible reactions that operate simultaneously or two reversible reactions that operate independently. Both these scenarios have advantages and disadvantages. In this contribution, we show how disulfide exchange and boronic ester transesterification can function simultaneous in dynamic combinatorial libraries under appropriate conditions. We describe the detailed studies necessary to establish suitable reaction conditions and highlight the analytical techniques appropriate to study this type of system.

  18. Replacing reprogramming factors with antibodies selected from combinatorial antibody libraries.

    Science.gov (United States)

    Blanchard, Joel W; Xie, Jia; El-Mecharrafie, Nadja; Gross, Simon; Lee, Sohyon; Lerner, Richard A; Baldwin, Kristin K

    2017-10-01

    The reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) is usually achieved by exogenous induction of transcription by factors acting in the nucleus. In contrast, during development, signaling pathways initiated at the membrane induce differentiation. The central idea of this study is to identify antibodies that can catalyze cellular de-differentiation and nuclear reprogramming by acting at the cell surface. We screen a lentiviral library encoding ∼100 million secreted and membrane-bound single-chain antibodies and identify antibodies that can replace either Sox2 and Myc (c-Myc) or Oct4 during reprogramming of mouse embryonic fibroblasts into iPSCs. We show that one Sox2-replacing antibody antagonizes the membrane-associated protein Basp1, thereby de-repressing nuclear factors WT1, Esrrb and Lin28a (Lin28) independent of Sox2. By manipulating this pathway, we identify three methods to generate iPSCs. Our results establish unbiased selection from autocrine combinatorial antibody libraries as a robust method to discover new biologics and uncover membrane-to-nucleus signaling pathways that regulate pluripotency and cell fate.

  19. Simultaneous Disulfide and Boronic Acid Ester Exchange in Dynamic Combinatorial Libraries

    DEFF Research Database (Denmark)

    Diemer, Sanna L.; Kristensen, Morten; Rasmussen, Brian

    2015-01-01

    combinatorial libraries (DCLs) ensuring thermodynamic control over the system. If more than one reversible reaction operates in a single dynamic combinatorial library, the complexity of the system increases dramatically, and so does its possible applications. One can imagine two reversible reactions...... that operate simultaneously or two reversible reactions that operate independently. Both these scenarios have advantages and disadvantages. In this contribution, we show how disulfide exchange and boronic ester transesterification can function simultaneous in dynamic combinatorial libraries under appropriate...... conditions. We describe the detailed studies necessary to establish suitable reaction conditions and highlight the analytical techniques appropriate to study this type of system....

  20. Intracellular directed evolution of proteins from combinatorial libraries based on conditional phage replication.

    Science.gov (United States)

    Brödel, Andreas K; Jaramillo, Alfonso; Isalan, Mark

    2017-09-01

    Directed evolution is a powerful tool to improve the characteristics of biomolecules. Here we present a protocol for the intracellular evolution of proteins with distinct differences and advantages in comparison with established techniques. These include the ability to select for a particular function from a library of protein variants inside cells, minimizing undesired coevolution and propagation of nonfunctional library members, as well as allowing positive and negative selection logics using basally active promoters. A typical evolution experiment comprises the following stages: (i) preparation of a combinatorial M13 phagemid (PM) library expressing variants of the gene of interest (GOI) and preparation of the Escherichia coli host cells; (ii) multiple rounds of an intracellular selection process toward a desired activity; and (iii) the characterization of the evolved target proteins. The system has been developed for the selection of new orthogonal transcription factors (TFs) but is capable of evolving any gene-or gene circuit function-that can be linked to conditional M13 phage replication. Here we demonstrate our approach using as an example the directed evolution of the bacteriophage λ cI TF against two synthetic bidirectional promoters. The evolved TF variants enable simultaneous activation and repression against their engineered promoters and do not cross-react with the wild-type promoter, thus ensuring orthogonality. This protocol requires no special equipment, allowing synthetic biologists and general users to evolve improved biomolecules within ∼7 weeks.

  1. Identification of SNARE complex modulators that inhibit exocytosis from an alpha-helix-constrained combinatorial library.

    Science.gov (United States)

    Blanes-Mira, Clara; Pastor, Maria T; Valera, Elvira; Fernández-Ballester, Gregorio; Merino, Jaime M; Gutierrez, Luis M; Perez-Payá, Enrique; Ferrer-Montiel, Antonio

    2003-01-01

    Synthetic peptides patterned after the proteins involved in vesicle fusion [the so-called SNARE (soluble N -ethylmaleimide-sensitive fusion protein attachment protein receptor) proteins] are potent inhibitors of SNARE complex assembly and neuronal exocytosis. It is noteworthy that the identification of peptide sequences not related to the SNARE proteins has not been accomplished yet; this is due, in part, to the structural constraints and the specificity of the protein interactions that govern the formation of the SNARE complex. Here we have addressed this question and used a combinatorial approach to identify peptides that modulate the assembly of the SNARE core complex and inhibit neuronal exocytosis. An alpha-helix-constrained, mixture-based, 17-mer combinatorial peptide library composed of 137180 sequences was synthesized in a positional scanning format. Peptide mixtures were assayed for their ability to prevent the formation of the in vitro -reconstituted SDS-resistant SNARE core complex. Library deconvolution identified eight peptides that inhibited the assembly of the SNARE core complex. Notably, the most potent 17-mer peptide (acetyl-SAAEAFAKLYAEAFAKG-NH2) abolished both Ca2+-evoked catecholamine secretion from detergent-permeabilized chromaffin cells and L-glutamate release from intact hippocampal primary cultures. Collectively, these findings indicate that amino acid sequences that prevent SNARE complex formation are not restricted to those that mimic domains of SNARE proteins, thus expanding the diversity of molecules that target neuronal exocytosis. Because of the implication of neurosecretion in the aetiology of several human neurological disorders, these newly identified peptides may be considered hits for the development of novel anti-spasmodic drugs. PMID:12852787

  2. Evaluating the Effect of Peptoid Lipophilicity on Antimicrobial Potency, Cytotoxicity, and Combinatorial Library Design.

    Science.gov (United States)

    Turkett, Jeremy A; Bicker, Kevin L

    2017-04-10

    Growing prevalence of antibiotic resistant bacterial infections necessitates novel antimicrobials, which could be rapidly identified from combinatorial libraries. We report the use of the peptoid library agar diffusion (PLAD) assay to screen peptoid libraries against the ESKAPE pathogens, including the optimization of assay conditions for each pathogen. Work presented here focuses on the tailoring of combinatorial peptoid library design through a detailed study of how peptoid lipophilicity relates to antibacterial potency and mammalian cell toxicity. The information gleaned from this optimization was then applied using the aforementioned screening method to examine the relative potency of peptoid libraries against Staphylococcus aureus, Acinetobacter baumannii, and Enterococcus faecalis prior to and following functionalization with long alkyl tails. The data indicate that overall peptoid hydrophobicity and not simply alkyl tail length is strongly correlated with mammalian cell toxicity. Furthermore, this work demonstrates the utility of the PLAD assay in rapidly evaluating the effect of molecular property changes in similar libraries.

  3. Design and spectroscopic reflectometry characterization of pulsed laser deposition combinatorial libraries

    International Nuclear Information System (INIS)

    Schenck, Peter K.; Bassim, Nabil D.; Otani, Makoto; Oguchi, Hiroyuki; Green, Martin L.

    2007-01-01

    The goal of the design of pulsed laser deposition (PLD) combinatorial library films is to optimize the compositional coverage of the films while maintaining a uniform thickness. The deposition pattern of excimer laser PLD films can be modeled with a bimodal cos n distribution. Deposited films were characterized using a spectroscopic reflectometer (250-1000 nm) to map the thickness of both single composition calibration films and combinatorial library films. These distribution functions were used to simulate the composition and thickness of multiple target combinatorial library films. The simulations were correlated with electron-probe microanalysis wavelength-dispersive spectroscopy (EPMA-WDS) composition maps. The composition and thickness of the library films can be fine-tuned by adjusting the laser spot size, fluence, background gas pressure, target geometry and other processing parameters which affect the deposition pattern. Results from compositionally graded combinatorial library films of the ternary system Al 2 O 3 -HfO 2 -Y 2 O 3 are discussed

  4. Combinatorial bulk ceramic magnetoelectric composite libraries of strontium hexaferrite and barium titanate.

    Science.gov (United States)

    Pullar, Robert C

    2012-07-09

    Bulk ceramic combinatorial libraries were produced via a novel, high-throughput (HT) process, in the form of polycrystalline strips with a gradient composition along the length of the library. Step gradient ceramic composite libraries with 10 mol % steps of SrFe12O19-BaTiO3 (SrM-BT) were made and characterized using HT methods, as a proof of principle of the combinatorial bulk ceramic process, and sintered via HT thermal processing. It was found that the SrM-BT libraries sintered at 1175 °C had the optimum morphology and density. The compositional, electrical and magnetic properties of this library were analyzed, and it was found that the SrM and BT phases did not react and remained discrete. The combinatorial synthesis method produced a relatively linear variation in composition. The magnetization of the library followed the measured compositions very well, as did the low frequency permittivity values of most compositions in the library. However, with high SrM content of ≥80 mol %, the samples became increasingly conductive, and no reliable dielectric measurements could be made. Such conductivity would also greatly inhibit any ferroelectricity and magnetoelectric coupling with these composites with high levels of the SrM hexagonal ferrite.

  5. Solid-phase synthesis and biological evaluation of a combinatorial library of philanthotoxin analogues

    DEFF Research Database (Denmark)

    Strømgaard, K; Brier, T J; Andersen, K

    2000-01-01

    The modular structure of philanthotoxins was exploited for construction of the first combinatorial library of these compounds using solid-phase parallel synthesis. (S)-Tyrosine and (S)-3-hydroxyphenylalanine were used as amino acid components, spermine, 1,12-dodecanediamine, and 4,9-dioxa-1,12-do...

  6. Automation in the high-throughput selection of random combinatorial libraries--different approaches for select applications.

    Science.gov (United States)

    Glökler, Jörn; Schütze, Tatjana; Konthur, Zoltán

    2010-04-08

    Automation in combination with high throughput screening methods has revolutionised molecular biology in the last two decades. Today, many combinatorial libraries as well as several systems for automation are available. Depending on scope, budget and time, a different combination of library and experimental handling might be most effective. In this review we will discuss several concepts of combinatorial libraries and provide information as what to expect from these depending on the given context.

  7. Combinatorial chemistry

    DEFF Research Database (Denmark)

    Nielsen, John

    1994-01-01

    An overview of combinatorial chemistry is presented. Combinatorial chemistry, sometimes referred to as `irrational drug design,' involves the generation of molecular diversity. The resulting chemical library is then screened for biologically active compounds.......An overview of combinatorial chemistry is presented. Combinatorial chemistry, sometimes referred to as `irrational drug design,' involves the generation of molecular diversity. The resulting chemical library is then screened for biologically active compounds....

  8. Dynamic combinatorial chemistry with hydrazones: cholate-based building blocks and libraries.

    Science.gov (United States)

    Simpson, Mark G; Pittelkow, Michael; Watson, Stephen P; Sanders, Jeremy K M

    2010-03-07

    We describe an efficient and general strategy for the synthesis of dimethyl acetal functionalised steroidal hydrazides based on the cholic acid skeleton with the aim of using these compounds as building blocks for dynamic combinatorial chemistry. Deprotection of the acetal protected building blocks with TFA leads to formation of libraries containing macrocyclic N-acyl hydrazone oligomers. The isolation of several of these, and their characterisation using NMR is described. The effects on the equilibrium library distribution by varying the substituents at C-7 and C-12, extending the side-chain with glycine, and inverting the configuration at C-3 are discussed. Finally, we report the exchange properties of these macrocycles and demonstrate new examples of proof-reading and self-sorting in dynamic combinatorial libraries.

  9. A Rapid Python-Based Methodology for Target-Focused Combinatorial Library Design.

    Science.gov (United States)

    Li, Shiliang; Song, Yuwei; Liu, Xiaofeng; Li, Honglin

    2016-01-01

    The chemical space is so vast that only a small portion of it has been examined. As a complementary approach to systematically probe the chemical space, virtual combinatorial library design has extended enormous impacts on generating novel and diverse structures for drug discovery. Despite the favorable contributions, high attrition rates in drug development that mainly resulted from lack of efficacy and side effects make it increasingly challenging to discover good chemical starting points. In most cases, focused libraries, which are restricted to particular regions of the chemical space, are deftly exploited to maximize hit rate and improve efficiency at the beginning of the drug discovery and drug development pipeline. This paper presented a valid methodology for fast target-focused combinatorial library design in both reaction-based and production-based ways with the library creating rates of approximately 70,000 molecules per second. Simple, quick and convenient operating procedures are the specific features of the method. SHAFTS, a hybrid 3D similarity calculation software, was embedded to help refine the size of the libraries and improve hit rates. Two target-focused (p38-focused and COX2-focused) libraries were constructed efficiently in this study. This rapid library enumeration method is portable and applicable to any other targets for good chemical starting points identification collaborated with either structure-based or ligand-based virtual screening.

  10. Enthalpy-Based Screening of Focused Combinatorial Libraries for the Identification of Potent and Selective Ligands.

    Science.gov (United States)

    Baggio, Carlo; Udompholkul, Parima; Barile, Elisa; Pellecchia, Maurizio

    2017-12-15

    In modern drug discovery, the ability of biophysical methods, including nuclear magnetic resonance spectroscopy or surface plasmon resonance, to detect and characterize ligand-protein interactions accurately and unambiguously makes these approaches preferred versus conventional biochemical high-throughput screening of large collections of compounds. Nonetheless, ligand screening strategies that address simultaneously potency and selectivity have not yet been fully developed. In this work, we propose a novel method for screening large collections of combinatorial libraries using enthalpy measurements as a primary screening technique. We demonstrate that selecting binders that are driven by enthalpy (ΔH) results in agents that are not only potent but also more selective for a given target. This general and novel approach, we termed ΔH screening of fPOS (enthalpy screening of focused positional scanning library), combines the principles of focused combinatorial chemistry with rapid calorimetry measurements to efficiently identify potent and selective inhibitors.

  11. Beating Bias in the Directed Evolution of Proteins: Combining High-Fidelity on-Chip Solid-Phase Gene Synthesis with Efficient Gene Assembly for Combinatorial Library Construction.

    Science.gov (United States)

    Li, Aitao; Acevedo-Rocha, Carlos G; Sun, Zhoutong; Cox, Tony; Xu, Jia Lucy; Reetz, Manfred T

    2018-02-02

    Saturation mutagenesis (SM) constitutes a widely used technique in the directed evolution of selective enzymes as catalysts in organic chemistry and in the manipulation of metabolic paths and genomes, but the quality of the libraries is far from optimal due to the inherent amino acid bias. Herein, it is shown how this fundamental problem can be solved by applying high-fidelity solid-phase chemical gene synthesis on silicon chips followed by efficient gene assembly. Limonene epoxide hydrolase was chosen as the catalyst in the model desymmetrization of cyclohexene oxide with the stereoselective formation of (R,R)- and (S,S)-cyclohexane-1,2-diol. A traditional combinatorial PCR-based SM library, produced by simultaneous randomization at several residues by using a reduced amino acid alphabet, and the respective synthetic library were constructed and compared. Statistical analysis at the DNA level with massive sequencing demonstrates that, in the synthetic approach, 97 % of the theoretically possible DNA mutants are formed, whereas the traditional SM library contained only about 50 %. Screening at the protein level also showed the superiority of the synthetic library; many highly (R,R)- and (S,S)-selective variants being discovered are not found in the traditional SM library. With the prices of synthetic genes decreasing, this approach may point the way to future directed evolution. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Immunoassays: biological tools for high throughput screening and characterisation of combinatorial libraries.

    Science.gov (United States)

    Taipa, M Angela

    2008-05-01

    In the demanding field of proteomics, there is an urgent need for affinity-catcher molecules to implement effective and high throughput methods for analysing the human proteome or parts of it. Antibodies have an essential role in this endeavour, and selection, isolation and characterisation of specific antibodies represent a key issue to meet success. Alternatively, it is expected that new, well-characterised affinity reagents generated in rapid and cost-effective manners will also be used to facilitate the deciphering of the function, location and interactions of the high number of encoded protein products. Combinatorial approaches combined with high throughput screening (HTS) technologies have become essential for the generation and identification of robust affinity reagents from biological combinatorial libraries and the lead discovery of active/mimic molecules in large chemical libraries. Phage and yeast display provide the means for engineering a multitude of antibody-like molecules against any desired antigen. The construction of peptide libraries is commonly used for the identification and characterisation of ligand-receptor specific interactions, and the search for novel ligands for protein purification. Further improvement of chemical and biological resistance of affinity ligands encouraged the "intelligent" design and synthesis of chemical libraries of low-molecular-weight bio-inspired mimic compounds. No matter what the ligand source, selection and characterisation of leads is a most relevant task. Immunological assays, in microtiter plates, biosensors or microarrays, are a biological tool of inestimable value for the iterative screening of combinatorial ligand libraries for tailored specificities, and improved affinities. Particularly, enzyme-linked immunosorbent assays are frequently the method of choice in a large number of screening strategies, for both biological and chemical libraries.

  13. Discovery of potent inhibitors of human β-tryptase from pre-equilibrated dynamic combinatorial libraries.

    Science.gov (United States)

    Jiang, Qian-Qian; Sicking, Wilhelm; Ehlers, Martin; Schmuck, Carsten

    2015-03-01

    Pre-equilibrated dynamic combinatorial libraries based on acyl hydrazone interchange of peptide-derived hydrazides and di- and tri-aldehydes have been used to discover potent inhibitors with nanomolar affinities for β-tryptase. To identify potent inhibitors the activity of the full library containing 95 members was compared with those of sub-libraries in which individual building blocks were missing. The most active library members contain a rigid central aromatic scaffold with three cationic peptide arms. The arms of the best inhibitors also contained a tailor-made GCP oxoanion binding motif attached to a lysine side chain. The most potent tri-armed hydrazones with peptide arms GKWR or GKWK(GCP) were shown to inhibit β-tryptase ( K i ca. 10-20 nM) reversibly, non-competitively and selectively (compared to related serine proteases, e.g. trypsin and chymotrypsin), most likely by binding to the protein surface, also in agreement with molecular modelling calculations. These new inhibitors are one order of magnitude more efficient than related tetravalent inhibitors obtained from previous work on a split-mix-combinatorial library and were identified with significantly less effort, demonstrating the usefulness of this approach for the identification of enzyme inhibitors in general.

  14. A new method for the screening of solid-phase combinatorial libraries for affinity chromatography.

    Science.gov (United States)

    Roque, A Cecília A; Taipa, M Angela; Lowe, Christopher R

    2004-01-01

    A new methodology for the rapid assessment of affinity ligands synthesized by combinatorial solid-phase chemistry is reported. This screening strategy utilizes the target protein conjugated to FITC, and represents an almost universal technique for the preliminary screening of solid-phase combinatorial libraries. The assessment of a triazine-scaffolded solid-phase combinatorial library of ligands, designed to bind to human IgG, was performed with FITC-human IgG, and the results compared with those obtained by conventional affinity chromatographic screening assays. The effect of different molar conjugation ratios of FITC-IgG (F/P) was evaluated. Independently of the F/P ratio, no false negative results were observed, although lower F/P ratios diminished non-specific interactions and the number of false positives. The nature of the substituents on the triazine scaffold was not related to the number of false positive IgG-binding ligands. The reproducibility of the FITC technique, using FITC-human IgG conjugates with low F/P ratio (F/P=2), was also evaluated. The FITC-based technique proved to be efficient and accurate in the identification of strongly binding ligands (binding >50% of loaded protein, by standard affinity chromatographic assays), and is envisaged as a versatile and cost-effective method to screen other systems, and evaluate several binding/elution conditions at small-scale, prior to scale-up to standard affinity chromatography. Copyright 2004 John Wiley & Sons, Ltd.

  15. A synthetic combinatorial strategy for developing a-conotoxin analogs as potent a7 nicotinic acetylcholine receptor antagonists

    DEFF Research Database (Denmark)

    Armishaw, Christopher J; Singh, Narender; Medina-Franco, Jose L

    2010-01-01

    ) nAChR Fluo-4/Ca2+ assay, allowing amino acids that confer antagonistic activity for this receptor to be identified. A second series of individual alpha-conotoxin analogs based on the combinations of defined active amino acid residues from positional scan synthetic combinatorial library screening...... of an acetylcholine-binding protein. Finally, a third series of refined analogs was synthesized based on modeling studies, which led to several analogs with refined pharmacological properties. Of the 96 individual alpha-conotoxin analogs synthesized, three displayed > or =10-fold increases in antagonist potency...

  16. Identification of osteoconductive and biodegradable polymers from a combinatorial polymer library.

    Science.gov (United States)

    Brey, Darren M; Chung, Cindy; Hankenson, Kurt D; Garino, Jonathon P; Burdick, Jason A

    2010-05-01

    Combinatorial polymer syntheses are now being utilized to create libraries of materials with potential utility for a wide variety of biomedical applications. We recently developed a library of photopolymerizable and biodegradable poly(beta-amino ester)s (PBAEs) that possess a range of tunable properties. In this study, the PBAE library was assessed for candidate materials that met design criteria (e.g., physical properties such as degradation and mechanical strength and in vitro cell viability and osteoconductive behavior) for scaffolding in mineralized tissue repair. The most promising candidate, A6, was then processed into three-dimensional porous scaffolds and implanted subcutaneously and only presented a mild inflammatory response. The scaffolds were then implanted intramuscularly and into a critical-sized cranial defect either alone or loaded with bone morphogenetic protein-2 (BMP-2). The samples in both locations displayed mineralized tissue formation in the presence of BMP-2, as evident through radiographs, micro-computed tomography, and histology, whereas samples without BMP-2 showed minimal or no mineralized tissue. These results illustrate a process to identify a candidate scaffolding material from a combinatorial polymer library, and specifically for the identification of an osteoconductive scaffold with osteoinductive properties via the inclusion of a growth factor. Copyright 2009 Wiley Periodicals, Inc.

  17. Affinity-based screening of combinatorial libraries using automated, serial-column chromatography

    Energy Technology Data Exchange (ETDEWEB)

    Evans, D.M.; Williams, K.P.; McGuinness, B. [PerSeptive Biosystems, Framingham, MA (United States)] [and others

    1996-04-01

    The authors have developed an automated serial chromatographic technique for screening a library of compounds based upon their relative affinity for a target molecule. A {open_quotes}target{close_quotes} column containing the immobilized target molecule is set in tandem with a reversed-phase column. A combinatorial peptide library is injected onto the target column. The target-bound peptides are eluted from the first column and transferred automatically to the reversed-phase column. The target-specific peptide peaks from the reversed-phase column are identified and sequenced. Using a monoclonal antibody (3E-7) against {beta}-endorphin as a target, we selected a single peptide with sequence YGGFL from approximately 5800 peptides present in a combinatorial library. We demonstrated the applicability of the technology towards selection of peptides with predetermined affinity for bacterial lipopolysaccharide (LPS, endotoxin). We expect that this technology will have broad applications for high throughput screening of chemical libraries or natural product extracts. 21 refs., 4 figs.

  18. Engineering of Immunoglobulin Fc Heterodimers Using Yeast Surface-Displayed Combinatorial Fc Library Screening.

    Directory of Open Access Journals (Sweden)

    Hye-Ji Choi

    Full Text Available Immunoglobulin Fc heterodimers, which are useful scaffolds for the generation of bispecific antibodies, have been mostly generated through structure-based rational design methods that introduce asymmetric mutations into the CH3 homodimeric interface to favor heterodimeric Fc formation. Here, we report an approach to generate heterodimeric Fc variants through directed evolution combined with yeast surface display. We developed a combinatorial heterodimeric Fc library display system by mating two haploid yeast cell lines, one haploid cell line displayed an Fc chain library (displayed FcCH3A with mutations in one CH3 domain (CH3A on the yeast cell surface, and the other cell line secreted an Fc chain library (secreted FcCH3B with mutations in the other CH3 domain (CH3B. In the mated cells, secreted FcCH3B is displayed on the cell surface through heterodimerization with the displayed FcCH3A, the detection of which enabled us to screen the library for heterodimeric Fc variants. We constructed combinatorial heterodimeric Fc libraries with simultaneous mutations in the homodimer-favoring electrostatic interaction pairs K370-E357/S364 or D399-K392/K409 at the CH3 domain interface. High-throughput screening of the libraries using flow cytometry yielded heterodimeric Fc variants with heterodimer-favoring CH3 domain interface mutation pairs, some of them showed high heterodimerization yields (~80-90% with previously unidentified CH3 domain interface mutation pairs, such as hydrogen bonds and cation-π interactions. Our study provides a new approach for engineering Fc heterodimers that could be used to engineer other heterodimeric protein-protein interactions through directed evolution combined with yeast surface display.

  19. Automating gene library synthesis by structure-based combinatorial protein engineering: examples from plant sesquiterpene synthases.

    Science.gov (United States)

    Dokarry, Melissa; Laurendon, Caroline; O'Maille, Paul E

    2012-01-01

    Structure-based combinatorial protein engineering (SCOPE) is a homology-independent recombination method to create multiple crossover gene libraries by assembling defined combinations of structural elements ranging from single mutations to domains of protein structure. SCOPE was originally inspired by DNA shuffling, which mimics recombination during meiosis, where mutations from parental genes are "shuffled" to create novel combinations in the resulting progeny. DNA shuffling utilizes sequence identity between parental genes to mediate template-switching events (the annealing and extension of one parental gene fragment on another) in PCR reassembly reactions to generate crossovers and hence recombination between parental genes. In light of the conservation of protein structure and degeneracy of sequence, SCOPE was developed to enable the "shuffling" of distantly related genes with no requirement for sequence identity. The central principle involves the use of oligonucleotides to encode for crossover regions to choreograph template-switching events during PCR assembly of gene fragments to create chimeric genes. This approach was initially developed to create libraries of hybrid DNA polymerases from distantly related parents, and later developed to create a combinatorial mutant library of sesquiterpene synthases to explore the catalytic landscapes underlying the functional divergence of related enzymes. This chapter presents a simplified protocol of SCOPE that can be integrated with different mutagenesis techniques and is suitable for automation by liquid-handling robots. Two examples are presented to illustrate the application of SCOPE to create gene libraries using plant sesquiterpene synthases as the model system. In the first example, we outline how to create an active-site library as a series of complex mixtures of diverse mutants. In the second example, we outline how to create a focused library as an array of individual clones to distil minimal combinations of

  20. WORKSHOP ON NEW DEVELOPMENTS IN CHEMICAL SEPARATIONS FROM COMBINATORIAL CHEMISTRY AND RELATED SYNTHETIC STRATEGIES

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Stephen G. [University of Pittsburgh, Pittsburgh, Pennsylvania

    1998-08-22

    The power of combinatorial chemistry and related high throughput synthetic strategies is currently being pursued as a fruitful way to develop molecules and materials with new properties. The strategy is motivated, for example in the pharmaceutical industry, by the difficulty of designing molecules to bind to specific sites on target biomolecules. By synthesizing a variety of similar structures, and then finding the one that has the most potent activity, new so-called lead structures will be found rapidly. Existing lead structures can be optimized. This relatively new approach has many implications for separation science. The most obvious is the call for more separations power: higher resolution, lower concentrations, higher speed. This pressure butresses the traditional directions of research into the development of more useful separations. The advent of chip-based, electroosmotically pumped systems1 will certainly accelerate progress in this traditional direction. The progress in combinatorial chemistry and related synthetic strategies gives rise to two other, broadly significant possibilities for large changes in separation science. One possibility results from the unique requirements of the synthesis of a huge number of products simultaneously. Can syntheses and separations be designed to work together to create strategies that lead to mixtures containing only desired products but without side products? The other possibility results from the need for molecular selectivity in separations. Can combinatorial syntheses and related strategies be used in the development of better separations media? A workshop in two parts was held. In one half-day session, pedagogical presentations educated across the barriers of discipline and scale. In the second half-day session, the participants broke into small groups to flesh out new ideas. A panel summarized the breakout discussions.

  1. Combinatorial Libraries on Rigid Scaffolds: Solid Phase Synthesis of Variably Substituted Pyrazoles and Isoxazoles

    Directory of Open Access Journals (Sweden)

    Eduard R. Felder

    1997-01-01

    Full Text Available The synthesis of combinatorial compound libraries has become a powerful lead finding tool in modern drug discovery. The ability to synthesize rapidly, in high yield, new chemical entities with low molecular weight on a solid support has a recognized strategic relevance (“small molecule libraries”. We designed and validated a novel solid phase synthesis scheme, suitable to generate diversity on small heterocycles of the pyrazole and isoxazole type. Appropriate conditions were worked out for each reaction, and a variety of more or less reactive agents (building blocks was utilized for discrete conversions, in order to exploit the system’s breadth of applicability. Four sequential reaction steps were validated, including the loading of the support with an acetyl bearing moiety, a Claisen condensation, an a-alkylation and a cyclization of a b-diketone with monosubstituted hydrazines. In a second stage, the reaction sequence was applied in a split and mix approach, in order to prepare a combinatorial library built-up from 4 acetyl carboxylic acids (R1, 35 carboxylic esters (R2 and 41 hydrazines (R4 (and 1 hydroxylamine to yield a total of 11,760 compounds divided into 41 pyrazole sublibraries with 140 pairs of regioisomers and 1 isoxazole sublibrary of equal size.

  2. A combinatorial approach to synthetic transcription factor-promoter combinations for yeast strain engineering

    DEFF Research Database (Denmark)

    Dossani, Zain Y.; Apel, Amanda Reider; Szmidt-Middleton, Heather

    2018-01-01

    . Correspondingly, the synthetic transcription factor (TF) consists of the DNA binding domain of the LexA protein, fused with the human estrogen binding domain and the viral activator domain, VP16. The resulting system with a bacterial DNA binding domain avoids the transcription of native S. cerevisiae genes...... regions, we have built a library of hybrid promoters that are regulated by a synthetic transcription factor. The hybrid promoters consist of native S. cerevisiae promoters, in which the operator regions have been replaced with sequences that are recognized by the bacterial LexA DNA binding protein...... levels, using the same synthetic TF and a given estradiol. This set of promoters, in combination with our synthetic TF, has the potential to regulate numerous genes or pathways simultaneously, to multiple desired levels, in a single strain....

  3. High Affinity, Developability and Functional Size: The Holy Grail of Combinatorial Antibody Library Generation

    Directory of Open Access Journals (Sweden)

    Kathrin Tissot

    2011-05-01

    Full Text Available Since the initial description of phage display technology for the generation of human antibodies, a variety of selection methods has been developed. The most critical parameter for all in vitro-based approaches is the quality of the antibody library. Concurrent evolution of the libraries has allowed display and selection technologies to reveal their full potential. They come in different flavors, from naïve to fully synthetic and differ in terms of size, quality, method of preparation, framework and CDR composition. Early on, the focus has mainly been on affinities and thus on library size and diversity. Subsequently, the increased awareness of developability and cost of goods as important success factors has spurred efforts to generate libraries with improved biophysical properties and favorable production characteristics. More recently a major focus on reduction of unwanted side effects through reduced immunogenicity and improved overall biophysical behavior has led to a re-evaluation of library design.

  4. Cosmix-plexing: a novel recombinatorial approach for evolutionary selection from combinatorial libraries.

    Science.gov (United States)

    Collins, J; Horn, N; Wadenbäck, J; Szardenings, M

    2001-06-01

    The efficiency of existing combinatorial biological library methods has been moderate in terms of the success rates, the affinities of the ligands selected and the time and effort involved in trying to optimize the initial leads. Although mimicking natural evolution, existing strategies take little notice of the importance of recombination within a selected population to generate increased diversity. We present an overview of our recent progress which has resulted in the successful development of such a strategy, which we designate cosmix-plexing. We incorporate recombination as a central feature in obtaining high success rates and high affinities, even for short monomer peptides, in a very short time. The method uses type II restriction enzymes to re-assort small hypervariable DNA cassettes from an intermediate pre-selected population (e.g. from a phagemid display library), while maintaining the original open-reading frame. Since, in the naive library, each cassette contains all possible combinations of the polypeptide sequences it encodes, much longer regions can be optimized than was possible with methods which depend on a simple selection from the naive library. Short peptides can now be rapidly selected, which exhibit the same, or higher, specificity and affinity for a defined target molecule, than (say) an antibody or even the natural ligand.

  5. Combinatorial library of five-membered iminocyclitol and the inhibitory activities against glyco-enzymes.

    Science.gov (United States)

    Saotome, C; Wong, C H; Kanie, O

    2001-11-01

    Oligosaccharide processing enzymes are important classes of catalysts involved in synthesizing specific oligosaccharide structures on proteins and sphingolipids. Development of specific inhibitors of such enzymes is of current interest as these inhibitors may be used to control cellular functions. Five-membered iminocyclitols have been shown to be potent inhibitors of such enzymes. Since a rational design and synthesis of inhibitors is often extremely difficult due to the limited information regarding the structure of the active site, we carried out a combinatorial library approach. To create diversity, we decided to use an aldehyde group of a protected iminocyclitol for reductive amination and the Strecker reaction. After transformation of the nitrile group introduced by the Strecker reaction into an amine and amide and complete deprotection, a small library of five-membered iminocyclitols consisting of 27 compounds was synthesized. A series of compounds obtained by reductive amination was first screened as potential inhibitors of glycosidases and glycosyltransferases. Among them, compounds carrying a C(10)-alkyl group showed marked enhancement of inhibitory activity against alpha-mannosidase at 10 microM concentration when compared with its parent compound and deoxymannojirimycin. Furthermore, compounds having the phenylethyl group showed an extremely strong inhibitory effect against alpha-galactosaminidase at a K(i) value of 29.4 nM. Compounds with an aminomethyl and amide group at the C-1' position of these two molecules showed a decrease in inhibitory activities. A combinatorial approach based on five-membered iminocyclitols with a galacto-configuration was exploited. The potential usefulness of the library as a source of inhibitors of glycoenzymes is clearly shown in this study.

  6. Isolation of Osteosarcoma-Associated Human Antibodies from a Combinatorial Fab Phage Display Library

    Directory of Open Access Journals (Sweden)

    Carmela Dantas-Barbosa

    2009-01-01

    Full Text Available Osteosarcoma, a highly malignant disease, is the most common primary bone tumor and is frequently found in children and adolescents. In order to isolate antibodies against osteosarcoma antigens, a combinatorial osteosarcoma Fab library displayed on the surface of phages was used. After three rounds of selection on the surface of tumor cells, several osteosarcoma-reactive Fabs were detected. From these Fabs, five were better characterized, and despite having differences in their VH (heavy chain variable domain and Vκ (kappa chain variable domain regions, they all bound to a protein with the same molecular mass. Further analysis by cell ELISA and immunocytochemistry suggested that the Fabs recognize a membrane-associated tumor antigen expressed in higher amounts in neoplasic cells than in normal tissue. These results suggest that the human Fabs selected in this work are a valuable tool for the study of this neoplasia.

  7. Combinatorial hexapeptide ligand libraries (ProteoMiner): an innovative fractionation tool for differential quantitative clinical proteomics.

    Science.gov (United States)

    Hartwig, Sonja; Czibere, Akos; Kotzka, Jorg; Passlack, Waltraud; Haas, Rainer; Eckel, Jürgen; Lehr, Stefan

    2009-07-01

    Blood serum samples are the major source for clinical proteomics approaches, which aim to identify diagnostically relevant or treatment-response related proteins. But, the presence of very high-abundance proteins and the enormous dynamic range of protein distribution hinders whole serum analysis. An innovative tool to overcome these limitations, utilizes combinatorial hexapeptide ligand libraries (ProteoMiner). Here, we demonstrate that ProteoMiner can be used for comparative and quantitative analysis of complex proteomes. We spiked serum samples with increasing amounts (3 microg to 300 microg) of whole E. coli lysate, processed it with ProteoMiner and performed quantitative analyses of 2D-gels. We found, that the concentration of the spiked bacteria proteome, reflected by the maintained proportional spot intensities, was not altered by ProteoMiner treatment. Therefore, we conclude that the ProteoMiner technology can be used for quantitative analysis of low abundant proteins in complex biological samples.

  8. Virtual screening of combinatorial library of novel benzenesulfonamides on mycobacterial carbonic anhydrase II

    Directory of Open Access Journals (Sweden)

    Dikant F.

    2016-12-01

    Full Text Available Combinatorial library of novel benzenesulfonamides was docked (Schrodinger Glide into mycobacterial carbonic anhydrase (mtCA II and human (hCA II isoforms with an aim to find drug candidates with selective activity on mtCA II. The predicted selectivity was calculated based on optimized MM-GBSA free energies for ligand enzyme interactions. Selectivity, LogP (o/w and interaction energy were used to calculate the selection index which determined the subset of best scoring molecules selected for further evaluation. Structure-activity relationship was found for fragment subsets, showing us the possible way regarding how to influence lipophilicity without affecting ligand-enzyme binding properties.

  9. Synthetic promoter libraries- tuning of gene expression

    DEFF Research Database (Denmark)

    Hammer, Karin; Mijakovic, Ivan; Jensen, Peter Ruhdal

    2006-01-01

    The study of gene function often requires changing the expression of a gene and evaluating the consequences. In principle, the expression of any given gene can be modulated in a quasi-continuum of discrete expression levels but the traditional approaches are usually limited to two extremes: gene...... be met by using promoter libraries. This approach generally consists of inserting a library of promoters in front of the gene to be studied, whereby the individual promoters might deviate either in their spacer sequences or bear slight deviations from the consensus sequence of a vegetative promoter. Here......, we describe the two different methods for obtaining promoter libraries and compare their applicability....

  10. Protein biomarkers for early detection of diseases: The decisive contribution of combinatorial peptide ligand libraries.

    Science.gov (United States)

    Boschetti, Egisto; D'Amato, Alfonsina; Candiano, Giovanni; Righetti, Pier Giorgio

    2017-09-04

    The present review deals with biomarker discovery, especially in regard to sample treatment via combinatorial peptide ligand libraries, perhaps the only technique at present allowing deep exploration of biological fluids and tissue extracts in search for low- to very-low-abundance proteins, which could possibly mark the onset of most pathologies. Early-stage biomarkers, in fact, might be the only way to detect the beginning of most diseases thus permitting proper intervention and care. The following cancers are reviewed, with lists of potential biomarkers suggested in various reports: hepatocellular carcinoma, ovarian cancer, breast cancer and pancreatic cancer, together with some other interesting applications. Although panels of proteins have been presented, with robust evidence, as potential early-stage biomarkers in these different pathologies, their approval by FDA as novel biomarkers in routine clinical chemistry settings would require plenty of additional work and efforts from the pharma industry. The science environment in universities could simply not afford such heavy monetary investments. After more than 16years of search for novel biomarkers, to be used in a clinical chemistry set-up, via proteomic analysis (mostly in biological fluids) it was felt a critical review was due. In the present report, though, only papers reporting biomarker discovery via combinatorial peptide ligand libraries are listed and assessed, since this methodology seems to be the most advanced one for digging in depth into low-to very-low-abundance proteins, which might represent important biomarkers for the onset of pathologies. In particular, a large survey has been made for the following diseases, since they appear to have a large incidence on human population and/or represent fatal diseases: ovarian cancer, breast cancer, pancreatic cancer and hepatocellular carcinoma. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Combinatorial biosynthesis of cyclic lipopeptide antibiotics: a model for synthetic biology to accelerate the evolution of secondary metabolite biosynthetic pathways.

    Science.gov (United States)

    Baltz, Richard H

    2014-10-17

    Nonribosomal peptide synthetases (NRPSs) are giant multi-enzymes that carry out sequencial assembly line couplings of amino acids to generate linear or cyclic peptides. NRPSs are composed of repeating enzyme domains with modular organization to activate and couple specific amino acids in a particular order. From a synthetic biology perspective, they can be considered as peptide assembly machines composed of devices to couple fatty acids to l-amino acids, l-amino acids to l-amino acids, and d-amino acids to l-amino acids. The coupling devices are composed of specific parts that contain two or more enzyme domains that can be exchanged combinatorially to generate novel peptide assembly machines to produce novel peptides. The potent lipopeptide antibiotics daptomycin and A54145E have identical cyclic depsipeptide ring structures and stereochemistry but have divergent amino acid sequences. As their biosynthetic gene clusters are derived from an ancient ancestral lipopetide pathway, these lipopeptides provided an attractive model to develop combinatorial biosynthesis to generate antibiotics superior to daptomycin. These studies on combinatorial biosynthesis have helped generate guidelines for the successful assembly of NRPS parts and devices that can be used to generate novel lipopeptide structures and have established a basis for future synthetic biology studies to further develop combinatorial biosynthesis as a robust approach to natural product drug discovery.

  12. Library Design-Facilitated High-Throughput Sequencing of Synthetic Peptide Libraries.

    Science.gov (United States)

    Vinogradov, Alexander A; Gates, Zachary P; Zhang, Chi; Quartararo, Anthony J; Halloran, Kathryn H; Pentelute, Bradley L

    2017-11-13

    A methodology to achieve high-throughput de novo sequencing of synthetic peptide mixtures is reported. The approach leverages shotgun nanoliquid chromatography coupled with tandem mass spectrometry-based de novo sequencing of library mixtures (up to 2000 peptides) as well as automated data analysis protocols to filter away incorrect assignments, noise, and synthetic side-products. For increasing the confidence in the sequencing results, mass spectrometry-friendly library designs were developed that enabled unambiguous decoding of up to 600 peptide sequences per hour while maintaining greater than 85% sequence identification rates in most cases. The reliability of the reported decoding strategy was additionally confirmed by matching fragmentation spectra for select authentic peptides identified from library sequencing samples. The methods reported here are directly applicable to screening techniques that yield mixtures of active compounds, including particle sorting of one-bead one-compound libraries and affinity enrichment of synthetic library mixtures performed in solution.

  13. Generation of new synthetic scaffolds using framework libraries selected and refined via medicinal chemist synthetic expertise.

    Science.gov (United States)

    Webb, Thomas R; Venegas, Ruben E; Wang, Jian; Deschenes, Alain

    2008-04-01

    With the expansion in the application of library methods in medicinal chemistry and chemical biology there is a growing need for improved technology for the design of novel templates that are well suited for the synthesis of libraries targeted toward specific subsets of protein families. In this report, we delineate an improved stepwise general method that is well suited for this purpose. This process uses virtual framework libraries to identify frameworks that rigidly match specific aspects of a ligand's bioactive conformation. The resulting frameworks can then be ranked and sequentially modified by a combination of computational scripts and human derived expertise, in order to develop rational proposals for new combinatorial templates or new sets of potential ligands.

  14. Proteomic fingerprinting of mistletoe (Viscum album L.) via combinatorial peptide ligand libraries and mass spectrometry analysis.

    Science.gov (United States)

    Vergara-Barberán, María; Lerma-García, María Jesús; Nicoletti, Maria; Simó-Alfonso, Ernesto Francisco; Herrero-Martínez, José Manuel; Fasoli, Elisa; Righetti, Pier Giorgio

    2017-07-05

    Combinatorial peptide ligand libraries (CPLLs), coupled to mass spectrometry (MS) analysis, have been used to investigate in depth the proteome of Viscum album L. (VA), commonly named European mistletoe, in order to provide a first proteomic fingerprinting. For this purpose, the proteins were captured via CPLLs at two different pH values (acidic and neutral). A total of 648 non-redundant proteins were identified by using two different databases. The two pH values, chosen for bead incubations, have contributed to increment the capture ability: 56% and 31% of CPLLs species were respectively recognized at pH7.2 and at pH2.2. Finally the biological function of identified proteins was evaluated in order to understand their role on human health and the potential benefits of mistletoe extracts in medicine. Viscum album L. (VA) extracts are recently used as supporting medicine for cancer therapy, improving patients' survival and increasing their quality of life in medicine. These anticancer effects are investigated and they are probably due to mistletoe's capability to favor tumor cell's death and to modulate the immune system. Although the increasing interest in VA medical benefits, the role of its components in human health remains unclear. In order to exploit this aspect, it is important to comprehensively study proteins present in Viscum album L. (VA) extracts. Nevertheless, since plant proteomics analysis is in most cases handicapped by the presence of high-abundance proteins masking the detection of the low-abundance ones, it is important to overcome this challenge. In this sense, combinatorial peptide ligand libraries (CPLLs) have been used to reduce the dynamic protein concentration range to enable the identification of a higher amount of proteins than employing conventional methods. In this work, a total of 648 non-redundant proteins were identified: 56% and 31% of CPLLs species were respectively recognized at pH7.2 and at pH2.2. This deep proteome identification

  15. Selective molecularly imprinted polymer obtained from a combinatorial library for the extraction of bisphenol A.

    Science.gov (United States)

    Martin-Esteban, Antonio; Tadeo, Jose Luis

    2006-12-01

    In the present work, an analytical methodology based on molecularly imprinted solid-phase extraction (MISPE) has been developed for the determination of bisphenol A (BPA) in environmental and food samples. In order to select the optimum material, a combinatorial library of molecularly imprinted polymers in small-scale (mini-MIPs) was prepared using BPA as template. Different monomers (methacrylic acid or 4-vinylpyridine), crosslinkers (ethylene glycol dimethacrylate or trimethylolpropane trimethacrylate) and porogens (methanol, acetonitrile or toluene) were used leading to 24 different polymerisation mixtures. After BPA removal, the ability of mini-MIPs to recognise BPA was evaluated by equilibrium rebinding-elution experiments. The copolymer of 4-vinylpyridine (4-VP) and trimethylolpropane trimethacrylate (TRIM) prepared in toluene showed the higher affinity for the template. Subsequently, a scaled-up version of the optimum polymer was prepared and used in the development of MISPE procedures for the extraction of BPA. The optimised MISPE protocols were successfully applied to the selective extraction of BPA from soils and aqueous canned peas samples.

  16. An exchangeable-tip scanning probe instrument for the analysis of combinatorial libraries of electrocatalysts

    Science.gov (United States)

    Rus, Eric D.; Wang, Hongsen; Legard, Anna E.; Ritzert, Nicole L.; Bruce Van Dover, Robert; Abruña, Héctor D.

    2013-02-01

    A combined scanning differential electrochemical mass spectrometer (SDEMS)-scanning electrochemical microscope (SECM) apparatus is described. The SDEMS is used to detect and spatially resolve volatile electrochemically generated species at the surface of a substrate electrode. The SECM can electrochemically probe the reactivity of the surface and also offers a convenient means of leveling the sample. It is possible to switch between these two different scanning tips and techniques without moving the sample and while maintaining potential control of the substrate electrode. A procedure for calibration of the SDEMS tip-substrate separation, based upon the transit time of electrogenerated species from the substrate to the tip is also described. This instrument can be used in the characterization of combinatorial libraries of direct alcohol fuel cell anode catalysts. The apparatus was used to analyze the products of methanol oxidation at a Pt substrate, with the SDEMS detecting carbon dioxide and methyl formate, and a PtPb-modified Pt SECM tip used for the selective detection of formic acid. As an example system, the electrocatalytic methanol oxidation activity of a sputter-deposited binary PtRu composition spread in acidic media was analyzed using the SDEMS. These results are compared with those obtained from a pH-sensitive fluorescence assay.

  17. In-depth proteomic analysis of banana (Musa spp.) fruit with combinatorial peptide ligand libraries.

    Science.gov (United States)

    Esteve, Clara; D'Amato, Alfonsina; Marina, María Luisa; García, María Concepción; Righetti, Pier Giorgio

    2013-01-01

    Musa ssp. is among the world's leading fruit crops. Although a strong interest on banana biochemistry exists in the scientific community, focused on metabolite composition, proteins have been scarcely investigated even if they play an important role in food allergy and stability, are a source of biologically active peptides, and can provide information about nutritional aspects of this fruit. In this work we have employed the combinatorial peptide ligand libraries after different types of protein extractions, for searching the very low-abundance proteins in banana. The use of advanced MS techniques and Musa ssp. mRNAs database in combination with the Uniprot_viridiplantae database allowed us to identify 1131 proteins. Among this huge amount of proteins we found several already known allergens such as Mus a 1, pectinesterase, superoxide dismutase, and potentially new allergens. Additionally several enzymes involved in degradation of starch granules and strictly correlated to ripening stage were identified. This is the first in-depth exploration of the banana fruit proteome and one of the largest descriptions of the proteome of any vegetable system. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Comparison of dissimilarity measures for cluster analysis of X-ray diffraction data from combinatorial libraries

    Science.gov (United States)

    Iwasaki, Yuma; Kusne, A. Gilad; Takeuchi, Ichiro

    2017-12-01

    Machine learning techniques have proven invaluable to manage the ever growing volume of materials research data produced as developments continue in high-throughput materials simulation, fabrication, and characterization. In particular, machine learning techniques have been demonstrated for their utility in rapidly and automatically identifying potential composition-phase maps from structural data characterization of composition spread libraries, enabling rapid materials fabrication-structure-property analysis and functional materials discovery. A key issue in development of an automated phase-diagram determination method is the choice of dissimilarity measure, or kernel function. The desired measure reduces the impact of confounding structural data issues on analysis performance. The issues include peak height changes and peak shifting due to lattice constant change as a function of composition. In this work, we investigate the choice of dissimilarity measure in X-ray diffraction-based structure analysis and the choice of measure's performance impact on automatic composition-phase map determination. Nine dissimilarity measures are investigated for their impact in analyzing X-ray diffraction patterns for a Fe-Co-Ni ternary alloy composition spread. The cosine, Pearson correlation coefficient, and Jensen-Shannon divergence measures are shown to provide the best performance in the presence of peak height change and peak shifting (due to lattice constant change) when the magnitude of peak shifting is unknown. With prior knowledge of the maximum peak shifting, dynamic time warping in a normalized constrained mode provides the best performance. This work also serves to demonstrate a strategy for rapid analysis of a large number of X-ray diffraction patterns in general beyond data from combinatorial libraries.

  19. Synthetic Biodegradable Hydrogels with Excellent Mechanical Properties and Good Cell Adhesion Characteristics Obtained by the Combinatorial Synthesis of Photo-Cross-Linked Networks

    NARCIS (Netherlands)

    Zant, Erwin; Grijpma, Dirk W.

    Major drawbacks of synthetic hydrogels are their poor mechanical properties and their limited ability to allow cell attachment and proliferation. By photo-cross-linking mixtures of dimethacrylate-functionalized oligomers (macromers) in a combinatorial manner in solution, synthetic hydrogels with

  20. Thiosemicarbazone Dynamic Combinatorial Chemistry: Equilibrator-Induced Dynamic State, Formation of Complex Libraries, and a Supramolecular On/Off Switch.

    Science.gov (United States)

    Larsen, Dennis; Jeppesen, Anne; Kleinlein, Claudia; Pittelkow, Michael

    2017-08-18

    Dynamic combinatorial libraries that equilibrate under thermodynamic control and can be trapped kinetically when desired are key to creating complex systems that can mimic dynamic biological systems, such as the biochemical system of life. A much-sought-after feature is the ability to turn off the dynamic exchange of the system, in order to investigate a transient state away from thermodynamic equilibrium, and then turn on the dynamic exchange again. We describe here the first use of thiosemicarbazone exchange to form dynamic combinatorial libraries. The libraries were found to require a nucleophilic catalyst, or equilibrator, in order to reach thermodynamic equilibrium. This equilibrator approach adds a supramolecular level of control over the dynamic system and allows the dynamic exchange to be turned off by addition of 18-crown-6, which binds the equilibrator in a nonnucleophilic complex. The dynamic exchange can be restarted by addition of potassium ions that competitively bind 18-crown-6, thus liberating the equilibrator. The highly complex thiosemicarbazone-based macrocyclic libraries contain both [2]catenanes and sequence isomers, which can be distinguished by HPLC-MS/MS.

  1. Proteomics analysis of Mahonia bealei leaves with induction of alkaloids via combinatorial peptide ligand libraries.

    Science.gov (United States)

    Zhang, Lin; Zhu, Wei; Zhang, Yanzhen; Yang, Bingxian; Fu, Zhirong; Li, Ximin; Tian, Jingkui

    2014-10-14

    Alkaloids are one of the most attractive sources for obtaining active natural products. However, alkaloids exist in the plants as the secondary metabolites with tracing amount, and there is an enormous demand for a large production. In the present study, we aimed to profile the modification of benzylisoquinoline alkaloids in Mahonia bealei seedlings under the binary stress of ultraviolet-B irradiation and dark incubation. Comparative proteomics analysis was carried out to address the underlying proteome variations that accounted for the alkaloid induction under treatment. Thirteen differential proteins were identified in the leaves under binary stress. Of note, the abundance of S-adenosyl-L-methionine synthetase was highly increased to sustain a high concentration of S-adenosyl-L-methionine for the enhanced biosynthesis of alkaloids. Additionally, we presented the application of CPLL to M. bealei leaf proteins. Three new secondary metabolism proteins and 12 additional differential proteins were identified only after CPLL treatment. Six genes in the benzylisoquinoline alkaloid biosynthesis pathway were selected to verify their variable expression using quantitative real time polymerase chain reaction. The results suggest that the benzylisoquinoline alkaloids in M. bealei leaf were increased to eliminate the adverse effect of UV-B exposure. The suppression of photosynthesis and respiratory rate may save an extra energy for the secondary metabolites, and the enhanced N-metabolism may supply sufficient primary metabolite precursors. To our best knowledge, this is the first work aimed at the secondary metabolism proteomic characterization of M. bealei using the CPLL technique. It also presented an effective and innovative process to improve the contents of alkaloids in medicinal plants for industrial production. Besides the effective and innovative process to improve the contents of alkaloids in M. bealei leaves for industrial production, the presented combinatorial

  2. Synthesis and screening of a rationally designed combinatorial library of affinity ligands mimicking protein L from Peptostreptococcus magnus.

    Science.gov (United States)

    Roque, A Cecília A; Taipa, M Angela; Lowe, Christopher R

    2005-01-01

    Rational design and combinatorial chemistry were utilized to search for lead protein L (PpL) mimetics for application as affinity ligands for the purification of antibodies and small fragments, such as Fab and scFv, and as potential diagnostic or therapeutic agents. Inspection of the key structural features of the complex between PpL and human Fab prompted the de novo design and combinatorial synthesis of a 169-membered solid-phase ligand library, which was assessed for binding to human IgG and subsequent selectivity for the Fab fragment. Eight ligands were selected, chemically characterized and compared with a commercial PpL-adsorbent for binding pure immunoglobulin fractions. The most promising lead, ligand 8/7, when immobilized on an agarose support, behaved in a similar fashion to PpL in isolating Fab fragments from papain digests of human IgG to a final purity of 97%. Copyright 2005 John Wiley & Sons, Ltd.

  3. INTRIGOSS: A new Library of High Resolution Synthetic Spectra

    Science.gov (United States)

    Franchini, Mariagrazia; Morossi, Carlo; Di Marcancantonio, Paolo; Chavez, Miguel; GES-Builders

    2018-01-01

    INTRIGOSS (INaf Trieste Grid Of Synthetic Spectra) is a new High Resolution (HiRes) synthetic spectral library designed for studying F, G, and K stars. The library is based on atmosphere models computed with specified individual element abundances via ATLAS12 code. Normalized SPectra (NSP) and surface Flux SPectra (FSP), in the 4800-5400 Å wavelength range, were computed by means of the SPECTRUM code. The synthetic spectra are computed with an atomic and bi-atomic molecular line list including "bona fide" Predicted Lines (PLs) built by tuning loggf to reproduce very high SNR Solar spectrum and the UVES-U580 spectra of five cool giants extracted from the Gaia-ESO survey (GES). The astrophysical gf-values were then assessed by using more than 2000 stars with homogenous and accurate atmosphere parameters and detailed chemical composition from GES. The validity and greater accuracy of INTRIGOSS NSPs and FSPs with respect to other available spectral libraries is discussed. INTRIGOSS will be available on the web and will be a valuable tool for both stellar atmospheric parameters and stellar population studies.

  4. Quantum Mechanical Energy-based Screening of Combinatorially Generated Library of Tautomers. TauTGen. A Tautomer Generator Program

    Energy Technology Data Exchange (ETDEWEB)

    Haranczyk, Maciej; Gutowski, Maciej S

    2007-03-01

    Many computational methods have been derived from quantum mechanics for molecular and extended systems. We advocate that these methods will soon become indispensable research tools of combinatorial chemistry. Although applications of these combinatorial methods driven by quantum-mechanics-derived computational engines seem to be distant, our recent experience suggests the opposite. We developed algorithms and codes to search for the most stable tautomers of molecules. In our approach, we: (i) create large libraries of molecular tautomers using combinatorial methods, and (ii) prescreen these libraries using quantum chemical electronic structure methods. We have identified many adiabatically bound and previously unknown tautomers of anionic nucleic acid bases. Our results unraveled that ordering of nucleic acid bases according to their affinity to an excess electron is: G > U > T > C > A , when all biologically relevant tautomers are considered. Acknowledgements This work was supported by the: (i) US DOE Office of Biological and Environmental Research, Low Dose Radiation Research Program (M.G.) and (ii) Polish State Committee for Scientific Research (KBN) Grant DS/8221-4-0140-4 (M.H.). M.H. thanks for financial support from the European Union Social Funds ZPORR/2.22/II/2.6/ARP/U/2/O5. M.H. is a holder of the award from the Fundation for Polish Science (FNP). R.A.B. acknowledges the financial support from Nanoquant EC Marie Curie Research Training Network, contract number: MRTN-506842. Computing resources were available through: (i) the Academic Computer Center in Gdansk (TASK) (ii) a Computational Grand Challenge Application grant from the Molecular Sciences Computing Facility (MSCF) in the Environmental Molecular Sciences Laboratory located at the Pacific Northwest National Laboratory, and (iii) the National Energy Research Scientific Computing Center (NERSC). The MSCF is funded by DOE’s Office of Biological and Environmental Research. PNNL is operated by Battelle

  5. A Combinatorial Library of Micro-Topographies and Chemical Compositions for Tailored Surface Wettability

    DEFF Research Database (Denmark)

    Kolind, Kristian; Bennetsen, Dines Tilsted; Arpanaei, Ayyoob

    2011-01-01

    Surface modification of topography and chemistry in order to achieve a specific water contact angle (CA) has been explored by using a novel combinatorial screening platform. The screening arrays consisted of 507 distinct combinations of micro-topographies and chemical compositions. By performing ...

  6. Searching for avidity by chemical ligation of combinatorially self-assembled DNA-encoded ligand libraries.

    Science.gov (United States)

    Matysiak, Stefan; Hellmuth, Klaus; El-Sagheer, Afaf H; Shivalingam, Arun; Ariyurek, Yavuz; de Jong, Marco; Hollestelle, Martine J; Out, Ruud; Brown, Tom

    2017-12-19

    DNA encoded ligands are self-assembled into bivalent complexes and chemically ligated to link their identities. To demonstrate their potential as a combinatorial screening platform for avidity interactions, the optimal bivalent aptamer design (examplar ligands) for human alpha-thrombin is determined in a single round of selection and the DNA scaffold replaced with minimal impact on the final design.

  7. Synthesis of aromatic glycoconjugates. Building blocks for the construction of combinatorial glycopeptide libraries

    Directory of Open Access Journals (Sweden)

    Markus Nörrlinger

    2014-10-01

    Full Text Available New aromatic glycoconjugate building blocks based on the trifunctional 3-aminomethyl-5-aminobenzoic acid backbone and sugars linked to the backbone by a malonyl moiety were prepared via peptide coupling. The orthogonally protected glycoconjugates, bearing an acetyl-protected glycoside, were converted into their corresponding acids which are suitable building blocks for combinatorial glycopeptide synthesis.

  8. Minimal Substrate Features for Erm Methyltransferases Defined by Using a Combinatorial Oligonucleotide Library

    DEFF Research Database (Denmark)

    Hansen, Lykke H; Lobedanz, Sune; Douthwaite, Stephen

    2011-01-01

    by Erm. Substrate molecules were constructed in a combinatorial manner from two separate sets (top and bottom strands) of short RNA sequences. Modifications, including LNA monomers with locked sugar residues, were incorporated into the substrates to stabilize their structures. In functional substrates......, the A2058 methylation target (on the 13- to 19-nucleotide top strand) was displayed in an unpaired sequence immediately following a conserved irregular helix, and these are the specific structural features recognized by Erm. Erm methylation was enhanced by stabilizing the top-strand conformation...... of Erm. The combinatorial approach for identifying small but functional RNA substrates is a step towards making RNA-Erm complexes suitable for cocrystal determination, and for designing molecules that might block the substrate-recognition site of the enzyme....

  9. CCLab--a multi-objective genetic algorithm based combinatorial library design software and an application for histone deacetylase inhibitor design.

    Science.gov (United States)

    Fang, Guanghua; Xue, Mengzhu; Su, Mingbo; Hu, Dingyu; Li, Yanlian; Xiong, Bing; Ma, Lanping; Meng, Tao; Chen, Yuelei; Li, Jingya; Li, Jia; Shen, Jingkang

    2012-07-15

    The introduction of the multi-objective optimization has dramatically changed the virtual combinatorial library design, which can consider many objectives simultaneously, such as synthesis cost and drug-likeness, thus may increase positive rates of biological active compounds. Here we described a software called CCLab (Combinatorial Chemistry Laboratory) for combinatorial library design based on the multi-objective genetic algorithm. Tests of the convergence ability and the ratio to re-take the building blocks in the reference library were conducted to assess the software in silico, and then it was applied to a real case of designing a 5×6 HDAC inhibitor library. Sixteen compounds in the resulted library were synthesized, and the histone deactetylase (HDAC) enzymatic assays proved that 14 compounds showed inhibitory ratios more than 50% against tested 3 HDAC enzymes at concentration of 20 μg/mL, with IC(50) values of 3 compounds comparable to SAHA. These results demonstrated that the CCLab software could enhance the hit rates of the designed library and would be beneficial for medicinal chemists to design focused library in drug development (the software can be downloaded at: http://202.127.30.184:8080/drugdesign.html). Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Combinatorial processing libraries for bulk BiFeO3-PbTiO3 piezoelectric ceramics

    International Nuclear Information System (INIS)

    Hu, W.; Tan, X.; Rajan, K.

    2010-01-01

    A high throughput approach for generating combinatorial libraries with varying processing conditions for bulk ceramics has been developed. This approach utilized the linear temperature gradient in a tube furnace to screen a whole temperature range for optimized preparation. With this approach, the processing of 0.98[0.6BiFeO 3 -0.4PbTiO 3 ]-0.02Pb(Mg 1/3 Nb 2/3 )O 3 ceramic powders and pellets for high-temperature piezoelectric applications was demonstrated to identify the best synthesis conditions for phase purity. The dielectric property measurement on the as-processed solid solution ceramics confirmed the high Curie temperature and the improved loss tangent with the Pb(Mg 1/3 Nb 2/3 )O 3 doping. (orig.)

  11. Toxin Inhibition - Deconvolution Strategies and Assay Screening of Combinatorial Peptide Libraries

    National Research Council Canada - National Science Library

    Lee, W. E; Chan, N. W; Marenco, A. J; Moore, G. J; Moore, D; Hayden, Lawrence J; Laing, T. D; Gregory, M; Mah, D. C; Hamilton, M. G

    2007-01-01

    .... We report on development of a capillary electrophoresis laser-induced fluorescence (CE LIF) method for measuring BoNTIA peptidase activity and for screening peptide libraries for inhibitory effects...

  12. Combinatorial solid-phase glycopeptide libraries - Synthesis and application in biomolecular interaction studies and biosensors

    NARCIS (Netherlands)

    Maljaars, C.E.P.

    2006-01-01

    Carbohydrates play vital roles in all forms of life. Attached to proteins and lipids they serve as recognition elements in several biological interaction processes, such as intercellular communication, immune response, viral and parasitical infections, signal transduction, and development. Synthetic

  13. Screening of a Combinatorial Library of Organic Polymers for the Solid-Phase Extraction of Patulin from Apple Juice.

    Science.gov (United States)

    Giovannoli, Cristina; Spano, Giulia; Di Nardo, Fabio; Anfossi, Laura; Baggiani, Claudio

    2017-05-20

    Patulin is a water-soluble mycotoxin produced by several species of fungi. Governmental bodies have placed it under scrutiny for its potential negative health effects, and maximum residue limits are fixed in specific food matrices to protect consumers' health. Confirmatory analysis of patulin in complex food matrices can be a difficult task, and sample clean-up treatments are frequently necessary before instrumental analyses. With the aim of simplifying the clean-up step, we prepared a 256-member combinatorial polymeric library based on 16 functional monomers, four cross-linkers and four different porogenic solvents. The library was screened for the binding towards patulin in different media (acetonitrile and citrate buffer at pH 3.2), with the goal of identifying polymer formulations with good binding properties towards the target compound. As a proof of concept, a methacrylic acid-co-pentaerithrytole tetraacrylate polymer prepared in chloroform was successfully used as a solid-phase extraction material for the clean-up and extraction of patulin from apple juice. Clean chromatographic patterns and acceptable recoveries were obtained for juice spiked with patulin at concentration levels of 25 (64 ± 12%), 50 (83 ± 5.6%) and 100 μg L -1 (76 ± 4.5%). The within-day and between-day reproducibility evaluated at a concentration level of 25 μg L -1 were 5.6 and 7.6%, respectively.

  14. Screening of a Combinatorial Library of Organic Polymers for the Solid-Phase Extraction of Patulin from Apple Juice

    Directory of Open Access Journals (Sweden)

    Cristina Giovannoli

    2017-05-01

    Full Text Available Patulin is a water-soluble mycotoxin produced by several species of fungi. Governmental bodies have placed it under scrutiny for its potential negative health effects, and maximum residue limits are fixed in specific food matrices to protect consumers’ health. Confirmatory analysis of patulin in complex food matrices can be a difficult task, and sample clean-up treatments are frequently necessary before instrumental analyses. With the aim of simplifying the clean-up step, we prepared a 256-member combinatorial polymeric library based on 16 functional monomers, four cross-linkers and four different porogenic solvents. The library was screened for the binding towards patulin in different media (acetonitrile and citrate buffer at pH 3.2, with the goal of identifying polymer formulations with good binding properties towards the target compound. As a proof of concept, a methacrylic acid-co-pentaerithrytole tetraacrylate polymer prepared in chloroform was successfully used as a solid-phase extraction material for the clean-up and extraction of patulin from apple juice. Clean chromatographic patterns and acceptable recoveries were obtained for juice spiked with patulin at concentration levels of 25 (64 ± 12%, 50 (83 ± 5.6% and 100 μg L−1 (76 ± 4.5%. The within-day and between-day reproducibility evaluated at a concentration level of 25 μg L−1 were 5.6 and 7.6%, respectively.

  15. Comparative proteomic analysis of egg white proteins during the rapid embryonic growth period by combinatorial peptide ligand libraries.

    Science.gov (United States)

    Liu, Yijun; Qiu, Ning; Ma, Meihu

    2015-10-01

    Egg white proteins provide essential nutrients and antimicrobial protection during embryonic development. Although various biological functions of major egg white proteins have been investigated via embryogenesis, understanding of global changes in low-abundance proteins has been limited. In the current study, a proteomic analysis of low-abundance egg white proteins was conducted using combinatorial peptide ligand libraries (CPLL), two-dimensional gel electrophoresis (2-DE), and matrix-assisted laser desorption/ionization-time-of-flight with two mass analyzers for tandem mass spectrometry (MALDI-TOF MS/MS) during the rapid embryonic growth period. Significant increases in the relative abundance of 88 protein spots (P ≤ 0.05), of which 47 spots were found to correspond to 10 proteins from 8 protein families were identified over 16 d incubation. During this developmental process, the protein concentration increased and the amount of albumin solid material decreased in the residual egg white. Clusterin precursors were observed over a wide range of pH values and the tenp protein increased continuously during embryonic development. Low-abundance proteins were identified in a comparison of optimal incubation conditions to the altered conditions of 2 control groups to better understand the function of these proteins in egg whites. Collectively, these findings provide insight into the supportive role of the egg white during embryonic development, enabling a broader understanding of chick embryogenesis. © 2015 Poultry Science Association Inc.

  16. Comparative Molecular Similarity Index Analysis (CoMSIA) to study hydrogen-bonding properties and to score combinatorial libraries

    Science.gov (United States)

    Klebe, Gerhard; Abraham, Ute

    1999-01-01

    Comparative molecular field analysis has been applied to a data set of thermolysin inhibitors. Fields expressed in terms of molecular similarity indices (CoMSIA) have been used instead of the usually applied Lennard-Jones- and Coulomb-type potentials (CoMFA). Five different properties, assumed to cover the major contributions responsible for ligand binding, have been considered: steric, electrostatic, hydrophobic, and hydrogen-bond donor or acceptor properties. The statistical evaluation of the field properties by PLS analysis reveals a similar predictive potential to CoMFA. However, significantly improved and easily interpretable contour maps are obtained. The features in these maps intuitively suggest where to modify a molecular structure in terms of physicochemical properties and functional groups in order to improve its binding affinity. They can also be interpreted with respect to the known structural protein environment of thermolysin. Most of the highlighted regions in the maps are mirrored by features in the surrounding environment required for binding. Using the derived correlation model, different members of a combinatorial library designed for thermolysin inhibition have been scored for affinity. The results obtained demonstrate the prediction power of the CoMSIA method.

  17. Identification of olive (Olea europaea) seed and pulp proteins by nLC-MS/MS via combinatorial peptide ligand libraries.

    Science.gov (United States)

    Esteve, Clara; D'Amato, Alfonsina; Marina, María Luisa; García, María Concepción; Citterio, Attilio; Righetti, Pier Giorgio

    2012-04-18

    Different types of extraction protocols are described for identifying proteins in seed and pulp of olive (Olea europea), by employing both conventional extraction methods and capture with ProteoMiner as well as with in house-made combinatorial peptide ligand libraries (HM-CPLLs) at pH 7.4 and at pH 2.2. Thanks to the use of CPLLs, able to dramatically amplify the signal of low-abundance species, a quite large number of compounds has been indeed identified: 61 in the seed (vs. only four reported in current literature) and 231 in the pulp (vs. 56 described so far), the deepest investigation up to the present of the olive proteome. In the seed, it highlights the presence of seed storage proteins, oleosins and histones. In the pulp, the allergenic thaumatin-like protein (Ole e 13) was confirmed, among the other 231, as the most abundant protein in the olive pulp. The present research has also been undertaken with the aim of identifying proteins in olive oil and ascertaining the relative contribution of seed and pulp proteins in their presence, if any, in oils. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. Generation of a synthetic mammalian promoter library by modification of sequences spacing transcription factor binding sites

    DEFF Research Database (Denmark)

    Tornøe, Jens; Kusk, P.; Johansen, T.E.

    2002-01-01

    The development of a set of synthetic mammalian promoters with different specific activities is described. The library is based on a synthetic promoter, JeT, constructed as a 200 bp chimeric promoter built from fragments of the viral SV40 early promoter and the human beta-actin and ubiquitin C...

  19. Quantum Efficiency and Bandgap Analysis for Combinatorial Photovoltaics: Sorting Activity of Cu–O Compounds in All-Oxide Device Libraries

    Science.gov (United States)

    2014-01-01

    All-oxide-based photovoltaics (PVs) encompass the potential for extremely low cost solar cells, provided they can obtain an order of magnitude improvement in their power conversion efficiencies. To achieve this goal, we perform a combinatorial materials study of metal oxide based light absorbers, charge transporters, junctions between them, and PV devices. Here we report the development of a combinatorial internal quantum efficiency (IQE) method. IQE measures the efficiency associated with the charge separation and collection processes, and thus is a proxy for PV activity of materials once placed into devices, discarding optical properties that cause uncontrolled light harvesting. The IQE is supported by high-throughput techniques for bandgap fitting, composition analysis, and thickness mapping, which are also crucial parameters for the combinatorial investigation cycle of photovoltaics. As a model system we use a library of 169 solar cells with a varying thickness of sprayed titanium dioxide (TiO2) as the window layer, and covarying thickness and composition of binary compounds of copper oxides (Cu–O) as the light absorber, fabricated by Pulsed Laser Deposition (PLD). The analysis on the combinatorial devices shows the correlation between compositions and bandgap, and their effect on PV activity within several device configurations. The analysis suggests that the presence of Cu4O3 plays a significant role in the PV activity of binary Cu–O compounds. PMID:24410367

  20. The human combinatorial antibody library HuCAL GOLD combines diversification of all six CDRs according to the natural immune system with a novel display method for efficient selection of high-affinity antibodies.

    Science.gov (United States)

    Rothe, Christine; Urlinger, Stefanie; Löhning, Corinna; Prassler, Josef; Stark, Yvonne; Jäger, Ute; Hubner, Bernd; Bardroff, Michael; Pradel, Ingrid; Boss, Melanie; Bittlingmaier, Renate; Bataa, Tschimegma; Frisch, Christian; Brocks, Bodo; Honegger, Annemarie; Urban, Margit

    2008-02-29

    This article describes the generation of the Human Combinatorial Antibody Library HuCAL GOLD. HuCAL GOLD is a synthetic human Fab library based on the HuCAL concept with all six complementarity-determining regions (CDRs) diversified according to the sequence and length variability of naturally rearranged human antibodies. The human antibody repertoire was analyzed in-depth, and individual CDR libraries were designed and generated for each CDR and each antibody family. Trinucleotide mixtures were used to synthesize the CDR libraries in order to ensure a high quality within HuCAL GOLD, and a beta-lactamase selection system was employed to eliminate frame-shifted clones after successive cloning of the CDR libraries. With these methods, a large, high-quality library with more than 10 billion functional Fab fragments was achieved. By using CysDisplay, the antibody fragments are displayed on the tip of the phage via a disulfide bridge between the phage coat protein pIII and the heavy chain of the antibody fragment. Efficient elution of specific phages is possible by adding reducing agents. HuCAL GOLD was challenged with a variety of different antigens and proved to be a reliable source of high-affinity human antibodies with best affinities in the picomolar range, thus functioning as an excellent source of antibodies for research, diagnostic, and therapeutic applications. Furthermore, the data presented in this article demonstrate that CysDisplay is a robust and broadly applicable display technology even for high-throughput applications.

  1. mRNA Display Based Selections Using Synthetic Peptide and Natural Protein Libraries

    Science.gov (United States)

    Cotten, Steve W.; Zou, Jianwei; Wang, Rong; Huang, Bao-cheng; Liu, Rihe

    2014-01-01

    mRNA display is a powerful in vitro selection technique that can be applied towards the identification of peptides or proteins with desired properties. The physical conjugation between a protein and its own RNA presents unique challenges in manipulating the displayed proteins in an RNase free environment. This protocol outlines the generation of synthetic peptide and natural proteome libraries as well as the steps required for generation of mRNA-protein fusion libraries, in vitro selection, and regeneration of the selected sequences. The selection procedures for the identification of Ca2+ dependent calmodulin binding proteins from synthetic peptide and natural proteome libraries are presented. PMID:22094812

  2. Using 99TcM-tripeptoid library as an example of radio-combinatorial screening in vivo for the discovery of tissue targeting drug

    International Nuclear Information System (INIS)

    Zeng Jun; Liu Ciyi; Xie Wenhui; Hu Silong; Jin Muxiu

    2004-01-01

    Libraries against a molecular target in vitro is an artificially idealized system that are not the real picture in vivo where biomolecules coexist to maintain life activities. Furthermore, the diagnostic and therapeutic efficiency of drug depends highly on the drug distribution in target tissues (tumor for example) both specifically and accumulatively. Radio-labeling technology can make a unique opportunity of tracing large number of compounds in a combinatorial way in vivo simultaneously, sensitively, quantitatively, dynamically, and noninvasively. Methods: The C-terminal amide tripeptide libraries were synthesized on Rink Amide-MBHA resin in the OXX aO1OXaO1O2O positional scanning format and iterative protoco. A technetium (V) oxo core[(TcO)3+] was bound to the N4-triligands of tripeptide libraries via four deprotonated amide nitrogen atoms to form a structure of 99Tcm-tripeptoid libraries. The radio-combinatorial screening (RCS) in vivo was then carded out after SD rats and A549 tumor bearing mice received i.v. with 99Tcm-tripeptoid libraries. Results: Using 99Tcm-tripeptoid libraries as an example, a new method of radio-combinatorial screening (RCS) in vivo was demonstrated successful in generation, optimization, and design of tissue targeting leads. Signals of tissue distribution and metabolism of libraries were recorded by g counting or imaging. From library of 8,000 99Tcm-tripeptoid members, the tissue targeting leads had been identified by RCS. Those included 99Tcm-DSG, 99Tcm-VAA, 99Tcm-VIG, and 99Tcm-RES that had specific tissue targeting in kidney, stomach, liver, and tumor respectively. The percent injected dose per gram tissue (%ID/g) of 99Tcm labeled leads in their target tissues was highly structure-dependent Because the nontarget tissue binding and the metabolism of 99Tcm-tripeptoid libraries was simultaneously monitored so successfully by RCS that the background activity was limited to the lowest level when a 99Tcm labeled lead finally generated

  3. Crystallographic Structure Analysis of a Ti-Ta Thin Film Materials Library Fabricated by Combinatorial Magnetron Sputtering.

    Science.gov (United States)

    Kadletz, Peter M; Motemani, Yahya; Iannotta, Joy; Salomon, Steffen; Khare, Chinmay; Grossmann, Lukas; Maier, Hans Jürgen; Ludwig, Alfred; Schmahl, Wolfgang W

    2018-03-12

    Ti-Ta thin films exhibit properties that are of interest for applications as microactuators and as biomedical implants. A Ti-Ta thin film materials library was deposited at T = 25 °C by magnetron sputtering employing the combinatorial approach, which led to a compositional range of Ti 87 Ta 13 to Ti 14 Ta 86 . Subsequent high-throughput characterization methods permitted a quick and comprehensive study of the crystallographic, microstructural, and morphological properties, which strongly depend on the chemical composition. SEM investigation revealed a columnar morphology having pyramidal, sharp tips with coarser columns in the Ti-rich and finer columns in the Ta-rich region. By grazing incidence X-ray diffraction four phases were identified, from Ta-lean to Ta-rich: ω phase, α″ martensite, β phase, and a tetragonal Ta-rich phase (Ta (tetr) ). The crystal structure and microstructure were analyzed by Rietveld refinement and clear trends could be determined as a function of Ta-content. The lattice correspondences between β as the parent phase and α″ and ω as derivative phases were expressed in matrix form. The β ⇌ α″ phase transition shows a discontinuity at the composition where the martensitic transformation temperatures fall below room temperature (between 34 and 38 at. % Ta) rendering it first order and confirming its martensitic nature. A short study of the α″ martensite employing the Landau theory is included for a mathematical quantification of the spontaneous lattice strain at room temperature (ϵ̂ max = 22.4(6) % for pure Ti). Martensitic properties of Ti-Ta are beneficial for the development of high-temperature actuators with actuation response at transformation temperatures higher than 100 °C.

  4. A Convergent Solid-Phase Synthesis of Actinomycin Analogues - Towards Implementation of Double-Combinatorial Chemistry

    DEFF Research Database (Denmark)

    Tong, Glenn; Nielsen, John

    1996-01-01

    The actinomycin antibiotics bind to nucleic acids via both intercalation and hydrogen bonding. We found this 'double-action attack' mechanism very attractive in our search for a novel class of nucleic acid binders. A highly convergent, solid-phase synthetic strategy has been developed for a class...... with the requirements for combinatorial synthesis and furthermore, the final segment condensation allows, for the first time, double-combinatorial chemistry to be performed where two combinatorial libraries can be reacted with each other. Copyright (C) 1996 Elsevier Science Ltd....

  5. Generation and analyses of human synthetic antibody libraries and their application for protein microarrays

    DEFF Research Database (Denmark)

    Säll, Anna; Walle, Maria; Wingren, Christer

    2016-01-01

    in a high-throughput manner. To address this we designed and constructed two human synthetic antibody fragment (scFv) libraries denoted HelL-11 and HelL-13. By the use of phage display technology, in total 466 unique scFv antibodies specific for 114 different antigens were generated. The specificities...... of these antibodies were analyzed in a variety of immunochemical assays and a subset was further evaluated for functionality in protein microarray applications. This high-throughput approach demonstrates the ability to rapidly generate a wealth of reagents not only for proteome research, but potentially also...... for diagnostics and therapeutics. In addition, this work provides a great example on how a synthetic approach can be used to optimize library designs. By having precise control of the diversity introduced into the antigen-binding sites, synthetic libraries offer increased understanding of how different diversity...

  6. De novo design, synthesis and screening of a combinatorial library of complementary ligands directed towards the surface of cutinase from Fusarium solani pisi.

    Science.gov (United States)

    Ruiu, L; Roque, A C A; Taipa, M A; Lowe, C R

    2006-01-01

    The protein surface is the interface through which a protein molecule senses the external world. The composition of this interface, in charged, polar and/or hydrophobic residues is crucial for both the activity and stability of the protein. Protein immobilization on surfaces has been extensively explored as one of the most effective approaches for stabilization. The mechanism of stabilization, however, is still poorly understood, and usually the success of any method is more a matter of trial and error rather than the result of rational concepts. The importance of local unfolding processes in a number of biologically significant processes has been recognized and attracted increasing attention. Unfolding regions have been localized in different proteins including the recombinant cutinase from Fusarium solani pisi. The study of three structural surface regions associated with early cutinase unfolding events was the basis for the approach followed in this work. A 64-member solid-phase combinatorial library of ligands was synthesized on a triazine-substituted agarose matrix using a modified 'mix and split' procedure. The combinatorial library was assessed for binding to cutinase from Fusarium solani pisi in a biologically active form. Four lead ligands (3/5, 3/7, 4/5, 4/7) have been selected in which immobilized cutinase presented a relative activity of 30-60% as compared to the free enzyme. Copyright 2006 John Wiley & Sons, Ltd.

  7. Optimization of Combinatorial Mutagenesis

    Science.gov (United States)

    Parker, Andrew S.; Griswold, Karl E.; Bailey-Kellogg, Chris

    Protein engineering by combinatorial site-directed mutagenesis evaluates a portion of the sequence space near a target protein, seeking variants with improved properties (stability, activity, immunogenicity, etc.). In order to improve the hit-rate of beneficial variants in such mutagenesis libraries, we develop methods to select optimal positions and corresponding sets of the mutations that will be used, in all combinations, in constructing a library for experimental evaluation. Our approach, OCoM (Optimization of Combinatorial Mutagenesis), encompasses both degenerate oligonucleotides and specified point mutations, and can be directed accordingly by requirements of experimental cost and library size. It evaluates the quality of the resulting library by one- and two-body sequence potentials, averaged over the variants. To ensure that it is not simply recapitulating extant sequences, it balances the quality of a library with an explicit evaluation of the novelty of its members. We show that, despite dealing with a combinatorial set of variants, in our approach the resulting library optimization problem is actually isomorphic to single-variant optimization. By the same token, this means that the two-body sequence potential results in an NP-hard optimization problem. We present an efficient dynamic programming algorithm for the one-body case and a practically-efficient integer programming approach for the general two-body case. We demonstrate the effectiveness of our approach in designing libraries for three different case study proteins targeted by previous combinatorial libraries - a green fluorescent protein, a cytochrome P450, and a beta lactamase. We found that OCoM worked quite efficiently in practice, requiring only 1 hour even for the massive design problem of selecting 18 mutations to generate 107 variants of a 443-residue P450. We demonstrate the general ability of OCoM in enabling the protein engineer to explore and evaluate trade-offs between quality and

  8. Synthesis of natural-product-based compound libraries

    NARCIS (Netherlands)

    Wessjohann, L.A.

    2000-01-01

    Natural products cover a diversity space not yet available from synthetic libraries, with an unrivalled success rate as drug leads. The combinatorial synthesis of non-oligomeric natural-product-based libraries, however, is still limited to few examples because access to easily modified units

  9. Evolution of dynamic combinatorial chemistry.

    Science.gov (United States)

    Cougnon, Fabien B L; Sanders, Jeremy K M

    2012-12-18

    Since its inception in the mid-1990s, dynamic combinatorial chemistry (DCC), the chemistry of complex systems under thermodynamic control, has proved valuable in identifying unexpected molecules with remarkable binding properties and in providing effective synthetic routes to complex species. Essentially, in this approach, one designs the experiment rather than the molecule. DCC has also provided us with insights into how some chemical systems respond to external stimuli. Using examples from the work of our laboratory and others, this Account shows how the concept of DCC, inspired by the evolution of living systems, has found an increasing range of applications in diverse areas and has evolved conceptually and experimentally. A dynamic combinatorial library (DCL) is a thermodynamically controlled mixture of interconverting species that can respond to various stimuli. The Cambridge version of dynamic combinatorial chemistry was initially inspired by the mammalian immune system and was conceived as a way to create and identify new unpredictable receptors. For example, an added template can select and stabilize a strongly binding member of the library which is then amplified at the expense of the unsuccessful library members, minimizing the free energy of the system. But researchers have exploited DCC in a variety of other ways: over the past two decades, this technique has contributed to the evolution of chemistry and to applications in the diverse fields of catalysis, fragrance release, and responsive materials. Among these applications, researchers have built intricate and well-defined architectures such as catenanes or hydrogen-bonded nanotubes, using the ability of complex chemical systems to reach a high level of organization. In addition, DCC has proved a powerful tool for the study of complex molecular networks and systems. The use of DCC is improving our understanding of chemical and biological systems. The study of folding or self-replicating macrocycles in

  10. Performance evaluation of phage-displayed synthetic human single-domain antibody libraries: A retrospective analysis.

    Science.gov (United States)

    Henry, Kevin A; Tanha, Jamshid

    2018-05-01

    Fully human synthetic single-domain antibodies (sdAbs) are desirable therapeutic molecules but their development is a considerable challenge. Here, using a retrospective analysis of in-house historical data, we examined the parameters that impact the outcome of screening phage-displayed synthetic human sdAb libraries to discover antigen-specific binders. We found no evidence for a differential effect of domain type (V H or V L ), library randomization strategy, incorporation of a stabilizing disulfide linkage or sdAb display format (monovalent vs. multivalent) on the probability of obtaining any antigen-binding human sdAbs, instead finding that the success of library screens was primarily related to properties of target antigens, especially molecular mass. The solubility and binding affinity of sdAbs isolated from successful screens depended both on properties of the sdAb libraries (primarily domain type) and the target antigens. Taking attrition of sdAbs with major manufacturability concerns (aggregation; low expression) and sdAbs that do not recognize native cell-surface antigens as independent probabilities, we calculate the overall likelihood of obtaining ≥1 antigen-binding human sdAb from a single library-target screen as ~24%. Successful library-target screens should be expected to yield ~1.3 human sdAbs on average, each with average binding affinity of ~2 μM. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. QuickLib, a method for building fully synthetic plasmid libraries by seamless cloning of degenerate oligonucleotides

    Science.gov (United States)

    Galka, Pierre; Jamez, Elisabeth; Joachim, Gilles

    2017-01-01

    Incorporation of synthetic degenerate oligonucleotides into plasmids for building highly diverse genetic libraries requires efficient and quantitative DNA manipulation. We present a fast and seamless method for generating libraries of PCR-synthesized plasmids designed with a degenerate sequence and short overlapping ends. Our method called QuickLib should find many applications in synthetic biology; as an example, we easily prepared genetic libraries of Escherichia coli expressing billions of different backbone cyclic peptides. PMID:28406948

  12. Identification of a small molecule inhibitor of the aminoglycoside 6'-N-acetyltransferase type ib [AAC(6')-ib] using mixture-based combinatorial libraries.

    Science.gov (United States)

    Tran, Tung; Chiem, Kevin; Jani, Saumya; Arivett, Brock A; Lin, David L; Lad, Rupali; Jimenez, Verónica; Farone, Mary B; Debevec, Ginamarie; Santos, Radleigh; Giulianotti, Marc; Pinilla, Clemencia; Tolmasky, Marcelo E

    2018-02-01

    The aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] is the most widely distributed enzyme among AAC(6')-I-producing Gram-negative pathogens and confers resistance to clinically relevant aminoglycosides including amikacin. This enzyme is therefore ideal to target with enzymatic inhibitors that could overcome resistance to aminoglycosides. The search for inhibitors was carried out using mixture-based combinatorial libraries, the scaffold ranking approach, and the positional scanning strategy. A library with high inhibitory activity had pyrrolidine pentamine scaffold and was selected for further analysis. This library contained 738,192 compounds with functionalities derived from 26 different amino acids (R1, R2 and R3) and 42 different carboxylic acids (R4) in four R group functionalities. The most active compounds all contained S-phenyl (R1 and R3) and S-hydromethyl (R2) functionalities at three locations and differed at the R4 position. The compound containing 3-phenylbutyl at R4 (compound 206) was a robust enzymatic inhibitor in vitro, in combination with amikacin potentiated the inhibition of growth of three resistant bacteria in culture, and improved survival when used as treatment of Galleria mellonella infected with aac(6')-Ib-harboring Klebsiella pneumoniae and Acinetobacter baumannii strains. Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  13. Isolation of scFv antibody fragments against HER2 and CEA tumor antigens from combinatorial antibody libraries derived from cancer patients.

    Science.gov (United States)

    Ayat, Hoda; Burrone, Oscar R; Sadghizadeh, Majid; Jahanzad, Eissa; Rastgou, Nasrin; Moghadasi, Sarrira; Arbabi, Mehdi

    2013-11-01

    Tumor cells expressing HER-2/neu and CEA antigens are potentially ideal targets for antibody-targeted therapy. In this study, two large human combinatorial libraries have been generated from the lymph nodes of breast cancer patients that express HER2 and CEA antigens in their tumors. These 'immune' libraries have been constructed in two different formats of scFv, differing in the length of the peptide linker connecting the two variable VH and VL domains. Libraries derived from these patients may contain a larger pool of anti-tumor antigen antibodies and are useful repertoire for isolating scFvs against any tumor markers. The results of this study showed that we were successful in obtaining human scFvs against HER-2/neu and CEA. For HER-2, cell-panning strategy was performed and resulted in two scFv binders that detected the complete HER-2 receptor on the cell membrane and internalized to the cells. Also, preliminary ELISA data showed that several anti-CEA scFv binders were isolated by panning. Copyright © 2013 The International Alliance for Biological Standardization. All rights reserved.

  14. Ribosome display of combinatorial antibody libraries derived from mice immunized with heat-killed Xylella fastidiosa and the selection of MopB-specific single-chain antibodies.

    Science.gov (United States)

    Azizi, Armaghan; Arora, Arinder; Markiv, Anatoliy; Lampe, David J; Miller, Thomas A; Kang, Angray S

    2012-04-01

    Pierce's disease is a devastating lethal disease of Vitus vinifera grapevines caused by the bacterium Xylella fastidiosa. There is no cure for Pierce's disease, and control is achieved predominantly by suppressing transmission of the glassy-winged sharpshooter insect vector. We present a simple robust approach for the generation of panels of recombinant single-chain antibodies against the surface-exposed elements of X. fastidiosa that may have potential use in diagnosis and/or disease transmission blocking studies. In vitro combinatorial antibody ribosome display libraries were assembled from immunoglobulin transcripts rescued from the spleens of mice immunized with heat-killed X. fastidiosa. The libraries were used in a single round of selection against an outer membrane protein, MopB, resulting in the isolation of a panel of recombinant antibodies. The potential use of selected anti-MopB antibodies was demonstrated by the successful application of the 4XfMopB3 antibody in an enzyme-linked immunosorbent assay (ELISA), a Western blot assay, and an immunofluorescence assay (IFA). These immortalized in vitro recombinant single-chain antibody libraries generated against heat-killed X. fastidiosa are a resource for the Pierce's disease research community that may be readily accessed for the isolation of antibodies against a plethora of X. fastidiosa surface-exposed antigenic molecules.

  15. High throughput discovery of influenza virus neutralizing antibodies from phage-displayed synthetic antibody libraries.

    Science.gov (United States)

    Chen, Ing-Chien; Chiu, Yi-Kai; Yu, Chung-Ming; Lee, Cheng-Chung; Tung, Chao-Ping; Tsou, Yueh-Liang; Huang, Yi-Jen; Lin, Chia-Lung; Chen, Hong-Sen; Wang, Andrew H-J; Yang, An-Suei

    2017-10-31

    Pandemic and epidemic outbreaks of influenza A virus (IAV) infection pose severe challenges to human society. Passive immunotherapy with recombinant neutralizing antibodies can potentially mitigate the threats of IAV infection. With a high throughput neutralizing antibody discovery platform, we produced artificial anti-hemagglutinin (HA) IAV-neutralizing IgGs from phage-displayed synthetic scFv libraries without necessitating prior memory of antibody-antigen interactions or relying on affinity maturation essential for in vivo immune systems to generate highly specific neutralizing antibodies. At least two thirds of the epitope groups of the artificial anti-HA antibodies resemble those of natural protective anti-HA antibodies, providing alternatives to neutralizing antibodies from natural antibody repertoires. With continuing advancement in designing and constructing synthetic scFv libraries, this technological platform is useful in mitigating not only the threats of IAV pandemics but also those from other newly emerging viral infections.

  16. Bacterial Microcolonies in Gel Beads for High-Throughput Screening of Libraries in Synthetic Biology.

    Science.gov (United States)

    Duarte, José M; Barbier, Içvara; Schaerli, Yolanda

    2017-11-17

    Synthetic biologists increasingly rely on directed evolution to optimize engineered biological systems. Applying an appropriate screening or selection method for identifying the potentially rare library members with the desired properties is a crucial step for success in these experiments. Special challenges include substantial cell-to-cell variability and the requirement to check multiple states (e.g., being ON or OFF depending on the input). Here, we present a high-throughput screening method that addresses these challenges. First, we encapsulate single bacteria into microfluidic agarose gel beads. After incubation, they harbor monoclonal bacterial microcolonies (e.g., expressing a synthetic construct) and can be sorted according their fluorescence by fluorescence activated cell sorting (FACS). We determine enrichment rates and demonstrate that we can measure the average fluorescent signals of microcolonies containing phenotypically heterogeneous cells, obviating the problem of cell-to-cell variability. Finally, we apply this method to sort a pBAD promoter library at ON and OFF states.

  17. Synthetic Promoter Library for Modulation of Actinorhodin Production in Streptomyces coelicolor A3(2)

    Science.gov (United States)

    Sohoni, Sujata Vijay; Fazio, Alessandro; Workman, Christopher T.; Mijakovic, Ivan; Lantz, Anna Eliasson

    2014-01-01

    The objective of this study was the application of the synthetic promoter library (SPL) technology for modulation of actinorhodin production in Streptomyces coelicolor A3(2). The SPL technology was used to optimize the expression of a pathway specific positive transcriptional regulator ActII orf4, which activates the transcription of the S. coelicolor actinorhodin biosynthetic gene cluster. The native actII orf4 promoter was replaced with synthetic promoters, generating a S. coelicolor library with a broad range of expression levels of actII orf4. The resulting library was screened based on the yield of actinorhodin. Selected strains were further physiologically characterized. One of the strains from the library, ScoSPL20, showed considerably higher yield of actinorhodin and final actinorhodin titer, compared to S. coelicolor wild type and S. coelicolor with actII orf4 expressed from a strong constitutive promoter. ScoSPL20 demonstrated exceptional productivity despite having a comparatively weak expression from the promoter. Interestingly, the ScoSPL20 promoter was activated at a much earlier stage of growth compared to the wild type, demonstrating the advantage of fine-tuning and temporal tuning of gene expression in metabolic engineering. Transcriptome studies were performed in exponential and actinorhodin-producing phase of growth to compare gene expression between ScoSPL20 and the wild type. To our knowledge, this is the first successful application of the SPL technology for secondary metabolite production in filamentous bacteria. PMID:24963940

  18. Codon-Precise, Synthetic, Antibody Fragment Libraries Built Using Automated Hexamer Codon Additions and Validated through Next Generation Sequencing

    Directory of Open Access Journals (Sweden)

    Laura Frigotto

    2015-05-01

    Full Text Available We have previously described ProxiMAX, a technology that enables the fabrication of precise, combinatorial gene libraries via codon-by-codon saturation mutagenesis. ProxiMAX was originally performed using manual, enzymatic transfer of codons via blunt-end ligation. Here we present Colibra™: an automated, proprietary version of ProxiMAX used specifically for antibody library generation, in which double-codon hexamers are transferred during the saturation cycling process. The reduction in process complexity, resulting library quality and an unprecedented saturation of up to 24 contiguous codons are described. Utility of the method is demonstrated via fabrication of complementarity determining regions (CDR in antibody fragment libraries and next generation sequencing (NGS analysis of their quality and diversity.

  19. Molecular Pathogenesis of Rickettsioses and Development of Novel Anti-Rickettsial Treatment by Combinatorial Peptide-Based Libraries

    National Research Council Canada - National Science Library

    Walker, David H; Olano, Juan P

    2007-01-01

    ...) library and challenge with R. prowazekii, R. rickettsii, and O. tsutsugamushi; 2) To determine the role of NF-kB, cytokines, ROS and NO in intracellular killing of rickettsia-infected monolayers containing adapteins and 3...

  20. PR01 Molecular Pathogenesis of Rickettsioses and Development of Anti-Rickettsial Treatment by Combinatorial Peptide-Based Libraries

    National Research Council Canada - National Science Library

    Walker, David H

    2006-01-01

    ...) library and challenge with R. prowazekii, R. rickettsii, and O. tsutsugamushi; 2) To determine the role of NF-kB, cytokines, ROS and NO in intracellular killing of rickettsia-infected monolayers containing adapteins and 3...

  1. Dynamic combinatorial chemistry with diselenides and disulfides in water

    DEFF Research Database (Denmark)

    Rasmussen, Brian; Sørensen, Anne; Gotfredsen, Henrik

    2014-01-01

    Diselenide exchange is introduced as a reversible reaction in dynamic combinatorial chemistry in water. At neutral pH, diselenides are found to mix with disulfides and form dynamic combinatorial libraries of diselenides, disulfides, and selenenylsulfides. This journal is...

  2.   Cell Penetrating Peptoids (CPPos: Synthesis of a Small Combinatorial Library by Using IRORI MiniKans

    Directory of Open Access Journals (Sweden)

    Dominik K. Kölmel

    2012-11-01

    Full Text Available Cell penetrating peptoids (CPPos are potent mimics of the corresponding cell penetrating peptides (CPPs. The synthesis of diverse oligomeric libraries that display a variety of backbone scaffolds and side-chain appendages are a very promising source of novel CPPos, which can be used to either target different cellular organelles or even different tissues and organs. In this study we established the submonomer-based solid phase synthesis of a “proof of principle” peptoid library in IRORI MiniKans to expand the amount for phenotypic high throughput screens of CPPos. The library consisting of tetrameric peptoids [oligo(N-alkylglycines] was established on Rink amide resin in a split and mix approach with hydrophilic and hydrophobic peptoid side chains. All CPPos of the presented library were labeled with rhodamine B to allow for the monitoring of cellular uptake by fluorescent confocal microscopy. Eventually, all the purified peptoids were subjected to live cell imaging to screen for CPPos with organelle specificity. While highly charged CPPos enter the cells by endocytosis with subsequent endosomal release, critical levels of lipophilicity allow other CPPos to specifically localize to mitochondria once a certain lipophilicity threshold is reached.

  3. Synthetic Promoter Library for Modulation of Actinorhodin Production in Streptomyces coelicolor A3(2)

    DEFF Research Database (Denmark)

    Sohoni, Sujata Vijay; Fazio, Alessandro; Workman, Christopher

    2014-01-01

    of gene expression in metabolic engineering. Transcriptome studies were performed in exponential and actinorhodin-producing phase of growth to compare gene expression between ScoSPL20 and the wild type. To our knowledge, this is the first successful application of the SPL technology for secondary......The objective of this study was the application of the synthetic promoter library (SPL) technology for modulation of actinorhodin production in Streptomyces coelicolor A3(2). The SPL technology was used to optimize the expression of a pathway specific positive transcriptional regulator Actll orf4...

  4. Process automation toward ultra-high-throughput screening of combinatorial one-bead-one-compound (OBOC) peptide libraries.

    Science.gov (United States)

    Cha, Junhoe; Lim, Jaehong; Zheng, Yiran; Tan, Sylvia; Ang, Yi Li; Oon, Jessica; Ang, Mei Wei; Ling, Jingjing; Bode, Marcus; Lee, Su Seong

    2012-06-01

    With an aim to develop peptide-based protein capture agents that can replace antibodies for in vitro diagnosis, an ultra-high-throughput screening strategy has been investigated by automating labor-intensive, time-consuming processes that are the construction of peptide libraries, sorting of positive beads, and peptide sequencing through analysis of tandem mass spectrometry data. Although instruments for automation, such as peptide synthesizers and automatic bead sorters, have been used in some groups, the overall process has not been well optimized to minimize time, cost, and efforts, as well as to maximize product quality and performance. Herein we suggest and explore several solutions to the existing problems with the automation of the key processes. The overall process optimization has been done successfully in orchestration with the technologies such as rapid cleavage of peptides from beads and semiautomatic peptide sequencing that we have developed previously. This optimization allowed one-round screening, from peptide library construction to peptide sequencing, to be completed within 4 to 5 days. We also successfully identified a 6-mer ligand for carcinoembryonic antigen-cell adhesion molecule 5 (CEACAM 5) through three-round screenings, including one-round screening of a focused library.

  5. High-content analysis screening for cell cycle regulators using arrayed synthetic crRNA libraries.

    Science.gov (United States)

    Strezoska, Žaklina; Perkett, Matthew R; Chou, Eldon T; Maksimova, Elena; Anderson, Emily M; McClelland, Shawn; Kelley, Melissa L; Vermeulen, Annaleen; Smith, Anja van Brabant

    2017-06-10

    The CRISPR-Cas9 system has been utilized for large-scale, loss-of-function screens mainly using lentiviral pooled formats and cell-survival phenotypic assays. Screening in an arrayed format expands the types of phenotypic readouts that can be used to now include high-content, morphology-based assays, and with the recent availability of synthetic crRNA libraries, new studies are emerging. Here, we use a cell cycle reporter cell line to perform an arrayed, synthetic crRNA:tracrRNA screen targeting 169 genes (>600 crRNAs) and used high content analysis (HCA) to identify genes that regulate the cell cycle. Seven parameters were used to classify cells into cell cycle categories and multiple parameters were combined using a new analysis technique to identify hits. Comprehensive hit follow-up experiments included target gene expression analysis, confirmation of DNA insertions/deletions, and validation with orthogonal reagents. Our results show that most hits had three or more independent crRNAs per gene that demonstrated a phenotype with consistent individual parameters, indicating that our screen produced high-confidence hits with low off-target effects and allowed us to identify hits with more subtle phenotypes. The results of our screen demonstrate the power of using arrayed, synthetic crRNAs for functional phenotypic screening using multiparameter HCA assays. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  6. Mesofluidic devices for DNA-programmed combinatorial chemistry.

    Directory of Open Access Journals (Sweden)

    Rebecca M Weisinger

    Full Text Available Hybrid combinatorial chemistry strategies that use DNA as an information-carrying medium are proving to be powerful tools for molecular discovery. In order to extend these efforts, we present a highly parallel format for DNA-programmed chemical library synthesis. The new format uses a standard microwell plate footprint and is compatible with commercially available automation technology. It can accommodate a wide variety of combinatorial synthetic schemes with up to 384 different building blocks per chemical step. We demonstrate that fluidic routing of DNA populations in the highly parallel format occurs with excellent specificity, and that chemistry on DNA arrayed into 384 well plates proceeds robustly, two requirements for the high-fidelity translation and efficient in vitro evolution of small molecules.

  7. The construction of a library of synthetic promoters revealed some specific features of strong Streptomyces promoters

    DEFF Research Database (Denmark)

    Seghezzi, Nicolas; Amar, Patrick; Købmann, Brian

    2011-01-01

    projects. Thirty-eight promoters were sequenced, and the sequences of the 14 weakest and 14 strongest promoters were compared using the WebLogo software with small sample correction. This comparison revealed that the −10 box, the −10 extended motif as well as the spacer of the strong Streptomyces promoters......Streptomyces are bacteria of industrial interest whose genome contains more than 73% of bases GC. In order to define, in these GC-rich bacteria, specific sequence features of strong promoters, a library of synthetic promoters of various sequence composition was constructed in Streptomyces. To do so...... concentrations of neomycin (20, 50, and 100 μg ml−1). Promoter strengths varied up to 12-fold, in small increments of activity increase, as determined by reverse transcriptase-PCR. This collection of promoters of various strengths can be useful for the fine-tuning of gene expression in genetic engineering...

  8. Predictive combinatorial design of mRNA translation initiation regions for systematic optimization of gene expression levels.

    Science.gov (United States)

    Seo, Sang Woo; Yang, Jae-Seong; Cho, Han-Saem; Yang, Jina; Kim, Seong Cheol; Park, Jong Moon; Kim, Sanguk; Jung, Gyoo Yeol

    2014-03-31

    Balancing the amounts of enzymes is one of the important factors to achieve optimum performance of a designed metabolic pathway. However, the random mutagenesis approach is impractical since it requires searching an unnecessarily large number of variants and often results in searching a narrow range of expression levels which are out of optimal level. Here, we developed a predictive combinatorial design method, called UTR Library Designer, which systematically searches a large combinatorial space of expression levels. It accomplishes this by designing synthetic translation initiation region of mRNAs in a predictive way based on a thermodynamic model and genetic algorithm. Using this approach, we successfully enhanced lysine and hydrogen production in Escherichia coli. Our method significantly reduced the number of variants to be explored for covering large combinatorial space and efficiently enhanced pathway efficiency, thereby facilitating future efforts in metabolic engineering and synthetic biology.

  9. Design, structure-based focusing and in silico screening of combinatorial library of peptidomimetic inhibitors of Dengue virus NS2B-NS3 protease

    Science.gov (United States)

    Frecer, Vladimir; Miertus, Stanislav

    2010-03-01

    Serine protease activity of the NS3 protein of Dengue virus is an important target of antiviral agents that interfere with the viral polyprotein precursor processing catalyzed by the NS3 protease (NS3pro), which is important for the viral replication and maturation. Recent studies showed that substrate-based peptidomimetics carrying an electrophilic warhead inhibit the NS2B-NS3pro cofactor-protease complex with inhibition constants in the low micromolar concentration range when basic amino acid residues occupy P1 and P2 positions of the inhibitor, and an aldehyde warhead is attached to the P1. We have used computer-assisted combinatorial techniques to design, focus using the NS2B-NS3pro receptor 3D structure, and in silico screen a virtual library of more than 9,200 peptidomimetic analogs targeted around the template inhibitor Bz-Nle-Lys-Arg-Arg- H (Bz—benzoyl) that are composed mainly of unusual amino acid residues in all positions P1-P4. The most promising virtual hits were analyzed in terms of computed enzyme-inhibitor interactions and Adsorption, Distribution, Metabolism and Excretion (ADME) related physico-chemical properties. Our study can direct the interest of medicinal chemists working on a next generation of antiviral chemotherapeutics against the Dengue Fever towards the explored subset of the chemical space that is predicted to contain peptide aldehydes with NS3pro inhibition potencies in nanomolar range which display ADME-related properties comparable to the training set inhibitors.

  10. Combinatorial synthesis of natural products

    DEFF Research Database (Denmark)

    Nielsen, John

    2002-01-01

    Combinatorial syntheses allow production of compound libraries in an expeditious and organized manner immediately applicable for high-throughput screening. Natural products possess a pedigree to justify quality and appreciation in drug discovery and development. Currently, we are seeing a rapid...... increase in application of natural products in combinatorial chemistry and vice versa. The therapeutic areas of infectious disease and oncology still dominate but many new areas are emerging. Several complex natural products have now been synthesised by solid-phase methods and have created the foundation...... for preparation of combinatorial libraries. In other examples, natural products or intermediates have served as building blocks or scaffolds in the synthesis of complex natural products, bioactive analogues or designed hybrid molecules. Finally, structural motifs from the biologically active parent molecule have...

  11. Synthetic Oligosaccharide Libraries and Microarray Technology: A Powerful Combination for the Success of Current Glycosaminoglycan Interactomics.

    Science.gov (United States)

    Pomin, Vitor H; Wang, Xu

    2017-11-20

    Glycosaminoglycans (GAGs) are extracellular matrix and/or cell-surface sulfated glycans crucial to the regulation of various signaling proteins, the functions of which are essential in many pathophysiological systems. Because structural heterogeneity is high in GAG chains and purification is difficult, the use of structurally defined GAG oligosaccharides from natural sources as molecular models in both biophysical and pharmacological assays is limited. To overcome this obstacle, GAG-like oligosaccharides of well-defined structures are currently being synthesized by chemical and/or enzymatic means in many research groups around the world. These synthetic GAG oligosaccharides serve as useful molecular tools in studies of GAG-protein interactions. In this review, besides discussing the commonest routes used for the synthesis of GAG oligosaccharides, we also survey some libraries of these synthetic models currently available for research and discuss their activities in interaction studies with functional proteins, especially through the microarray approach. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Combinatorial synthesis of ceramic materials

    Science.gov (United States)

    Lauf, Robert J.; Walls, Claudia A.; Boatner, Lynn A.

    2006-11-14

    A combinatorial library includes a gelcast substrate defining a plurality of cavities in at least one surface thereof; and a plurality of gelcast test materials in the cavities, at least two of the test materials differing from the substrate in at least one compositional characteristic, the two test materials differing from each other in at least one compositional characteristic.

  13. A two-channel detection method for autofluorescence correction and efficient on-bead screening of one-bead one-compound combinatorial libraries using the COPAS fluorescence activated bead sorting system

    International Nuclear Information System (INIS)

    Hintersteiner, Martin; Auer, Manfred

    2013-01-01

    One-bead one-compound combinatorial library beads exhibit varying levels of autofluorescence after solid phase combinatorial synthesis. Very often this causes significant problems for automated on-bead screening using TentaGel beads and fluorescently labeled target proteins. Herein, we present a method to overcome this limitation when fluorescence activated bead sorting is used as the screening method. We have equipped the COPAS bead sorting instrument with a high-speed profiling unit and developed a spectral autofluorescence correction method. The correction method is based on a simple algebraic operation using the fluorescence data from two detection channels and is applied on-the-fly in order to reliably identify hit beads by COPAS bead sorting. Our method provides a practical tool for the fast and efficient isolation of hit beads from one-bead one-compound library screens using either fluorescently labeled target proteins or biotinylated target proteins. This method makes hit bead identification easier and more reliable. It reduces false positives and eliminates the need for time-consuming pre-sorting of library beads in order to remove autofluorescent beads. (technical note)

  14. Identification of cancer specific ligands from one-bead one compound combinatorial libraries to develop theranostics agents against oral squamous cell carcinoma

    Science.gov (United States)

    Yang, Frances Fan

    Background: Oral squamous cell carcinoma (OSCC) is one of the most prevalent disease worldwide. One-bead one-compound (OBOC) combinatorial technology is a powerful method to identify peptidomimetic ligands against a variety of receptors on cell surfaces. We therefore hypothesized that cancer specific ligands against OSCC might be identified and can be conjugated to optical dyes or nanocarriers to develop theranostic agents against OSCC. Material and methods: Different OSCC cell lines were incubated with OBOC libraries and beads with cell binding were sorted and then screened with normal human cells to identify peptide-beads binding to different OSCC cell lines but not binding to normal human cells. The molecular probes of OSCC were developed by biotinylating the carboxyl end of the ligands. OSCC theranostic agents were developed by decorating LLY13 with NPs and evaluated by using orthotopic bioluminescent oral cancer model. Results: Six OSCC specific ligands were discovered. Initial peptide-histochemistry study indicated that LLY12 and LLY13 were able to specifically detect OSCC cells grown on chamber slides at the concentration of 1 muM. In addition, LLY13 was found to penetrate into the OSCC cells and accumulate in the cytoplasm, and nucleus. After screened with a panel of integrin antibodies, only anti-alpha3 antibody was able to block most of OSCC cells binding to the LLY13 beads. OSCC theranostic agents developed using targeting LLY13 micelles (25+/- 4nm in diameter) were more efficient in binding to HSC-3 cancer cells compared to non-targeting micelles. Ex vivo images demonstrated that xenografts from the mice with targeting micelles appeared to have higher signals than the non-targeting groups. Conclusion: LLY13 has promising in vitro and in vivo targeting activity against OSCC. In addition, LLY13 is also able to penetrate into cancer cells via endocytosis. Initial study indicated that alpha3 integrin might partially be the corresponding receptor involved

  15. Isolation of anti-toxin single domain antibodies from a semi-synthetic spiny dogfish shark display library

    Directory of Open Access Journals (Sweden)

    Goldman Ellen R

    2007-11-01

    Full Text Available Abstract Background Shark heavy chain antibody, also called new antigen receptor (NAR, consists of one single Variable domain (VH, containing only two complementarity-determining regions (CDRs. The antigen binding affinity and specificity are mainly determined by these two CDRs. The good solubility, excellent thermal stability and complex sequence variation of small single domain antibodies (sdAbs make them attractive alternatives to conventional antibodies. In this report, we construct and characterize a diversity enhanced semi-synthetic NAR V display library based on naturally occurring NAR V sequences. Results A semi-synthetic shark sdAb display library with a complexity close to 1e9 was constructed. This was achieved by introducing size and sequence variations in CDR3 using randomized CDR3 primers of three different lengths. Binders against three toxins, staphylococcal enterotoxin B (SEB, ricin, and botulinum toxin A (BoNT/A complex toxoid, were isolated from panning the display library. Soluble sdAbs from selected binders were purified and evaluated using direct binding and thermal stability assays on the Luminex 100. In addition, sandwich assays using sdAb as the reporter element were developed to demonstrate their utility for future sensor applications. Conclusion We demonstrated the utility of a newly created hyper diversified shark NAR displayed library to serve as a source of thermal stable sdAbs against a variety of toxins.

  16. Dynamic Combinatorial Chemistry and Organocatalysis with Thiosemicarbazones and Organocatalysts for Hydrazone and Oxime Bioconjugations

    DEFF Research Database (Denmark)

    Larsen, Dennis

    The first part of this thesis describes the use of thiosemicarbazones for dynamic combinatorial chemistry. Building blocks incorporating thiosemicarbazides and acetalprotected aldehydes were synthesised and conditions where these building blocks formed dynamic combinatorial libraries under...

  17. Heterogenous phase as a mean in combinatorial chemistry

    International Nuclear Information System (INIS)

    Abdel-Hamid, S.G.

    2007-01-01

    Combinatorial chemistry is a rapid and inexpensive technique for the synthesis of hundreds of thousands of organic compounds of potential medicinal activity. In the past few decades a large number of combinatorial libraries have been constructed, and significantly supplement the chemical diversity of the traditional collections of the potentially active medicinal compounds. Solid phase synthesis was used to enrich the combinatorial chemistry libraries, through the use of solid supports (resins) and their modified forms. Most of the new libraries of compounds appeared recently, were synthesized by the use of solid-phase. Solid-phase combinatorial chemistry (SPCC) is now considered as an outstanding branch in pharmaceutical chemistry research and used extensively as a tool for drug discovery within the context of high-throughput chemical synthesis. The best pure libraries synthesized by the use of solid phase combinatorial chemistry (SPCC) may well be those of intermediate complexity that are free of artifact-causing nuisance compounds. (author)

  18. 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.

  19. Combined in vitro transcription and reverse transcription to amplify and label complex synthetic oligonucleotide probe libraries

    Science.gov (United States)

    Murgha, Yusuf; Beliveau, Brian; Semrau, Kassandra; Schwartz, Donald; Wu, Chao-ting; Gulari, Erdogan; Rouillard, Jean-Marie

    2016-01-01

    Oligonucleotide microarrays allow the production of complex custom oligonucleotide libraries for nucleic acid detection–based applications such as fluorescence in situ hybridization (FISH). We have developed a PCR-free method to make single-stranded DNA (ssDNA) fluorescent probes through an intermediate RNA library. A double-stranded oligonucleotide library is amplified by transcription to create an RNA library. Next, dye- or hapten-conjugate primers are used to reverse transcribe the RNA to produce a dye-labeled cDNA library. Finally the RNA is hydrolyzed under alkaline conditions to obtain the single-stranded fluorescent probes library. Starting from unique oligonucleotide library constructs, we present two methods to produce single-stranded probe libraries. The two methods differ in the type of reverse transcription (RT) primer, the incorporation of fluorescent dye, and the purification of fluorescent probes. The first method employs dye-labeled reverse transcription primers to produce multiple differentially single-labeled probe subsets from one microarray library. The fluorescent probes are purified from excess primers by oligonucleotide-bead capture. The second method uses an RNA:DNA chimeric primer and amino-modified nucleotides to produce amino-allyl probes. The excess primers and RNA are hydrolyzed under alkaline conditions, followed by probe purification and labeling with amino-reactive dyes. The fluorescent probes created by the combination of transcription and reverse transcription can be used for FISH and to detect any RNA and DNA targets via hybridization. PMID:26054766

  20. Combined in vitro transcription and reverse transcription to amplify and label complex synthetic oligonucleotide probe libraries.

    Science.gov (United States)

    Murgha, Yusuf; Beliveau, Brian; Semrau, Kassandra; Schwartz, Donald; Wu, Chao-Ting; Gulari, Erdogan; Rouillard, Jean-Marie

    2015-06-01

    Oligonucleotide microarrays allow the production of complex custom oligonucleotide libraries for nucleic acid detection-based applications such as fluorescence in situ hybridization (FISH). We have developed a PCR-free method to make single-stranded DNA (ssDNA) fluorescent probes through an intermediate RNA library. A double-stranded oligonucleotide library is amplified by transcription to create an RNA library. Next, dye- or hapten-conjugate primers are used to reverse transcribe the RNA to produce a dye-labeled cDNA library. Finally the RNA is hydrolyzed under alkaline conditions to obtain the single-stranded fluorescent probes library. Starting from unique oligonucleotide library constructs, we present two methods to produce single-stranded probe libraries. The two methods differ in the type of reverse transcription (RT) primer, the incorporation of fluorescent dye, and the purification of fluorescent probes. The first method employs dye-labeled reverse transcription primers to produce multiple differentially single-labeled probe subsets from one microarray library. The fluorescent probes are purified from excess primers by oligonucleotide-bead capture. The second method uses an RNA:DNA chimeric primer and amino-modified nucleotides to produce amino-allyl probes. The excess primers and RNA are hydrolyzed under alkaline conditions, followed by probe purification and labeling with amino-reactive dyes. The fluorescent probes created by the combination of transcription and reverse transcription can be used for FISH and to detect any RNA and DNA targets via hybridization.

  1. 3D virtual screening of large combinatorial spaces.

    Science.gov (United States)

    Muegge, Ingo; Zhang, Qiang

    2015-01-01

    A new method for 3D in silico screening of large virtual combinatorial chemistry spaces is described. The software PharmShape screens millions of individual compounds applying a multi-conformational pharmacophore and shape based approach. Its extension, PharmShapeCC, is capable of screening trillions of compounds from tens of thousands of combinatorial libraries. Key elements of PharmShape and PharmShapeCC are customizable pharmacophore features, a composite inclusion sphere, library core intermediate clustering, and the determination of combinatorial library consensus orientations that allow for orthogonal enumeration of libraries. The performance of the software is illustrated by the prospective identification of a novel CXCR5 antagonist and examples of finding novel chemotypes from synthesizing and evaluating combinatorial hit libraries identified from PharmShapeCC screens for CCR1, LTA4 hydrolase, and MMP-13. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Model, prediction, and experimental verification of composition and thickness in continuous spread thin film combinatorial libraries grown by pulsed laser deposition

    International Nuclear Information System (INIS)

    Bassim, N. D.; Schenck, P. K.; Otani, M.; Oguchi, H.

    2007-01-01

    Pulsed laser deposition was used to grow continuous spread thin film libraries of continuously varying composition as a function of position on a substrate. The thickness of each component that contributes to a library can be empirically modeled to a bimodal cosine power distribution. We deposited ternary continuous spread thin film libraries from Al 2 O 3 , HfO 2 , and Y 2 O 3 targets, at two different background pressures of O 2 : 1.3 and 13.3 Pa. Prior to library deposition, we deposited single component calibration films at both pressures in order to measure and fit the thickness distribution. Following the deposition and fitting of the single component films, we predict both the compositional coverage and the thickness of the libraries. Then, we map the thickness of the continuous spread libraries using spectroscopic reflectometry and measure the composition of the libraries as a function of position using mapping wavelength-dispersive spectrometry (WDS). We then compare the compositional coverage of the libraries and observe that compositional coverage is enhanced in the case of 13.3 Pa library. Our models demonstrate linear correlation coefficients of 0.98 for 1.3 Pa and 0.98 for 13.3 Pa with the WDS

  3. Isolation of high-affinity human IgE and IgG antibodies recognising Bet v 1 and Humicola lanuginosa lipase from combinatorial phage libraries

    DEFF Research Database (Denmark)

    Jakobsen, Charlotte G; Bodtger, Uffe; Kristensen, Peter

    2004-01-01

    . Human IgE and IgG libraries have been created from patients allergic to birch pollen or lipase. These libraries have been used to select binders recognising the major birch pollen allergen Bet v 1 and Humicola lanuginosa lipase. A panel of allergen-specific IgE and IgG antibodies were identified...

  4. Combinatorial investigation of magnetic materials

    Science.gov (United States)

    Aronova, Maria A.

    Combinatorial synthesis is an efficient tool that can be used to discover new materials. It allows one to systemically study a large number of materials simultaneously as their physical properties change with the varying chemical composition. Using this technique, we study various multifunctional electronic materials. Different designs of libraries, such as discrete libraries and composition spreads, are fabricated and characterized in order to rapidly map composition-structure-property relationships in a variety of systems. We have made gas sensor device libraries to optimize the performance of gas sensing materials. We have utilized the combinatorial pulsed laser deposition (PLD) flange for fabricating the discrete device library of doped SnO2 thin films. Several libraries were made with different amounts of dopants such as In2O3, WO3, ZnO, Pt, and Pd. After exposing the whole library to chloroform, formaldehyde, and benzene gases, the compositions most sensitive to these gases were found. We have also demonstrated the use of a gas sensor library as an electronic nose where responses from different devices are multiplexed to perform pattern recognition for distinguishing different gases at concentrations down to 12.5 ppm with high repeatability of response signals. Magnetic properties of composition spreads and discrete libraries are analyzed by a scanning SQUID microscope. The in-plane and out-of-plane magnetization distributions are calculated from the magnetic field data using the inversion technique. Various parameters that control the inversion technique are discussed in detail and optimized with the help of simulated data. By applying the inversion technique to thin-film discrete libraries, we have mapped the functional phase diagram of Ni-Mn-Ga system whose Heusler composition Ni2MnGa is a well known ferromagnetic shape memory alloys (FSMAs). A large, previously unexplored compositional region of FSMAs outside the Heusler composition is found. In search

  5. Semi-synthetic vNAR libraries screened against therapeutic antibodies primarily deliver anti-idiotypic binders.

    Science.gov (United States)

    Könning, Doreen; Rhiel, Laura; Empting, Martin; Grzeschik, Julius; Sellmann, Carolin; Schröter, Christian; Zielonka, Stefan; Dickgießer, Stephan; Pirzer, Thomas; Yanakieva, Desislava; Becker, Stefan; Kolmar, Harald

    2017-08-29

    Anti-idiotypic binders which specifically recognize the variable region of monoclonal antibodies have proven to be robust tools for pharmacokinetic studies of antibody therapeutics and for the development of cancer vaccines. In the present investigation, we focused on the identification of anti-idiotypic, shark-derived IgNAR antibody variable domains (vNARs) targeting the therapeutic antibodies matuzumab and cetuximab for the purpose of developing specific capturing ligands. Using yeast surface display and semi-synthetic, CDR3-randomized libraries, we identified several highly specific binders targeting both therapeutic antibodies in their corresponding variable region, without applying any counter selections during screening. Importantly, anti-idiotypic vNAR binders were not cross-reactive towards cetuximab or matuzumab, respectively, and comprised good target recognition in the presence of human and mouse serum. When coupled to magnetic beads, anti-idiotypic vNAR variants could be used as efficient capturing tools. Moreover, a two-step procedure involving vNAR-functionalized beads was employed for the enrichment of potentially bispecific cetuximab × matuzumab antibody constructs. In conclusion, semi-synthetic and CDR3-randomized vNAR libraries in combination with yeast display enable the fast and facile identification of anti-idiotypic vNAR domains targeting monoclonal antibodies primarily in an anti-idiotypic manner.

  6. Identification and characterization of epitopes on Plasmodium knowlesi merozoite surface protein-142 (MSP-142) using synthetic peptide library and phage display library.

    Science.gov (United States)

    Cheong, Fei Wen; Fong, Mun Yik; Lau, Yee Ling

    2016-02-01

    Plasmodium knowlesi can cause potentially life threatening human malaria. The Plasmodium merozoite surface protein-142 (MSP-142) is a potential target for malaria blood stage vaccine, and for diagnosis of malaria. Two epitope mapping techniques were used to identify the potential epitopes within P. knowlesi MSP-142. Nine and 14 potential epitopes were identified using overlapping synthetic peptide library and phage display library, respectively. Two regions on P. knowlesi MSP-142 (amino acid residues 37-95 and residues 240-289) were identified to be the potential dominant epitope regions. Two of the prominent epitopes, P10 (TAKDGMEYYNKMGELYKQ) and P31 (RCLLGFKEVGGKCVPASI), were evaluated using mouse model. P10- and P31-immunized mouse sera reacted with recombinant P. knowlesi MSP-142, with the IgG isotype distribution of IgG2b>IgG1>IgG2a>IgG3. Significant higher level of cytokines interferon-gamma and interleukin-2 was detected in P31-immunized mice. Both P10 and P31 could be the suitable epitope candidates to be used in malaria vaccine designs and immunodiagnostic assays, provided further evaluation is needed to validate the potential uses of these epitopes. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. 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

  8. Synthetic

    Directory of Open Access Journals (Sweden)

    Anna Maria Manferdini

    2010-06-01

    Full Text Available Traditionally materials have been associated with a series of physical properties that can be used as inputs to production and manufacturing. Recently we witnessed an interest in materials considered not only as ‘true matter’, but also as new breeds where geometry, texture, tooling and finish are able to provoke new sensations when they are applied to a substance. These artificial materials can be described as synthetic because they are the outcome of various qualities that are not necessarily true to the original matter, but they are the combination of two or more parts, whether by design or by natural processes. The aim of this paper is to investigate the potential of architectural surfaces to produce effects through the invention of new breeds of artificial matter, using micro-scale details derived from Nature as an inspiration.

  9. Combinatorial Biosynthesis of Polyketides – A Perspective

    Science.gov (United States)

    Wong, Fong T.; Khosla, Chaitan

    2012-01-01

    Since their discovery, polyketide synthases have been attractive targets of biosynthetic engineering to make “unnatural” natural products. Although combinatorial biosynthesis has made encouraging advances over the past two decades, the field remains in its infancy. In this enzyme-centric perspective, we discuss the scientific and technological challenges that could accelerate the adoption of combinatorial biosynthesis as a method of choice for the preparation of encoded libraries of bioactive small molecules. Borrowing a page from the protein structure prediction community, we propose a periodic challenge program to vet the most promising methods in the field, and to foster the collective development of useful tools and algorithms. PMID:22342766

  10. Discovery of potent inhibitors of human β-tryptase from pre-equilibrated dynamic combinatorial libraries† †Electronic supplementary information (ESI) available: Details of the synthetic procedures and characterization data, as well as detailed preparation of DCLs, enzyme assay procedures, and description of the molecular modeling calculations. See DOI: 10.1039/c4sc02943g Click here for additional data file.

    Science.gov (United States)

    Jiang, Qian-Qian; Sicking, Wilhelm; Ehlers, Martin

    2015-01-01

    Pre-equilibrated dynamic combinatorial libraries based on acyl hydrazone interchange of peptide-derived hydrazides and di- and tri-aldehydes have been used to discover potent inhibitors with nanomolar affinities for β-tryptase. To identify potent inhibitors the activity of the full library containing 95 members was compared with those of sub-libraries in which individual building blocks were missing. The most active library members contain a rigid central aromatic scaffold with three cationic peptide arms. The arms of the best inhibitors also contained a tailor-made GCP oxoanion binding motif attached to a lysine side chain. The most potent tri-armed hydrazones with peptide arms GKWR or GKWK(GCP) were shown to inhibit β-tryptase (K i ca. 10–20 nM) reversibly, non-competitively and selectively (compared to related serine proteases, e.g. trypsin and chymotrypsin), most likely by binding to the protein surface, also in agreement with molecular modelling calculations. These new inhibitors are one order of magnitude more efficient than related tetravalent inhibitors obtained from previous work on a split-mix-combinatorial library and were identified with significantly less effort, demonstrating the usefulness of this approach for the identification of enzyme inhibitors in general. PMID:29163876

  11. Characterization of biases in phosphopeptide enrichment by Ti(4+)-immobilized metal affinity chromatography and TiO2 using a massive synthetic library and human cell digests

    NARCIS (Netherlands)

    Matheron, Lucrece; van den Toorn, Henk; Heck, Albert J R; Mohammed, Shabaz

    2014-01-01

    Outcomes of comparative evaluations of enrichment methods for phosphopeptides depend highly on the experimental protocols used, the operator, the source of the affinity matrix, and the samples analyzed. Here, we attempt such a comparative study exploring a very large synthetic library containing

  12. Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases.

    Science.gov (United States)

    Xu, Yuquan; Zhou, Tong; Zhang, Shuwei; Espinosa-Artiles, Patricia; Wang, Luoyi; Zhang, Wei; Lin, Min; Gunatilaka, A A Leslie; Zhan, Jixun; Molnár, István

    2014-08-26

    Combinatorial biosynthesis aspires to exploit the promiscuity of microbial anabolic pathways to engineer the synthesis of new chemical entities. Fungal benzenediol lactone (BDL) polyketides are important pharmacophores with wide-ranging bioactivities, including heat shock response and immune system modulatory effects. Their biosynthesis on a pair of sequentially acting iterative polyketide synthases (iPKSs) offers a test case for the modularization of secondary metabolic pathways into "build-couple-pair" combinatorial synthetic schemes. Expression of random pairs of iPKS subunits from four BDL model systems in a yeast heterologous host created a diverse library of BDL congeners, including a polyketide with an unnatural skeleton and heat shock response-inducing activity. Pairwise heterocombinations of the iPKS subunits also helped to illuminate the innate, idiosyncratic programming of these enzymes. Even in combinatorial contexts, these biosynthetic programs remained largely unchanged, so that the iPKSs built their cognate biosynthons, coupled these building blocks into chimeric polyketide intermediates, and catalyzed intramolecular pairing to release macrocycles or α-pyrones. However, some heterocombinations also provoked stuttering, i.e., the relaxation of iPKSs chain length control to assemble larger homologous products. The success of such a plug and play approach to biosynthesize novel chemical diversity bodes well for bioprospecting unnatural polyketides for drug discovery.

  13. 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

  14. Enzyme engineering: A synthetic biology approach for more effective library generation and automated high-throughput screening

    Science.gov (United States)

    Ebert, Maximilian C. C. J. C.; Mugford, Paul F.; Pelletier, Joelle N.

    2017-01-01

    The Golden Gate strategy entails the use of type IIS restriction enzymes, which cut outside of their recognition sequence. It enables unrestricted design of unique DNA fragments that can be readily and seamlessly recombined. Successfully employed in other synthetic biology applications, we demonstrate its advantageous use to engineer a biocatalyst. Hot-spots for mutations were individuated in three distinct regions of Candida antarctica lipase A (Cal-A), the biocatalyst chosen as a target to demonstrate the versatility of this recombination method. The three corresponding gene segments were subjected to the most appropriate method of mutagenesis (targeted or random). Their straightforward reassembly allowed combining products of different mutagenesis methods in a single round for rapid production of a series of diverse libraries, thus facilitating directed evolution. Screening to improve discrimination of short-chain versus long-chain fatty acid substrates was aided by development of a general, automated method for visual discrimination of the hydrolysis of varied substrates by whole cells. PMID:28178357

  15. Enzyme engineering: A synthetic biology approach for more effective library generation and automated high-throughput screening.

    Directory of Open Access Journals (Sweden)

    Daniela Quaglia

    Full Text Available The Golden Gate strategy entails the use of type IIS restriction enzymes, which cut outside of their recognition sequence. It enables unrestricted design of unique DNA fragments that can be readily and seamlessly recombined. Successfully employed in other synthetic biology applications, we demonstrate its advantageous use to engineer a biocatalyst. Hot-spots for mutations were individuated in three distinct regions of Candida antarctica lipase A (Cal-A, the biocatalyst chosen as a target to demonstrate the versatility of this recombination method. The three corresponding gene segments were subjected to the most appropriate method of mutagenesis (targeted or random. Their straightforward reassembly allowed combining products of different mutagenesis methods in a single round for rapid production of a series of diverse libraries, thus facilitating directed evolution. Screening to improve discrimination of short-chain versus long-chain fatty acid substrates was aided by development of a general, automated method for visual discrimination of the hydrolysis of varied substrates by whole cells.

  16. Comparative proteomic analysis of hen egg white proteins during early phase of embryonic development by combinatorial peptide ligand library and matrix-assisted laser desorption ionization-time of flight.

    Science.gov (United States)

    Liu, Yijun; Qiu, Ning; Ma, Meihu

    2013-07-01

    Little is known regarding the diversification of relative low-abundance proteins in hen egg white that underlie the process of chicken embryonic development. The purpose of this study was to identify changes that may be involved in the development of chick embryos. Comparative proteomic analysis was conducive to revealing the potential biological function of low-abundance proteins and embryonic development demand. In addition, those proteins that are increased in abundance seem to have advantages to be targeted as new biomarkers for animal disease or animal production. However, the huge disparity in abundance in chicken egg white and poor performance of affinity depletion methods were specific challenges. This study applied combinatorial peptide ligand library for expanding the deep proteomics. Two-dimensional gel electrophoresis (2-DE) was performed with the hen embryo egg white, which was obtained from embryos at d 0 and 7. The protein spots showing significant increases were selected for identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry/mass spectrometry (2 mass analyzers for tandem mass spectrometry). Many precursors were identified as strongly increased after 7 d of incubation. They were ovoinhibitor precursor, clusterin precursor, apolipoprotein D precursor, and extracellular fatty acid-binding protein precursor. Moreover, clusterin precursor were observed concentrated in 2 regions: one is the range of molecular weight increase and the other is the range of high pH. In addition, ovalbumin and ovotransferrin were observed in high pH area in a 2-DE map. These findings will give insight into the changes in fertilized egg white proteins during hatching and provide a better understanding of the biochemical changes in the egg development process.

  17. Nonparametric combinatorial sequence models.

    Science.gov (United States)

    Wauthier, Fabian L; Jordan, Michael I; Jojic, Nebojsa

    2011-11-01

    This work considers biological sequences that exhibit combinatorial structures in their composition: groups of positions of the aligned sequences are "linked" and covary as one unit across sequences. If multiple such groups exist, complex interactions can emerge between them. Sequences of this kind arise frequently in biology but methodologies for analyzing them are still being developed. This article presents a nonparametric prior on sequences which allows combinatorial structures to emerge and which induces a posterior distribution over factorized sequence representations. We carry out experiments on three biological sequence families which indicate that combinatorial structures are indeed present and that combinatorial sequence models can more succinctly describe them than simpler mixture models. We conclude with an application to MHC binding prediction which highlights the utility of the posterior distribution over sequence representations induced by the prior. By integrating out the posterior, our method compares favorably to leading binding predictors.

  18. EcoFlex: A Multifunctional MoClo Kit for E. coli Synthetic Biology.

    Science.gov (United States)

    Moore, Simon J; Lai, Hung-En; Kelwick, Richard J R; Chee, Soo Mei; Bell, David J; Polizzi, Karen Marie; Freemont, Paul S

    2016-10-21

    Golden Gate cloning is a prominent DNA assembly tool in synthetic biology for the assembly of plasmid constructs often used in combinatorial pathway optimization, with a number of assembly kits developed specifically for yeast and plant-based expression. However, its use for synthetic biology in commonly used bacterial systems such as Escherichia coli has surprisingly been overlooked. Here, we introduce EcoFlex a simplified modular package of DNA parts for a variety of applications in E. coli, cell-free protein synthesis, protein purification and hierarchical assembly of transcription units based on the MoClo assembly standard. The kit features a library of constitutive promoters, T7 expression, RBS strength variants, synthetic terminators, protein purification tags and fluorescence proteins. We validate EcoFlex by assembling a 68-part containing (20 genes) plasmid (31 kb), characterize in vivo and in vitro library parts, and perform combinatorial pathway assembly, using pooled libraries of either fluorescent proteins or the biosynthetic genes for the antimicrobial pigment violacein as a proof-of-concept. To minimize pathway screening, we also introduce a secondary module design site to simplify MoClo pathway optimization. In summary, EcoFlex provides a standardized and multifunctional kit for a variety of applications in E. coli synthetic biology.

  19. Graph theory and combinatorial optimization

    CERN Document Server

    Marcotte, Odile; Avis, David

    2006-01-01

    A current treatment of cutting-edge topics in Graph Theory and Combinatorial Optimization by leading researchersIncludes heuristic advances and novel approaches to solving combinatorial optimization problems.

  20. Combinatorial scientific computing

    CERN Document Server

    Naumann, Uwe

    2012-01-01

    Combinatorial Scientific Computing explores the latest research on creating algorithms and software tools to solve key combinatorial problems on large-scale high-performance computing architectures. It includes contributions from international researchers who are pioneers in designing software and applications for high-performance computing systems. The book offers a state-of-the-art overview of the latest research, tool development, and applications. It focuses on load balancing and parallelization on high-performance computers, large-scale optimization, algorithmic differentiation of numeric

  1. Introduction to combinatorial designs

    CERN Document Server

    Wallis, WD

    2007-01-01

    Combinatorial theory is one of the fastest growing areas of modern mathematics. Focusing on a major part of this subject, Introduction to Combinatorial Designs, Second Edition provides a solid foundation in the classical areas of design theory as well as in more contemporary designs based on applications in a variety of fields. After an overview of basic concepts, the text introduces balanced designs and finite geometries. The author then delves into balanced incomplete block designs, covering difference methods, residual and derived designs, and resolvability. Following a chapter on the e

  2. Combinatorial Biosynthesis – Potential and Problems

    Science.gov (United States)

    Floss, Heinz G.

    2007-01-01

    Because of their ecological functions, natural products have been optimized in evolution for interaction with biological systems and receptors. However, they have not necessarily been optimized for other desirable drug properties and thus can often be improved by structural modification. Using examples from the literature, this paper reviews the opportunities for increasing structural diversity among natural products by combinatorial biosynthesis, i.e., the genetic manipulation of biosynthetic pathways. It distinguishes between combinatorial biosynthesis in a narrower sense to generate libraries of modified structures, and metabolic engineering for the targeted formation of specific structural analogs. Some of the problems and limitations encountered with these approaches are also discussed. Work from the author’s laboratory on ansamycin antibiotics is presented which illustrates some of the opportunities and limitations. PMID:16414140

  3. Combinatorial biosynthesis of polyketides--a perspective.

    Science.gov (United States)

    Wong, Fong T; Khosla, Chaitan

    2012-04-01

    Since their discovery, polyketide synthases have been attractive targets of biosynthetic engineering to make 'unnatural' natural products. Although combinatorial biosynthesis has made encouraging advances over the past two decades, the field remains in its infancy. In this enzyme-centric perspective, we discuss the scientific and technological challenges that could accelerate the adoption of combinatorial biosynthesis as a method of choice for the preparation of encoded libraries of bioactive small molecules. Borrowing a page from the protein structure prediction community, we propose a periodic challenge program to vet the most promising methods in the field, and to foster the collective development of useful tools and algorithms. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Combinatorial Group Theory

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 1; Issue 11. Combinatorial Group Theory Group Theory via Generators and Relations. B Sury. General Article Volume 1 Issue 11 November 1996 pp 42-50. Fulltext. Click here to view fulltext PDF. Permanent link:

  5. Infinitary Combinatory Reduction Systems

    NARCIS (Netherlands)

    Ketema, J.; Simonsen, Jakob Grue

    We define infinitary Combinatory Reduction Systems (iCRSs), thus providing the first notion of infinitary higher-order rewriting. The systems defined are sufficiently general that ordinary infinitary term rewriting and infinitary $\\lambda$-calculus are special cases. Furthermore, we generalise a

  6. Introduction to combinatorial geometry

    International Nuclear Information System (INIS)

    Gabriel, T.A.; Emmett, M.B.

    1985-01-01

    The combinatorial geometry package as used in many three-dimensional multimedia Monte Carlo radiation transport codes, such as HETC, MORSE, and EGS, is becoming the preferred way to describe simple and complicated systems. Just about any system can be modeled using the package with relatively few input statements. This can be contrasted against the older style geometry packages in which the required input statements could be large even for relatively simple systems. However, with advancements come some difficulties. The users of combinatorial geometry must be able to visualize more, and, in some instances, all of the system at a time. Errors can be introduced into the modeling which, though slight, and at times hard to detect, can have devastating effects on the calculated results. As with all modeling packages, the best way to learn the combinatorial geometry is to use it, first on a simple system then on more complicated systems. The basic technique for the description of the geometry consists of defining the location and shape of the various zones in terms of the intersections and unions of geometric bodies. The geometric bodies which are generally included in most combinatorial geometry packages are: (1) box, (2) right parallelepiped, (3) sphere, (4) right circular cylinder, (5) right elliptic cylinder, (6) ellipsoid, (7) truncated right cone, (8) right angle wedge, and (9) arbitrary polyhedron. The data necessary to describe each of these bodies are given. As can be easily noted, there are some subsets included for simplicity

  7. Synthesis and cell-free cloning of DNA libraries using programmable microfluidics.

    Science.gov (United States)

    Ben Yehezkel, Tuval; Rival, Arnaud; Raz, Ofir; Cohen, Rafael; Marx, Zipora; Camara, Miguel; Dubern, Jean-Frédéric; Koch, Birgit; Heeb, Stephan; Krasnogor, Natalio; Delattre, Cyril; Shapiro, Ehud

    2016-02-29

    Microfluidics may revolutionize our ability to write synthetic DNA by addressing several fundamental limitations associated with generating novel genetic constructs. Here we report the first de novo synthesis and cell-free cloning of custom DNA libraries in sub-microliter reaction droplets using programmable digital microfluidics. Specifically, we developed Programmable Order Polymerization (POP), Microfluidic Combinatorial Assembly of DNA (M-CAD) and Microfluidic In-vitro Cloning (MIC) and applied them to de novo synthesis, combinatorial assembly and cell-free cloning of genes, respectively. Proof-of-concept for these methods was demonstrated by programming an autonomous microfluidic system to construct and clone libraries of yeast ribosome binding sites and bacterial Azurine, which were then retrieved in individual droplets and validated. The ability to rapidly and robustly generate designer DNA molecules in an autonomous manner should have wide application in biological research and development. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  8. TATA is a modular component of synthetic promoters.

    Science.gov (United States)

    Mogno, Ilaria; Vallania, Francesco; Mitra, Robi D; Cohen, Barak A

    2010-10-01

    The expression of most genes is regulated by multiple transcription factors. The interactions between transcription factors produce complex patterns of gene expression that are not always obvious from the arrangement of cis-regulatory elements in a promoter. One critical element of promoters is the TATA box, the docking site for the RNA polymerase holoenzyme. Using a synthetic promoter system coupled to a thermodynamic model of combinatorial regulation, we analyze the effects of different strength TATA boxes on various aspects of combinatorial cis-regulation. The thermodynamic model explains 75% of the variance in gene expression in synthetic promoter libraries with different strength TATA boxes, suggesting that many of the salient aspects of cis-regulation are captured by the model. Our results demonstrate that the effect of changing the TATA box on gene expression is the same for all synthetic promoters regardless of the arrangement of cis-regulatory sites we studied. Our analysis also showed that in our synthetic system the strength of the RNA polymerase-TATA interaction does not alter the combinatorial interactions between transcription factors, or between transcription factors and RNA polymerase. Finally, we show that although stronger TATA boxes increase expression in a predictable fashion, stronger TATA boxes have very little effect on noise in our synthetic promoters, regardless of the arrangement of cis-regulatory sites. Our results support a modular model of promoter function, where cis-regulatory elements can be mixed and matched (programmed) with outcomes on expression that are predictable based on the rules of simple protein-protein and protein-DNA interactions.

  9. Approaches for introducing high molecular diversity in scaffolds: fast parallel synthesis of highly substituted 1H-quinolin-4-one libraries.

    Science.gov (United States)

    Kuznetsov, Vladimir; Gorohovsky, Sofia; Levy, Amalia; Meir, Simcha; Shkoulev, Vladimir; Menashe, Naim; Greenwald, Moshe; Aizikovich, Alexander; Ofer, Dror; Byk, Gerardo; Gellerman, Garry

    2004-01-01

    We have developed a two steps strategy for the parallel synthesis of highly diversified quinolin-ones. In the first step we have combined and improved different synthetic methods for generating quinolin-4-ones bearing four different substitutions at specific positions using round bottomed flasks. The synthesis was assessed for a large number of substituted quinolin-4-ones. In the second step, the improved method was adapted to a parallel array synthesis using a 12 positions carrousel as demonstrated for the synthesis of 42-variable quinolin-4-ones. The first combinatorial library set 14(a-x) was obtained with a chemical purity of more than 95% without purification, the second library set 15(a-r), which included two synthetic steps, needed combinatorial purification using an innovative parallel purifier. The proposed approach contributes to a more extensive diversification of molecular scaffolds in general and provides access to highly substituted quinolinones in particular.

  10. Accessing Specific Peptide Recognition by Combinatorial Chemistry

    DEFF Research Database (Denmark)

    Li, Ming

    in recognition, a hook peptide library was built as sequence blocks containing two L-prolines, facilitating peptide back-bones to organize into a bend “hook” shape. Selection of pairs recognizing each other by entanglement with the conformational shape as a fundamental mechanism of molecular recognition...... was studied with this hook peptide library via the beadbead adhesion screening approach. The recognition pairs interlocked and formed a complex. (chapter 8) During accessing peptide molecular recognition by combinatorial chemistry, we faced several problems, which were solved by a range of analytical...... separation of is developed and used to select the best hits from the “hook” peptide library. The association strength of complex was also evaluated by MS-MS analysis. (chapter 8) a microchannel flow device was designed and utilized to measure binding constants on a single bead. (chapter 5) An important...

  11. Automatic design of synthetic gene circuits through mixed integer non-linear programming.

    Science.gov (United States)

    Huynh, Linh; Kececioglu, John; Köppe, Matthias; Tagkopoulos, Ilias

    2012-01-01

    Automatic design of synthetic gene circuits poses a significant challenge to synthetic biology, primarily due to the complexity of biological systems, and the lack of rigorous optimization methods that can cope with the combinatorial explosion as the number of biological parts increases. Current optimization methods for synthetic gene design rely on heuristic algorithms that are usually not deterministic, deliver sub-optimal solutions, and provide no guaranties on convergence or error bounds. Here, we introduce an optimization framework for the problem of part selection in synthetic gene circuits that is based on mixed integer non-linear programming (MINLP), which is a deterministic method that finds the globally optimal solution and guarantees convergence in finite time. Given a synthetic gene circuit, a library of characterized parts, and user-defined constraints, our method can find the optimal selection of parts that satisfy the constraints and best approximates the objective function given by the user. We evaluated the proposed method in the design of three synthetic circuits (a toggle switch, a transcriptional cascade, and a band detector), with both experimentally constructed and synthetic promoter libraries. Scalability and robustness analysis shows that the proposed framework scales well with the library size and the solution space. The work described here is a step towards a unifying, realistic framework for the automated design of biological circuits.

  12. Isocyanide based multi component reactions in combinatorial chemistry.

    NARCIS (Netherlands)

    Dömling, A.

    1998-01-01

    Although usually regarded as a recent development, the combinatorial approach to the synthesis of libraries of new drug candidates was first described as early as 1961 using the isocyanide-based one-pot multicomponent Ugi reaction. Isocyanide-based multi component reactions (MCR's) markedly differ

  13. Introducing Dynamic Combinatorial Chemistry: Probing the Substrate Selectivity of Acetylcholinesterase

    Science.gov (United States)

    Angelin, Marcus; Larsson, Rikard; Vongvilai, Pornrapee; Ramstrom, Olof

    2010-01-01

    In this laboratory experiment, college students are introduced to dynamic combinatorial chemistry (DCC) and apply it to determine the substrate selectivity of acetylcholinesterase (AChE). Initially, the students construct a chemical library of dynamically interchanging thioesters and thiols. Then, AChE is added and allowed to select and hydrolyze…

  14. Stability-Diversity Tradeoffs Impose Fundamental Constraints on Selection of Synthetic Human VH/VL Single-Domain Antibodies from In Vitro Display Libraries

    Directory of Open Access Journals (Sweden)

    Kevin A. Henry

    2017-12-01

    Full Text Available Human autonomous VH/VL single-domain antibodies (sdAbs are attractive therapeutic molecules, but often suffer from suboptimal stability, solubility and affinity for cognate antigens. Most commonly, human sdAbs have been isolated from in vitro display libraries constructed via synthetic randomization of rearranged VH/VL domains. Here, we describe the design and characterization of three novel human VH/VL sdAb libraries through a process of: (i exhaustive biophysical characterization of 20 potential VH/VL sdAb library scaffolds, including assessment of expression yield, aggregation resistance, thermostability and tolerance to complementarity-determining region (CDR substitutions; (ii in vitro randomization of the CDRs of three VH/VL sdAb scaffolds, with tailored amino acid representation designed to promote solubility and expressibility; and (iii systematic benchmarking of the three VH/VL libraries by panning against five model antigens. We isolated ≥1 antigen-specific human sdAb against four of five targets (13 VHs and 7 VLs in total; these were predominantly monomeric, had antigen-binding affinities ranging from 5 nM to 12 µM (average: 2–3 µM, but had highly variable expression yields (range: 0.1–19 mg/L. Despite our efforts to identify the most stable VH/VL scaffolds, selection of antigen-specific binders from these libraries was unpredictable (overall success rate for all library-target screens: ~53% with a high attrition rate of sdAbs exhibiting false positive binding by ELISA. By analyzing VH/VL sdAb library sequence composition following selection for monomeric antibody expression (binding to protein A/L followed by amplification in bacterial cells, we found that some VH/VL sdAbs had marked growth advantages over others, and that the amino acid composition of the CDRs of this set of sdAbs was dramatically restricted (bias toward Asp and His and away from aromatic and hydrophobic residues. Thus, CDR sequence clearly

  15. Stability-Diversity Tradeoffs Impose Fundamental Constraints on Selection of Synthetic Human VH/VLSingle-Domain Antibodies fromIn VitroDisplay Libraries.

    Science.gov (United States)

    Henry, Kevin A; Kim, Dae Young; Kandalaft, Hiba; Lowden, Michael J; Yang, Qingling; Schrag, Joseph D; Hussack, Greg; MacKenzie, C Roger; Tanha, Jamshid

    2017-01-01

    Human autonomous V H /V L single-domain antibodies (sdAbs) are attractive therapeutic molecules, but often suffer from suboptimal stability, solubility and affinity for cognate antigens. Most commonly, human sdAbs have been isolated from in vitro display libraries constructed via synthetic randomization of rearranged V H /V L domains. Here, we describe the design and characterization of three novel human V H /V L sdAb libraries through a process of: (i) exhaustive biophysical characterization of 20 potential V H /V L sdAb library scaffolds, including assessment of expression yield, aggregation resistance, thermostability and tolerance to complementarity-determining region (CDR) substitutions; (ii) in vitro randomization of the CDRs of three V H /V L sdAb scaffolds, with tailored amino acid representation designed to promote solubility and expressibility; and (iii) systematic benchmarking of the three V H /V L libraries by panning against five model antigens. We isolated ≥1 antigen-specific human sdAb against four of five targets (13 V H s and 7 V L s in total); these were predominantly monomeric, had antigen-binding affinities ranging from 5 nM to 12 µM (average: 2-3 µM), but had highly variable expression yields (range: 0.1-19 mg/L). Despite our efforts to identify the most stable V H /V L scaffolds, selection of antigen-specific binders from these libraries was unpredictable (overall success rate for all library-target screens: ~53%) with a high attrition rate of sdAbs exhibiting false positive binding by ELISA. By analyzing V H /V L sdAb library sequence composition following selection for monomeric antibody expression (binding to protein A/L followed by amplification in bacterial cells), we found that some V H /V L sdAbs had marked growth advantages over others, and that the amino acid composition of the CDRs of this set of sdAbs was dramatically restricted (bias toward Asp and His and away from aromatic and hydrophobic residues). Thus, CDR sequence

  16. Combinatorial group theory

    CERN Document Server

    Lyndon, Roger C

    2001-01-01

    From the reviews: "This book (...) defines the boundaries of the subject now called combinatorial group theory. (...)it is a considerable achievement to have concentrated a survey of the subject into 339 pages. This includes a substantial and useful bibliography; (over 1100 ÄitemsÜ). ...the book is a valuable and welcome addition to the literature, containing many results not previously available in a book. It will undoubtedly become a standard reference." Mathematical Reviews, AMS, 1979.

  17. Improved biocatalysts from a synthetic circular permutation library of the flavin-dependent oxidoreductase old yellow enzyme.

    Science.gov (United States)

    Daugherty, Ashley B; Govindarajan, Sridhar; Lutz, Stefan

    2013-09-25

    Members of the old yellow enzyme (OYE) family are widely used, effective biocatalysts for the stereoselective trans-hydrogenation of activated alkenes. To further expand their substrate scope and improve catalytic performance, we have applied a protein engineering strategy called circular permutation (CP) to enhance the function of OYE1 from Saccharomyces pastorianus. CP can influence a biocatalyst's function by altering protein backbone flexibility and active site accessibility, both critical performance features because the catalytic cycle for OYE1 is thought to involve rate-limiting conformational changes. To explore the impact of CP throughout the OYE1 protein sequence, we implemented a highly efficient approach for cell-free cpOYE library preparation by combining whole-gene synthesis with in vitro transcription/translation. The versatility of such an ex vivo system was further demonstrated by the rapid and reliable functional evaluation of library members under variable environmental conditions with three reference substrates ketoisophorone, cinnamaldehyde, and (S)-carvone. Library analysis identified over 70 functional OYE1 variants with several biocatalysts exhibiting over an order of magnitude improved catalytic activity. Although catalytic gains of individual cpOYE library members vary by substrate, the locations of new protein termini in functional variants for all tested substates fall within the same four distinct loop/lid regions near the active site. Our findings demonstrate the importance of these structural elements in enzyme function and support the hypothesis of conformational flexibility as a limiting factor for catalysis in wild type OYE.

  18. Combinatorial Mechanical Metamaterials

    Science.gov (United States)

    van Hecke, Martin

    The structure of most mechanical metamaterials is periodic so that their design space is that of the unit cell. Here we introduce a combinatorial strategy to create a vast number of distinct mechanical metamaterials, each with a unique spatial texture and response. These are aperiodic stackings of anisotropic building blocks, and their functionality rests on both the block design and their stacking configuration which is governed by a tiling problem. We realize such metamaterials by 3D printing, and show that they act as soft machines, capable of pattern recognition and pattern analysis.

  19. Infinitary Combinatory Reduction Systems

    DEFF Research Database (Denmark)

    Ketema, Jeroen; Simonsen, Jakob Grue

    2011-01-01

    of knownresults fromfirst-order infinitary rewriting and infinitary ¿-calculus to iCRSs. In particular, for fully-extended, left-linear iCRSs we prove the well-known compression property, and for orthogonal iCRSs we prove that (1) if a set of redexes U has a complete development, then all complete developments......We define infinitary Combinatory Reduction Systems (iCRSs), thus providing the first notion of infinitary higher-order rewriting. The systems defined are sufficiently general that ordinary infinitary term rewriting and infinitary ¿-calculus are special cases. Furthermore,we generalise a number...

  20. Dynamic Combinatorial Chemistry

    DEFF Research Database (Denmark)

    Lisbjerg, Micke

    This thesis is divided into seven chapters, which can all be read individually. The first chapter, however, contains a general introduction to the chemistry used in the remaining six chapters, and it is therefore recommended to read chapter one before reading the other chapters. Chapter 1...... is a general introductory chapter for the whole thesis. The history and concepts of dynamic combinatorial chemistry are described, as are some of the new and intriguing results recently obtained. Finally, the properties of a broad range of hexameric macrocycles are described in detail. Chapter 2 gives...

  1. On 3-way combinatorial identities

    Indian Academy of Sciences (India)

    A K Agarwal

    2018-03-19

    Mar 19, 2018 ... associated lattice paths. This tool is very useful in graphical representation of an n-color partition as well as an n-color composition. In this paper, we are using this combinatorial object as an aid to interpret some Rogers and Slater's q-identities combinatorially. Before we state our main results we, first recall ...

  2. Polyhedral Techniques in Combinatorial Optimization

    NARCIS (Netherlands)

    Aardal, K.I.; van Hoesel, S.

    1995-01-01

    Combinatorial optimization problems arise in several areas ranging from management to mathematics and graph theory. Most combinatorial optimization problems are compu- tationally hard due to the restriction that a subset of the variables have to take integral values. During the last two decades

  3. Combinatorial auctions for electronic business

    Indian Academy of Sciences (India)

    They are proving to be extremely useful in numerous e-business applications such as eselling, e-procurement, e-logistics, and B2B exchanges. In this article, we introduce combinatorial auctions and bring out important issues in the design of combinatorial auctions. We also highlight important contributions in current ...

  4. Combinatorial matrix theory

    CERN Document Server

    Mitjana, Margarida

    2018-01-01

    This book contains the notes of the lectures delivered at an Advanced Course on Combinatorial Matrix Theory held at Centre de Recerca Matemàtica (CRM) in Barcelona. These notes correspond to five series of lectures. The first series is dedicated to the study of several matrix classes defined combinatorially, and was delivered by Richard A. Brualdi. The second one, given by Pauline van den Driessche, is concerned with the study of spectral properties of matrices with a given sign pattern. Dragan Stevanović delivered the third one, devoted to describing the spectral radius of a graph as a tool to provide bounds of parameters related with properties of a graph. The fourth lecture was delivered by Stephen Kirkland and is dedicated to the applications of the Group Inverse of the Laplacian matrix. The last one, given by Ángeles Carmona, focuses on boundary value problems on finite networks with special in-depth on the M-matrix inverse problem.

  5. A robust family of Golden Gate Agrobacterium vectors for plant synthetic biology

    Directory of Open Access Journals (Sweden)

    Shahram eEmami

    2013-09-01

    Full Text Available Tools that allow for rapid, accurate and inexpensive assembly of multi-component combinatorial libraries of DNA for transformation into plants will accelerate the progress of synthetic biology research. Recent progress in molecular cloning methods has vastly expanded the repertoire with which plant biologists can engineer a transgene. Here we describe a new set of binary vectors for use in Agrobacterium-mediated plant transformation that utilizes the Golden-Gate cloning approach. Our optimized protocol facilitates the rapid and inexpensive generation of multi-component transgenes for later introduction into plants.

  6. Applying combinatorial chemistry and biology to food research.

    Science.gov (United States)

    Wong, Dominic; Robertson, George

    2004-12-01

    In the past decade combinatorial chemistry has become a major focus of research activity in the pharmaceutical industry for accelerating the development of novel therapeutic compounds. The same combinatorial strategies could be applied to a broad spectrum of areas in agricultural and food research, including food safety and nutrition, development of product ingredients, and processing and conversion of natural products. In contrast to "rational design", the combinatorial approach relies on molecular diversity and high-throughput screening. The capability of exploring the structural and functional limits of a vast population of diverse chemical and biochemical molecules makes it possible to expedite the creation and isolation of compounds of desirable and useful properties. Several studies in recent years have demonstrated the utility of combinatorial methods for food research. These include the discovery of synthetic antimicrobial, antioxidative, and aflatoxin-binding peptides, the identification and analysis of unique flavor compounds, the generation of new enzyme inhibitors, the development of therapeutic antibodies for botulinum neurotoxins, the synthesis of unnatural polyketides and carotenoids, and the modification of food enzymes with novel properties. The results of such activities could open a large area of applications with potential benefits to the food industry. This review describes the current techniques of combinatorial chemistry and their applications, with emphasis on examples in food science research.

  7. Combinatorial Testing for VDM

    DEFF Research Database (Denmark)

    Larsen, Peter Gorm; Lausdahl, Kenneth; Battle, Nick

    2010-01-01

    Abstract—Combinatorial testing in VDM involves the automatic generation and execution of a large collection of test cases derived from templates provided in the form of trace definitions added to a VDM specification. The main value of this is the rapid detection of run-time errors caused...... by forgotten preconditions as well as broken invariants and post-conditions. Trace definitions are defined as regular expressions describing possible sequences of operation calls, and are conceptually similar to UML sequence diagrams. In this paper we present a tool enabling test automation based on VDM traces......, and explain how it is possible to reduce large collections of test cases in different ways. Its use is illustrated with a small case study....

  8. Evaluation of the Optimum Composition of Low-Temperature Fuel Cell Electrocatalysts for Methanol Oxidation by Combinatorial Screening.

    Science.gov (United States)

    Antolini, Ermete

    2017-02-13

    Combinatorial chemistry and high-throughput screening represent an innovative and rapid tool to prepare and evaluate a large number of new materials, saving time and expense for research and development. Considering that the activity and selectivity of catalysts depend on complex kinetic phenomena, making their development largely empirical in practice, they are prime candidates for combinatorial discovery and optimization. This review presents an overview of recent results of combinatorial screening of low-temperature fuel cell electrocatalysts for methanol oxidation. Optimum catalyst compositions obtained by combinatorial screening were compared with those of bulk catalysts, and the effect of the library geometry on the screening of catalyst composition is highlighted.

  9. A green synthetic approach toward the synthesis of structurally diverse spirooxindole derivative libraries under catalyst-free conditions.

    Science.gov (United States)

    Kausar, Nazia; Masum, Abdulla Al; Islam, Md Maidul; Das, Asish R

    2017-05-01

    A catalyst-free green methodology for the synthesis of pharmacologically important spirooxindole derivatives has been developed by a three-component domino reaction between isatin, various amino compounds, and 1,3-dicarbonyl or 3-phenylisoxazolone compounds in ethyl L-lactate medium at room temperature. This new efficient synthetic method facilitated the formation of a wide range of biologically significant spirooxindole derivatives (including 17 new spirooxindoles) under very mild conditions. The cytotoxic activity of one of the isoxazole-fused spirooxindoles was evaluated in MDA-MB 468 breast cancer cell line. It was found that cell survivability decreases with increasing concentration of the selected compound in MDA-MB 468 breast cancer cells.

  10. On an extension of a combinatorial identity

    Indian Academy of Sciences (India)

    to an infinite family of 4-way combinatorial identities. In some particular cases we get even 5-way combinatorial identities which give us four new combinatorial versions of. Göllnitz–Gordon identities. Keywords. n-Color partitions; lattice paths; Frobenius partitions; Göllnitz–Gordon identities; combinatorial interpretations. 1.

  11. Combinatorial designs constructions and analysis

    CERN Document Server

    Stinson, Douglas R

    2004-01-01

    Created to teach students many of the most important techniques used for constructing combinatorial designs, this is an ideal textbook for advanced undergraduate and graduate courses in combinatorial design theory. The text features clear explanations of basic designs, such as Steiner and Kirkman triple systems, mutual orthogonal Latin squares, finite projective and affine planes, and Steiner quadruple systems. In these settings, the student will master various construction techniques, both classic and modern, and will be well-prepared to construct a vast array of combinatorial designs. Design theory offers a progressive approach to the subject, with carefully ordered results. It begins with simple constructions that gradually increase in complexity. Each design has a construction that contains new ideas or that reinforces and builds upon similar ideas previously introduced. A new text/reference covering all apsects of modern combinatorial design theory. Graduates and professionals in computer science, applie...

  12. Combinatorial Solid-Phase Synthesis of Balanol Analogues

    DEFF Research Database (Denmark)

    Nielsen, John; Lyngsø, Lars Ole

    1996-01-01

    The natural product balanol has served as a template for the design and synthesis of a combinatorial library using solid-phase chemistry. Using a retrosynthetic analysis, the structural analogues have been assembled from three relatively accessible building blocks. The solid-phase chemistry...... including MSNT-mediated esterification of both support-bound alcohols and carboxylic acids has been implemented successfully. Copyright (C) 1996 Elsevier Science Ltd....

  13. Relativity in Combinatorial Gravitational Fields

    Directory of Open Access Journals (Sweden)

    Mao Linfan

    2010-04-01

    Full Text Available A combinatorial spacetime $(mathscr{C}_G| uboverline{t}$ is a smoothly combinatorial manifold $mathscr{C}$ underlying a graph $G$ evolving on a time vector $overline{t}$. As we known, Einstein's general relativity is suitable for use only in one spacetime. What is its disguise in a combinatorial spacetime? Applying combinatorial Riemannian geometry enables us to present a combinatorial spacetime model for the Universe and suggest a generalized Einstein gravitational equation in such model. Forfinding its solutions, a generalized relativity principle, called projective principle is proposed, i.e., a physics law ina combinatorial spacetime is invariant under a projection on its a subspace and then a spherically symmetric multi-solutions ofgeneralized Einstein gravitational equations in vacuum or charged body are found. We also consider the geometrical structure in such solutions with physical formations, and conclude that an ultimate theory for the Universe maybe established if all such spacetimes in ${f R}^3$. Otherwise, our theory is only an approximate theory and endless forever.

  14. Relativity in Combinatorial Gravitational Fields

    Directory of Open Access Journals (Sweden)

    Mao L.

    2010-07-01

    Full Text Available A combinatorial spacetime ( C G j t is a smoothly combinatorial manifold C underlying a graph G evolving on a time vector t . As we known, Einstein’s general relativity is suit- able for use only in one spacetime. What is its disguise in a combinatorial spacetime ? Applying combinatorial Riemannian geometry enables us to present a combinatorial spacetime model for the Universe and suggest a generalized Einstein gravitational equa- tion in such model. For finding its solutions, a generalized relativity principle, called projective principle is proposed, i.e., a physics law in a combinatorial spacetime is invariant under a projection on its a subspace and then a spherically symmetric multi- solutions of generalized Einstein gravitational equations in vacuum or charged body are found. We also consider the geometrical structure in such solutions with physical for- mations, and conclude that an ultimate theory for the Universe maybe established if all such spacetimes in R 3 . Otherwise, our theory is only an approximate theory and endless forever.

  15. A Synthetic Lethality Screen Using a Focused siRNA Library to Identify Sensitizers to Dasatinib Therapy for the Treatment of Epithelial Ovarian Cancer.

    Directory of Open Access Journals (Sweden)

    Harsh B Pathak

    Full Text Available Molecular targeted therapies have been the focus of recent clinical trials for the treatment of patients with recurrent epithelial ovarian cancer (EOC. The majority have not fared well as monotherapies for improving survival of these patients. Poor bioavailability, lack of predictive biomarkers, and the presence of multiple survival pathways can all diminish the success of a targeted agent. Dasatinib is a tyrosine kinase inhibitor of the Src-family kinases (SFK and in preclinical studies shown to have substantial activity in EOC. However, when evaluated in a phase 2 clinical trial for patients with recurrent or persistent EOC, it was found to have minimal activity. We hypothesized that synthetic lethality screens performed using a cogently designed siRNA library would identify second-site molecular targets that could synergize with SFK inhibition and improve dasatinib efficacy. Using a systematic approach, we performed primary siRNA screening using a library focused on 638 genes corresponding to a network centered on EGFR, HER2, and the SFK-scaffolding proteins BCAR1, NEDD9, and EFS to screen EOC cells in combination with dasatinib. We followed up with validation studies including deconvolution screening, quantitative PCR to confirm effective gene silencing, correlation of gene expression with dasatinib sensitivity, and assessment of the clinical relevance of hits using TCGA ovarian cancer data. A refined list of five candidates (CSNK2A1, DAG1, GRB2, PRKCE, and VAV1 was identified as showing the greatest potential for improving sensitivity to dasatinib in EOC. Of these, CSNK2A1, which codes for the catalytic alpha subunit of protein kinase CK2, was selected for additional evaluation. Synergistic activity of the clinically relevant inhibitor of CK2, CX-4945, with dasatinib in reducing cell proliferation and increasing apoptosis was observed across multiple EOC cell lines. This overall approach to improving drug efficacy can be applied to other

  16. DNA-library assembly programmed by on-demand nano-liter droplets from a custom microfluidic chip.

    Science.gov (United States)

    Tangen, Uwe; Minero, Gabriel Antonio S; Sharma, Abhishek; Wagler, Patrick F; Cohen, Rafael; Raz, Ofir; Marx, Tzipy; Ben-Yehezkel, Tuval; McCaskill, John S

    2015-07-01

    Nanoscale synthetic biology can benefit from programmable nanoliter-scale processing of DNA in microfluidic chips if they are interfaced effectively to biochemical arrays such as microwell plates. Whereas active microvalve chips require complex fabrication and operation, we show here how a passive and readily fabricated microchip can be employed for customizable nanoliter scale pipetting and reaction control involving DNA. This recently developed passive microfluidic device, supporting nanoliter scale combinatorial droplet generation and mixing, is here used to generate a DNA test library with one member per droplet exported to addressed locations on microwell plates. Standard DNA assembly techniques, such as Gibson assembly, compatible with isothermal on-chip operation, are employed and checked using off-chip PCR and assembly PCR. The control of output droplet sequences and mixing performance was verified using dyes and fluorescently labeled DNA solutions, both on-chip and in external capillary channels. Gel electrophoresis of products and DNA sequencing were employed to further verify controlled combination and functional enzymatic assembly. The scalability of the results to larger DNA libraries is also addressed by combinatorial input expansion using sequential injection plugs from a multiwell plate. Hence, the paper establishes a proof of principle of the production of functional combinatorial mixtures at the nanoliter scale for one sequence per well DNA libraries.

  17. Combinatorial optimization theory and algorithms

    CERN Document Server

    Korte, Bernhard

    2018-01-01

    This comprehensive textbook on combinatorial optimization places special emphasis on theoretical results and algorithms with provably good performance, in contrast to heuristics. It is based on numerous courses on combinatorial optimization and specialized topics, mostly at graduate level. This book reviews the fundamentals, covers the classical topics (paths, flows, matching, matroids, NP-completeness, approximation algorithms) in detail, and proceeds to advanced and recent topics, some of which have not appeared in a textbook before. Throughout, it contains complete but concise proofs, and also provides numerous exercises and references. This sixth edition has again been updated, revised, and significantly extended. Among other additions, there are new sections on shallow-light trees, submodular function maximization, smoothed analysis of the knapsack problem, the (ln 4+ɛ)-approximation for Steiner trees, and the VPN theorem. Thus, this book continues to represent the state of the art of combinatorial opti...

  18. Dynamic combinatorial chemistry to identify binders of ThiT, an S-component of the energy-coupling factor transporter for thiamine

    NARCIS (Netherlands)

    Monjas, Leticia; Swier, Lotteke J Y M; Setyawati, Inda; Slotboom, Dirk Jan; Hirsch, Anna Katharina Herta

    2017-01-01

    We applied dynamic combinatorial chemistry (DCC) to identify ligands of ThiT, the S-component of the energy-coupling factor (ECF) transporter for thiamine in Lactococcus lactis. We used a pre-equilibrated dynamic combinatorial library (DCL) and saturation-transfer difference (STD) NMR spectroscopy

  19. On an extension of a combinatorial identity

    Indian Academy of Sciences (India)

    Using Frobenius partitions we extend the main results of [4]. This leads to an infinite family of 4-way combinatorial identities. In some particular cases we get even 5-way combinatorial identities which give us four new combinatorial versions of Göllnitz–Gordon identities.

  20. Dynamic Combinatorial Chemistry with Diselenides, Disulfides, Imines and Metal Coordination

    DEFF Research Database (Denmark)

    Sørensen, Anne

    The design and preparation of strong and selective artificial receptors, especially biomi-metic receptors that function in aqueous solution, has proved truly challenging. In this thesis it will be described how the strengths of dynamic combinatorial chemistry can be used to great advantage...... in this field. The aim of this project has therefore been to develop new ways of using dynamic combinatorial libraries for molecular recognition in aqueous media. The focus has been on using what has been learned from the well-established di-sulfide exchange chemistry to incorporate a new reaction into dynamic...... experimentally and theoretically and found to be unique in organoselenium chemistry by proceeding through a four-membered cyclic transition state following first-order kinetics. Subsequently, this thesis illustrates how an aliphatic diselenide could be used to catalyse the formation of a disulfide based dynamic...

  1. Gaming in Combinatorial Clock Auctions

    NARCIS (Netherlands)

    M.C.W. Janssen (Maarten); V.A. Karamychev (Vladimir)

    2013-01-01

    textabstractIn recent years, Combinatorial Clock Auctions (CCAs) have been used around the world to allocate frequency spectrum for mobile telecom licenses. CCAs are claimed to significantly reduce the scope for gaming or strategic bidding. In this paper, we show, however, that CCAs significantly

  2. Combinatorial optimization networks and matroids

    CERN Document Server

    Lawler, Eugene

    2011-01-01

    Perceptively written text examines optimization problems that can be formulated in terms of networks and algebraic structures called matroids. Chapters cover shortest paths, network flows, bipartite matching, nonbipartite matching, matroids and the greedy algorithm, matroid intersections, and the matroid parity problems. A suitable text or reference for courses in combinatorial computing and concrete computational complexity in departments of computer science and mathematics.

  3. Computational Complexity of Combinatorial Surfaces

    NARCIS (Netherlands)

    Vegter, Gert; Yap, Chee K.

    1990-01-01

    We investigate the computational problems associated with combinatorial surfaces. Specifically, we present an algorithm (based on the Brahana-Dehn-Heegaard approach) for transforming the polygonal schema of a closed triangulated surface into its canonical form in O(n log n) time, where n is the

  4. Combinatorial Group Theory -42-----------------------------~-----------R ...

    Indian Academy of Sciences (India)

    GENERAL I ARTICLE. Combinatorial Group Theory. Group Theory via Generators and Relations. B Sury is with the School of Mathematics, TIFR,. Mumbai. The concept of groups surfaced with the fundamental works of the great mathematicians. Evariste Galois and Niels Henrik. Abel. The advent of group theory.

  5. Algorithms in combinatorial design theory

    CERN Document Server

    Colbourn, CJ

    1985-01-01

    The scope of the volume includes all algorithmic and computational aspects of research on combinatorial designs. Algorithmic aspects include generation, isomorphism and analysis techniques - both heuristic methods used in practice, and the computational complexity of these operations. The scope within design theory includes all aspects of block designs, Latin squares and their variants, pairwise balanced designs and projective planes and related geometries.

  6. Combinatorial reasoning to solve problems

    NARCIS (Netherlands)

    Coenen, Tom Johannes Maria; Hof, Frits; Verhoef, Neeltje Cornelia

    2016-01-01

    This study reports combinatorial reasoning to solve problems. We observed the mathematical thinking of students aged 14-16. We study the variation of the students’ solution strategies in the context of emergent modelling. The results show that the students are tempted to begin the problem solving

  7. Combinatorial auctions for electronic business

    Indian Academy of Sciences (India)

    R. Narasimhan (Krishtel eMaging) 1461 1996 Oct 15 13:05:22

    In travel package planning, the problem is to allocate flights, hotel ... hotels, etc. Here, combinations are important because a hotel room without a flight ticket or an entertainment ticket has no value. 5. Combinatorial auctions for spectrum ... spread their fixed costs of technology acquisition and customer-base development.

  8. Synthetic affinity ligands as a novel tool to improve protein stability.

    Science.gov (United States)

    Sousa, I T; Ruiu, L; Lowe, C R; Taipa, M A

    2009-01-01

    Cutinase from Fusarium solani pisi is the model-system for a new approach to assess and enhance protein stability based on the use of synthetic triazine-scaffolded affinity ligands as a novel protein-stabilizing tool. The active site of cutinase is excluded from the main surface regions postulated to be involved in early protein's thermal unfolding events. Hence, these regions are suitable targets for binding complementary affinity ligands with a potential stabilizing effect. A random solid-phase combinatorial library of triazine-bisubstituted molecules was screened for binding cutinase by a rapid fluorescence-based method and affinity chromatography. The best binding substituents were combined with those previously selected by screening a rationally designed library. A second-generation solid-phase biased library was designed and synthesized, following a semi-rational methodology. A dual screening of this library enabled the selection of ligands binding cutinase with higher affinity while retaining its functionality. These compounds were utilized for thermostability assessment with adsorbed cutinase at 60 degrees C and pH 8.0. When bound to different types of ligands, the enzyme showed markedly distinct activity retention profiles, with some synthetic affinity ligands displaying a stabilizing effect on cutinase and others a clearly destabilizing effect, when compared with the free enzyme. Copyright (c) 2008 John Wiley & Sons, Ltd.

  9. The Pictet-Spengler reaction in solid-phase combinatorial chemistry

    DEFF Research Database (Denmark)

    Nielsen, Thomas E; Diness, Frederik; Meldal, Morten

    2003-01-01

    -phase routes toward a range of complex heterocyclic ring systems, with focus on experimental conditions, efficiency and diastereoselectivity. This is illustrated by the application of this reaction to the synthesis of combinatorial libraries, natural product analogs and drug-like scaffolds....

  10. Combinatorial algebra syntax and semantics

    CERN Document Server

    Sapir, Mark V

    2014-01-01

    Combinatorial Algebra: Syntax and Semantics provides a comprehensive account of many areas of combinatorial algebra. It contains self-contained proofs of  more than 20 fundamental results, both classical and modern. This includes Golod–Shafarevich and Olshanskii's solutions of Burnside problems, Shirshov's solution of Kurosh's problem for PI rings, Belov's solution of Specht's problem for varieties of rings, Grigorchuk's solution of Milnor's problem, Bass–Guivarc'h theorem about the growth of nilpotent groups, Kleiman's solution of Hanna Neumann's problem for varieties of groups, Adian's solution of von Neumann-Day's problem, Trahtman's solution of the road coloring problem of Adler, Goodwyn and Weiss. The book emphasize several ``universal" tools, such as trees, subshifts, uniformly recurrent words, diagrams and automata.   With over 350 exercises at various levels of difficulty and with hints for the more difficult problems, this book can be used as a textbook, and aims to reach a wide and diversified...

  11. Combinatorial aspects of covering arrays

    Directory of Open Access Journals (Sweden)

    Charles J. Colbourn

    2004-11-01

    Full Text Available Covering arrays generalize orthogonal arrays by requiring that t -tuples be covered, but not requiring that the appearance of t -tuples be balanced.Their uses in screening experiments has found application in software testing, hardware testing, and a variety of fields in which interactions among factors are to be identified. Here a combinatorial view of covering arrays is adopted, encompassing basic bounds, direct constructions, recursive constructions, algorithmic methods, and applications.

  12. Combinatorial aspects of Escher tilings

    OpenAIRE

    Massé, Alexandre Blondin; Brlek, Srecko; Labbé, Sébastien

    2010-01-01

    International audience; In the late 30's, Maurits Cornelis Escher astonished the artistic world by producing some puzzling drawings. In particular, the tesselations of the plane obtained by using a single tile appear to be a major concern in his work, drawing attention from the mathematical community. Since a tile in the continuous world can be approximated by a path on a sufficiently small square grid - a widely used method in applications using computer displays - the natural combinatorial ...

  13. Neurite outgrowth induced by a synthetic peptide ligand of neural cell adhesion molecule requires fibroblast growth factor receptor activation

    DEFF Research Database (Denmark)

    Rønn, L C; Doherty, P; Holm, A

    2000-01-01

    identified a neuritogenic ligand, termed the C3 peptide, of the first immunoglobulin (lg) module of NCAM using a combinatorial library of synthetic peptides. Here we investigate whether stimulation of neurite outgrowth by this synthetic ligand of NCAM involves FGFRs. In primary cultures of cerebellar neurons...... from wild-type mice, the C3 peptide stimulated neurite outgrowth. This response was virtually absent in cultures of cerebellar neurons from transgenic mice expressing a dominant-negative form of the FGFR1. Likewise, in PC12E2 cells transiently expressing a dominant-negative form of the mouse FGFR1......, induction of neurites by the C3 peptide was abrogated. These findings suggest that the neuritogenic effect of the C3 peptide requires the presence of functional FGFRs and support the hypothesis that FGFRs are essential in cell adhesion molecule-stimulated neurite outgrowth. The C3 peptide appears...

  14. The Safety Evaluation of a Potent Angiogenic Activator, Synthetic Peptide (SFKLRY-NH2) for the Skin Application

    Science.gov (United States)

    Kim, Dong Ha; Lim, Yun Young; Kim, Hyeong Mi; Kim, So Young; Park, Sung-Gil; Lee, Taehoon

    2012-01-01

    A novel synthetic hexapeptide (SFKLRY-NH2) that displays angiogenic activity has been identified by positional scanning of a synthetic peptide combinatorial library (PS-SPCL). This study was carried out to investigate the irritation of the SFKLRY-NH2 on the skin. The tests were performed on the basis of Korea Food and Drug Administration (KFDA) guidelines. In results, cell toxicity is not appeared for SFKLRY-NH2 in HaCaT cells and B16F10 cells. SFKLRY-NH2 induced no skin irritation at low concentration (10 μM), mild irritation at high concentration (10mM). We consider that this result is helpful for saying about the safety of SFKLRY-NH2 in clinical use. PMID:24278589

  15. Development of Combinatorial Methods for Alloy Design and Optimization

    International Nuclear Information System (INIS)

    Pharr, George M.; George, Easo P.; Santella, Michael L

    2005-01-01

    The primary goal of this research was to develop a comprehensive methodology for designing and optimizing metallic alloys by combinatorial principles. Because conventional techniques for alloy preparation are unavoidably restrictive in the range of alloy composition that can be examined, combinatorial methods promise to significantly reduce the time, energy, and expense needed for alloy design. Combinatorial methods can be developed not only to optimize existing alloys, but to explore and develop new ones as well. The scientific approach involved fabricating an alloy specimen with a continuous distribution of binary and ternary alloy compositions across its surface--an ''alloy library''--and then using spatially resolved probing techniques to characterize its structure, composition, and relevant properties. The three specific objectives of the project were: (1) to devise means by which simple test specimens with a library of alloy compositions spanning the range interest can be produced; (2) to assess how well the properties of the combinatorial specimen reproduce those of the conventionally processed alloys; and (3) to devise screening tools which can be used to rapidly assess the important properties of the alloys. As proof of principle, the methodology was applied to the Fe-Ni-Cr ternary alloy system that constitutes many commercially important materials such as stainless steels and the H-series and C-series heat and corrosion resistant casting alloys. Three different techniques were developed for making alloy libraries: (1) vapor deposition of discrete thin films on an appropriate substrate and then alloying them together by solid-state diffusion; (2) co-deposition of the alloying elements from three separate magnetron sputtering sources onto an inert substrate; and (3) localized melting of thin films with a focused electron-beam welding system. Each of the techniques was found to have its own advantages and disadvantages. A new and very powerful technique for

  16. Development of Combinatorial Methods for Alloy Design and Optimization

    Energy Technology Data Exchange (ETDEWEB)

    Pharr, George M.; George, Easo P.; Santella, Michael L

    2005-07-01

    The primary goal of this research was to develop a comprehensive methodology for designing and optimizing metallic alloys by combinatorial principles. Because conventional techniques for alloy preparation are unavoidably restrictive in the range of alloy composition that can be examined, combinatorial methods promise to significantly reduce the time, energy, and expense needed for alloy design. Combinatorial methods can be developed not only to optimize existing alloys, but to explore and develop new ones as well. The scientific approach involved fabricating an alloy specimen with a continuous distribution of binary and ternary alloy compositions across its surface--an ''alloy library''--and then using spatially resolved probing techniques to characterize its structure, composition, and relevant properties. The three specific objectives of the project were: (1) to devise means by which simple test specimens with a library of alloy compositions spanning the range interest can be produced; (2) to assess how well the properties of the combinatorial specimen reproduce those of the conventionally processed alloys; and (3) to devise screening tools which can be used to rapidly assess the important properties of the alloys. As proof of principle, the methodology was applied to the Fe-Ni-Cr ternary alloy system that constitutes many commercially important materials such as stainless steels and the H-series and C-series heat and corrosion resistant casting alloys. Three different techniques were developed for making alloy libraries: (1) vapor deposition of discrete thin films on an appropriate substrate and then alloying them together by solid-state diffusion; (2) co-deposition of the alloying elements from three separate magnetron sputtering sources onto an inert substrate; and (3) localized melting of thin films with a focused electron-beam welding system. Each of the techniques was found to have its own advantages and disadvantages. A new and very

  17. Probabilistic methods in combinatorial analysis

    CERN Document Server

    Sachkov, Vladimir N

    2014-01-01

    This 1997 work explores the role of probabilistic methods for solving combinatorial problems. These methods not only provide the means of efficiently using such notions as characteristic and generating functions, the moment method and so on but also let us use the powerful technique of limit theorems. The basic objects under investigation are nonnegative matrices, partitions and mappings of finite sets, with special emphasis on permutations and graphs, and equivalence classes specified on sequences of finite length consisting of elements of partially ordered sets; these specify the probabilist

  18. Three Syntactic Theories for Combinatory Graph Reduction

    DEFF Research Database (Denmark)

    Danvy, Olivier; Zerny, Ian

    2013-01-01

    here therefore properly account for combinatory graph reduction As We Know It. These three syntactic theories scale to handling the Y combinator. This article therefore illustrates the scientic consensus of theoreticians and implementors about graph reduction: it is the same combinatory elephant....

  19. Combinatorial algorithms for the seriation problem

    NARCIS (Netherlands)

    Seminaroti, Matteo

    2016-01-01

    In this thesis we study the seriation problem, a combinatorial problem arising in data analysis, which asks to sequence a set of objects in such a way that similar objects are ordered close to each other. We focus on the combinatorial structure and properties of Robinsonian matrices, a special class

  20. Enabling techniques in the search for new antibiotics: Combinatorial biosynthesis of sugar-containing antibiotics.

    Science.gov (United States)

    Park, Je Won; Nam, Sang-Jip; Yoon, Yeo Joon

    2017-06-15

    Nature has a talent for inventing a vast number of natural products, including hybrids generated by blending different scaffolds, resulting in a myriad of bioactive chemical entities. Herein, we review the highlights and recent trends (2010-2016) in the combinatorial biosynthesis of sugar-containing antibiotics where nature's structural diversification capabilities are exploited to enable the creation of new anti-infective and anti-proliferative drugs. In this review, we describe the modern combinatorial biosynthetic approaches for polyketide synthase-derived complex and aromatic polyketides, non-ribosomal peptide synthetase-directed lipo-/glycopeptides, aminoglycosides, nucleoside antibiotics, and alkaloids, along with their therapeutic potential. Finally, we present the feasible nexus between combinatorial biosynthesis, systems biology, and synthetic biology as a toolbox to provide new antibiotics that will be indispensable in the post-antibiotic era. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. A comprehensive library-based, automated screening procedure for 46 synthetic cannabinoids in serum employing liquid chromatography-quadrupole ion trap mass spectrometry with high-temperature electrospray ionization.

    Science.gov (United States)

    Huppertz, Laura M; Kneisel, Stefan; Auwärter, Volker; Kempf, Jürgen

    2014-02-01

    Considering the vast variety of synthetic cannabinoids and herbal mixtures - commonly known as 'Spice' or 'K2' - on the market and the resulting increase of severe intoxications related to their consumption, there is a need in clinical and forensic toxicology for comprehensive up-to-date screening methods. The focus of this project aimed at developing and implementing an automated screening procedure for the detection of synthetic cannabinoids in serum using a liquid chromatography-ion trap-MS (LC-MS(n)) system and a spectra library-based approach, currently including 46 synthetic cannabinoids and 8 isotope labelled analogues. In the process of method development, a high-temperature ESI source (IonBooster(TM), Bruker Daltonik) and its effects on the ionization efficiency of the investigated synthetic cannabinoids were evaluated and compared to a conventional ESI source. Despite their structural diversity, all investigated synthetic cannabinoids benefitted from high-temperature ionization by showing remarkably higher MS intensities compared to conventional ESI. The employed search algorithm matches retention time, MS and MS(2)/MS(3) spectra. With the utilization of the ionBooster source, limits for the automated detection comparable to cut-off values of routine MRM methods were achieved for the majority of analytes. Even compounds not identified when using a conventional ESI source were detected using the ionBooster-source. LODs in serum range from 0.1 ng/ml to 0.5 ng/ml. The use of parent compounds as analytical targets offers the possibility of instantly adding new emerging compounds to the library and immediately applying the updated method to serum samples, allowing the rapid adaptation of the screening method to ongoing forensic or clinical requirements. The presented approach can also be applied to other specimens, such as oral fluid or hair, and herbal mixtures and was successfully applied to authentic serum samples. Quantitative MRM results of samples with

  2. Combinatorial Strategies for Synthesis and Characterization of Alloy Microstructures over Large Compositional Ranges.

    Science.gov (United States)

    Li, Yanglin; Jensen, Katharine E; Liu, Yanhui; Liu, Jingbei; Gong, Pan; Scanley, B Ellen; Broadbridge, Christine C; Schroers, Jan

    2016-10-10

    The exploration of new alloys with desirable properties has been a long-standing challenge in materials science because of the complex relationship between composition and microstructure. In this Research Article, we demonstrate a combinatorial strategy for the exploration of composition dependence of microstructure. This strategy is comprised of alloy library synthesis followed by high-throughput microstructure characterization. As an example, we synthesized a ternary Au-Cu-Si composition library containing over 1000 individual alloys using combinatorial sputtering. We subsequently melted and resolidified the entire library at controlled cooling rates. We used scanning optical microscopy and X-ray diffraction mapping to explore trends in phase formation and microstructural length scale with composition across the library. The integration of combinatorial synthesis with parallelizable analysis methods provides a efficient method for examining vast compositional ranges. The availability of microstructures from this vast composition space not only facilitates design of new alloys by controlling effects of composition on phase selection, phase sequence, length scale, and overall morphology, but also will be instrumental in understanding the complex process of microstructure formation in alloys.

  3. Plant expression of chicken secretory antibodies derived from combinatorial libraries

    NARCIS (Netherlands)

    Wieland, W.H.; Lammers, A.; Schots, A.; Orzaéz, D.V.

    2006-01-01

    Delivery of secretory IgA antibodies (sIgA) to mucosal surfaces is a promising strategy to passively prevent infectious diseases. Plants have been proposed as biofactories for such complex immunoglobulin molecules. Recently, the molecular characterization of all four monomers of chicken sIgA (IgA

  4. A combinatorial wind field model

    DEFF Research Database (Denmark)

    Soleimanzadeh, Maryam; Wisniewski, Rafal; Sloth, Christoffer

    2010-01-01

    of ordinary dierential equations (ODE). Considering some assumptions on the ow model (e.g. steadiness), the sys- tem can be approximated by a linear n dimensional system. Partitioning the state space into cells is performed by dening Lyapunov function sets, such that each cell is the region between two......This report is the deliverable 2.4 in the project Distributed Control of Large-Scale Oshore Wind Farms with the acronym Aeolus. The objective of this deliverable is to provide an understanding of the wind eld model and dynamic variations superimposed on the mean eld. In this report a dynamical...... model is developed for the wind ow in a wind farm based on nite volume method. Afterwards the model is transferred into a discrete framework called combinatorial, which determines the future behavior of the discrete system. In this regard, the dynamical model is de- rived and it is explained in terms...

  5. Dynamical System Approaches to Combinatorial Optimization

    DEFF Research Database (Denmark)

    Starke, Jens

    2013-01-01

    Several dynamical system approaches to combinatorial optimization problems are described and compared. These include dynamical systems derived from penalty methods; the approach of Hopfield and Tank; self-organizing maps, that is, Kohonen networks; coupled selection equations; and hybrid methods...

  6. Jack superpolynomials: physical and combinatorial definitions

    International Nuclear Information System (INIS)

    Desrosiers, P.; Mathieu, P.; Lapointe, L.

    2004-01-01

    Jack superpolynomials are eigenfunctions of the supersymmetric extension of the quantum trigonometric Calogero-Moser-Sutherland Hamiltonian. They are orthogonal with respect to the scalar product, dubbed physical, that is naturally induced by this quantum-mechanical problem. But Jack superpolynomials can also be defined more combinatorially, starting from the multiplicative bases of symmetric superpolynomials, enforcing orthogonality with respect to a one-parameter deformation of the combinatorial scalar product. Both constructions turn out to be equivalent. (author)

  7. Conferences on Combinatorial and Additive Number Theory

    CERN Document Server

    2014-01-01

    This proceedings volume is based on papers presented at the Workshops on Combinatorial and Additive Number Theory (CANT), which were held at the Graduate Center of the City University of New York in 2011 and 2012. The goal of the workshops is to survey recent progress in combinatorial number theory and related parts of mathematics. The workshop attracts researchers and students who discuss the state-of-the-art, open problems, and future challenges in number theory.

  8. Physicochemical Profiles of the Marketed Agrochemicals and Clues for Agrochemical Lead Discovery and Screening Library Development.

    Science.gov (United States)

    Rao, Hanbing; Huangfu, Changxin; Wang, Yanying; Wang, Xianxiang; Tang, Tiansheng; Zeng, Xianyin; Li, Zerong; Chen, Yuzong

    2015-05-01

    Combinatorial chemistry, high-throughput and virtual screening technologies have been extensively used for discovering agrochemical leads from chemical libraries. The knowledge of the physicochemical properties of the marketed agrochemicals is useful for guiding the design and selection of such libraries. Since the earlier profiling of marketed agrochemicals, the number and types of marketed agrochemicals have significantly increased. Recent studies have shown the change of some physicochemical properties of oral drugs with time. There is a need to also profile the physicochemical properties of the marketed agrochemicals. In this work, we analyzed the key physicochemical properties of 1751 marketed agrochemicals in comparison with the previously-analyzed herbicides and insecticides, 106 391 natural products and 57 548 diverse synthetic libraries compounds. Our study revealed the distribution profiles and evolution trend of different types of agrochemicals that in many respects are broadly similar to the reported profiles for oral drugs, with the most marked difference being that agrochemicals have a lower number of hydrogen bond donors. The derived distribution patterns provided the rule of thumb guidelines for selecting potential agrochemical leads and also provided clues for further improving the libraries for agrochemical lead discovery. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Synthesis and Evaluation of a Library of Trifunctional Scaffold-Derived Compounds as Modulators of the Insulin Receptor.

    Science.gov (United States)

    Fabre, Benjamin; Pícha, Jan; Vaněk, Václav; Selicharová, Irena; Chrudinová, Martina; Collinsová, Michaela; Žáková, Lenka; Buděšínský, Miloš; Jiráček, Jiří

    2016-12-12

    We designed a combinatorial library of trifunctional scaffold-derived compounds, which were derivatized with 30 different in-house-made azides. The compounds were proposed to mimic insulin receptor (IR)-binding epitopes in the insulin molecule and bind to and activate this receptor. This work has enabled us to test our synthetic and biological methodology and to prove its robustness and reliability for the solid-phase synthesis and testing of combinatorial libraries of the trifunctional scaffold-derived compounds. Our effort resulted in the discovery of two compounds, which were able to weakly induce the autophosphorylation of IR and weakly bind to this receptor at a 0.1 mM concentration. Despite these modest biological results, which well document the well-known difficulty in modulating protein-protein interactions, this study represents a unique example of targeting the IR with a set of nonpeptide compounds that were specifically designed and synthesized for this purpose. We believe that this work can open new perspectives for the development of next-generation insulin mimetics based on the scaffold structure.

  10. Immobilized OBOC combinatorial bead array to facilitate multiplicative screening

    Science.gov (United States)

    Townsend, Jared; Li, Yuanpei; Liu, Ruiwu; Lam, Kit S.

    2015-01-01

    One-bead-one-compound (OBOC) combinatorial library screening has been broadly utilized for the last two decades to identify small molecules, peptides or peptidomimetics targeting variable screening probes such as cell surface receptors, bacteria, protein kinases, phosphatases, proteases etc. In previous screening methods, library beads were suspended in solution and screened against one single probe. Only the positive beads were tracked and isolated for additional screens and finally selected for chemical decoding. During this process, the remaining negative beads were not tracked and discarded. Here we report a novel bead immobilization method such that a bead library array can be conveniently prepared and screened in its entirety, sequentially many times with a series of distinct probes. This method not only allows us to increase the screening efficiency but also permits us to determine the binding profile of each and every library bead against a large number of target receptors. As proof of concept, we serially screened a random OBOC disulfide containing cyclic heptapeptide library with three water soluble dyes as model probes: malachite green, bromocresol purple and indigo carmine. This multiplicative screening approach resulted in a rapid determination of the binding profile of each and every bead respective to each of the three dyes. Beads that interacted with malachite green only, bromocresol purple only, or both indigo carmine and bromocresol purple were isolated, and their peptide sequences were determined with microsequencer. Ultimately, the novel OBOC multiplicative screening approach could play a key role in the enhancement of existing on-bead assays such as whole cell binding, bacteria binding, protein binding, post-translational modifications etc. with increased efficiency, capacity, and specificity. PMID:23488896

  11. Combinatorial pooling enables selective sequencing of the barley gene space.

    Directory of Open Access Journals (Sweden)

    Stefano Lonardi

    2013-04-01

    Full Text Available For the vast majority of species - including many economically or ecologically important organisms, progress in biological research is hampered due to the lack of a reference genome sequence. Despite recent advances in sequencing technologies, several factors still limit the availability of such a critical resource. At the same time, many research groups and international consortia have already produced BAC libraries and physical maps and now are in a position to proceed with the development of whole-genome sequences organized around a physical map anchored to a genetic map. We propose a BAC-by-BAC sequencing protocol that combines combinatorial pooling design and second-generation sequencing technology to efficiently approach denovo selective genome sequencing. We show that combinatorial pooling is a cost-effective and practical alternative to exhaustive DNA barcoding when preparing sequencing libraries for hundreds or thousands of DNA samples, such as in this case gene-bearing minimum-tiling-path BAC clones. The novelty of the protocol hinges on the computational ability to efficiently compare hundred millions of short reads and assign them to the correct BAC clones (deconvolution so that the assembly can be carried out clone-by-clone. Experimental results on simulated data for the rice genome show that the deconvolution is very accurate, and the resulting BAC assemblies have high quality. Results on real data for a gene-rich subset of the barley genome confirm that the deconvolution is accurate and the BAC assemblies have good quality. While our method cannot provide the level of completeness that one would achieve with a comprehensive whole-genome sequencing project, we show that it is quite successful in reconstructing the gene sequences within BACs. In the case of plants such as barley, this level of sequence knowledge is sufficient to support critical end-point objectives such as map-based cloning and marker-assisted breeding.

  12. Stochastic dynamics and combinatorial optimization

    Science.gov (United States)

    Ovchinnikov, Igor V.; Wang, Kang L.

    2017-11-01

    Natural dynamics is often dominated by sudden nonlinear processes such as neuroavalanches, gamma-ray bursts, solar flares, etc., that exhibit scale-free statistics much in the spirit of the logarithmic Ritcher scale for earthquake magnitudes. On phase diagrams, stochastic dynamical systems (DSs) exhibiting this type of dynamics belong to the finite-width phase (N-phase for brevity) that precedes ordinary chaotic behavior and that is known under such names as noise-induced chaos, self-organized criticality, dynamical complexity, etc. Within the recently proposed supersymmetric theory of stochastic dynamics, the N-phase can be roughly interpreted as the noise-induced “overlap” between integrable and chaotic deterministic dynamics. As a result, the N-phase dynamics inherits the properties of the both. Here, we analyze this unique set of properties and conclude that the N-phase DSs must naturally be the most efficient optimizers: on one hand, N-phase DSs have integrable flows with well-defined attractors that can be associated with candidate solutions and, on the other hand, the noise-induced attractor-to-attractor dynamics in the N-phase is effectively chaotic or aperiodic so that a DS must avoid revisiting solutions/attractors thus accelerating the search for the best solution. Based on this understanding, we propose a method for stochastic dynamical optimization using the N-phase DSs. This method can be viewed as a hybrid of the simulated and chaotic annealing methods. Our proposition can result in a new generation of hardware devices for efficient solution of various search and/or combinatorial optimization problems.

  13. Synthetic Plant Defense Elicitors

    Directory of Open Access Journals (Sweden)

    Yasemin eBektas

    2015-01-01

    Full Text Available To defend themselves against invading pathogens plants utilize a complex regulatory network that coordinates extensive transcriptional and metabolic reprogramming. Although many of the key players of this immunity-associated network are known, the details of its topology and dynamics are still poorly understood. As an alternative to forward and reverse genetic studies, chemical genetics-related approaches based on bioactive small molecules have gained substantial popularity in the analysis of biological pathways and networks. Use of such molecular probes can allow researchers to access biological space that was previously inaccessible to genetic analyses due to gene redundancy or lethality of mutations. Synthetic elicitors are small drug like molecules that induce plant defense responses, but are distinct from known natural elicitors of plant immunity. While the discovery of the some synthetic elicitors had already been reported in the 1970s, recent breakthroughs in combinatorial chemical synthesis now allow for inexpensive high-throughput screens for bioactive plant defense-inducing compounds. Along with powerful reverse genetics tools and resources available for model plants and crop systems, comprehensive collections of new synthetic elicitors will likely allow plant scientists to study the intricacies of plant defense signaling pathways and networks in an unparalleled fashion. As synthetic elicitors can protect crops from diseases, without the need to be directly toxic for pathogenic organisms, they may also serve as promising alternatives to conventional biocidal pesticides, which often are harmful for the environment, farmers and consumers. Here we are discussing various types of synthetic elicitors that have been used for studies on the plant immune system, their modes-of-action as well as their application in crop protection.

  14. Assembly and use of high-density recombinant peptide chips for large-scale ligand screening is a practical alternative to synthetic peptide libraries.

    Science.gov (United States)

    Hundsberger, Harald; Önder, Kamil; Schuller-Götzburg, Peter; Virok, Dezso P; Herzog, Julia; Rid, Raphaela

    2017-06-08

    Recombinant peptide chips could constitute a versatile complementation to state-of-the-art in situ (chemical on-chip) synthesis, particle-based printing, or pre-manufactured peptide spotting. Bottlenecks still impeding a routine implementation - from restricted peptide lengths, low diversity and low array densities to high costs - could so be overcome. To assess overall performance, we assembled recombinant chips composed of 38,400 individual peptide spots on the area of a standard 96-well microtiter plate from comprehensive, highly diverse (>107 single clones) short random peptide libraries. Screening of altogether 476,160 clones against Streptavidin uncovered 2 discrete new binders: a characteristic HPQ-motif containing VSHPQAPF and a cyclic CSGSYGSC peptide. Interactions were technically confirmed by fluorescence polarization as well as biolayer-interferometry, and their potential suitability as novel detection tags evaluated by detection of a peptide-fused exemplary test protein. From our data we conclude that the presented technical pipeline can reliably identify novel hits, useful as first-generation binders or templates for subsequent ligand design plus engineering.

  15. Systematic identification of combinatorial drivers and targets in cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Adel Tabchy

    Full Text Available There is an urgent need to elicit and validate highly efficacious targets for combinatorial intervention from large scale ongoing molecular characterization efforts of tumors. We established an in silico bioinformatic platform in concert with a high throughput screening platform evaluating 37 novel targeted agents in 669 extensively characterized cancer cell lines reflecting the genomic and tissue-type diversity of human cancers, to systematically identify combinatorial biomarkers of response and co-actionable targets in cancer. Genomic biomarkers discovered in a 141 cell line training set were validated in an independent 359 cell line test set. We identified co-occurring and mutually exclusive genomic events that represent potential drivers and combinatorial targets in cancer. We demonstrate multiple cooperating genomic events that predict sensitivity to drug intervention independent of tumor lineage. The coupling of scalable in silico and biologic high throughput cancer cell line platforms for the identification of co-events in cancer delivers rational combinatorial targets for synthetic lethal approaches with a high potential to pre-empt the emergence of resistance.

  16. Combinatorial designs a tribute to Haim Hanani

    CERN Document Server

    Hartman, A

    1989-01-01

    Haim Hanani pioneered the techniques for constructing designs and the theory of pairwise balanced designs, leading directly to Wilson''s Existence Theorem. He also led the way in the study of resolvable designs, covering and packing problems, latin squares, 3-designs and other combinatorial configurations.The Hanani volume is a collection of research and survey papers at the forefront of research in combinatorial design theory, including Professor Hanani''s own latest work on Balanced Incomplete Block Designs. Other areas covered include Steiner systems, finite geometries, quasigroups, and t-designs.

  17. Efficient exploration of large combinatorial chemistry spaces by monomer-based similarity searching.

    Science.gov (United States)

    Yu, Ning; Bakken, Gregory A

    2009-04-01

    In modern drug discovery, 2-D similarity searching is widely employed as a cost-effective way to screen large compound collections and select subsets of molecules that may have interesting biological activity prior to experimental screening. Nowadays, there is a growing interest in applying the existing 2-D similarity searching methods to combinatorial chemistry libraries to search for novel hits or to evolve lead series. A dilemma thus arises when many identical substructures recur in library products and they have to be considered repeatedly in descriptor calculations. The dilemma is exacerbated by the astronomical number of combinatorial products. This problem imposes a major barrier to similarity searching of large combinatorial chemistry spaces. An efficient approach, termed Monomer-based Similarity Searching (MoBSS), is proposed to remedy the problem. MoBSS calculates atom pair (AP) descriptors based on interatomic topological distances, which lend themselves to pair additivity. A fast algorithm is employed in MoBSS to rapidly compute product atom pairs from those of the constituent fragments. The details of the algorithm are presented along with a series of proof-of-concept studies, which demonstrate the speed, accuracy, and utility of the MoBSS approach.

  18. Synthesis of two D-glucosamine derived 3,4-epoxides as potential scaffolds for combinatorial chemistry

    DEFF Research Database (Denmark)

    Svejgaard, L.; Fuglsang, H.; Jensen, P.B.

    2003-01-01

    Combinatorial chemistry allows the synthesis of libraries of compounds by combination of building blocks or by combinatorial elaboration of a central scaffold.([1,2]) Carbohydrates hold great promise as scaffolds due to their high degree of functionalization, relative conformational rigidity......, commercial availability of many stereoisomeric forms, and their well-described chemistry. Hirschmann, Nicolaou, Smith, and their coworkers pioneered the use of carbohydrates as scaffolds in their design and synthesis Of beta-D-glucose derived non-peptide peptidomimetics of the peptide hormone somatostatin...... (SRIF).([3,4]) However, only relatively few examples on the application of carbohydrates as scaffolds in combinatorial chemistry have been described.([5-11]) For example, Brill et al. anchored a 1,6-anhydro-beta-D-glucopyranoside (levoglucosan) derived epoxide to a solid support and introduced diversity...

  19. Directed combinatorial mutagenesis of Escherichia coli for complex phenotype engineering

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Rongming; Liang, Liya; Garst, Andrew D.; Choudhury, Alaksh; Nogué, Violeta Sànchez i.; Beckham, Gregg T.; Gill, Ryan T.

    2018-05-01

    Strain engineering for industrial production requires a targeted improvement of multiple complex traits, which range from pathway flux to tolerance to mixed sugar utilization. Here, we report the use of an iterative CRISPR EnAbled Trackable genome Engineering (iCREATE) method to engineer rapid glucose and xylose co-consumption and tolerance to hydrolysate inhibitors in E. coli. Deep mutagenesis libraries were rationally designed, constructed, and screened to target ~40,000 mutations across 30 genes. These libraries included global and high-level regulators that regulate global gene expression, transcription factors that play important roles in genome-level transcription, enzymes that function in the sugar transport system, NAD(P)H metabolism, and the aldehyde reduction system. Specific mutants that conferred increased growth in mixed sugars and hydrolysate tolerance conditions were isolated, confirmed, and evaluated for changes in genome-wide expression levels. We tested the strain with positive combinatorial mutations for 3-hydroxypropionic acid (3HP) production under high furfural and high acetate hydrolysate fermentation, which demonstrated a 7- and 8-fold increase in 3HP productivity relative to the parent strain, respectively.

  20. Discovery of Cationic Polymers for Non-viral Gene Delivery using Combinatorial Approaches

    Science.gov (United States)

    Barua, Sutapa; Ramos, James; Potta, Thrimoorthy; Taylor, David; Huang, Huang-Chiao; Montanez, Gabriela; Rege, Kaushal

    2015-01-01

    Gene therapy is an attractive treatment option for diseases of genetic origin, including several cancers and cardiovascular diseases. While viruses are effective vectors for delivering exogenous genes to cells, concerns related to insertional mutagenesis, immunogenicity, lack of tropism, decay and high production costs necessitate the discovery of non-viral methods. Significant efforts have been focused on cationic polymers as non-viral alternatives for gene delivery. Recent studies have employed combinatorial syntheses and parallel screening methods for enhancing the efficacy of gene delivery, biocompatibility of the delivery vehicle, and overcoming cellular level barriers as they relate to polymer-mediated transgene uptake, transport, transcription, and expression. This review summarizes and discusses recent advances in combinatorial syntheses and parallel screening of cationic polymer libraries for the discovery of efficient and safe gene delivery systems. PMID:21843141

  1. Combinatorial Algorithms to Enable Computational Science and Engineering: Work from the CSCAPES Institute

    Energy Technology Data Exchange (ETDEWEB)

    Boman, Erik G. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Scalable Algorithms Dept.; Catalyurek, Umit V. [The Ohio State Univ., Columbus, OH (United States). Biomedical Informatics. Electrical and Computer Engineering; Chevalier, Cedric [Alternative Energies and Atomic Energy Commission (CEA), Cadarache (France); Devine, Karen D. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Scalable Algorithms Dept.; Gebremedhin, Assefaw H. [Purdue Univ., West Lafayette, IN (United States). Computer Science; Hovland, Paul D. [Argonne National Lab. (ANL), Argonne, IL (United States). Mathematics and Computer Science Division; Pothen, Alex [Purdue Univ., West Lafayette, IN (United States). Computer Science; Rajamanickam, Sivasankaran [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Scalable Algorithms Dept.; Safro, Ilya [Argonne National Lab. (ANL), Argonne, IL (United States). Mathematics and Computer Science Division; Wolf, Michael M. [Massachusetts Inst. of Technology (MIT), Lexington, MA (United States). Lincoln Lab.; Zhou, Min [Rensselaer Polytechnic Inst., Troy, NY (United States). Scientific Computation Research Center

    2015-01-16

    This final progress report summarizes the work accomplished at the Combinatorial Scientific Computing and Petascale Simulations Institute. We developed Zoltan, a parallel mesh partitioning library that made use of accurate hypergraph models to provide load balancing in mesh-based computations. We developed several graph coloring algorithms for computing Jacobian and Hessian matrices and organized them into a software package called ColPack. We developed parallel algorithms for graph coloring and graph matching problems, and also designed multi-scale graph algorithms. Three PhD students graduated, six more are continuing their PhD studies, and four postdoctoral scholars were advised. Six of these students and Fellows have joined DOE Labs (Sandia, Berkeley), as staff scientists or as postdoctoral scientists. We also organized the SIAM Workshop on Combinatorial Scientific Computing (CSC) in 2007, 2009, and 2011 to continue to foster the CSC community.

  2. Combinatorial Proofs and Algebraic Proofs–II

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 18; Issue 8. Combinatorial Proofs and Algebraic Proofs - II. Shailesh A Shirali. General Article Volume 18 Issue 8 August 2013 pp 738-747. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/018/08/0738-0747 ...

  3. On an extension of a combinatorial identity

    Indian Academy of Sciences (India)

    On an extension of a combinatorial identity. M RANA and A K AGARWAL. Center for Advanced Study in Mathematics, Panjab University, Chandigarh 160 014,. India. E-mail: aka@pu.ac.in. MS received 22 August 2007. Abstract. Using Frobenius partitions we extend the main results of [4]. This leads to an infinite family of ...

  4. Polyhredral techniques in combinatorial optimization I: theory

    NARCIS (Netherlands)

    Aardal, K.; Hoesel, S. van

    1995-01-01

    Combinatorial optimization problems appear in many disciplines ranging from management and logistics to mathematics, physics, and chemistry. These problems are usually relatively easy to formulate mathematically, but most of them are computationally hard due to the restriction that a subset of

  5. Combinatorial Proofs and Algebraic Proofs–I

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 18; Issue 7. Combinatorial Proofs and Algebraic Proofs - I. Shailesh A Shirali. General Article Volume 18 Issue 7 July 2013 pp 630-645. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/018/07/0630-0645 ...

  6. Combinatorial biosynthesis of medicinal plant secondary metabolites

    NARCIS (Netherlands)

    Julsing, Mattijs K.; Koulman, Albert; Woerdenbag, Herman J.; Quax, Wim J.; Kayser, Oliver

    2006-01-01

    Combinatorial biosynthesis is a new tool in the generation of novel natural products and for the production of rare and expensive natural products. The basic concept is combining metabolic pathways in different organisms on a genetic level. As a consequence heterologous organisms provide precursors

  7. Combinatorial Proofs and Algebraic Proofs – I

    Indian Academy of Sciences (India)

    IAS Admin

    outreach projects in teacher education. It is sometimes the case in mathematics that the ... coefficients. These may be proved using either the bi- nomial theorem or by combinatorial arguments; but we present only the latter. The prototypical example of. The basic strategy followed in such proofs is that of counting the same.

  8. Infinitary Combinatory Reduction Systems: Normalising Reduction Strategies

    NARCIS (Netherlands)

    Ketema, J.; Simonsen, Jakob Grue

    2010-01-01

    We study normalising reduction strategies for infinitary Combinatory Reduction Systems (iCRSs). We prove that all fair, outermost-fair, and needed-fair strategies are normalising for orthogonal, fully-extended iCRSs. These facts properly generalise a number of results on normalising strategies in

  9. ACRE: Absolute concentration robustness exploration in module-based combinatorial networks

    KAUST Repository

    Kuwahara, Hiroyuki

    2017-03-01

    To engineer cells for industrial-scale application, a deep understanding of how to design molecular control mechanisms to tightly maintain functional stability under various fluctuations is crucial. Absolute concentration robustness (ACR) is a category of robustness in reaction network models in which the steady-state concentration of a molecular species is guaranteed to be invariant even with perturbations in the other molecular species in the network. Here, we introduce a software tool, absolute concentration robustness explorer (ACRE), which efficiently explores combinatorial biochemical networks for the ACR property. ACRE has a user-friendly interface, and it can facilitate efficient analysis of key structural features that guarantee the presence and the absence of the ACR property from combinatorial networks. Such analysis is expected to be useful in synthetic biology as it can increase our understanding of how to design molecular mechanisms to tightly control the concentration of molecular species. ACRE is freely available at https://github.com/ramzan1990/ACRE.

  10. High-throughput combinatorial chemical bath deposition: The case of doping Cu (In, Ga) Se film with antimony

    Science.gov (United States)

    Yan, Zongkai; Zhang, Xiaokun; Li, Guang; Cui, Yuxing; Jiang, Zhaolian; Liu, Wen; Peng, Zhi; Xiang, Yong

    2018-01-01

    The conventional methods for designing and preparing thin film based on wet process remain a challenge due to disadvantages such as time-consuming and ineffective, which hinders the development of novel materials. Herein, we present a high-throughput combinatorial technique for continuous thin film preparation relied on chemical bath deposition (CBD). The method is ideally used to prepare high-throughput combinatorial material library with low decomposition temperatures and high water- or oxygen-sensitivity at relatively high-temperature. To check this system, a Cu(In, Ga)Se (CIGS) thin films library doped with 0-19.04 at.% of antimony (Sb) was taken as an example to evaluate the regulation of varying Sb doping concentration on the grain growth, structure, morphology and electrical properties of CIGS thin film systemically. Combined with the Energy Dispersive Spectrometer (EDS), X-ray Photoelectron Spectroscopy (XPS), automated X-ray Diffraction (XRD) for rapid screening and Localized Electrochemical Impedance Spectroscopy (LEIS), it was confirmed that this combinatorial high-throughput system could be used to identify the composition with the optimal grain orientation growth, microstructure and electrical properties systematically, through accurately monitoring the doping content and material composition. According to the characterization results, a Sb2Se3 quasi-liquid phase promoted CIGS film-growth model has been put forward. In addition to CIGS thin film reported here, the combinatorial CBD also could be applied to the high-throughput screening of other sulfide thin film material systems.

  11. FOREWORD: Focus on Combinatorial Materials Science Focus on Combinatorial Materials Science

    Science.gov (United States)

    Chikyo, Toyohiro

    2011-10-01

    About 15 years have passed since the introduction of modern combinatorial synthesis and high-throughput techniques for the development of novel inorganic materials; however, similar methods existed before. The most famous was reported in 1970 by Hanak who prepared composition-spread films of metal alloys by sputtering mixed-material targets. Although this method was innovative, it was rarely used because of the large amount of data to be processed. This problem is solved in the modern combinatorial material research, which is strongly related to computer data analysis and robotics. This field is still at the developing stage and may be enriched by new methods. Nevertheless, given the progress in measurement equipment and procedures, we believe the combinatorial approach will become a major and standard tool of materials screening and development. The first article of this journal, published in 2000, was titled 'Combinatorial solid state materials science and technology', and this focus issue aims to reintroduce this topic to the Science and Technology of Advanced Materials audience. It covers recent progress in combinatorial materials research describing new results in catalysis, phosphors, polymers and metal alloys for shape memory materials. Sophisticated high-throughput characterization schemes and innovative synthesis tools are also presented, such as spray deposition using nanoparticles or ion plating. On a technical note, data handling systems are introduced to familiarize researchers with the combinatorial methodology. We hope that through this focus issue a wide audience of materials scientists can learn about recent and future trends in combinatorial materials science and high-throughput experimentation.

  12. Library Automation

    OpenAIRE

    Dhakne, B. N.; Giri, V. V; Waghmode, S. S.

    2010-01-01

    New technologies library provides several new materials, media and mode of storing and communicating the information. Library Automation reduces the drudgery of repeated manual efforts in library routine. By use of library automation collection, Storage, Administration, Processing, Preservation and communication etc.

  13. Iterative optimization of xylose catabolism in Saccharomyces cerevisiae using combinatorial expression tuning.

    Science.gov (United States)

    Latimer, Luke N; Dueber, John E

    2017-06-01

    A common challenge in metabolic engineering is rapidly identifying rate-controlling enzymes in heterologous pathways for subsequent production improvement. We demonstrate a workflow to address this challenge and apply it to improving xylose utilization in Saccharomyces cerevisiae. For eight reactions required for conversion of xylose to ethanol, we screened enzymes for functional expression in S. cerevisiae, followed by a combinatorial expression analysis to achieve pathway flux balancing and identification of limiting enzymatic activities. In the next round of strain engineering, we increased the copy number of these limiting enzymes and again tested the eight-enzyme combinatorial expression library in this new background. This workflow yielded a strain that has a ∼70% increase in biomass yield and ∼240% increase in xylose utilization. Finally, we chromosomally integrated the expression library. This library enriched for strains with multiple integrations of the pathway, which likely were the result of tandem integrations mediated by promoter homology. Biotechnol. Bioeng. 2017;114: 1301-1309. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  14. Improving the thermostability of alpha-amylase by combinatorial coevolving-site saturation mutagenesis

    Directory of Open Access Journals (Sweden)

    Wang Chenghua

    2012-10-01

    Full Text Available Abstract Background The generation of focused mutant libraries at hotspot residues is an important strategy in directed protein evolution. Existing methods, such as combinatorial active site testing and residual coupling analysis, depend primarily on the evolutionary conserved information to find the hotspot residues. Hardly any attention has been paid to another important functional and structural determinants, the functionally correlated variation information--coevolution. Results In this paper, we suggest a new method, named combinatorial coevolving-site saturation mutagenesis (CCSM, in which the functionally correlated variation sites of proteins are chosen as the hotspot sites to construct focused mutant libraries. The CCSM approach was used to improve the thermal stability of α-amylase from Bacillus subtilis CN7 (Amy7C. The results indicate that the CCSM can identify novel beneficial mutation sites, and enhance the thermal stability of wild-type Amy7C by 8°C (T5030, which could not be achieved with the ordinarily rational introduction of single or a double point mutation. Conclusions Our method is able to produce more thermostable mutant α-amylases with novel beneficial mutations at new sites. It is also verified that the coevolving sites can be used as the hotspots to construct focused mutant libraries in protein engineering. This study throws new light on the active researches of the molecular coevolution.

  15. Two-dimensional parallel array technology as a new approach to automated combinatorial solid-phase organic synthesis

    Science.gov (United States)

    Brennan; Biddison; Frauendorf; Schwarcz; Keen; Ecker; Davis; Tinder; Swayze

    1998-01-01

    An automated, 96-well parallel array synthesizer for solid-phase organic synthesis has been designed and constructed. The instrument employs a unique reagent array delivery format, in which each reagent utilized has a dedicated plumbing system. An inert atmosphere is maintained during all phases of a synthesis, and temperature can be controlled via a thermal transfer plate which holds the injection molded reaction block. The reaction plate assembly slides in the X-axis direction, while eight nozzle blocks holding the reagent lines slide in the Y-axis direction, allowing for the extremely rapid delivery of any of 64 reagents to 96 wells. In addition, there are six banks of fixed nozzle blocks, which deliver the same reagent or solvent to eight wells at once, for a total of 72 possible reagents. The instrument is controlled by software which allows the straightforward programming of the synthesis of a larger number of compounds. This is accomplished by supplying a general synthetic procedure in the form of a command file, which calls upon certain reagents to be added to specific wells via lookup in a sequence file. The bottle position, flow rate, and concentration of each reagent is stored in a separate reagent table file. To demonstrate the utility of the parallel array synthesizer, a small combinatorial library of hydroxamic acids was prepared in high throughput mode for biological screening. Approximately 1300 compounds were prepared on a 10 μmole scale (3-5 mg) in a few weeks. The resulting crude compounds were generally >80% pure, and were utilized directly for high throughput screening in antibacterial assays. Several active wells were found, and the activity was verified by solution-phase synthesis of analytically pure material, indicating that the system described herein is an efficient means for the parallel synthesis of compounds for lead discovery. Copyright 1998 John Wiley & Sons, Inc.

  16. Quantum fields and processes a combinatorial approach

    CERN Document Server

    Gough, John

    2018-01-01

    Wick ordering of creation and annihilation operators is of fundamental importance for computing averages and correlations in quantum field theory and, by extension, in the Hudson–Parthasarathy theory of quantum stochastic processes, quantum mechanics, stochastic processes, and probability. This book develops the unified combinatorial framework behind these examples, starting with the simplest mathematically, and working up to the Fock space setting for quantum fields. Emphasizing ideas from combinatorics such as the role of lattice of partitions for multiple stochastic integrals by Wallstrom–Rota and combinatorial species by Joyal, it presents insights coming from quantum probability. It also introduces a 'field calculus' which acts as a succinct alternative to standard Feynman diagrams and formulates quantum field theory (cumulant moments, Dyson–Schwinger equation, tree expansions, 1-particle irreducibility) in this language. Featuring many worked examples, the book is aimed at mathematical physicists,...

  17. Three Syntactic Theories for Combinatory Graph Reduction

    DEFF Research Database (Denmark)

    Danvy, Olivier; Zerny, Ian

    2011-01-01

    We present a purely syntactic theory of graph reduction for the canonical combinators S, K, and I, where graph vertices are represented with evaluation contexts and let expressions. We express this syntactic theory as a reduction semantics, which we refocus into the first storeless abstract machine...... for combinatory graph reduction, which we refunctionalize into the first storeless natural semantics for combinatory graph reduction.We then factor out the introduction of let expressions to denote as many graph vertices as possible upfront instead of on demand, resulting in a second syntactic theory, this one...... of term graphs in the sense of Barendregt et al. The corresponding storeless abstract machine and natural semantics follow mutatis mutandis. We then interpret let expressions as operations over a global store (thus shifting, in Strachey's words, from denotable entities to storable entities), resulting...

  18. Gems of combinatorial optimization and graph algorithms

    CERN Document Server

    Skutella, Martin; Stiller, Sebastian; Wagner, Dorothea

    2015-01-01

    Are you looking for new lectures for your course on algorithms, combinatorial optimization, or algorithmic game theory?  Maybe you need a convenient source of relevant, current topics for a graduate student or advanced undergraduate student seminar?  Or perhaps you just want an enjoyable look at some beautiful mathematical and algorithmic results, ideas, proofs, concepts, and techniques in discrete mathematics and theoretical computer science?   Gems of Combinatorial Optimization and Graph Algorithms is a handpicked collection of up-to-date articles, carefully prepared by a select group of international experts, who have contributed some of their most mathematically or algorithmically elegant ideas.  Topics include longest tours and Steiner trees in geometric spaces, cartograms, resource buying games, congestion games, selfish routing, revenue equivalence and shortest paths, scheduling, linear structures in graphs, contraction hierarchies, budgeted matching problems, and motifs in networks.   This ...

  19. A COMBINATORIAL PROBLEM ON A DIRECTED GRAPH

    Directory of Open Access Journals (Sweden)

    Osvaldo Marrero

    2016-08-01

    Full Text Available We consider two options for a particle’s entire journey through a certaindirectedgraph. Both options involve a random assignment to the journey route to be followed. We are interested in the option that offers, on average, the shortest route. Therefore, we determine the average journey length for each of the two options. As part of our analysis, we provesome combinatorial identities that appear to be new. Some suggestions for further work are given.

  20. The Combinatorial Trace Method in Action

    Science.gov (United States)

    Krebs, Mike; Martinez, Natalie C.

    2013-01-01

    On any finite graph, the number of closed walks of length k is equal to the sum of the kth powers of the eigenvalues of any adjacency matrix. This simple observation is the basis for the combinatorial trace method, wherein we attempt to count (or bound) the number of closed walks of a given length so as to obtain information about the graph's…

  1. Switched Systems and Motion Coordination: Combinatorial Challenges

    Science.gov (United States)

    Sadovsky, Alexander V.

    2016-01-01

    Problems of routing commercial air traffic in a terminal airspace encounter different constraints: separation assurance, aircraft performance limitations, regulations. The general setting of these problems is that of a switched control system. Such a system combines the differentiable motion of the aircraft with the combinatorial choices of choosing precedence when traffic routes merge and choosing branches when the routes diverge. This presentation gives an overview of the problem, the ATM context, related literature, and directions for future research.

  2. The strange algebra of combinatorial games

    OpenAIRE

    Wästlund, Johan

    2009-01-01

    We present an algebraic framework for the analysis of combinatorial games. This framework embraces the classical theory of partizan games as well as a number of misere games, comply-constrain games, and card games that have been studied more recently. It focuses on the construction of the quotient monoid of a game, an idea that has been successively applied to several classes of games.

  3. Química combinatória: moderna ferramenta para a obtenção de candidatos a protótipos de novos fármacos Combinatorial chemistry: advanced tool for drug leads discovery

    Directory of Open Access Journals (Sweden)

    Patrícia de Aguiar Amaral

    2003-12-01

    Full Text Available A Química Combinatória (QC é atualmente uma das mais promissoras ferramentas para a descoberta e o desenvolvimento de novas moléculas com potencialidades terapêuticas. Nesta metodologia de síntese os produtos são formados simultaneamente e podem ser testados biologicamente em uma só vez, seja em forma de misturas ou separadamente. A principal meta desta nova metodologia é reduzir o tempo necessário para a obtenção de um novo fármaco. A síntese de quimiotecas pode ser realizada através da utilização de polímeros insolúveis, solúveis ou pela tradicional síntese em solução, sendo que cada uma delas apresenta características que podem ser vantajosas ou não, dependendo da metodologia utilizada. O desenvolvimento de técnicas de high throughput screening (HTS devido às suas características peculiares necessita de tempo, razão pela qual a síntese de quimiotecas pequenas e racionais é enfatizada.Nowadays, Combinatorial Chemistry is one of the most promising tools used in the design and discovery of new molecules potentially useful in the therapeutics. In this methodology, the reaction products are synthesized simultaneously and can be evaluated once, either in a complex mixture or as isolated compounds. The main aim of this new approach is the time for the development of new drugs. The synthesis of combinatorial libraries can be performed using either insoluble or soluble polymers and also by the traditional organic synthesis in solution. Each one of these approaches presents features that may be advantageous depending on the final objective of the synthetic process. The development of high throughput screening (HTS assays takes much time, which makes the synthesis of small and well designed combinatorial libraries the most recommended strategy.

  4. Synthetic promoter libraries for Corynebacterium glutamicum

    DEFF Research Database (Denmark)

    Rytter, Jakob Vang; Helmark, Søren; Chen, Jun

    2014-01-01

    The ability to modulate gene expression is an important genetic tool in systems biology and biotechnology. Here, we demonstrate that a previously published easy and fast PCR-based method for modulating gene expression in lactic acid bacteria is also applicable to Corynebacterium glutamicum. We co...

  5. Synthetic Cannabinoids

    Directory of Open Access Journals (Sweden)

    Aslihan Okan Ibiloglu

    2017-09-01

    Full Text Available Synthetic cannabinoids which is a subgroup of cannabinoids are commonly used for recreational drug use throughout the whole world. Although both marijuana and synthetic cannabinoids stimulate the same receptors, cannabinoid receptor 1 (CB1 and cannabinoid receptor 2 (CB2, studies have shown that synthetic cannabinoids are much more potent than marijuana. The longer use of synthetic cannabinoids can cause severe physical and psychological symptoms that might even result in death, similar to many known illicit drugs. Main treatment options mostly involve symptom management and supportive care. The aim of this article is to discuss clinical and pharmacological properties of the increasingly used synthetic cannabinoids. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2017; 9(3.000: 317-328

  6. Generalized topological spaces in evolutionary theory and combinatorial chemistry.

    Science.gov (United States)

    Stadler, Bärbel M R; Stadler, Peter F

    2002-01-01

    The search spaces in combinatorial chemistry as well as the sequence spaces underlying (molecular) evolution are conventionally thought of as graphs. Recombination, however, implies a nongraphical structure of the combinatorial search spaces. These structures, and their implications for search process itself, are heretofore not well understood in general. In this contribution we review a very general formalism from point set topology and discuss its application to combinatorial search spaces, fitness landscapes, evolutionary trajectories, and artificial chemistries.

  7. Neural Meta-Memes Framework for Combinatorial Optimization

    Science.gov (United States)

    Song, Li Qin; Lim, Meng Hiot; Ong, Yew Soon

    In this paper, we present a Neural Meta-Memes Framework (NMMF) for combinatorial optimization. NMMF is a framework which models basic optimization algorithms as memes and manages them dynamically when solving combinatorial problems. NMMF encompasses neural networks which serve as the overall planner/coordinator to balance the workload between memes. We show the efficacy of the proposed NMMF through empirical study on a class of combinatorial problem, the quadratic assignment problem (QAP).

  8. 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.

  9. Combinatorially selected peptides for protection of soybean against Phakopsora pachyrhizi.

    Science.gov (United States)

    Fang, Zhiwei D; Marois, James J; Stacey, Gary; Schoelz, James E; English, James T; Schmidt, Francis J

    2010-10-01

    Phakopsora pachyrhizi, the fungal pathogen that causes Asian soybean rust, has the potential to cause significant losses in soybean yield in many production regions of the United States. Germplasm with durable, single-gene resistance is lacking, and control of rust depends on timely application of fungicides. To assist the development of new modes of soybean resistance, we identified peptides from combinatorial phage-display peptide libraries that inhibit germ tube growth from urediniospores of P. pachyrhizi. Two peptides, Sp2 and Sp39, were identified that inhibit germ tube development when displayed as fusions with the coat protein of M13 phage or as fusions with maize cytokinin oxidase/dehydrogenase (ZmCKX1). In either display format, the inhibitory effect of the peptides on germ tube growth was concentration dependent. In addition, when peptides Sp2 or Sp39 in either format were mixed with urediniospores and inoculated to soybean leaves with an 8-h wetness period, rust lesion development was reduced. Peptides Sp2 and Sp39, displayed on ZmCKX1, were found to interact with a 20-kDa protein derived from germinated urediniospores. Incorporating peptides that inhibit pathogen development and pathogenesis into breeding programs may contribute to the development of soybean cultivars with improved, durable rust tolerance.

  10. De novo designed proteins from a library of artificial sequences function in Escherichia coli and enable cell growth.

    Directory of Open Access Journals (Sweden)

    Michael A Fisher

    Full Text Available A central challenge of synthetic biology is to enable the growth of living systems using parts that are not derived from nature, but designed and synthesized in the laboratory. As an initial step toward achieving this goal, we probed the ability of a collection of >10(6 de novo designed proteins to provide biological functions necessary to sustain cell growth. Our collection of proteins was drawn from a combinatorial library of 102-residue sequences, designed by binary patterning of polar and nonpolar residues to fold into stable 4-helix bundles. We probed the capacity of proteins from this library to function in vivo by testing their abilities to rescue 27 different knockout strains of Escherichia coli, each deleted for a conditionally essential gene. Four different strains--ΔserB, ΔgltA, ΔilvA, and Δfes--were rescued by specific sequences from our library. Further experiments demonstrated that a strain simultaneously deleted for all four genes was rescued by co-expression of four novel sequences. Thus, cells deleted for ∼0.1% of the E. coli genome (and ∼1% of the genes required for growth under nutrient-poor conditions can be sustained by sequences designed de novo.

  11. Rational and combinatorial tailoring of bioactive cyclic dipeptides

    Directory of Open Access Journals (Sweden)

    Tobias Wolfgang Giessen

    2015-07-01

    Full Text Available Modified cyclic dipeptides represent a diverse family of microbial secondary metabolites. They display a broad variety of biological and pharmacological activities and have long been recognized as privileged structures with the ability to bind to a wide range of receptors. This is due to their conformationally constrained 2, 5-diketopiperazine (DKP scaffold and the diverse set of DKP tailoring enzymes present in nature. After initial DKP assembly through different biosynthetic systems modifying enzymes are responsible for installing functional groups crucial for the biological activities of the resulting modified DKPs. They represent a vast and largely untapped enzyme repository very useful for synthetic biology approaches aiming at introducing structural variations into DKP scaffolds. In this review we focus on these DKP modification enzymes found in various microbial secondary metabolite gene clusters. We will give a brief overview of their distribution and highlight a select number of characterized DKP tailoring enzymes before turning to their application potential in combinatorial biosynthesis with the aim of producing molecules with improved or entirely new biological and medicinally relevant properties.

  12. Advanced Aqueous Phase Catalyst Development using Combinatorial Methods, Phase II

    Data.gov (United States)

    National Aeronautics and Space Administration — Combinatorial methods are proposed to develop advanced Aqueous Oxidation Catalysts (AOCs) with the capability to mineralize organic contaminants present in effluents...

  13. "One-sample concept" micro-combinatory for high throughput TEM of binary films.

    Science.gov (United States)

    Sáfrán, György

    2018-04-01

    Phases of thin films may remarkably differ from that of bulk. Unlike to the comprehensive data files of Binary Phase Diagrams [1] available for bulk, complete phase maps for thin binary layers do not exist. This is due to both the diverse metastable, non-equilibrium or instable phases feasible in thin films and the required volume of characterization work with analytical techniques like TEM, SAED and EDS. The aim of the present work was to develop a method that remarkably facilitates the TEM study of the diverse binary phases of thin films, or the creation of phase maps. A micro-combinatorial method was worked out that enables both preparation and study of a gradient two-component film within a single TEM specimen. For a demonstration of the technique thin Mn x Al 1- x binary samples with evolving concentration from x = 0 to x = 1 have been prepared so that the transition from pure Mn to pure Al covers a 1.5 mm long track within the 3 mm diameter TEM grid. The proposed method enables the preparation and study of thin combinatorial samples including all feasible phases as a function of composition or other deposition parameters. Contrary to known "combinatorial chemistry", in which a series of different samples are deposited in one run, and investigated, one at a time, the present micro-combinatorial method produces a single specimen condensing a complete library of a binary system that can be studied, efficiently, within a single TEM session. That provides extremely high throughput for TEM characterization of composition-dependent phases, exploration of new materials, or the construction of phase diagrams of binary films. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. Library Computing

    Science.gov (United States)

    Library Computing, 1985

    1985-01-01

    Special supplement to "Library Journal" and "School Library Journal" covers topics of interest to school, public, academic, and special libraries planning for automation: microcomputer use, readings in automation, online searching, databases of microcomputer software, public access to microcomputers, circulation, creating a…

  15. A Barcoding Strategy Enabling Higher-Throughput Library Screening by Microscopy.

    Science.gov (United States)

    Chen, Robert; Rishi, Harneet S; Potapov, Vladimir; Yamada, Masaki R; Yeh, Vincent J; Chow, Thomas; Cheung, Celia L; Jones, Austin T; Johnson, Terry D; Keating, Amy E; DeLoache, William C; Dueber, John E

    2015-11-20

    Dramatic progress has been made in the design and build phases of the design-build-test cycle for engineering cells. However, the test phase usually limits throughput, as many outputs of interest are not amenable to rapid analytical measurements. For example, phenotypes such as motility, morphology, and subcellular localization can be readily measured by microscopy, but analysis of these phenotypes is notoriously slow. To increase throughput, we developed microscopy-readable barcodes (MiCodes) composed of fluorescent proteins targeted to discernible organelles. In this system, a unique barcode can be genetically linked to each library member, making possible the parallel analysis of phenotypes of interest via microscopy. As a first demonstration, we MiCoded a set of synthetic coiled-coil leucine zipper proteins to allow an 8 × 8 matrix to be tested for specific interactions in micrographs consisting of mixed populations of cells. A novel microscopy-readable two-hybrid fluorescence localization assay for probing candidate interactions in the cytosol was also developed using a bait protein targeted to the peroxisome and a prey protein tagged with a fluorescent protein. This work introduces a generalizable, scalable platform for making microscopy amenable to higher-throughput library screening experiments, thereby coupling the power of imaging with the utility of combinatorial search paradigms.

  16. Chromatin regulation at the frontier of synthetic biology

    Science.gov (United States)

    Keung, Albert J.; Joung, J. Keith; Khalil, Ahmad S.; Collins, James J.

    2016-01-01

    As synthetic biology approaches are extended to diverse applications throughout medicine, biotechnology and basic biological research, there is an increasing need to engineer yeast, plant and mammalian cells. Eukaryotic genomes are regulated by the diverse biochemical and biophysical states of chromatin, which brings distinct challenges, as well as opportunities, over applications in bacteria. Recent synthetic approaches, including `epigenome editing', have allowed the direct and functional dissection of many aspects of physiological chromatin regulation. These studies lay the foundation for biomedical and biotechnological engineering applications that could take advantage of the unique combinatorial and spatiotemporal layers of chromatin regulation to create synthetic systems of unprecedented sophistication. PMID:25668787

  17. Effects of Suboptimal Bidding in Combinatorial Auctions

    Science.gov (United States)

    Schneider, Stefan; Shabalin, Pasha; Bichler, Martin

    Though the VCG auction assumes a central place in the mechanism design literature, there are a number of reasons for favoring iterative combinatorial auction designs. Several promising ascending auction formats have been developed throughout the past few years based on primal-dual and subgradient algorithms and linear programming theory. Prices are interpreted as a feasible dual solution and the provisional allocation is interpreted as a feasible primal solution. iBundle( 3) (Parkes and Ungar 2000), dVSV (de Vries et al. 2007) and the Ascending Proxy auction (Ausubel and Milgrom 2002) result in VCG payoffs when the coalitional value function satisfies the buyer submodularity condition and bidders bid straightforward, which is an expost Nash equilibrium in that case. iBEA and CreditDebit auctions (Mishra and Parkes 2007) do not even require the buyer submodularity condition and achieve the same properties for general valuations. In many situations, however, one cannot assume bidders to bid straightforward and it is not clear from the theory how these non-linear personalized price auctions (NLPPAs) perform in this case. Robustness of auctions with respect to different bidding behavior is therefore a critical issue for any application. We have conducted a large number of computational experiments to analyze the performance of NLPPA designs with respect to different bidding strategies and different valuation models. We compare the results of NLPPAs to those of the VCG auction and those of iterative combinatorial auctions with approximate linear prices, such as ALPS (Bichler et al. 2009) and the Combinatorial Clock auction (Porter et al. 2003).

  18. A combinatorial study on catalytic synergism in supported metal catalysts for fuel cell technology

    Science.gov (United States)

    Kobayashi, Tetsuhiko; Ueda, Atsushi; Yamada, Yusuke; Shioyama, Hiroshi

    2004-02-01

    In order to accelerate the catalyst development for the increasing demand on the fuel cell technology, it has been attempted to adopt a combinatorial approach. The catalytic synergism, often observed on the supported metal catalysts for the fuel cell utilization, has been subjected to study. It is proposed herein that not only a comparison of catalysts in one reaction, but also the comparison of interrelated reactions by use of a common catalyst library brings about important information to elucidate the catalytic synergism. Preliminary results of the comparison between the water-gas shift reaction and the steam reforming of MeOH on a given set of catalyst library are presented. An important indicator to predict the serendipitous synergism is expected to be obtained from such information by use of artificial intelligence.

  19. Automatic generation of combinatorial test data

    CERN Document Server

    Zhang, Jian; Ma, Feifei

    2014-01-01

    This book reviews the state-of-the-art in combinatorial testing, with particular emphasis on the automatic generation of test data. It describes the most commonly used approaches in this area - including algebraic construction, greedy methods, evolutionary computation, constraint solving and optimization - and explains major algorithms with examples. In addition, the book lists a number of test generation tools, as well as benchmarks and applications. Addressing a multidisciplinary topic, it will be of particular interest to researchers and professionals in the areas of software testing, combi

  20. Developing New Antibiotics with Combinatorial Biosynthesis

    Science.gov (United States)

    Pohl, Nicola L.

    2000-11-01

    Polyketide synthases (PKSs), a class of enzymes found in soil bacteria that produce antibiotics such as erythromycin, string together acetate units using basic organic reactions. The manipulation of the sequence of these reactions at the genetic level has resulted in an alteration of the corresponding chemical structure of the antibiotic produced by the bacteria. This process, called combinatorial biosynthesis, allows the generation of many presently unknown complex structures that can be tested for antibacterial activity, thereby contributing to the race against antibiotic-resistant infectious bacteria.

  1. Method and apparatus for combinatorial chemistry

    Science.gov (United States)

    Foote, Robert S [Oak Ridge, TN

    2012-06-05

    A method and apparatus are provided for performing light-directed reactions in spatially addressable channels within a plurality of channels. One aspect of the invention employs photoactivatable reagents in solutions disposed into spatially addressable flow streams to control the parallel synthesis of molecules immobilized within the channels. The reagents may be photoactivated within a subset of channels at the site of immobilized substrate molecules or at a light-addressable site upstream from the substrate molecules. The method and apparatus of the invention find particularly utility in the synthesis of biopolymer arrays, e.g., oligonucleotides, peptides and carbohydrates, and in the combinatorial synthesis of small molecule arrays for drug discovery.

  2. Synthetic oils

    Science.gov (United States)

    Hatton, R. E.

    1973-01-01

    Synthetic lubricants are discussed by chemical class and their general strengths and weaknesses in terms of lubrication properties are analyzed. Comparative ratings are given for 14 chemical classes and are used as a guide for lubricant selection. The effects of chemical structure on the properties of the lubricant are described with special emphasis on thermal stability. The diversity of synthetic lubricants which is provided by the wide range of properties permits many applications, some of which are reported.

  3. Combinatorial Screening for Transgenic Yeasts with High Cellulase Activities in Combination with a Tunable Expression System.

    Directory of Open Access Journals (Sweden)

    Yoichiro Ito

    Full Text Available Combinatorial screening used together with a broad library of gene expression cassettes is expected to produce a powerful tool for the optimization of the simultaneous expression of multiple enzymes. Recently, we proposed a highly tunable protein expression system that utilized multiple genome-integrated target genes to fine-tune enzyme expression in yeast cells. This tunable system included a library of expression cassettes each composed of three gene-expression control elements that in different combinations produced a wide range of protein expression levels. In this study, four gene expression cassettes with graded protein expression levels were applied to the expression of three cellulases: cellobiohydrolase 1, cellobiohydrolase 2, and endoglucanase 2. After combinatorial screening for transgenic yeasts simultaneously secreting these three cellulases, we obtained strains with higher cellulase expressions than a strain harboring three cellulase-expression constructs within one high-performance gene expression cassette. These results show that our method will be of broad use throughout the field of metabolic engineering.

  4. On Definitions and Existence of Combinatorial Entropy of 2d Fields

    DEFF Research Database (Denmark)

    Forchhammer, Søren Otto; Shtarkov, Yuri; Justesen, Jørn

    1998-01-01

    Different definitions of combinatorial entropy is presented and conditions for their existence examined.......Different definitions of combinatorial entropy is presented and conditions for their existence examined....

  5. Programming languages for synthetic biology.

    Science.gov (United States)

    Umesh, P; Naveen, F; Rao, Chanchala Uma Maheswara; Nair, Achuthsankar S

    2010-12-01

    In the backdrop of accelerated efforts for creating synthetic organisms, the nature and scope of an ideal programming language for scripting synthetic organism in-silico has been receiving increasing attention. A few programming languages for synthetic biology capable of defining, constructing, networking, editing and delivering genome scale models of cellular processes have been recently attempted. All these represent important points in a spectrum of possibilities. This paper introduces Kera, a state of the art programming language for synthetic biology which is arguably ahead of similar languages or tools such as GEC, Antimony and GenoCAD. Kera is a full-fledged object oriented programming language which is tempered by biopart rule library named Samhita which captures the knowledge regarding the interaction of genome components and catalytic molecules. Prominent feature of the language are demonstrated through a toy example and the road map for the future development of Kera is also presented.

  6. Combinatorial Quantum Field Theory and Gluing Formula for Determinants

    NARCIS (Netherlands)

    Reshetikhin, N.; Vertman, B.

    2015-01-01

    We define the combinatorial Dirichlet-to-Neumann operator and establish a gluing formula for determinants of discrete Laplacians using a combinatorial Gaussian quantum field theory. In case of a diagonal inner product on cochains we provide an explicit local expression for the discrete

  7. Cultural emergence of combinatorial structure in an artificial whistled language

    NARCIS (Netherlands)

    Verhoef, T.; Kirby, S.; Padden, C.; Carlson, L.; Hoelscher, C.; Shipley, T.F.

    2011-01-01

    Speech sounds within a linguistic system are both categorical and combinatorial and there are constraints on how elements can be recombined. To investigate the origins of this combinatorial structure, we conducted an iterated learning experiment with human participants, studying the transmission of

  8. Locating Minimal Fault Interaction in Combinatorial Testing

    Directory of Open Access Journals (Sweden)

    Wei Zheng

    2016-01-01

    Full Text Available Combinatorial testing (CT technique could significantly reduce testing cost and increase software system quality. By using the test suite generated by CT as input to conduct black-box testing towards a system, we are able to detect interactions that trigger the system’s faults. Given a test case, there may be only part of all its parameters relevant to the defects in system and the interaction constructed by those partial parameters is key factor of triggering fault. If we can locate those parameters accurately, this will facilitate the software diagnosing and testing process. This paper proposes a novel algorithm named complete Fault Interaction Location (comFIL to locate those interactions that cause system’s failures and meanwhile obtains the minimal set of target interactions in test suite produced by CT. By applying this method, testers can analyze and locate the factors relevant to defects of system more precisely, thus making the process of software testing and debugging easier and more efficient. The results of our empirical study indicate that comFIL performs better compared with known fault location techniques in combinatorial testing because of its improved effectiveness and precision.

  9. Combinatorial design of textured mechanical metamaterials.

    Science.gov (United States)

    Coulais, Corentin; Teomy, Eial; de Reus, Koen; Shokef, Yair; van Hecke, Martin

    2016-07-28

    The structural complexity of metamaterials is limitless, but, in practice, most designs comprise periodic architectures that lead to materials with spatially homogeneous features. More advanced applications in soft robotics, prosthetics and wearable technology involve spatially textured mechanical functionality, which requires aperiodic architectures. However, a naive implementation of such structural complexity invariably leads to geometrical frustration (whereby local constraints cannot be satisfied everywhere), which prevents coherent operation and impedes functionality. Here we introduce a combinatorial strategy for the design of aperiodic, yet frustration-free, mechanical metamaterials that exhibit spatially textured functionalities. We implement this strategy using cubic building blocks-voxels-that deform anisotropically, a local stacking rule that allows cooperative shape changes by guaranteeing that deformed building blocks fit together as in a three-dimensional jigsaw puzzle, and three-dimensional printing. These aperiodic metamaterials exhibit long-range holographic order, whereby the two-dimensional pixelated surface texture dictates the three-dimensional interior voxel arrangement. They also act as programmable shape-shifters, morphing into spatially complex, but predictable and designable, shapes when uniaxially compressed. Finally, their mechanical response to compression by a textured surface reveals their ability to perform sensing and pattern analysis. Combinatorial design thus opens up a new avenue towards mechanical metamaterials with unusual order and machine-like functionalities.

  10. A Review on Recent T-way Combinatorial Testing Strategy

    Directory of Open Access Journals (Sweden)

    Ramli Nuraminah

    2017-01-01

    Full Text Available T-way combinatorial testing aims to generate a smaller test suite size. The purpose of t-way combinatorial testing is to overcome exhaustive testing. Although many existing strategies have been developed for t-way combinatorial testing, study in this area is encouraging as it falls under NP-hard optimization problem. This paper focuses on the analysis of existing algorithms or tools for the past seven years. Taxonomy of combinatorial testing is proposed to ease the analysis. 20 algorithms or tools were analysed based on strategy approach, search technique, supported interaction and year published. 2015 was the most active year in which researchers developed t-way algorithms or tools. OTAT strategy and metaheuristic search technique are the most encouraging research areas for t-way combinatorial testing. There is a slight difference in the type of interaction support. However, uniform strength is the most utilized form of interaction from 2010 to the first quarter of 2017.

  11. Synthetic environments

    Science.gov (United States)

    Lukes, George E.; Cain, Joel M.

    1996-02-01

    The Advanced Distributed Simulation (ADS) Synthetic Environments Program seeks to create robust virtual worlds from operational terrain and environmental data sources of sufficient fidelity and currency to interact with the real world. While some applications can be met by direct exploitation of standard digital terrain data, more demanding applications -- particularly those support operations 'close to the ground' -- are well-served by emerging capabilities for 'value-adding' by the user working with controlled imagery. For users to rigorously refine and exploit controlled imagery within functionally different workstations they must have a shared framework to allow interoperability within and between these environments in terms of passing image and object coordinates and other information using a variety of validated sensor models. The Synthetic Environments Program is now being expanded to address rapid construction of virtual worlds with research initiatives in digital mapping, softcopy workstations, and cartographic image understanding. The Synthetic Environments Program is also participating in a joint initiative for a sensor model applications programer's interface (API) to ensure that a common controlled imagery exploitation framework is available to all researchers, developers and users. This presentation provides an introduction to ADS and the associated requirements for synthetic environments to support synthetic theaters of war. It provides a technical rationale for exploring applications of image understanding technology to automated cartography in support of ADS and related programs benefitting from automated analysis of mapping, earth resources and reconnaissance imagery. And it provides an overview and status of the joint initiative for a sensor model API.

  12. Protocols for the Design of Kinase-Focused Compound Libraries.

    Science.gov (United States)

    Jacoby, Edgar; Wroblowski, Berthold; Buyck, Christophe; Neefs, Jean-Marc; Meyer, Christophe; Cummings, Maxwell D; van Vlijmen, Herman

    2017-11-08

    Protocols for the design of kinase-focused compound libraries are presented. Kinase-focused compound libraries can be differentiated based on the design goal. Depending on whether the library should be a discovery library specific for one particular kinase, a general discovery library for multiple distinct kinase projects, or even phenotypic screening, there exists today a variety of in silico methods to design candidate compound libraries. We address the following scenarios: 1) Datamining of SAR databases and kinase focused vendor catalogues; 2) Predictions and virtual screening; 3) Structure-based design of combinatorial kinase inhibitors; 4) Design of covalent kinase inhibitors; 5) Design of macrocyclic kinase inhibitors; and 6) Design of allosteric kinase inhibitors and activators. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Library holdings for Synthetic Aperture Sonar Survey to Locate Archaeological Resources in the Stellwagen Bank National Marine Sanctuary on NOAA Office of National Marine Sanctuaries vessel SRVx between August 23, 2010 and September 1, 2010

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Library Catalog may include: Data Management Plans, Cruise Plans, Cruise Summary Reports, Scientific "Quick Look Reports", Video Annotation Logs, Image Collections,...

  14. Forecasting elections in Europe: Synthetic models

    Directory of Open Access Journals (Sweden)

    Michael S. Lewis-Beck

    2015-01-01

    Full Text Available Scientific work on national election forecasting has become most developed for the United States case, where three dominant approaches can be identified: Structuralists, Aggregators, and Synthesizers. For European cases, election forecasting models remain almost exclusively Structuralist. Here we join together structural modeling and aggregate polling results, to form a hybrid, which we label a Synthetic Model. This model contains a political economy core, to which poll numbers are added (to tap omitted variables. We apply this model to a sample of three Western European countries: Germany, Ireland, and the United Kingdom. This combinatory strategy appears to offer clear forecasting gains, in terms of lead and accuracy.

  15. Approaches towards the automated interpretation and prediction of electrospray tandem mass spectra of non-peptidic combinatorial compounds.

    Science.gov (United States)

    Klagkou, Katerina; Pullen, Frank; Harrison, Mark; Organ, Andy; Firth, Alistair; Langley, G John

    2003-01-01

    Combinatorial chemistry is widely used within the pharmaceutical industry as a means of rapid identification of potential drugs. With the growth of combinatorial libraries, mass spectrometry (MS) became the key analytical technique because of its speed of analysis, sensitivity, accuracy and ability to be coupled with other analytical techniques. In the majority of cases, electrospray mass spectrometry (ES-MS) has become the default ionisation technique. However, due to the absence of fragment ions in the resulting spectra, tandem mass spectrometry (MS/MS) is required to provide structural information for the identification of an unknown analyte. This work discusses the first steps of an investigation into the fragmentation pathways taking place in electrospray tandem mass spectrometry. The ultimate goal for this project is to set general fragmentation rules for non-peptidic, pharmaceutical, combinatorial compounds. As an aid, an artificial intelligence (AI) software package is used to facilitate interpretation of the spectra. This initial study has focused on determining the fragmentation rules for some classes of compound types that fit the remit as outlined above. Based on studies carried out on several combinatorial libraries of these compounds, it was established that different classes of drug molecules follow unique fragmentation pathways. In addition to these general observations, the specific ionisation processes and the fragmentation pathways involved in the electrospray mass spectra of these systems were explored. The ultimate goal will be to incorporate our findings into the computer program and allow identification of an unknown, non-peptidic compound following insertion of its ES-MS/MS spectrum into the AI package. The work herein demonstrates the potential benefit of such an approach in addressing the issue of high-throughput, automated MS/MS data interpretation. Copyright 2003 John Wiley & Sons, Ltd.

  16. Combinatorial aspects of boundary loop models

    International Nuclear Information System (INIS)

    Lykke Jacobsen, Jesper; Saleur, Hubert

    2008-01-01

    We discuss in this paper combinatorial aspects of boundary loop models, that is models of self-avoiding loops on a strip where loops get different weights depending on whether they touch the left, the right, both or no boundary. These models are described algebraically by a generalization of the Temperley–Lieb algebra, dubbed the two-boundary TL algebra. We give results for the dimensions of TL representations and the corresponding degeneracies in the partition functions. We interpret these results in terms of fusion and in the light of the recently uncovered A n large symmetry present in loop models, paving the way for the analysis of the conformal field theory properties. Finally, we propose conjectures for determinants of Gram matrices in all cases, including the two-boundary one, which has recently been discussed by de Gier and Nichols

  17. Identification and Interrogation of Combinatorial Histone Modifications

    Directory of Open Access Journals (Sweden)

    Kelly R Karch

    2013-12-01

    Full Text Available Histone proteins are dynamically modified to mediate a variety of cellular processes including gene transcription, DNA damage repair, and apoptosis. Regulation of these processes occurs through the recruitment of non-histone proteins to chromatin by specific combinations of histone post-translational modifications (PTMs. Mass spectrometry has emerged as an essential tool to discover and quantify histone PTMs both within and between samples in an unbiased manner. Developments in mass spectrometry that allow for characterization of large histone peptides or intact protein has made it possible to determine which modifications occur simultaneously on a single histone polypeptide. A variety of techniques from biochemistry, biophysics, and chemical biology have been employed to determine the biological relevance of discovered combinatorial codes. This review first describes advancements in the field of mass spectrometry that have facilitated histone PTM analysis and then covers notable approaches to probe the biological relevance of these modifications in their nucleosomal context.

  18. Characterizing the combinatorial beam angle selection problem

    International Nuclear Information System (INIS)

    Bangert, Mark; Ziegenhein, Peter; Oelfke, Uwe

    2012-01-01

    The beam angle selection (BAS) problem in intensity-modulated radiation therapy is often interpreted as a combinatorial optimization problem, i.e. finding the best combination of η beams in a discrete set of candidate beams. It is well established that the combinatorial BAS problem may be solved efficiently with metaheuristics such as simulated annealing or genetic algorithms. However, the underlying parameters of the optimization process, such as the inclusion of non-coplanar candidate beams, the angular resolution in the space of candidate beams, and the number of evaluated beam ensembles as well as the relative performance of different metaheuristics have not yet been systematically investigated. We study these open questions in a meta-analysis of four strategies for combinatorial optimization in order to provide a reference for future research related to the BAS problem in intensity-modulated radiation therapy treatment planning. We introduce a high-performance inverse planning engine for BAS. It performs a full fluence optimization for ≈3600 treatment plans per hour while handling up to 50 GB of dose influence data (≈1400 candidate beams). For three head and neck patients, we compare the relative performance of a genetic, a cross-entropy, a simulated annealing and a naive iterative algorithm. The selection of ensembles with 5, 7, 9 and 11 beams considering either only coplanar or all feasible candidate beams is studied for an angular resolution of 5°, 10°, 15° and 20° in the space of candidate beams. The impact of different convergence criteria is investigated in comparison to a fixed termination after the evaluation of 10 000 beam ensembles. In total, our simulations comprise a full fluence optimization for about 3000 000 treatment plans. All four combinatorial BAS strategies yield significant improvements of the objective function value and of the corresponding dose distributions compared to standard beam configurations with equi

  19. Characterizing the combinatorial beam angle selection problem

    Science.gov (United States)

    Bangert, Mark; Ziegenhein, Peter; Oelfke, Uwe

    2012-10-01

    The beam angle selection (BAS) problem in intensity-modulated radiation therapy is often interpreted as a combinatorial optimization problem, i.e. finding the best combination of η beams in a discrete set of candidate beams. It is well established that the combinatorial BAS problem may be solved efficiently with metaheuristics such as simulated annealing or genetic algorithms. However, the underlying parameters of the optimization process, such as the inclusion of non-coplanar candidate beams, the angular resolution in the space of candidate beams, and the number of evaluated beam ensembles as well as the relative performance of different metaheuristics have not yet been systematically investigated. We study these open questions in a meta-analysis of four strategies for combinatorial optimization in order to provide a reference for future research related to the BAS problem in intensity-modulated radiation therapy treatment planning. We introduce a high-performance inverse planning engine for BAS. It performs a full fluence optimization for ≈3600 treatment plans per hour while handling up to 50 GB of dose influence data (≈1400 candidate beams). For three head and neck patients, we compare the relative performance of a genetic, a cross-entropy, a simulated annealing and a naive iterative algorithm. The selection of ensembles with 5, 7, 9 and 11 beams considering either only coplanar or all feasible candidate beams is studied for an angular resolution of 5°, 10°, 15° and 20° in the space of candidate beams. The impact of different convergence criteria is investigated in comparison to a fixed termination after the evaluation of 10 000 beam ensembles. In total, our simulations comprise a full fluence optimization for about 3000 000 treatment plans. All four combinatorial BAS strategies yield significant improvements of the objective function value and of the corresponding dose distributions compared to standard beam configurations with equi

  20. Combinatorial nuclear level-density model

    International Nuclear Information System (INIS)

    Uhrenholt, H.; Åberg, S.; Dobrowolski, A.; Døssing, Th.; Ichikawa, T.; Möller, P.

    2013-01-01

    A microscopic nuclear level-density model is presented. The model is a completely combinatorial (micro-canonical) model based on the folded-Yukawa single-particle potential and includes explicit treatment of pairing, rotational and vibrational states. The microscopic character of all states enables extraction of level-distribution functions with respect to pairing gaps, parity and angular momentum. The results of the model are compared to available experimental data: level spacings at neutron separation energy, data on total level-density functions from the Oslo method, cumulative level densities from low-lying discrete states, and data on parity ratios. Spherical and deformed nuclei follow basically different coupling schemes, and we focus on deformed nuclei

  1. Synthetic Rutile

    International Nuclear Information System (INIS)

    Burastero, J.

    1975-01-01

    This work is about the laboratory scale investigation of the conditions in the rutile synthetic production from one me nita in Aguas Dulces reservoir. The iron mineral is chlorinated and volatilized selectively leaving a residue enriched in titanium dioxide which can be used as a substitute of rutile mineral

  2. Combinatorial experiment in Ni-Ti thin films by laser interference structuring

    International Nuclear Information System (INIS)

    Liu, K.W.; Gachot, C.; Leibenguth, P.; Muecklich, F.

    2005-01-01

    Combinatorial experiments are achieved on periodically structured Ni-Ti thin film composition spreads by laser interference irradiation using a Nd:YAG laser. Continuous Ni-Ti compositional spreads covering almost the whole binary system are prepared by combining sputter mask, shutter and movement of substrate. The continuous compositional spread is subsequently micro-structured into a sample library consisting of well-defined lines of individual samples by laser interference irradiation. The composition and microstructure effects in continuous spread and sample libraries after laser structuring are explored by scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS), X-ray diffraction (XRD) and white light interferometry (WLI) microscopy. The sample library consists of individual samples with a distance of about 5 μm and a composition resolution as high as 0.1 at.% in between. Although, there are certain difficulties so far in obtaining the optimized laser fluence for the spread, the laser interference irradiation provides an effective way to prepare thin film libraries with around 200 sample lines within 1 mm

  3. America's Star Libraries: Top-Rated Libraries

    Science.gov (United States)

    Lance, Keith Curry; Lyons, Ray

    2009-01-01

    "Library Journal"'s national rating of public libraries, the "LJ" Index of Public Library Service 2009, Round 2, identifies 258 "star" libraries. Created by Keith Curry Lance and Ray Lyons and based on 2007 data from the IMLS, it rates 7,268 public libraries. The top libraries in each group get five, four, or three stars. All included libraries,…

  4. Minnesota: Library Automation and Technology in Libraries.

    Science.gov (United States)

    Feye-Stukas, Jan

    1996-01-01

    Provides an overview of library automation in Minnesota. Topics include regional public library systems; library automation vendors; multitype library systems; postsecondary and academic libraries; state government libraries; the Internet; telecommunications and statewide online system legislation and funding; and state library agency involvement…

  5. Privatizing Libraries

    Science.gov (United States)

    Jerrard, Jane; Bolt, Nancy; Strege, Karen

    2012-01-01

    This timely special report from ALA Editions provides a succinct but comprehensive overview of the "privatization" of public libraries. It provides a history of the trend of local and state governments privatizing public services and assets, and then examines the history of public library privatization right up to the California…

  6. Library Use

    DEFF Research Database (Denmark)

    Konzack, Lars

    2012-01-01

    A seminar paper about a survey of role-playing games in public libraries combined with three cases and a presentation of a model.......A seminar paper about a survey of role-playing games in public libraries combined with three cases and a presentation of a model....

  7. academic libraries

    African Journals Online (AJOL)

    Information Impact: Journal of Information and Knowledge Management

    Enhancing research visibility of academics: the role of academic libraries. Information Impact: Journal of Information and. Knowledge Management. 2017, Vol. .... Social media platforms allow users to connect, create, promote, share and follow interest groups. With these capabilities, academic libraries can make use of ...

  8. Selective solid phase extraction of JWH synthetic cannabinoids by using computationally designed peptides.

    Science.gov (United States)

    Mascini, Marcello; Montesano, Camilla; Perez, German; Wang, Joseph; Compagnone, Dario; Sergi, Manuel

    2017-05-15

    The objective of the present work is to demonstrate a rational way to prepare selective sorbents able to extract simultaneously several structural analogs. For this purpose the binding specificity of two hexapeptides computationally designed (VYWLVW and YYIGGF) versus four synthetic cannabinoids Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH 018), naphthalen-1-yl-(1-butylindol-3-yl)methanone (JWH 073), (R)-(1-((1-methylpiperidin-2-yl)methyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone (AM 1220) and (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN 55) was computationally studied and then experimentally tested by solid-phase extraction (SPE) clean-up and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. The two peptides were chosen using a semi combinatorial virtual technique by generating 4 cycles of peptide libraries (around 2.3×10 4 elements). To select the two peptides, the simulated binding scores between synthetic cannabinoids and peptides was used by maximizing the recognition properties of amino acid motif between the two JWH and the other synthetic cannabinoids. In particular, the peptide YYIGGF, having also affinity for AM 120, was selected as control because it was the only one without tryptophan residues within the best peptides obtained from simulation. Experimentally, the two hexapeptides were tested as SPE sorbent using nanomolar solutions of the four drugs. After optimization of best retentions the binding constants were calculated by loading synthetic cannabinoids solutions at different concentrations. The results indicated a strong interaction between hexapeptide VYWLVW and JWH 018 (15.58±2.03×10 6 M -1 ), 3-fold and 40-fold larger compared to the analog JWH 073 and both AM 1220 and the WIN 55. Similar trend was observed for the hexapeptide YYIGGF but the binding constants were at least three times lower highlighting the key role of

  9. Target-directed Dynamic Combinatorial Chemistry: A Study on Potentials and Pitfalls as Exemplified on a Bacterial Target.

    Science.gov (United States)

    Frei, Priska; Pang, Lijuan; Silbermann, Marleen; Eriş, Deniz; Mühlethaler, Tobias; Schwardt, Oliver; Ernst, Beat

    2017-08-25

    Target-directed dynamic combinatorial chemistry (DCC) is an emerging technique for the efficient identification of inhibitors of pharmacologically relevant targets. In this contribution, we present an application for a bacterial target, the lectin FimH, a crucial virulence factor of uropathogenic E. coli being the main cause of urinary tract infections. A small dynamic library of acylhydrazones was formed from aldehydes and hydrazides and equilibrated at neutral pH in presence of aniline as nucleophilic catalyst. The major success factors turned out to be an accordingly adjusted ratio of scaffolds and fragments, an adequate sample preparation prior to HPLC analysis, and the data processing. Only then did the ranking of the dynamic library constituents correlate well with affinity data. Furthermore, as a support of DCC applications especially to larger libraries, a new protocol for improved hit identification was established. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Engineering emergent multicellular behavior through synthetic adhesion

    Science.gov (United States)

    Glass, David; Riedel-Kruse, Ingmar

    In over a decade, synthetic biology has developed increasingly robust gene networks within single cells, but constructed very few systems that demonstrate multicellular spatio-temporal dynamics. We are filling this gap in synthetic biology's toolbox by developing an E. coli self-assembly platform based on modular cell-cell adhesion. We developed a system in which adhesive selectivity is provided by a library of outer membrane-displayed peptides with intra-library specificities, while affinity is provided by consistent expression across the entire library. We further provide a biophysical model to help understand the parameter regimes in which this tool can be used to self-assemble into cellular clusters, filaments, or meshes. The combined platform will enable future development of synthetic multicellular systems for use in consortia-based metabolic engineering, in living materials, and in controlled study of minimal multicellular systems. Stanford Bio-X Bowes Fellowship.

  11. Library Weeds

    Science.gov (United States)

    Martin, Jess A.; Manch, Steven B.

    1971-01-01

    Weeding is essential to the efficient operation of medical libraries and should be conducted in spite of certain barriers that exist. The mechanics of weeding are simple, and the criteria are widely known. A questionnaire survey of ninety-four medical school libraries reveals that weeding is most often shared by professional staff members, that weeding is done primarily when space is needed, and that librarians when weeding do not as a rule seek the advice or assistance of users or the Library Committee. PMID:5128703

  12. Advanced Aqueous Phase Catalyst Development using Combinatorial Methods, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — The use of combinatorial methods is proposed to rapidly screen catalyst formulations for the advanced development of aqueous phase oxidation catalysts with greater...

  13. Olefin Metathesis in Peptidomimetics, Dynamic Combinatorial Chemistry, and Molecular Imprinting

    National Research Council Canada - National Science Library

    Low, Tammy K

    2006-01-01

    .... Our research goals consisted of employing olefin metathesis in the synthesis of peptidomimetics, and studying the feasibility of this method in dynamic combinatorial chemistry and molecular imprinting of nerve agents...

  14. Mild and cost-effective green fluorescent protein purification employing small synthetic ligands.

    Science.gov (United States)

    Pina, Ana Sofia; Dias, Ana Margarida G C; Ustok, Fatma Isik; El Khoury, Graziella; Fernandes, Cláudia S M; Branco, Ricardo J F; Lowe, Christopher R; Roque, A Cecília A

    2015-10-30

    The green fluorescent protein (GFP) is a useful indicator in a broad range of applications including cell biology, gene expression and biosensing. However, its full potential is hampered by the lack of a selective, mild and low-cost purification scheme. In order to address this demand, a novel adsorbent was developed as a generic platform for the purification of GFP or GFP fusion proteins, giving GFP a dual function as reporter and purification tag. After screening a solid-phase combinatorial library of small synthetic ligands based on the Ugi-reaction, the lead ligand (A4C7) selectively recovered GFP with 94% yield and 94% purity under mild conditions and directly from Escherichia coli extracts. Adsorbents containing the ligand A4C7 maintained the selectivity to recover other proteins fused to GFP. The performance of A4C7 adsorbents was compared with two commercially available methods (immunoprecipitation and hydrophobic interaction chromatography), confirming the new adsorbent as a low-cost viable alternative for GFP purification. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Combinatorial Therapies for Neurofibroma and MPNST Treatment and Prevention

    Science.gov (United States)

    2017-08-01

    AWARD NUMBER: W81XWH-15-1-0193 TITLE: Combinatorial Therapies for Neurofibroma and MPNST Treatment and Prevention PRINCIPAL INVESTIGATOR...2016 - 31 Jul 2017 4. TITLE AND SUBTITLE Combinatorial Therapies for Neurofibroma and MPNST Treatment and Prevention 5a. CONTRACT NUMBER 5b. GRANT...with these drugs will prevent neurofibroma and MPNST pathogenesis. To test these hypotheses, we will: 1) determine whether tamoxifen, trifluoperazine

  16. On the combinatorial foundations of Regge-calculus

    International Nuclear Information System (INIS)

    Budach, L.

    1989-01-01

    Lipschitz-Killing curvatures of piecewise flat spaces are combinatorial analogues of Lipschitz-Killing curvatures of Riemannian manifolds. In the following paper rigorous combinatorial representations and proofs of all basic results for Lipschitz-Killing curvatures not using analytic arguments are given. The principal tools for an elementary representation of Regge calculus can be developed by means of basic properties of dihedral angles. (author)

  17. The Combinatorial Rigidity Conjecture is False for Cubic Polynomials

    DEFF Research Database (Denmark)

    Henriksen, Christian

    2003-01-01

    We show that there exist two cubic polynomials with connected Julia sets which are combinatorially equivalent but not topologically conjugate on their Julia sets. This disproves a conjecture by McMullen from 1995.......We show that there exist two cubic polynomials with connected Julia sets which are combinatorially equivalent but not topologically conjugate on their Julia sets. This disproves a conjecture by McMullen from 1995....

  18. Enabling high performance computational science through combinatorial algorithms

    International Nuclear Information System (INIS)

    Boman, Erik G; Bozdag, Doruk; Catalyurek, Umit V; Devine, Karen D; Gebremedhin, Assefaw H; Hovland, Paul D; Pothen, Alex; Strout, Michelle Mills

    2007-01-01

    The Combinatorial Scientific Computing and Petascale Simulations (CSCAPES) Institute is developing algorithms and software for combinatorial problems that play an enabling role in scientific and engineering computations. Discrete algorithms will be increasingly critical for achieving high performance for irregular problems on petascale architectures. This paper describes recent contributions by researchers at the CSCAPES Institute in the areas of load balancing, parallel graph coloring, performance improvement, and parallel automatic differentiation

  19. Nigerian Libraries

    African Journals Online (AJOL)

    Bridging the digital divide: the potential role of the National Library of Nigeria · EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. Juliana Obiageri Akidi, Joy Chituru Onyenachi, 11-19 ...

  20. Library Locations

    Data.gov (United States)

    Allegheny County / City of Pittsburgh / Western PA Regional Data Center — Carnegie Library of Pittsburgh locations including address, coordinates, phone number, square footage, and standard operating hours. The map below does not display...

  1. LAS0811: From Combinatorial Chemistry to Activation of Antioxidant Response Element

    Directory of Open Access Journals (Sweden)

    Ming Zhu

    2009-01-01

    Full Text Available The antioxidant response element (ARE and its transcription factor, nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, are potential targets for cancer chemoprevention. We sought to screen small molecules synthesized with combinatorial chemistry for activation of ARE. By high-throughput screening of 9400 small molecules from 10 combinatorial chemical libraries using HepG2 cells with an ARE-driven reporter, we have identified a novel small molecule, 1,2-dimethoxy-4,5-dinitrobenzene (LAS0811, as an activator of the ARE. LAS0811 upregulated the activity of NAD(PH:quinone oxidoreductase 1 (NQO1, a representative antioxidative enzyme regulated by ARE. It enhanced production of an endogenous reducing agent, glutathione (GSH. In addition, LAS0811 induced expression of heme oxygenase 1 (HO1, which is an ARE-regulated enzyme with anti-inflammatory activity. Furthermore, LAS0811 reduced cell death due to the cytotoxic stress of a strong oxidant, t-butyl hydroperoxide (t-BOOH. Mechanistically, LAS0811 upregulated the expression of Nrf2 and promoted its translocation into the nuclei leading to subsequent ARE activation. Taken together, LAS0811 is a novel activator of the ARE and its associated detoxifying genes and, thus, a potential agent for cancer chemoprevention.

  2. Mapping protease substrates using a biotinylated phage substrate library.

    Energy Technology Data Exchange (ETDEWEB)

    Scholle, M. D.; Kriplani, U.; Pabon, A.; Sishtla, K.; Glucksman, M. J.; Kay, B. K.; Biosciences Division; Chicago Medical School

    2005-05-05

    We describe a bacteriophage M13 substrate library encoding the AviTag (BirA substrate) and combinatorial heptamer peptides displayed at the N terminus of the mature form of capsid protein III. Phages are biotinylated efficiently (> or = 50%) when grown in E. coli cells coexpressing BirA, and such viral particles can be immobilized on a streptavidin-coated support and released by protease cleavage within the combinatorial peptide. We have used this library to map the specificity of human Factor Xa and a neuropeptidase, neurolysin (EC3.4.24.16). Validation by analysis of isolated peptide substrates has revealed that neurolysin recognizes the motif hydrophobic-X-Pro-Arg-hydrophobic, where Arg-hydrophobic is the scissile bond.

  3. Exact combinatorial approach to finite coagulating systems

    Science.gov (United States)

    Fronczak, Agata; Chmiel, Anna; Fronczak, Piotr

    2018-02-01

    This paper outlines an exact combinatorial approach to finite coagulating systems. In this approach, cluster sizes and time are discrete and the binary aggregation alone governs the time evolution of the systems. By considering the growth histories of all possible clusters, an exact expression is derived for the probability of a coagulating system with an arbitrary kernel being found in a given cluster configuration when monodisperse initial conditions are applied. Then this probability is used to calculate the time-dependent distribution for the number of clusters of a given size, the average number of such clusters, and that average's standard deviation. The correctness of our general expressions is proved based on the (analytical and numerical) results obtained for systems with the constant kernel. In addition, the results obtained are compared with the results arising from the solutions to the mean-field Smoluchowski coagulation equation, indicating its weak points. The paper closes with a brief discussion on the extensibility to other systems of the approach presented herein, emphasizing the issue of arbitrary initial conditions.

  4. A combinatorial approach to angiosperm pollen morphology.

    Science.gov (United States)

    Mander, Luke

    2016-11-30

    Angiosperms (flowering plants) are strikingly diverse. This is clearly expressed in the morphology of their pollen grains, which are characterized by enormous variety in their shape and patterning. In this paper, I approach angiosperm pollen morphology from the perspective of enumerative combinatorics. This involves generating angiosperm pollen morphotypes by algorithmically combining character states and enumerating the results of these combinations. I use this approach to generate 3 643 200 pollen morphotypes, which I visualize using a parallel-coordinates plot. This represents a raw morphospace. To compare real-world and theoretical morphologies, I map the pollen of 1008 species of Neotropical angiosperms growing on Barro Colorado Island (BCI), Panama, onto this raw morphospace. This highlights that, in addition to their well-documented taxonomic diversity, Neotropical rainforests also represent an enormous reservoir of morphological diversity. Angiosperm pollen morphospace at BCI has been filled mostly by pollen morphotypes that are unique to single plant species. Repetition of pollen morphotypes among higher taxa at BCI reflects both constraint and convergence. This combinatorial approach to morphology addresses the complexity that results from large numbers of discrete character combinations and could be employed in any situation where organismal form can be captured by discrete morphological characters. © 2016 The Author(s).

  5. Scalable Combinatorial Tools for Health Disparities Research

    Directory of Open Access Journals (Sweden)

    Michael A. Langston

    2014-10-01

    Full Text Available Despite staggering investments made in unraveling the human genome, current estimates suggest that as much as 90% of the variance in cancer and chronic diseases can be attributed to factors outside an individual’s genetic endowment, particularly to environmental exposures experienced across his or her life course. New analytical approaches are clearly required as investigators turn to complicated systems theory and ecological, place-based and life-history perspectives in order to understand more clearly the relationships between social determinants, environmental exposures and health disparities. While traditional data analysis techniques remain foundational to health disparities research, they are easily overwhelmed by the ever-increasing size and heterogeneity of available data needed to illuminate latent gene x environment interactions. This has prompted the adaptation and application of scalable combinatorial methods, many from genome science research, to the study of population health. Most of these powerful tools are algorithmically sophisticated, highly automated and mathematically abstract. Their utility motivates the main theme of this paper, which is to describe real applications of innovative transdisciplinary models and analyses in an effort to help move the research community closer toward identifying the causal mechanisms and associated environmental contexts underlying health disparities. The public health exposome is used as a contemporary focus for addressing the complex nature of this subject.

  6. Combinatorial discovery of new methanol-tolerant non-noble metal cathode electrocatalysts for direct methanol fuel cells.

    Science.gov (United States)

    Yu, Jong-Sung; Kim, Min-Sik; Kim, Jung Ho

    2010-12-14

    Combinatorial synthesis and screening were used to identify methanol-tolerant non-platinum cathode electrocatalysts for use in direct methanol fuel cells (DMFCs). Oxygen reduction consumes protons at the surface of DMFC cathode catalysts. In combinatorial screening, this pH change allows one to differentiate active catalysts using fluorescent acid-base indicators. Combinatorial libraries of carbon-supported catalyst compositions containing Ru, Mo, W, Sn, and Se were screened. Ternary and quaternary compositions containing Ru, Sn, Mo, Se were more active than the "standard" Alonso-Vante catalyst, Ru(3)Mo(0.08)Se(2), when tested in liquid-feed DMFCs. Physical characterization of the most active catalysts by powder X-ray diffraction, gas adsorption, and X-ray photoelectron spectroscopy revealed that the predominant crystalline phase was hexagonal close-packed (hcp) ruthenium, and showed a surface mostly covered with oxide. The best new catalyst, Ru(7.0)Sn(1.0)Se(1.0), was significantly more active than Ru(3)Se(2)Mo(0.08), even though the latter contained smaller particles.

  7. Synthetic Cannabinoids.

    Science.gov (United States)

    Mills, Brooke; Yepes, Andres; Nugent, Kenneth

    2015-07-01

    Synthetic cannabinoids (SCBs), also known under the brand names of "Spice," "K2," "herbal incense," "Cloud 9," "Mojo" and many others, are becoming a large public health concern due not only to their increasing use but also to their unpredictable toxicity and abuse potential. There are many types of SCBs, each having a unique binding affinity for cannabinoid receptors. Although both Δ-tetrahydrocannabinol (THC) and SCBs stimulate the same receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), studies have shown that SCBs are associated with higher rates of toxicity and hospital admissions than is natural cannabis. This is likely due to SCBs being direct agonists of the cannabinoid receptors, whereas THC is a partial agonist. Furthermore, the different chemical structures of SCBs found in Spice or K2 may interact in unpredictable ways to elicit previously unknown, and the commercial products may have unknown contaminants. The largest group of users is men in their 20s who participate in polydrug use. The most common reported toxicities with SCB use based on studies using Texas Poison Control records are tachycardia, agitation and irritability, drowsiness, hallucinations, delusions, hypertension, nausea, confusion, dizziness, vertigo and chest pain. Acute kidney injury has also been strongly associated with SCB use. Treatment mostly involves symptom management and supportive care. More research is needed to identify which contaminants are typically found in synthetic marijuana and to understand the interactions between different SBCs to better predict adverse health outcomes.

  8. Synthesis and screening of materials libraries of buried compound semiconductors by ion beam implantation

    OpenAIRE

    Stritzker, Bernd

    2004-01-01

    Synthesis and screening of materials libraries of buried compound semiconductors by ion beam implantation / I. Großhans, H. Karl and B. Stritzker. - In: Combinatorial and artificial intelligence methods in materials science II : symposium held December 1 - 4, 2003, Boston, Massachusetts, USA / ed.: Radislav A. Potyrailo ... - Warrendale, Pa. : Materials Research Society, 2004. - (Materials Research Society symposium proceedings ; 804)

  9. Mapping the Materials Genome through Combinatorial Informatics

    Science.gov (United States)

    Rajan, Krishna

    2012-02-01

    The recently announced White House Materials Genome Initiative provides an exciting challenge to the materials science community. To meet that challenge one needs to address a critical question, namely what is the materials genome? Some guide on how to the answer this question can be gained by recognizing that a ``gene'' is a carrier of information. In the biological sciences, discovering how to manipulate these genes has generated exciting discoveries in fundamental molecular biology as well as significant advances in biotechnology. Scaling that up to molecular, cellular length scales and beyond, has spawned from genomics, fields such as proteomics, metabolomics and essentially systems biology. The ``omics'' approach requires that one needs to discover and track these ``carriers of information'' and then correlate that information to predict behavior. A similar challenge lies in materials science, where there is a diverse array of modalities of materials ``discovery'' ranging from new materials chemistries and molecular arrangements with novel properties, to the development and design of new micro- and mesoscale structures. Hence to meaningfully adapt the spirit of ``genomics'' style research in materials science, we need to first identify and map the ``genes'' across different materials science applications On the experimental side, combinatorial experiments have opened a new approach to generate data in a high throughput manner, but without a clear way to link that to models, the full value of that data is not realized. Hence along with experimental and computational materials science, we need to add a ``third leg'' to our toolkit to make the ``Materials Genome'' a reality, the science of Materials Informatics. In this presentation we provide an overview of how information science coupled to materials science can in fact achieve the goal of mapping the ``Materials Genome''.

  10. Synthetic Botany.

    Science.gov (United States)

    Boehm, Christian R; Pollak, Bernardo; Purswani, Nuri; Patron, Nicola; Haseloff, Jim

    2017-07-05

    Plants are attractive platforms for synthetic biology and metabolic engineering. Plants' modular and plastic body plans, capacity for photosynthesis, extensive secondary metabolism, and agronomic systems for large-scale production make them ideal targets for genetic reprogramming. However, efforts in this area have been constrained by slow growth, long life cycles, the requirement for specialized facilities, a paucity of efficient tools for genetic manipulation, and the complexity of multicellularity. There is a need for better experimental and theoretical frameworks to understand the way genetic networks, cellular populations, and tissue-wide physical processes interact at different scales. We highlight new approaches to the DNA-based manipulation of plants and the use of advanced quantitative imaging techniques in simple plant models such as Marchantia polymorpha. These offer the prospects of improved understanding of plant dynamics and new approaches to rational engineering of plant traits. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  11. Synthetic Brainbows

    KAUST Repository

    Wan, Y.

    2013-06-01

    Brainbow is a genetic engineering technique that randomly colorizes cells. Biological samples processed with this technique and imaged with confocal microscopy have distinctive colors for individual cells. Complex cellular structures can then be easily visualized. However, the complexity of the Brainbow technique limits its applications. In practice, most confocal microscopy scans use different florescence staining with typically at most three distinct cellular structures. These structures are often packed and obscure each other in rendered images making analysis difficult. In this paper, we leverage a process known as GPU framebuffer feedback loops to synthesize Brainbow-like images. In addition, we incorporate ID shuffing and Monte-Carlo sampling into our technique, so that it can be applied to single-channel confocal microscopy data. The synthesized Brainbow images are presented to domain experts with positive feedback. A user survey demonstrates that our synthetic Brainbow technique improves visualizations of volume data with complex structures for biologists.

  12. A powerful selection assay for mixture libraries of DNA alkylating agents.

    Science.gov (United States)

    Ham, Young-Wan; Boger, Dale L

    2004-08-04

    A simple and powerful selection assay that permits the separation (rpHPLC), quantitation (ELSD), and identification (ESI-MS) of thermally released adenine adducts derived from duocarmycin analogues is detailed that can establish the most effective DNA alkylating agents in synthetic combinatorial mixtures.

  13. The library

    International Nuclear Information System (INIS)

    1980-01-01

    A specialized library is essential for conducting the research work of the Uranium Institute. The need was recognized at the foundation of the Institute and a full-time librarian was employed in 1976 to establish the necessary systems and begin the task of building up the collection. A brief description is given of the services offered by the library which now contains books, periodicals, pamphlets and press cuttings, focussed on uranium and nuclear energy, but embracing economics, politics, trade, legislation, geology, mining and mineral processing, environmental protection and nuclear technology. (author)

  14. Synthetic biology: an emerging engineering discipline.

    Science.gov (United States)

    Cheng, Allen A; Lu, Timothy K

    2012-01-01

    Over the past decade, synthetic biology has emerged as an engineering discipline for biological systems. Compared with other substrates, biology poses a unique set of engineering challenges resulting from an incomplete understanding of natural biological systems and tools for manipulating them. To address these challenges, synthetic biology is advancing from developing proof-of-concept designs to focusing on core platforms for rational and high-throughput biological engineering. These platforms span the entire biological design cycle, including DNA construction, parts libraries, computational design tools, and interfaces for manipulating and probing synthetic circuits. The development of these enabling technologies requires an engineering mindset to be applied to biology, with an emphasis on generalizable techniques in addition to application-specific designs. This review aims to discuss the progress and challenges in synthetic biology and to illustrate areas where synthetic biology may impact biomedical engineering and human health.

  15. The priming of basic combinatory responses in MEG.

    Science.gov (United States)

    Blanco-Elorrieta, Esti; Ferreira, Victor S; Del Prato, Paul; Pylkkänen, Liina

    2018-01-01

    Priming has been a powerful tool for the study of human memory and especially the memory representations relevant for language. However, although it is well established that lexical access can be primed, we do not know exactly what types of computations can be primed above the word level. This work took a neurobiological approach and assessed the ways in which the complex representation of a minimal combinatory phrase, such as red boat, can be primed, as evidenced by the spatiotemporal profiles of magnetoencephalography (MEG) signals. Specifically, we built upon recent progress on the neural signatures of phrasal composition and tested whether the brain activities implicated for the basic combination of two words could be primed. In two experiments, MEG was recorded during a picture naming task where the prime trials were designed to replicate previously reported combinatory effects and the target trials to test whether those combinatory effects could be primed. The manipulation of the primes was successful in eliciting larger activity for adjective-noun combinations than single nouns in left anterior temporal and ventromedial prefrontal cortices, replicating prior MEG studies on parallel contrasts. Priming of similarly timed activity was observed during target trials in anterior temporal cortex, but only when the prime and target shared an adjective. No priming in temporal cortex was observed for single word repetition and two control tasks showed that the priming effect was not elicited if the prime pictures were simply viewed but not named. In sum, this work provides evidence that very basic combinatory operations can be primed, with the necessity for some lexical overlap between prime and target suggesting combinatory conceptual, as opposed to syntactic processing. Both our combinatory and priming effects were early, onsetting between 100 and 150ms after picture onset and thus are likely to reflect the very earliest planning stages of a combinatory message

  16. America's Star Libraries

    Science.gov (United States)

    Lyons, Ray; Lance, Keith Curry

    2009-01-01

    "Library Journal"'s new national rating of public libraries, the "LJ" Index of Public Library Service, identifies 256 "star" libraries. It rates 7,115 public libraries. The top libraries in each group get five, four, or three Michelin guide-like stars. All included libraries, stars or not, can use their scores to learn from their peers and improve…

  17. Invention as a combinatorial process: evidence from US patents.

    Science.gov (United States)

    Youn, Hyejin; Strumsky, Deborah; Bettencourt, Luis M A; Lobo, José

    2015-05-06

    Invention has been commonly conceptualized as a search over a space of combinatorial possibilities. Despite the existence of a rich literature, spanning a variety of disciplines, elaborating on the recombinant nature of invention, we lack a formal and quantitative characterization of the combinatorial process underpinning inventive activity. Here, we use US patent records dating from 1790 to 2010 to formally characterize invention as a combinatorial process. To do this, we treat patented inventions as carriers of technologies and avail ourselves of the elaborate system of technology codes used by the United States Patent and Trademark Office to classify the technologies responsible for an invention's novelty. We find that the combinatorial inventive process exhibits an invariant rate of 'exploitation' (refinements of existing combinations of technologies) and 'exploration' (the development of new technological combinations). This combinatorial dynamic contrasts sharply with the creation of new technological capabilities-the building blocks to be combined-that has significantly slowed down. We also find that, notwithstanding the very reduced rate at which new technologies are introduced, the generation of novel technological combinations engenders a practically infinite space of technological configurations.

  18. The Synthetic Biology Open Language (SBOL) provides a community standard for communicating designs in synthetic biology.

    Science.gov (United States)

    Galdzicki, Michal; Clancy, Kevin P; Oberortner, Ernst; Pocock, Matthew; Quinn, Jacqueline Y; Rodriguez, Cesar A; Roehner, Nicholas; Wilson, Mandy L; Adam, Laura; Anderson, J Christopher; Bartley, Bryan A; Beal, Jacob; Chandran, Deepak; Chen, Joanna; Densmore, Douglas; Endy, Drew; Grünberg, Raik; Hallinan, Jennifer; Hillson, Nathan J; Johnson, Jeffrey D; Kuchinsky, Allan; Lux, Matthew; Misirli, Goksel; Peccoud, Jean; Plahar, Hector A; Sirin, Evren; Stan, Guy-Bart; Villalobos, Alan; Wipat, Anil; Gennari, John H; Myers, Chris J; Sauro, Herbert M

    2014-06-01

    The re-use of previously validated designs is critical to the evolution of synthetic biology from a research discipline to an engineering practice. Here we describe the Synthetic Biology Open Language (SBOL), a proposed data standard for exchanging designs within the synthetic biology community. SBOL represents synthetic biology designs in a community-driven, formalized format for exchange between software tools, research groups and commercial service providers. The SBOL Developers Group has implemented SBOL as an XML/RDF serialization and provides software libraries and specification documentation to help developers implement SBOL in their own software. We describe early successes, including a demonstration of the utility of SBOL for information exchange between several different software tools and repositories from both academic and industrial partners. As a community-driven standard, SBOL will be updated as synthetic biology evolves to provide specific capabilities for different aspects of the synthetic biology workflow.

  19. Library rooms or Library halls

    Directory of Open Access Journals (Sweden)

    Alfredo Serrai

    2013-12-01

    Full Text Available Library Halls, understood as Renaissance and Baroque architectural creations, along with the furnishings and decorations, accomplish a cognitive task and serve to transmit knowledge. The design of these spaces based on the idea that they should reflect the merits and content of the collections housed within them, in order to prepare the mind of the reader to respect and admire the volumes. In accordance with this principle, in the fifteenth century library rooms had a basilican shape, with two or three naves, like churches, reflecting thus the spiritual value of the books contained there. Next to that inspiring function, library rooms had also the task of representing the entire logical and conceptual universe of human knowledge in a figurative way, including for this purpose also the and Kunst- und Wunderkammern, namely the collections of natural, artficial objects, and works of art. The importance of library rooms and their function was understood already in the early decades of the seventeenth century, as underlined in the treatise, Musei sive Bibliothecae tam privatae quam publicae Extructio, Instructio, Cura, Usus, written by the Jesuit Claude Clément and published in 1635. Almost the entire volume is dedicated to the decoration and ornamentation of the Saloni, and the function of the library is identified exclusively with the preservation and decoration of the collection, neglecting more specifically bibliographic aspects or those connected to library science. The architectural structure of the Saloni was destined to change in relation to two factors, namely the form of books, and the sources of light. As a consequence, from the end of the sixteenth century – or perhaps even before if one considers the fragments of the Library of Urbino belonging to Federico da Montefeltro – shelves and cabinets have been placed no longer in the center of the room, but were set against the walls. This new disposition of the furniture, surmounted by

  20. Library Automation.

    Science.gov (United States)

    Husby, Ole

    1990-01-01

    The challenges and potential benefits of automating university libraries are reviewed, with special attention given to cooperative systems. Aspects discussed include database size, the role of the university computer center, storage modes, multi-institutional systems, resource sharing, cooperative system management, networking, and intelligent…

  1. Summation on the basis of combinatorial representation of equal powers

    Directory of Open Access Journals (Sweden)

    Alexander I. Nikonov

    2016-03-01

    Full Text Available In the paper the conclusion of combinatorial expressions for the sums of members of several sequences is considered. Conclusion is made on the basis of combinatorial representation of the sum of the weighted equal powers. The weighted members of a geometrical progression, the simple arithmetic-geometrical and combined progressions are subject to summation. One of principal places in the given conclusion occupies representation of members of each of the specified progressions in the form of matrix elements. The row of this matrix is formed with use of a gang of equal powers with the set weight factor. Besides, in work formulas of combinatorial identities with participation of free components of the sums of equal powers, and also separate power-member of sequence of equal powers or a geometrical progression are presented. All presented formulas have the general basis-components of the sums of equal powers.

  2. Key Updating Methods for Combinatorial Design Based Key Management Schemes

    Directory of Open Access Journals (Sweden)

    Chonghuan Xu

    2014-01-01

    Full Text Available Wireless sensor network (WSN has become one of the most promising network technologies for many useful applications. However, for the lack of resources, it is different but important to ensure the security of the WSNs. Key management is a corner stone on which to build secure WSNs for it has a fundamental role in confidentiality, authentication, and so on. Combinatorial design theory has been used to generate good-designed key rings for each sensor node in WSNs. A large number of combinatorial design based key management schemes have been proposed but none of them have taken key updating into consideration. In this paper, we point out the essence of key updating for the unital design based key management scheme and propose two key updating methods; then, we conduct performance analysis on the two methods from three aspects; at last, we generalize the two methods to other combinatorial design based key management schemes and enhance the second method.

  3. Recent advances in combinatorial biosynthesis for drug discovery

    Directory of Open Access Journals (Sweden)

    Sun H

    2015-02-01

    Full Text Available Huihua Sun,1,* Zihe Liu,1,* Huimin Zhao,1,2 Ee Lui Ang1 1Metabolic Engineering Research Laboratory, Institute of Chemical and Engineering Sciences, Agency for Science, Technology and Research, Singapore; 2Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA *These authors contributed equally to this work Abstract: Because of extraordinary structural diversity and broad biological activities, natural products have played a significant role in drug discovery. These therapeutically important secondary metabolites are assembled and modified by dedicated biosynthetic pathways in their host living organisms. Traditionally, chemists have attempted to synthesize natural product analogs that are important sources of new drugs. However, the extraordinary structural complexity of natural products sometimes makes it challenging for traditional chemical synthesis, which usually involves multiple steps, harsh conditions, toxic organic solvents, and byproduct wastes. In contrast, combinatorial biosynthesis exploits substrate promiscuity and employs engineered enzymes and pathways to produce novel “unnatural” natural products, substantially expanding the structural diversity of natural products with potential pharmaceutical value. Thus, combinatorial biosynthesis provides an environmentally friendly way to produce natural product analogs. Efficient expression of the combinatorial biosynthetic pathway in genetically tractable heterologous hosts can increase the titer of the compound, eventually resulting in less expensive drugs. In this review, we will discuss three major strategies for combinatorial biosynthesis: 1 precursor-directed biosynthesis; 2 enzyme-level modification, which includes swapping of the entire domains, modules and subunits, site-specific mutagenesis, and directed evolution; 3 pathway-level recombination. Recent examples of combinatorial biosynthesis employing these

  4. Combinatorial approaches for high-throughput characterization of mechanical properties

    Directory of Open Access Journals (Sweden)

    Xiaokun Zhang

    2017-09-01

    Full Text Available Since the first successful story was reported in the middle of 1990s, combinatorial materials science has attracted more and more attentions in the materials community. In the past two decades, a great amount of effort has been made to develop combinatorial high-throughput approaches for materials research. However, few high-throughput mechanical characterization methods and tools were reported. To date, a number of micro-scale mechanical characterization tools have been developed, which provided a basis for combinatorial high-throughput mechanical characterization. Many existing micro-mechanical testing apparatuses can be pertinently modified for high-throughput characterization. For example, automated scanning nanoindentation is used for measuring the hardness and elastic modulus of diffusion multiple alloy samples, and cantilever beam arrays are used to parallelly characterize the thermal mechanical behavior of thin films with wide composition gradients. The interpretation of micro-mechanical testing data from thin films and micro-scale samples is most critical and challenging, as the mechanical properties of their bulk counterparts cannot be intuitively extrapolated due to the well-known size and microstructure dependence. Nevertheless, high-throughput mechanical characterization data from combinatorial micro-scale samples still reflect the dependence trend of the mechanical properties on compositions and microstructure, which facilitates the understanding of intrinsic materials behavior and the fast screening of bulk mechanical properties. After the promising compositions and microstructure are pinned down, bulk samples can be prepared to measure the accurate properties and verify the combinatorial high-throughput characterization results. By developing combinatorial high-throughput mechanical characterization methods and tools, in combination with high-throughput synthesis, the structural materials research would be promoted by

  5. On some interconnections between combinatorial optimization and extremal graph theory

    Directory of Open Access Journals (Sweden)

    Cvetković Dragoš M.

    2004-01-01

    Full Text Available The uniting feature of combinatorial optimization and extremal graph theory is that in both areas one should find extrema of a function defined in most cases on a finite set. While in combinatorial optimization the point is in developing efficient algorithms and heuristics for solving specified types of problems, the extremal graph theory deals with finding bounds for various graph invariants under some constraints and with constructing extremal graphs. We analyze by examples some interconnections and interactions of the two theories and propose some conclusions.

  6. Applying Bayesian Approach to Combinatorial Problem in Chemistry.

    Science.gov (United States)

    Okamoto, Yasuharu

    2017-05-04

    A Bayesian optimization procedure, in combination with density functional theory calculations, was applied to a combinatorial problem in chemistry. As a specific example, we examined the stable structures of lithium-graphite intercalation compounds (Li-GICs). We found that this approach efficiently identified the stable structure of stage-I and -II Li-GICs by calculating 4-6% of the full search space. We expect that this approach will be helpful in solving problems in chemistry that can be regarded as a kind of combinatorial problem.

  7. Combinatorial algebraic geometry selected papers from the 2016 apprenticeship program

    CERN Document Server

    Sturmfels, Bernd

    2017-01-01

    This volume consolidates selected articles from the 2016 Apprenticeship Program at the Fields Institute, part of the larger program on Combinatorial Algebraic Geometry that ran from July through December of 2016. Written primarily by junior mathematicians, the articles cover a range of topics in combinatorial algebraic geometry including curves, surfaces, Grassmannians, convexity, abelian varieties, and moduli spaces. This book bridges the gap between graduate courses and cutting-edge research by connecting historical sources, computation, explicit examples, and new results.

  8. Combinatorial reasoning an introduction to the art of counting

    CERN Document Server

    DeTemple, Duane

    2014-01-01

    Written by well-known scholars in the field, this book introduces combinatorics alongside modern techniques, showcases the interdisciplinary aspects of the topic, and illustrates how to problem solve with a multitude of exercises throughout. The authors' approach is very reader-friendly and avoids the ""scholarly tone"" found in many books on this topic. Combinatorial Reasoning: An Introduction to the Art of Counting: Focuses on enumeration and combinatorial thinking as a way to develop a variety of effective approaches to solving counting problemsIncludes brief summaries of basic concepts f

  9. Bioinspired computation in combinatorial optimization: algorithms and their computational complexity

    DEFF Research Database (Denmark)

    Neumann, Frank; Witt, Carsten

    2012-01-01

    Bioinspired computation methods, such as evolutionary algorithms and ant colony optimization, are being applied successfully to complex engineering and combinatorial optimization problems, and it is very important that we understand the computational complexity of these algorithms. This tutorials...... explains the most important results achieved in this area. The presenters show how runtime behavior can be analyzed in a rigorous way, in particular for combinatorial optimization. They present well-known problems such as minimum spanning trees, shortest paths, maximum matching, and covering and scheduling...

  10. Learned pattern recognition using synthetic-discriminant-functions

    Science.gov (United States)

    Jared, David A.; Ennis, David J.

    1986-01-01

    A method of using synthetic-discriminant-functions to facilitate learning in a pattern recognition system is discussed. Learning is accomplished by continually adding images to the training set used for synthetic discriminant functions (SDF) construction. Object identification is performed by efficiently searching a library of SDF filters for the maximum optical correlation. Two library structures are discussed - binary tree and multilinked graph - along with maximum ascent, back-tracking, perturbation, and simulated annealing searching techniques. By incorporating the distortion invariant properties of SDFs within a library structure, a robust pattern recognition system can be produced.

  11. Library news

    CERN Multimedia

    CERN Library

    2010-01-01

    The CERN Library has been providing electronic access to the "Techniques de l'Ingénieur" database for the past 8 months. As a reminder, this is a multidisciplinary database of over 4000 technical and scientific articles in French, covering a broad range of topics such as mechanical engineering, safety, electronics and the environment. In a few simple steps, you can create your own account, select the types of documents you are interested in and configure your settings so as to receive alerts when articles in your field of activity are published. You can now access this resource from outside CERN using the "remote access to electronic resources" service. Further information is available here. Direct access to the database. Remote access to electronic resources. If you have any questions or comments, don't hesitate to contact us at: library.desk@cern.ch.

  12. Library Benchmarking

    Directory of Open Access Journals (Sweden)

    Wiji Suwarno

    2017-02-01

    Full Text Available The term benchmarking has been encountered in the implementation of total quality (TQM or in Indonesian termed holistic quality management because benchmarking is a tool to look for ideas or learn from the library. Benchmarking is a processof measuring and comparing for continuous business process of systematic and continuous measurement, the process of measuring and comparing for continuous business process of an organization to get information that can help these organization improve their performance efforts.

  13. Integrating medicinal chemistry, organic/combinatorial chemistry, and computational chemistry for the discovery of selective estrogen receptor modulators with Forecaster, a novel platform for drug discovery.

    Science.gov (United States)

    Therrien, Eric; Englebienne, Pablo; Arrowsmith, Andrew G; Mendoza-Sanchez, Rodrigo; Corbeil, Christopher R; Weill, Nathanael; Campagna-Slater, Valérie; Moitessier, Nicolas

    2012-01-23

    As part of a large medicinal chemistry program, we wish to develop novel selective estrogen receptor modulators (SERMs) as potential breast cancer treatments using a combination of experimental and computational approaches. However, one of the remaining difficulties nowadays is to fully integrate computational (i.e., virtual, theoretical) and medicinal (i.e., experimental, intuitive) chemistry to take advantage of the full potential of both. For this purpose, we have developed a Web-based platform, Forecaster, and a number of programs (e.g., Prepare, React, Select) with the aim of combining computational chemistry and medicinal chemistry expertise to facilitate drug discovery and development and more specifically to integrate synthesis into computer-aided drug design. In our quest for potent SERMs, this platform was used to build virtual combinatorial libraries, filter and extract a highly diverse library from the NCI database, and dock them to the estrogen receptor (ER), with all of these steps being fully automated by computational chemists for use by medicinal chemists. As a result, virtual screening of a diverse library seeded with active compounds followed by a search for analogs yielded an enrichment factor of 129, with 98% of the seeded active compounds recovered, while the screening of a designed virtual combinatorial library including known actives yielded an area under the receiver operating characteristic (AU-ROC) of 0.78. The lead optimization proved less successful, further demonstrating the challenge to simulate structure activity relationship studies.

  14. Combinatorial synthetic peptide vaccine strategy protects against hypervirulent CovR/S mutant streptococci

    DEFF Research Database (Denmark)

    Pandey, Manisha; Mortensen, Rasmus; Calcutt, Ainslie

    2016-01-01

    ), and it would be to the organism's advantage if the host did not induce a strong Ab response against it. However, S2 conjugated to diphtheria toxoid is highly immunogenic and induces Abs that recognize and neutralize SpyCEP. Hence, we describe a two-component peptide vaccine that induces Abs (anti-S2...

  15. Biomimicry-Based Strategy Towards the Development of a Structure-Function Map of the Glutamate Receptor Pore

    National Research Council Canada - National Science Library

    Montal, Mauricio

    2001-01-01

    .... The functional assay to identify channel blockers from synthetic combinatorial libraries involved blockade of the glutamate-evoked current from Xenopus oocytes expressing recombinant NMDA receptors...

  16. Library Buildings and Equipment.

    Science.gov (United States)

    Oringdulph, Robert E.; And Others

    1990-01-01

    Six articles discuss library buildings and construction: (1) library buildings and their parts; (2) the North Campus Library of California State University at Long Beach in 1995; (3) new structures for teaching libraries; (4) construction standards for California public libraries; (5) Sick (Library) Building Syndrome; and (6) using focus-group…

  17. Library Automation in Pakistan.

    Science.gov (United States)

    Haider, Syed Jalaluddin

    1998-01-01

    Examines the state of library automation in Pakistan. Discusses early developments; financial support by the Netherlands Library Development Project (Pakistan); lack of automated systems in college/university and public libraries; usage by specialist libraries; efforts by private-sector libraries and the National Library in Pakistan; commonly used…

  18. In silico–based combinatorial pharmacophore modelling and ...

    Indian Academy of Sciences (India)

    2013-10-01

    Oct 1, 2013 ... Type 2 diabetes is an inevitably progressive disease, with irreversible β cell failure. Glycogen synthase kinase and Glukokinase, two important enzymes with diverse biological actions in carbohydrate metabolism, are promising targets for developing novel antidiabetic drugs. A combinatorial structure-based ...

  19. In silico–based combinatorial pharmacophore modelling and ...

    Indian Academy of Sciences (India)

    Type 2 diabetes is an inevitably progressive disease, with irreversible cell failure. Glycogen synthase kinase and Glukokinase, two important enzymes with diverse biological actions in carbohydrate metabolism, are promising targets for developing novel antidiabetic drugs. A combinatorial structure-based molecular ...

  20. Combinatorial structures and processing in neural blackboard architectures

    NARCIS (Netherlands)

    van der Velde, Frank; van der Velde, Frank; de Kamps, Marc; Besold, Tarek R.; d'Avila Garcez, Artur; Marcus, Gary F.; Miikkulainen, Risto

    2015-01-01

    We discuss and illustrate Neural Blackboard Architectures (NBAs) as the basis for variable binding and combinatorial processing the brain. We focus on the NBA for sentence structure. NBAs are based on the notion that conceptual representations are in situ, hence cannot be copied or transported.

  1. ON 3-WAY COMBINATORIAL IDENTITIES A. K. AGARWAL MEGHA ...

    Indian Academy of Sciences (India)

    36

    representations for restricted n-color compositions and in [12] a relation between the number of integer partitions and compositions of an integer under certain conditions is studied. Several basic series identities had been interpreted combinatorially using ordinary partitions, colored partitions, Frobenius partitions, lattice ...

  2. Combinatorial structure and iconicity in artificial whistled languages

    NARCIS (Netherlands)

    Verhoef, T.; Kirby, S.; de Boer, B.; Knauff, M.; Pauen, M.; Sebanz, N.; Wachsmuth, I.

    2013-01-01

    This article reports on an experiment in which artificial languages with whistle words for novel objects are culturally transmitted in the laboratory. The aim of this study is to investigate the origins and evolution of combinatorial structure in speech. Participants learned the whistled language

  3. A combinatorial enumeration problem of RNA secondary structures

    African Journals Online (AJOL)

    use

    2011-12-21

    Dec 21, 2011 ... interesting combinatorial questions (Chen et al., 2005;. Liu, 2006; Schmitt and Waterman 1994; Stein and. Waterman 1978). The research on the enumeration of. RNA secondary structures becomes one of the hot topics in Computational Molecular Biology. An RNA molecule is described by its sequences of.

  4. Combinatorial algorithms enabling computational science: tales from the front

    International Nuclear Information System (INIS)

    Bhowmick, Sanjukta; Boman, Erik G; Devine, Karen; Gebremedhin, Assefaw; Hendrickson, Bruce; Hovland, Paul; Munson, Todd; Pothen, Alex

    2006-01-01

    Combinatorial algorithms have long played a crucial enabling role in scientific and engineering computations. The importance of discrete algorithms continues to grow with the demands of new applications and advanced architectures. This paper surveys some recent developments in this rapidly changing and highly interdisciplinary field

  5. A Combinatorial Proof of a Result on Generalized Lucas Polynomials

    Directory of Open Access Journals (Sweden)

    Laugier Alexandre

    2016-09-01

    Full Text Available We give a combinatorial proof of an elementary property of generalized Lucas polynomials, inspired by [1]. These polynomials in s and t are defined by the recurrence relation 〈n〉 = s〈n-1〉+t〈n-2〉 for n ≥ 2. The initial values are 〈0〉 = 2; 〈1〉= s, respectively.

  6. A mixed multi-unit combinatorial auctions test suite

    NARCIS (Netherlands)

    Giovannucci, A.; Cerquides, J.; Endriss, U.; Vinyals, M.; Rodriguez, J.A.; Rosell, B.; Decker, K.S.; Sichman, J.S.; Sierra, C.; Castelfranchi, C.

    2009-01-01

    Supply Chain Formation (SCF) is the process of determining the participants in a supply chain, who will exchange what with whom, and the terms of the exchanges. Mixed multi-unit combinatorial auctions (MMUCAs) offer a high potential to solve SCF problems, and thus be employed for the automated

  7. Dithioacetal Exchange: A New Reversible Reaction for Dynamic Combinatorial Chemistry.

    Science.gov (United States)

    Orrillo, A Gastón; Escalante, Andrea M; Furlan, Ricardo L E

    2016-05-10

    Reversibility of dithioacetal bond formation is reported under acidic mild conditions. Its utility for dynamic combinatorial chemistry was explored by combining it with orthogonal disulfide exchange. In such a setup, thiols are positioned at the intersection of both chemistries, constituting a connecting node between temporally separated networks. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Dormitory libraries: libraries in dormitories

    Directory of Open Access Journals (Sweden)

    Peter Pavletič

    2004-01-01

    Full Text Available Dormitory libries are not justly treated in Slovenia. They have a double purpose: to develop student literacy, especially reading, critical and creative competence and, moreover, to provide students with opportunities for learning and active spending of free-time. This is made possible by means of a good collection of expertly arranged library material, which is regulary updated and presented to its users, both students and tutors alike. A questionnaire has helped us to find out that libraries in secondary school dormitories carry out their work rather successfully, especially from the viewpoint of poor facilities. The major problems are, nevertheless, the appropriate qualifications of those who fill the posts of librarian and low financial resources. Therefore, such activities should be thoroughly analysed and reconsidered in terms of possible effective solutions, if we want to at least maintain them, let alone develop them.

  9. MARKETING LIBRARY SERVICES IN ACADEMIC LIBRARIES: A ...

    African Journals Online (AJOL)

    This article discusses the concept of marketing library and information services as an important library activity. It also stresses the need for librarians and information specialists especially those in academic libraries in developing countries to become proactive and to take marketing as a serious and obligatory library function ...

  10. Paths and partitions: Combinatorial descriptions of the parafermionic states

    Science.gov (United States)

    Mathieu, Pierre

    2009-09-01

    The Zk parafermionic conformal field theories, despite the relative complexity of their modes algebra, offer the simplest context for the study of the bases of states and their different combinatorial representations. Three bases are known. The classic one is given by strings of the fundamental parafermionic operators whose sequences of modes are in correspondence with restricted partitions with parts at distance k -1 differing at least by 2. Another basis is expressed in terms of the ordered modes of the k -1 different parafermionic fields, which are in correspondence with the so-called multiple partitions. Both types of partitions have a natural (Bressoud) path representation. Finally, a third basis, formulated in terms of different paths, is inherited from the solution of the restricted solid-on-solid model of Andrews-Baxter-Forrester. The aim of this work is to review, in a unified and pedagogical exposition, these four different combinatorial representations of the states of the Zk parafermionic models. The first part of this article presents the different paths and partitions and their bijective relations; it is purely combinatorial, self-contained, and elementary; it can be read independently of the conformal-field-theory applications. The second part links this combinatorial analysis with the bases of states of the Zk parafermionic theories. With the prototypical example of the parafermionic models worked out in detail, this analysis contributes to fix some foundations for the combinatorial study of more complicated theories. Indeed, as we briefly indicate in ending, generalized versions of both the Bressoud and the Andrews-Baxter-Forrester paths emerge naturally in the description of the minimal models.

  11. Libraries for users services in academic libraries

    CERN Document Server

    Alvite, Luisa

    2010-01-01

    This book reviews the quality and evolution of academic library services. It revises service trends offered by academic libraries and the challenge of enhancing traditional ones such as: catalogues, repositories and digital collections, learning resources centres, virtual reference services, information literacy and 2.0 tools.studies the role of the university library in the new educational environment of higher educationrethinks libraries in academic contextredefines roles for academic libraries

  12. Synthetic virology: engineering viruses for gene delivery.

    Science.gov (United States)

    Guenther, Caitlin M; Kuypers, Brianna E; Lam, Michael T; Robinson, Tawana M; Zhao, Julia; Suh, Junghae

    2014-01-01

    The success of gene therapy relies heavily on the performance of vectors that can effectively deliver transgenes to desired cell populations. As viruses have evolved to deliver genetic material into cells, a prolific area of research has emerged over the last several decades to leverage the innate properties of viruses as well as to engineer new features into them. Specifically, the field of synthetic virology aims to capitalize on knowledge accrued from fundamental virology research in order to design functionally enhanced gene delivery vectors. The enhanced viral vectors, or 'bionic' viruses, feature engineered components, or 'parts', that are natural (intrinsic to viruses or from other organisms) and synthetic (such as man-made polymers or inorganic nanoparticles). Various design strategies--rational, combinatorial, and pseudo-rational--have been pursued to create the hybrid viruses. The gene delivery vectors of the future will likely criss-cross the boundaries between natural and synthetic domains to harness the unique strengths afforded by the various functional parts that can be grafted onto virus capsids. Such research endeavors will further expand and enable enhanced control over the functional capacity of these nanoscale devices for biomedicine. © 2014 Wiley Periodicals, Inc.

  13. Rapid Discovery of Functional Small Molecule Ligands against Proteomic Targets through Library-Against-Library Screening.

    Science.gov (United States)

    Wu, Chun-Yi; Wang, Don-Hong; Wang, Xiaobing; Dixon, Seth M; Meng, Liping; Ahadi, Sara; Enter, Daniel H; Chen, Chao-Yu; Kato, Jason; Leon, Leonardo J; Ramirez, Laura M; Maeda, Yoshiko; Reis, Carolina F; Ribeiro, Brianna; Weems, Brittany; Kung, Hsing-Jien; Lam, Kit S

    2016-06-13

    Identifying "druggable" targets and their corresponding therapeutic agents are two fundamental challenges in drug discovery research. The one-bead-one-compound (OBOC) combinatorial library method has been developed to discover peptides or small molecules that bind to a specific target protein or elicit a specific cellular response. The phage display cDNA expression proteome library method has been employed to identify target proteins that interact with specific compounds. Here, we combined these two high-throughput approaches, efficiently interrogated approximately 10(13) possible molecular interactions, and identified 91 small molecule compound beads that interacted strongly with the phage library. Of 19 compounds resynthesized, 4 were cytotoxic against cancer cells; one of these compounds was found to interact with EIF5B and inhibit protein translation. As more binding pairs are confirmed and evaluated, the "library-against-library" screening approach and the resulting small molecule-protein domain interaction database may serve as a valuable tool for basic research and drug development.

  14. In-depth proteomic analysis of non-alcoholic beverages with peptide ligand libraries. I: Almond milk and orgeat syrup.

    Science.gov (United States)

    Fasoli, Elisa; D'Amato, Alfonsina; Kravchuk, Alexander V; Citterio, Attilio; Righetti, Pier Giorgio

    2011-06-10

    Combinatorial peptide ligand libraries, both commercial and home-made, have been adopted to investigate the proteome of non-alcoholic beverages, in order to assess their genuineness and detect also trace proteins, in search of potential allergens. Two such beverages have been studied: almond milk and orgeat syrup. In the first product we have been able to identify 132 unique protein species, the deepest investigation so far of the almond proteome. In the second beverage, a handful of proteins (just 14) have been detected, belonging to a bitter almond extract. In both cases, the genuineness of such products has been verified, as well as the fact that almond milk, judging on the total protein and fat content, must have been produced with 100g ground almonds per litre of beverage, as required by authorities. On the contrary, cheap orgeat syrups produced by local supermarkets and sold as their own brands, where found not to contain any residual proteins, suggesting that they contained only synthetic aromas and no natural plant extracts. This could be the starting point for investigating the myriad of beverages that in the last decades have invaded the shelves of supermarkets the world over, whose genuineness and natural origin have never been properly assessed. Copyright © 2011 Elsevier B.V. All rights reserved.

  15. Toxin Inhibition - Deconvolution Strategies and Assay Screening of Combinatorial Peptide Libraries

    Science.gov (United States)

    2007-08-01

    The work assembled a multi-disciplinary team of protein chemists, biochemists , molecular biologist, computational chemists, analytical chemists and...24. Dickinson Laing, T., Mah, D.C., Poirier, R.T., Bekkaoui, F., Lee, W.E., Bader, D.E. (2004). Genomic DNA detection using cycling probe technology

  16. Virtual Combinatorial Library Design, Synthesis and In vitro Anticancer Assessment of -2-Amino-3-Cyanopyridine Derivatives.

    Science.gov (United States)

    Dev, Sanal; Dhaneshwar, Sunil R; Mathew, Bijo

    2018-02-27

    For the development of new class of anticancer agents, a series of novel 2-amino-3-cyanopyridine derivatives were designed from virtual screening with Glide program by setting Topoisomerase II as the target. The top ranked ten molecules from the virtual screening were synthesized by microwave assisted technique and investigated for their cytotoxic activity against MCF-7 and A-549 cell lines by using sulforhodamine B assay method. The most active compound 2-amino-4-(3,5-dibromo-4-hydroxyphenyl)-6-(2,4-dichlorophenyl) nicotinonitrile (CG-5) showed significant cytotoxic profile with (LC50 = 97.1, TGI = 29.9 and GI50 = <0.1 µM) in MCF-7 and (LC50= 93.0, TGI= 50.0 and GI50= <7 µM) in A-549 cell lines. A molecular docking study was performed to explore the binding interaction of CG-5with the active site of Topoisomerase II. It can be concluded that halogen substituent pyridine ring was benefit for cytotoxicity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Marketing the Virtual Library

    Science.gov (United States)

    Fagan, Jody Condit

    2009-01-01

    Far more people are familiar with their local public or college library facility than their library's website and online resources. In fact, according to a recent survey, 96% of Americans said they had visited a library in person, but less than one-third have visited their online library. Since everyone agrees that online library resources are…

  18. CUNY Graduate Center Workshops on Combinatorial and Additive Number Theory

    CERN Document Server

    2017-01-01

    Based on talks from the 2015 and 2016 Combinatorial and Additive Number Theory (CANT) workshops at the City University of New York, these proceedings offer 19 peer-reviewed and edited papers on current topics in number theory. Held every year since 2003, the workshop series surveys state-of-the-art open problems in combinatorial and additive number theory and related parts of mathematics. Sumsets, partitions, convex polytopes and discrete geometry, Ramsey theory, primality testing, and cryptography are among the topics featured in this volume. Each contribution is dedicated to a specific topic that reflects the latest results by experts in the field. Researchers and graduate students interested in the current progress in number theory will find this selection of articles relevant and compelling. .

  19. A Combinatorial Interpretation of the Eigensequence for Composition

    Science.gov (United States)

    Callan, David

    2006-01-01

    The monic sequence that shifts left under convolution with itself is the Catalan numbers with 130+ combinatorial interpretations. Here we establish a combinatorial interpretation for the monic sequence that shifts left under composition: it counts permutations that contain a 3241 pattern only as part of a 35241 pattern. We give two recurrences, the first allowing relatively fast computation, the second similar to one for the Catalan numbers. Among the 4 x 4!=96 similarly restricted patterns involving 4 letters (such as 4\\underline{2}31: a 431 pattern occurs only as part of a 4231), four different counting sequences arise: 64 give the Catalan numbers, 16 give the Bell numbers, 12 give sequence A051295, in OEIS, and 4 give a new sequence with an explicit formula.

  20. Non-unique factorizations algebraic, combinatorial and analytic theory

    CERN Document Server

    Geroldinger, Alfred

    2006-01-01

    From its origins in algebraic number theory, the theory of non-unique factorizations has emerged as an independent branch of algebra and number theory. Focused efforts over the past few decades have wrought a great number and variety of results. However, these remain dispersed throughout the vast literature. For the first time, Non-Unique Factorizations: Algebraic, Combinatorial, and Analytic Theory offers a look at the present state of the theory in a single, unified resource.Taking a broad look at the algebraic, combinatorial, and analytic fundamentals, this book derives factorization results and applies them in concrete arithmetical situations using appropriate transfer principles. It begins with a basic introduction that can be understood with knowledge of standard basic algebra. The authors then move to the algebraic theory of monoids, arithmetic theory of monoids, the structure of sets of lengths, additive group theory, arithmetical invariants, and the arithmetic of Krull monoids. They also provide a s...

  1. Theory of Randomized Search Heuristics in Combinatorial Optimization

    DEFF Research Database (Denmark)

    complex population-based EAs. The combinatorial optimization problems that we discuss include the maximum matching problem, the partition problem and, in particular, the minimum spanning tree problem as an example where Simulated Annealing beats the Metropolis algorithm in combinatorial optimization......), the Metropolis Algorithm (MA), Simulated Annealing (SA), and Evolutionary Algorithms (EAs) as well as more recent approaches such as Ant Colony Optimization (ACO) and Particle Swarm Optimization (PSO). Such heuristics are often applied to problems whose structure is not known or if there are not enough resources...... analysis of randomized algorithms to RSHs. Mostly, the expected runtime of RSHs on selected problems is analzyed. Thereby, we understand why and when RSHs are efficient optimizers and, conversely, when they cannot be efficient. The tutorial will give an overview on the analysis of RSHs for solving...

  2. On the Cut-off Point for Combinatorial Group Testing

    DEFF Research Database (Denmark)

    Fischer, Paul; Klasner, N.; Wegener, I.

    1999-01-01

    The following problem is known as group testing problem for n objects. Each object can be essential (defective) or non-essential (intact). The problem is to determine the set of essential objects by asking queries adaptively. A query can be identified with a set Q of objects and the query Q...... group testing is equal to p* = 12(3 - 5), i.e., the strategy of testing each object individually minimizes the average number of queries iff p >= p* or n = 1. In the combinatorial setting the worst case number of queries is of interest. It has been conjectured that the cut-off point of combinatorial...... group testing is equal to alpha* = 13, i.e., the strategy of testing n - 1 objects individually minimizes the worst case number of queries iff k/n >= alpha* and k

  3. Combinatorial nuclear level density by a Monte Carlo method

    International Nuclear Information System (INIS)

    Cerf, N.

    1994-01-01

    We present a new combinatorial method for the calculation of the nuclear level density. It is based on a Monte Carlo technique, in order to avoid a direct counting procedure which is generally impracticable for high-A nuclei. The Monte Carlo simulation, making use of the Metropolis sampling scheme, allows a computationally fast estimate of the level density for many fermion systems in large shell model spaces. We emphasize the advantages of this Monte Carlo approach, particularly concerning the prediction of the spin and parity distributions of the excited states,and compare our results with those derived from a traditional combinatorial or a statistical method. Such a Monte Carlo technique seems very promising to determine accurate level densities in a large energy range for nuclear reaction calculations

  4. Combinatorial Optimization in Project Selection Using Genetic Algorithm

    Science.gov (United States)

    Dewi, Sari; Sawaluddin

    2018-01-01

    This paper discusses the problem of project selection in the presence of two objective functions that maximize profit and minimize cost and the existence of some limitations is limited resources availability and time available so that there is need allocation of resources in each project. These resources are human resources, machine resources, raw material resources. This is treated as a consideration to not exceed the budget that has been determined. So that can be formulated mathematics for objective function (multi-objective) with boundaries that fulfilled. To assist the project selection process, a multi-objective combinatorial optimization approach is used to obtain an optimal solution for the selection of the right project. It then described a multi-objective method of genetic algorithm as one method of multi-objective combinatorial optimization approach to simplify the project selection process in a large scope.

  5. An Atlas of Combinatorial Transcriptional Regulation in Mouse and Man

    KAUST Repository

    Ravasi, Timothy

    2010-03-01

    Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution.

  6. On the Combinatorial Part of the UNIFAC and UNIQUAC Models

    DEFF Research Database (Denmark)

    Kikic, I.; Alessi, P.; Rasmussen, Peter

    1980-01-01

    The excess Cibbs energy of liquid mixtures may be predicted using group contribution models (f.ex. UNIFAC and ASOG), or it may be correlated using molecular models such as UNIQUAC. Group contribution models and the UNIQUAC model contain a combinatorial contribution which accounts for size.......g., mixtures of aliphatic hydrocarbons). It is shown that it is advantageous to incorporate the new combinational expression into future modifications of the UNIFAC model....

  7. On the likelihood of normalisation in combinatory logic

    OpenAIRE

    Bendkowski, Maciej; Grygiel, Katarzyna; Zaionc, Marek

    2016-01-01

    We present a quantitative basis-independent analysis of combinatory logic. Using a general argument regarding plane binary trees with labelled leaves, we generalise the results of David et al. and Bendkowski et al. to all Turing-complete combinator bases proving, inter alia, that asymptotically almost no combinator is strongly normalising nor typeable. We exploit the structure of recently discovered normal-order reduction grammars showing that for each positive $n$, the set of $\\mathbf{S} \\ma...

  8. Distributing the computation in combinatorial optimization experiments over the cloud

    Directory of Open Access Journals (Sweden)

    Mario Brcic

    2017-12-01

    Full Text Available Combinatorial optimization is an area of great importance since many of the real-world problems have discrete parameters which are part of the objective function to be optimized. Development of combinatorial optimization algorithms is guided by the empirical study of the candidate ideas and their performance over a wide range of settings or scenarios to infer general conclusions. Number of scenarios can be overwhelming, especially when modeling uncertainty in some of the problem’s parameters. Since the process is also iterative and many ideas and hypotheses may be tested, execution time of each experiment has an important role in the efficiency and successfulness. Structure of such experiments allows for significant execution time improvement by distributing the computation. We focus on the cloud computing as a cost-efficient solution in these circumstances. In this paper we present a system for validating and comparing stochastic combinatorial optimization algorithms. The system also deals with selection of the optimal settings for computational nodes and number of nodes in terms of performance-cost tradeoff. We present applications of the system on a new class of project scheduling problem. We show that we can optimize the selection over cloud service providers as one of the settings and, according to the model, it resulted in a substantial cost-savings while meeting the deadline.

  9. Combinatorial methodologies for determination of glass-forming region

    Science.gov (United States)

    Inoue, Satoru; Todoroki, Shinichi; Matsumoto, Takehisa; Hondo, Takaharu; Araki, Tetsuo; Watanabe, Yuichi

    2002-04-01

    The combinatorial methodologies have been studied to automate the process for the determination of glass-forming region. The glass batches were prepared automatically and were melted simultaneously by applying various heating techniques, followed by cooling to room temperature to get the melt-quench samples. In this study, the combinatorial methods for the preparation of batches and the melting in the crucibles have been developed. The apparatus for the preparation of glass batches (automatic batch preparation apparatus) has been developed firstly in the world. The apparatus can prepare 24 different glass batches at one time in a 4-component system. The furnace designed for melting some glass batches simultaneously (automatic batch-melting apparatus) has been developed. The automatic batch-melting apparatus can work on the melting of 10 glass batches and the casting of the 10 melts onto the metal plates. The other possible methods for the determination of glass-forming regions have been discussed to develop the further advancements of the combinatorial methodologies.

  10. View discovery in OLAP databases through statistical combinatorial optimization

    Energy Technology Data Exchange (ETDEWEB)

    Hengartner, Nick W [Los Alamos National Laboratory; Burke, John [PNNL; Critchlow, Terence [PNNL; Joslyn, Cliff [PNNL; Hogan, Emilie [PNNL

    2009-01-01

    OnLine Analytical Processing (OLAP) is a relational database technology providing users with rapid access to summary, aggregated views of a single large database, and is widely recognized for knowledge representation and discovery in high-dimensional relational databases. OLAP technologies provide intuitive and graphical access to the massively complex set of possible summary views available in large relational (SQL) structured data repositories. The capability of OLAP database software systems to handle data complexity comes at a high price for analysts, presenting them a combinatorially vast space of views of a relational database. We respond to the need to deploy technologies sufficient to allow users to guide themselves to areas of local structure by casting the space of 'views' of an OLAP database as a combinatorial object of all projections and subsets, and 'view discovery' as an search process over that lattice. We equip the view lattice with statistical information theoretical measures sufficient to support a combinatorial optimization process. We outline 'hop-chaining' as a particular view discovery algorithm over this object, wherein users are guided across a permutation of the dimensions by searching for successive two-dimensional views, pushing seen dimensions into an increasingly large background filter in a 'spiraling' search process. We illustrate this work in the context of data cubes recording summary statistics for radiation portal monitors at US ports.

  11. View Discovery in OLAP Databases through Statistical Combinatorial Optimization

    Energy Technology Data Exchange (ETDEWEB)

    Joslyn, Cliff A.; Burke, Edward J.; Critchlow, Terence J.

    2009-05-01

    The capability of OLAP database software systems to handle data complexity comes at a high price for analysts, presenting them a combinatorially vast space of views of a relational database. We respond to the need to deploy technologies sufficient to allow users to guide themselves to areas of local structure by casting the space of ``views'' of an OLAP database as a combinatorial object of all projections and subsets, and ``view discovery'' as an search process over that lattice. We equip the view lattice with statistical information theoretical measures sufficient to support a combinatorial optimization process. We outline ``hop-chaining'' as a particular view discovery algorithm over this object, wherein users are guided across a permutation of the dimensions by searching for successive two-dimensional views, pushing seen dimensions into an increasingly large background filter in a ``spiraling'' search process. We illustrate this work in the context of data cubes recording summary statistics for radiation portal monitors at US ports.

  12. High-flexibility combinatorial peptide synthesis with laser-based transfer of monomers in solid matrix material.

    Science.gov (United States)

    Loeffler, Felix F; Foertsch, Tobias C; Popov, Roman; Mattes, Daniela S; Schlageter, Martin; Sedlmayr, Martyna; Ridder, Barbara; Dang, Florian-Xuan; von Bojničić-Kninski, Clemens; Weber, Laura K; Fischer, Andrea; Greifenstein, Juliane; Bykovskaya, Valentina; Buliev, Ivan; Bischoff, F Ralf; Hahn, Lothar; Meier, Michael A R; Bräse, Stefan; Powell, Annie K; Balaban, Teodor Silviu; Breitling, Frank; Nesterov-Mueller, Alexander

    2016-06-14

    Laser writing is used to structure surfaces in many different ways in materials and life sciences. However, combinatorial patterning applications are still limited. Here we present a method for cost-efficient combinatorial synthesis of very-high-density peptide arrays with natural and synthetic monomers. A laser automatically transfers nanometre-thin solid material spots from different donor slides to an acceptor. Each donor bears a thin polymer film, embedding one type of monomer. Coupling occurs in a separate heating step, where the matrix becomes viscous and building blocks diffuse and couple to the acceptor surface. Furthermore, we can consecutively deposit two material layers of activation reagents and amino acids. Subsequent heat-induced mixing facilitates an in situ activation and coupling of the monomers. This allows us to incorporate building blocks with click chemistry compatibility or a large variety of commercially available non-activated, for example, posttranslationally modified building blocks into the array's peptides with >17,000 spots per cm(2).

  13. LIBRARY SKILL INSTRUCTION IN NIGERIAN ACADEMIC LIBRARIES

    African Journals Online (AJOL)

    DJFLEX

    www.globaljournalseries.com; Info@globaljournalseries.com. LIBRARY SKILL INSTRUCTION IN NIGERIAN ACADEMIC. LIBRARIES. P. C. AZIAGBA AND E. H. UZOEZI. (Received 10, September 2009; Revision Accepted 8, February 2010). ABSTRACT. This survey was undertaken to portray the level of library involvement ...

  14. LIBRARY SKILL INSTRUCTION IN NIGERIAN ACADEMIC LIBRARIES

    African Journals Online (AJOL)

    DJFLEX

    ISSN 1596-6224 www.globaljournalseries.com; Info@globaljournalseries.com. LIBRARY SKILL INSTRUCTION IN NIGERIAN ACADEMIC. LIBRARIES ... analysis indicate that library skill instruction courses are taught in most tertiary institutions in Nigeria, but this has not attained a ..... Adolescents the information seeking ...

  15. Plant synthetic biology.

    Science.gov (United States)

    Liu, Wusheng; Stewart, C Neal

    2015-05-01

    Plant synthetic biology is an emerging field that combines engineering principles with plant biology toward the design and production of new devices. This emerging field should play an important role in future agriculture for traditional crop improvement, but also in enabling novel bioproduction in plants. In this review we discuss the design cycles of synthetic biology as well as key engineering principles, genetic parts, and computational tools that can be utilized in plant synthetic biology. Some pioneering examples are offered as a demonstration of how synthetic biology can be used to modify plants for specific purposes. These include synthetic sensors, synthetic metabolic pathways, and synthetic genomes. We also speculate about the future of synthetic biology of plants. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Use of Mixed Micelles for Presentation of Building Blocks in a New Combinatorial Discovery Methodology: Proof-of-Concept Studies

    Directory of Open Access Journals (Sweden)

    Istvan Toth

    2013-03-01

    Full Text Available We describe a new method of combinatorial screening in which building blocks, instead of being linked together chemically, are placed on the surface of nanoparticles. Two- or three-dimensional structures form on the surface of these particles through the close approach of different building blocks, with sufficient flexibility to be able to adapt and interact with putative binding sites in biological systems. The particles assemble without the need for formation of chemical bonds, so libraries comprised of many structures can be prepared rapidly, with large quantities of material available for testing. Screening methods can include solid and solution-phase binding assays, or tissue culture models, for example looking for structures which can change the behaviour of cells in a disease-modifying manner.

  17. Synthetic antifreeze peptide

    OpenAIRE

    1991-01-01

    A synthetic antifreeze peptide and a synthetic gene coding for the antifreeze peptide have been produced. The antifreeze peptide has a greater number of repeating amino acid sequences than is present in the native antifreeze peptides from winter flounder upon which the synthetic antifreeze peptide was modeled. Each repeating amino acid sequence has two polar amino acid residues which are spaced a controlled distance apart so that the antifreeze peptide may inhibit ice formation. The synthetic...

  18. [SYNTHETIC PEPTIDE VACCINES].

    Science.gov (United States)

    Sergeyev, O V; Barinsky, I F

    2016-01-01

    An update on the development and trials of synthetic peptide vaccines is reviewed. The review considers the successful examples of specific protection as a result of immunization with synthetic peptides using various protocols. The importance of conformation for the immunogenicity of the peptide is pointed out. An alternative strategy of the protection of the organism against the infection using synthetic peptides is suggested.

  19. Rational, combinatorial, and genomic approaches for engineering L-tyrosine production in Escherichia coli.

    Science.gov (United States)

    Santos, Christine Nicole S; Xiao, Wenhai; Stephanopoulos, Gregory

    2012-08-21

    Although microbial metabolic engineering has traditionally relied on rational and knowledge-driven techniques, significant improvements in strain performance can be further obtained through the use of combinatorial approaches exploiting phenotypic diversification and screening. Here, we demonstrate the combined use of global transcriptional machinery engineering and a high-throughput L-tyrosine screen towards improving L-tyrosine production in Escherichia coli. This methodology succeeded in generating three strains from two separate mutagenesis libraries (rpoA and rpoD) exhibiting up to a 114% increase in L-tyrosine titer over a rationally engineered parental strain with an already high capacity for production. Subsequent strain characterization through transcriptional analysis and whole genome sequencing allowed complete phenotype reconstruction from well-defined mutations and point to important roles for both the acid stress resistance pathway and the stringent response of E. coli in imparting this phenotype. As such, this study presents one of the first examples in which cell-wide measurements have helped to elucidate the genetic and biochemical underpinnings of an engineered cellular property, leading to the total restoration of metabolite overproduction from specific chromosomal mutations.

  20. High-throughput bubble screening method for combinatorial discovery of electrocatalysts for water splitting.

    Science.gov (United States)

    Xiang, Chengxiang; Suram, Santosh K; Haber, Joel A; Guevarra, Dan W; Soedarmadji, Ed; Jin, Jian; Gregoire, John M

    2014-02-10

    Combinatorial synthesis and screening for discovery of electrocatalysts has received increasing attention, particularly for energy-related technologies. High-throughput discovery strategies typically employ a fast, reliable initial screening technique that is able to identify active catalyst composition regions. Traditional electrochemical characterization via current-voltage measurements is inherently throughput-limited, as such measurements are most readily performed by serial screening. Parallel screening methods can yield much higher throughput and generally require the use of an indirect measurement of catalytic activity. In a water-splitting reaction, the change of local pH or the presence of oxygen and hydrogen in the solution can be utilized for parallel screening of active electrocatalysts. Previously reported techniques for measuring these signals typically function in a narrow pH range and are not suitable for both strong acidic and basic environments. A simple approach to screen the electrocatalytic activities by imaging the oxygen and hydrogen bubbles produced by the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) is reported here. A custom built electrochemical cell was employed to record the bubble evolution during the screening, where the testing materials were subject to desired electrochemical potentials. The transient of the bubble intensity obtained from the screening was quantitatively analyzed to yield a bubble figure of merit (FOM) that represents the reaction rate. Active catalysts in a pseudoternary material library, (Ni-Fe-Co)Ox, which contains 231 unique compositions, were identified in less than one minute using the bubble screening method. An independent, serial screening method on the same material library exhibited excellent agreement with the parallel bubble screening. This general approach is highly parallel and is independent of solution pH.

  1. Enumeration of Combinatorial Classes of Single Variable Complex Polynomial Vector Fields

    DEFF Research Database (Denmark)

    Dias, Kealey

    A vector field in the space of degree d monic, centered single variable complex polynomial vector fields has a combinatorial structure which can be fully described by a combinatorial data set consisting of an equivalence relation and a marked subset on the integers mod 2d-2, satisfying certain...... in a valid way. We first enumerate all combinatorial classes with respect to degree d, and then we enumerate the combinatorial classes having a specific dimension q in parameter space. In both cases, a recursion equation and implicit expressions for the algebraic generating functions are calculated...

  2. Accessing Nature's diversity through metabolic engineering and synthetic biology.

    Science.gov (United States)

    King, Jason R; Edgar, Steven; Qiao, Kangjian; Stephanopoulos, Gregory

    2016-01-01

    In this perspective, we highlight recent examples and trends in metabolic engineering and synthetic biology that demonstrate the synthetic potential of enzyme and pathway engineering for natural product discovery. In doing so, we introduce natural paradigms of secondary metabolism whereby simple carbon substrates are combined into complex molecules through "scaffold diversification", and subsequent "derivatization" of these scaffolds is used to synthesize distinct complex natural products. We provide examples in which modern pathway engineering efforts including combinatorial biosynthesis and biological retrosynthesis can be coupled to directed enzyme evolution and rational enzyme engineering to allow access to the "privileged" chemical space of natural products in industry-proven microbes. Finally, we forecast the potential to produce natural product-like discovery platforms in biological systems that are amenable to single-step discovery, validation, and synthesis for streamlined discovery and production of biologically active agents.

  3. Apology for Local Library

    Directory of Open Access Journals (Sweden)

    Silva Novljan

    2014-04-01

    Full Text Available ABSTRACTPurpose: The purpose of the article is to strengthen the importance of a local library and its role in offering equal access to library services even to inhabitants of the smallest local communities.Methodology: Fulfilling the mission of a public library, a local library exercises equal human rights and fundamental freedoms for inhabitants of a local community. The research indicates that inhabitants of a small community having no local library are deprived of human rights and fundamental freedoms. The questionnaire was completed by central public libraries responsible for the accessibility of library services in their region. The research is based on the analysis of publicly available statistical data and responses to a questionnaire on library services in communities with no local library. The results place a public library among institutions behaving in a socially responsible way thus developing a democratic and responsible society.Results: The results confirmed that small communities having no local libraries are deprived of library services although they, together with the Ministry of Culture, co-finance a local library in a neighbouring community and have access to its services.Research limitations: The research is focused on verifying the accessibility of library services on a selected sample of communities and does not assess the entire scope and quality of public libraries' activity in realising common recommendations on the accessibility of public library services.Originality/practical implications: Testing the accessibility of library services on a selected sample of communities and the effect of solidarity on equal access to library services encourage the consideration of suitability of regulations on local library organisation, the attitude of the state, communities and central public libraries in preserving and developing a local library.

  4. Inside Prison Libraries.

    Science.gov (United States)

    Vogel, Brenda; And Others

    1989-01-01

    Issues related to prison libraries are discussed in six articles. Topics covered include the history of American penitentiary ideology; standards for prison libraries; the controversy as to whether prison libraries should serve prisoners or be used as penological tools; and the lack of knowledge about prison libraries within the general library…

  5. Libraries and Learning

    Science.gov (United States)

    Rainie, Lee

    2016-01-01

    The majority of Americans think local libraries serve the educational needs of their communities and families pretty well and library users often outpace others in learning activities. But many do not know about key education services libraries provide. This report provides statistics on library usage and presents key education services provided…

  6. The library marketing toolkit

    CERN Document Server

    Potter, Ned

    2012-01-01

    A guide that offers coverage of various elements of library marketing and branding for different sectors including archives and academic, public and special libraries. It is suitable for those who are involved in promoting their library or information service, whether at an academic, public or special library or in archives or records management.

  7. Growing Competition for Libraries.

    Science.gov (United States)

    Gibbons, Susan

    2001-01-01

    Describes the Questia subscription-based online academic digital books library. Highlights include weaknesses of the collection; what college students want from a library; importance of marketing; competition for traditional academic libraries that may help improve library services; and the ability of Questia to overcome barriers and…

  8. Automating the Small Library.

    Science.gov (United States)

    Skapura, Robert

    1987-01-01

    Discusses the use of microcomputers for automating school libraries, both for entire systems and for specific library tasks. Highlights include available library management software, newsletters that evaluate software, constructing an evaluation matrix, steps to consider in library automation, and a brief discussion of computerized card catalogs.…

  9. Teleporting the library?

    DEFF Research Database (Denmark)

    Heilesen, Simon

    2009-01-01

    In 2007, six Danish public libraries established a virtual library, Info Island DK, in Second Life. This article discusses the library project in terms of design. The design processes include the planning and implementation of the virtual library structure and its equipment, as well as the organi...

  10. First steps in combinatorial optimization on graphons: matchings

    Czech Academy of Sciences Publication Activity Database

    Doležal, Martin; Hladký, J.; Hu, P.; Piguet, Diana

    2017-01-01

    Roč. 61, August (2017), s. 359-365 ISSN 1571-0653 R&D Projects: GA ČR GA16-07378S; GA ČR GJ16-07822Y EU Projects: European Commission(XE) 628974 - PAECIDM Institutional support: RVO:67985840 ; RVO:67985807 Keywords : graphon * graph limits * matching * combinatorial optimization Subject RIV: BA - General Mathematics ; BA - General Mathematics (UIVT-O) OBOR OECD: Pure mathematics ; Pure mathematics (UIVT-O) http://www.sciencedirect.com/science/article/pii/S1571065317301452

  11. First steps in combinatorial optimization on graphons: matchings

    Czech Academy of Sciences Publication Activity Database

    Doležal, Martin; Hladký, J.; Hu, P.; Piguet, Diana

    2017-01-01

    Roč. 61, August (2017), s. 359-365 ISSN 1571-0653 R&D Projects: GA ČR GA16-07378S; GA ČR GJ16-07822Y EU Projects: European Commission(XE) 628974 - PAECIDM Institutional support: RVO:67985840 ; RVO:67985807 Keywords : graphon * graph limits * matching * combinatorial optimization Subject RIV: BA - General Mathematics; BA - General Mathematics (UIVT-O) OBOR OECD: Pure mathematics; Pure mathematics (UIVT-O) http://www. science direct.com/ science /article/pii/S1571065317301452

  12. Advances in bio-inspired computing for combinatorial optimization problems

    CERN Document Server

    Pintea, Camelia-Mihaela

    2013-01-01

    Advances in Bio-inspired Combinatorial Optimization Problems' illustrates several recent bio-inspired efficient algorithms for solving NP-hard problems.Theoretical bio-inspired concepts and models, in particular for agents, ants and virtual robots are described. Large-scale optimization problems, for example: the Generalized Traveling Salesman Problem and the Railway Traveling Salesman Problem, are solved and their results are discussed.Some of the main concepts and models described in this book are: inner rule to guide ant search - a recent model in ant optimization, heterogeneous sensitive a

  13. Toy Library and International Toy Library Association

    OpenAIRE

    KAMARAJ, Işık

    2013-01-01

    Toy libraries are resource centers that provides assistance to young children and theirfamilies, gives consultancy service and information about plays, offers play materials andeducational activities and supplies appropriate materials and toys for child development aswell as contributing the development of children. Toy libraries are in commission all over theworld since 1935. The first toy library is opened in America, then in Sweden, England,Canada and Australia respectively. Today, there a...

  14. America's Star Libraries, 2010: Top-Rated Libraries

    Science.gov (United States)

    Lyons, Ray; Lance, Keith Curry

    2010-01-01

    The "LJ" Index of Public Library Service 2010, "Library Journal"'s national rating of public libraries, identifies 258 "star" libraries. Created by Ray Lyons and Keith Curry Lance, and based on 2008 data from the IMLS, it rates 7,407 public libraries. The top libraries in each group get five, four, or three stars. All included libraries, stars or…

  15. Discovery and investigation of anticancer ruthenium-arene Schiff-base complexes via water-promoted combinatorial three-component assembly.

    Science.gov (United States)

    Chow, Mun Juinn; Licona, Cynthia; Yuan Qiang Wong, Daniel; Pastorin, Giorgia; Gaiddon, Christian; Ang, Wee Han

    2014-07-24

    The structural diversity of metal scaffolds makes them a viable alternative to traditional organic scaffolds for drug design. Combinatorial chemistry and multicomponent reactions, coupled with high-throughput screening, are useful techniques in drug discovery, but they are rarely used in metal-based drug design. We report the optimization and validation of a new combinatorial, metal-based, three-component assembly reaction for the synthesis of a library of 442 Ru-arene Schiff-base (RAS) complexes. These RAS complexes were synthesized in a one-pot, on-a-plate format using commercially available starting materials under aqueous conditions. The library was screened for their anticancer activity, and several cytotoxic lead compounds were identified. In particular, [(η6-1,3,5-triisopropylbenzene)RuCl(4-methoxy-N-(2-quinolinylmethylene)aniline)]Cl (4) displayed low micromolar IC50 values in ovarian cancers (A2780, A2780cisR), breast cancer (MCF7), and colorectal cancer (HCT116, SW480). The absence of p53 activation or changes in IC50 value between p53+/+ and p53-/- cells suggests that 4 and possibly the other lead compounds may act independently of the p53 tumor suppressor gene frequently mutated in cancer.

  16. Validation of an Instrument and Testing Protocol for Measuring the Combinatorial Analysis Schema.

    Science.gov (United States)

    Staver, John R.; Harty, Harold

    1979-01-01

    Designs a testing situation to examine the presence of combinatorial analysis, to establish construct validity in the use of an instrument, Combinatorial Analysis Behavior Observation Scheme (CABOS), and to investigate the presence of the schema in young adolescents. (Author/GA)

  17. Combinatorial enzyme technology for the conversion of agricultural fibers to functional properties

    Science.gov (United States)

    The concept of combinatorial chemistry has received little attention in agriculture and food research, although its applications in this area were described more than fifteen years ago (1, 2). More recently, interest in the use of combinatorial chemistry in agrochemical discovery has been revitalize...

  18. [From synthetic biology to synthetic humankind].

    Science.gov (United States)

    Nouvel, Pascal

    2015-01-01

    In this paper, we propose an historical survey of the expression "synthetic biology" in order to identify its main philosophical components. The result of the analysis is then used to investigate the meaning of the notion of "synthetic man". It is shown that both notions share a common philosophical background that can be summed up by the short but meaningful assertion: "biology is technology". The analysis allows us to distinguish two notions that are often confused in transhumanist literature: the notion of synthetic man and the notion of renewed man. The consequences of this crucial distinction are discussed. Copyright © 2015 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  19. Libraries and Accessibility: Istanbul Public Libraries Case

    Directory of Open Access Journals (Sweden)

    Gül Yücel

    2016-12-01

    Full Text Available In the study; the assessment of accessibility has been conducted in Istanbul public libraries within the scope of public area. Public libraries commonly serve with its user of more than 20 million in total, spread to the general of Turkey, having more than one thousand branches in the centrums and having more than one million registered members. The building principles and standards covering the subjects such as the selection of place, historical and architectural specification of the region, distance to the centre of population and design in a way that the disabled people could benefit from the library services fully have been determined with regulations in the construction of new libraries. There are works for the existent libraries such as access for the disabled, fire safety precautions etc. within the scope of the related standards. Easy access by everyone is prioritized in the public libraries having a significant role in life-long learning. The purpose of the study is to develop solution suggestions for the accessibility problems in the public libraries. The study based on the eye inspection and assessments carried out within the scope of accessibility in the public libraries subsidiary to Istanbul Culture and Tourism Provincial Directorate Library and Publications Department within the provincial borders of Istanbul. The arrangements such as reading halls, study areas, book shelves etc. have been examined within the frame of accessible building standards. Building entrances, ramps and staircases, horizontal and vertical circulation of building etc. have been taken into consideration within the scope of accessible building standards. The subjects such as the reading and studying areas and book shelf arrangements for the library have been assessed within the scope of specific buildings. There are a total of 34 public libraries subsidiary to Istanbul Culture and Tourism Provincial Directorate on condition that 20 ea. of them are in the

  20. Synthetic Cathinones ("Bath Salts")

    Science.gov (United States)

    ... cathinones? Behavioral therapy can be used to treat addiction to synthetic cathinones. Examples include: cognitive-behavioral therapy contingency management, or motivational incentives—providing rewards to ...

  1. A combinatorial approach to diffeomorphism invariant quantum gauge theories

    International Nuclear Information System (INIS)

    Zapata, J.A.

    1997-01-01

    Quantum gauge theory in the connection representation uses functions of holonomies as configuration observables. Physical observables (gauge and diffeomorphism invariant) are represented in the Hilbert space of physical states; physical states are gauge and diffeomorphism invariant distributions on the space of functions of the holonomies of the edges of a certain family of graphs. Then a family of graphs embedded in the space manifold (satisfying certain properties) induces a representation of the algebra of physical observables. We construct a quantum model from the set of piecewise linear graphs on a piecewise linear manifold, and another manifestly combinatorial model from graphs defined on a sequence of increasingly refined simplicial complexes. Even though the two models are different at the kinematical level, they provide unitarily equivalent representations of the algebra of physical observables in separable Hilbert spaces of physical states (their s-knot basis is countable). Hence, the combinatorial framework is compatible with the usual interpretation of quantum field theory. copyright 1997 American Institute of Physics

  2. Combinatorial therapy discovery using mixed integer linear programming.

    Science.gov (United States)

    Pang, Kaifang; Wan, Ying-Wooi; Choi, William T; Donehower, Lawrence A; Sun, Jingchun; Pant, Dhruv; Liu, Zhandong

    2014-05-15

    Combinatorial therapies play increasingly important roles in combating complex diseases. Owing to the huge cost associated with experimental methods in identifying optimal drug combinations, computational approaches can provide a guide to limit the search space and reduce cost. However, few computational approaches have been developed for this purpose, and thus there is a great need of new algorithms for drug combination prediction. Here we proposed to formulate the optimal combinatorial therapy problem into two complementary mathematical algorithms, Balanced Target Set Cover (BTSC) and Minimum Off-Target Set Cover (MOTSC). Given a disease gene set, BTSC seeks a balanced solution that maximizes the coverage on the disease genes and minimizes the off-target hits at the same time. MOTSC seeks a full coverage on the disease gene set while minimizing the off-target set. Through simulation, both BTSC and MOTSC demonstrated a much faster running time over exhaustive search with the same accuracy. When applied to real disease gene sets, our algorithms not only identified known drug combinations, but also predicted novel drug combinations that are worth further testing. In addition, we developed a web-based tool to allow users to iteratively search for optimal drug combinations given a user-defined gene set. Our tool is freely available for noncommercial use at http://www.drug.liuzlab.org/. zhandong.liu@bcm.edu Supplementary data are available at Bioinformatics online.

  3. Functional completeness of the mixed λ-calculus and combinatory logic

    DEFF Research Database (Denmark)

    Nielson, Hanne Riis; Nielson, Flemming

    1990-01-01

    Functional completeness of the combinatory logic means that every lambda-expression may be translated into an equivalent combinator expression and this is the theoretical basis for the implementation of functional languages on combinator-based abstract machines. To obtain efficient implementations...... it is important to distinguish between early and late binding times, i.e. to distinguish between compile-time and run-time computations. The authors therefore introduce a two-level version of the lambda-calculus where this distinction is made in an explicit way. Turning to the combinatory logic they generate...... combinator-code for the run-time computations. The two-level version of the combinatory logic therefore is a mixed lambda-calculus and combinatory logic. They extend the mixed lambda-calculus and combinatory logic with a new combinator, Psi, and show that this suffices for the mixed lambda...

  4. Libraries serving dialogue

    CERN Document Server

    Dupont, Odile

    2014-01-01

    This book based on experiences of libraries serving interreligious dialogue, presents themes like library tools serving dialogue between cultures, collections dialoguing, children and young adults dialoguing beyond borders, story telling as dialog, librarians serving interreligious dialogue.

  5. Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.

    Directory of Open Access Journals (Sweden)

    Fouad Brahimi

    Full Text Available A library of peptidomimetics was assembled combinatorially into dimers on a triazine-based core. The pharmacophore corresponds to β-turns of the neurotrophin polypeptides neurotrophin-3 (NT-3, nerve growth factor (NGF, or brain-derived neurotrophic factor (BDNF. These are the natural ligands for TrkC, TrkA, and TrkB receptors, respectively. The linker length and the side-chain orientation of each monomer within the bivalent mimics were systematically altered, and the impact of these changes on the function of each ligand was evaluated. While the monovalent peptidomimetics had no detectable binding or bioactivity, four bivalent peptidomimetics (2c, 2d, 2e, 3f are selective TrkC ligands with antagonistic activity, and two bivalent peptidomimetics (1a, 1b are TrkC and TrkA ligands with antagonistic activity. All these bivalent compounds block ligand-dependent receptor activation and cell survival, without affecting neuritogenic differentiation. This work adds to our understanding of how the neurotrophins function through Trk receptors, and demonstrates that peptidomimetics can be designed to selectively disturb specific biological signals, and may be used as pharmacological probes or as therapeutic leads. The concept of altering side-chain, linker length, and sequence orientation of a subunit within a pharmacophore provides an easy modular approach to generate larger libraries with diversified bioactivity.

  6. Quantum synthetic aperture radar

    Science.gov (United States)

    Lanzagorta, Marco; Jitrik, Oliverio; Uhlmann, Jeffrey; Venegas-Andraca, Salvador E.

    2017-05-01

    Synthetic aperture radar (SAR) uses sensor motion to generate finer spatial resolution of a given target area. In this paper we explore the theoretical potential of quantum synthetic aperture quantum radar (QSAR). We provide theoretical analysis and simulation results which suggest that QSAR can provide improved detection performance over classical SAR in the high-noise low-brightness regime.

  7. Designing synthetic biology.

    Science.gov (United States)

    Agapakis, Christina M

    2014-03-21

    Synthetic biology is frequently defined as the application of engineering design principles to biology. Such principles are intended to streamline the practice of biological engineering, to shorten the time required to design, build, and test synthetic gene networks. This streamlining of iterative design cycles can facilitate the future construction of biological systems for a range of applications in the production of fuels, foods, materials, and medicines. The promise of these potential applications as well as the emphasis on design has prompted critical reflection on synthetic biology from design theorists and practicing designers from many fields, who can bring valuable perspectives to the discipline. While interdisciplinary connections between biologists and engineers have built synthetic biology via the science and the technology of biology, interdisciplinary collaboration with artists, designers, and social theorists can provide insight on the connections between technology and society. Such collaborations can open up new avenues and new principles for research and design, as well as shed new light on the challenging context-dependence-both biological and social-that face living technologies at many scales. This review is inspired by the session titled "Design and Synthetic Biology: Connecting People and Technology" at Synthetic Biology 6.0 and covers a range of literature on design practice in synthetic biology and beyond. Critical engagement with how design is used to shape the discipline opens up new possibilities for how we might design the future of synthetic biology.

  8. FENDL multigroup libraries

    International Nuclear Information System (INIS)

    Ganesan, S.; Muir, D.W.

    1992-01-01

    Selected neutron reaction nuclear data libraries and photon-atomic interaction cross section libraries for elements of interest to the IAEA's program on Fusion Evaluated Nuclear Data Library (FENDL) have been processed into MATXSR format using the NJOY system on the VAX4000 computer of the IAEA. This document lists the resulting multigroup data libraries. All the multigroup data generated are available cost-free upon request from the IAEA Nuclear Data Section. (author). 9 refs

  9. Combinatorial metabolic engineering of Pseudomonas putida KT2440 for efficient mineralization of 1,2,3-trichloropropane.

    Science.gov (United States)

    Gong, Ting; Xu, Xiaoqing; Che, You; Liu, Ruihua; Gao, Weixia; Zhao, Fengjie; Yu, Huilei; Liang, Jingnan; Xu, Ping; Song, Cunjiang; Yang, Chao

    2017-08-01

    An industrial waste, 1,2,3-trichloropropane (TCP), is toxic and extremely recalcitrant to biodegradation. To date, no natural TCP degraders able to mineralize TCP aerobically have been isolated. In this work, we engineered a biosafety Pseudomonas putida strain KT2440 for aerobic mineralization of TCP by implantation of a synthetic biodegradation pathway into the chromosome and further improved TCP mineralization using combinatorial engineering strategies. Initially, a synthetic pathway composed of haloalkane dehalogenase, haloalcohol dehalogenase and epoxide hydrolase was functionally assembled for the conversion of TCP into glycerol in P. putida KT2440. Then, the growth lag-phase of using glycerol as a growth precursor was eliminated by deleting the glpR gene, significantly enhancing the flux of carbon through the pathway. Subsequently, we improved the oxygen sequestering capacity of this strain through the heterologous expression of Vitreoscilla hemoglobin, which makes this strain able to mineralize TCP under oxygen-limited conditions. Lastly, we further improved intracellular energy charge (ATP/ADP ratio) and reducing power (NADPH/NADP + ratio) by deleting flagella-related genes in the genome of P. putida KT2440. The resulting strain (named KTU-TGVF) could efficiently utilize TCP as the sole source of carbon for growth. Degradation studies in a bioreactor highlight the value of this engineered strain for TCP bioremediation.

  10. Merchandising Your Library.

    Science.gov (United States)

    Sivulich, Kenneth G.

    1989-01-01

    Discusses library circulation figures as a reflection of the success of library services and describes merchandising techniques that have produced a 137 percent circulation increase at Queens Borough Public Library over the past seven years. Merchandising techniques such as minibranches, displays, signage, dumps, and modified shelving are…

  11. Virtual Libraries: Service Realities.

    Science.gov (United States)

    Novak, Jan

    2002-01-01

    Discussion of changes in society that have resulted from information and communication technologies focuses on changes in libraries and a new market for library services with new styles of clients. Highlights client service issues to be considered when transitioning to a virtual library situation. (Author/LRW)

  12. California Library Laws, 2009

    Science.gov (United States)

    Smith, Paul G., Ed.

    2009-01-01

    California Library Laws 2009 is a selective guide to state laws and related materials that most directly affect the everyday operations of public libraries and organizations that work with public libraries. It is intended as a convenient reference, not as a replacement for the annotated codes or for legal advice. The guide is organized as follows.…

  13. School Libraries and Innovation

    Science.gov (United States)

    McGrath, Kevin G.

    2015-01-01

    School library programs have measured success by improved test scores. But how do next-generation school libraries demonstrate success as they strive to be centers of innovation and creativity? These libraries offer solutions for school leaders who struggle to restructure existing systems built around traditional silos of learning (subjects and…

  14. Marketing Academic Libraries

    Science.gov (United States)

    Mallon, Melissa, Ed.

    2013-01-01

    Ask any academic librarian if marketing their library and its services is an important task, and the answer will most likely be a resounding "yes!" Particularly in economically troubled times, librarians are increasingly called upon to promote their services and defend their library's worth. Since few academic libraries have in-house marketing…

  15. Joint-Use Libraries

    Science.gov (United States)

    Casstevens, Susan

    2017-01-01

    The joint-use library is a place where people of all ages, interests, and income levels can find items of interest at no personal cost. The mission of A. H. Meadows Public and High School Library in Midlothian, Texas, is to offer what other public libraries provide: educational and entertainment resources to a community. Yet, the staff also wants…

  16. Nigerian School Library Journal

    African Journals Online (AJOL)

    The Nigerian School Library Journal is a scholarly publication of the Nigerian School Library Association that focuses on issues relating to school library media centers' establishment, administration, organization, media resources management, reading development, e-learning/m-learning, and other related topics of ...

  17. Automation in College Libraries.

    Science.gov (United States)

    Werking, Richard Hume

    1991-01-01

    Reports the results of a survey of the "Bowdoin List" group of liberal arts colleges. The survey obtained information about (1) automation modules in place and when they had been installed; (2) financing of automation and its impacts on the library budgets; and (3) library director's views on library automation and the nature of the…

  18. The Library Morphs

    Science.gov (United States)

    Waters, John K.

    2008-01-01

    As campus renovation projects go, the Ohio State University's plan to turn its main library into "a library for the 21st century" is ambitious. The author describes the decade-long, $109 million transformation of the William Oxley Thompson Memorial Library. The overhaul calls for a complete replacement of all mechanical and electrical…

  19. School Libraries in Fiji.

    Science.gov (United States)

    Singh, Harry

    1995-01-01

    Presents a 50-year history of school library development and national educational programs in Fiji and discusses the future of Fiji's elementary and secondary school libraries. Examines obstacles to school library development including government ignorance, lack of trained librarians, changes in school curriculum, lack of financing, and high costs…

  20. Learning Boost C++ libraries

    CERN Document Server

    Mukherjee, Arindam

    2015-01-01

    If you are a C++ programmer who has never used Boost libraries before, this book will get you up-to-speed with using them. Whether you are developing new C++ software or maintaining existing code written using Boost libraries, this hands-on introduction will help you decide on the right library and techniques to solve your practical programming problems.

  1. FY 2009 Public Libraries Survey

    Data.gov (United States)

    Institute of Museum and Library Services — Dig into FY 2009 data on public library systems (referred to as administrative entities in the Public Libraries Survey) and main libraries, branches, and bookmobiles...

  2. FY 2008 Public Libraries Survey

    Data.gov (United States)

    Institute of Museum and Library Services — Dig into FY 2008 data on public library systems (referred to as administrative entities in the Public Libraries Survey) and main libraries, branches, and bookmobiles...

  3. FY 2011 Public Libraries Survey

    Data.gov (United States)

    Institute of Museum and Library Services — Dig into FY 2011 data on public library systems (referred to as administrative entities in the Public Libraries Survey) and main libraries, branches, and bookmobiles...

  4. FY 2010 Public Libraries Survey

    Data.gov (United States)

    Institute of Museum and Library Services — Dig into FY 2010 data on public library systems (referred to as administrative entities in the Public Libraries Survey) and main libraries, branches, and bookmobiles...

  5. German Librarianship and Munich Libraries

    Directory of Open Access Journals (Sweden)

    Osman Ümit Özen

    1994-06-01

    Full Text Available There are 27 municipal libraries including the Central Public Library in Munich. The other important libraries in the city are Bayern State National Library, Maximillian University Library, a technical highschool library and the "Deutsches Musuem" Library. All these libraries are financed locally. The author introduces these libraries briefly and compares German libraries with Turkish libraries. He concludes that although theoretically there are not distinctive differences, in practice, buildings and their layout are better in Germany where more variety of services are offered. In Turkey standardization has not been realized yet. Turkey needs to computerize and network to improve the services offered in an efficient way.

  6. Library/vendor relationships

    CERN Document Server

    Brooks, Sam

    2014-01-01

    A view of the mutual dependence between libraries and vendorsAs technology advances, libraries are forced to reach beyond their own resources to find effective ways to maintain accuracy and superior service levels. Vendors provide databases and integrated library systems that perform those functions for profit. Library/Vendor Relationships examines the increasing cooperation in which libraries find they must participate in, and vice versa, with the vendors that provide system infrastructure and software. Expert contributors provide insights from all sides of this unique collaboration, offering

  7. Combinatorial approach to Mathieu and Lamé equations

    Energy Technology Data Exchange (ETDEWEB)

    He, Wei, E-mail: weihephys@gmail.com [Center of Mathematical Sciences, Zhejiang University, Hangzhou 310027, China and Instituto de Física Teórica, Universidade Estadual Paulista, Barra Funda 01140-070, São Paulo, SP (Brazil)

    2015-07-15

    Based on some recent progress on a relation between four dimensional super Yang-Mills gauge theory and quantum integrable system, we study the asymptotic spectrum of the quantum mechanical problems described by the Mathieu equation and the Lamé equation. The large momentum asymptotic expansion of the eigenvalue is related to the instanton partition function of supersymmetric gauge theories which can be evaluated by a combinatorial method. The electro-magnetic duality of gauge theory indicates that in the parameter space, there are three asymptotic expansions for the eigenvalue, and we confirm this fact by performing the Wentzel–Kramers–Brillouin (WKB) analysis in each asymptotic expansion region. The results presented here give some new perspective on the Floquet theory about periodic differential equation.

  8. Combinatorial approach to Mathieu and Lamé equations

    Science.gov (United States)

    He, Wei

    2015-07-01

    Based on some recent progress on a relation between four dimensional super Yang-Mills gauge theory and quantum integrable system, we study the asymptotic spectrum of the quantum mechanical problems described by the Mathieu equation and the Lamé equation. The large momentum asymptotic expansion of the eigenvalue is related to the instanton partition function of supersymmetric gauge theories which can be evaluated by a combinatorial method. The electro-magnetic duality of gauge theory indicates that in the parameter space, there are three asymptotic expansions for the eigenvalue, and we confirm this fact by performing the Wentzel-Kramers-Brillouin (WKB) analysis in each asymptotic expansion region. The results presented here give some new perspective on the Floquet theory about periodic differential equation.

  9. Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities

    DEFF Research Database (Denmark)

    Radic-Sarikas, Branka; Tsafou, Kalliopi P; Emdal, Kristina B.

    2017-01-01

    Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any...... associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three pediatric tumor types, we identified Ewing sarcoma-specific interactions of a diverse set of targeted agents...... including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong...

  10. Topological transition in disordered planar matching: combinatorial arcs expansion

    Science.gov (United States)

    Lokhov, Andrey Y.; Valba, Olga V.; Nechaev, Sergei K.; Tamm, Mikhail V.

    2014-12-01

    In this paper, we investigate analytically the properties of the disordered Bernoulli model of planar matching. This model is characterized by a topological phase transition, yielding complete planar matching solutions only above a critical density threshold. We develop a combinatorial procedure of arcs expansion that explicitly takes into account the contribution of short arcs and allows us to obtain an accurate analytical estimation of the critical value by reducing the global constrained problem to a set of local ones. As an application to a toy representation of the RNA secondary structures, we suggest generalized models that incorporate a one-to-one correspondence between the contact matrix and the RNA-type sequence, thus giving sense to the notion of effective non-integer alphabets.

  11. Combinatorial strategies for the induction of immunogenic cell death

    Directory of Open Access Journals (Sweden)

    Lorenzo eGalluzzi

    2015-04-01

    Full Text Available The term immunogenic cell death (ICD is commonly employed to indicate a peculiar instance of regulated cell death (RCD that engages the adaptive arm of the immune system. The inoculation of cancer cells undergoing ICD into immunocompetent animals elicits a specific immune response associated with the establishment of immunological memory. Only a few agents are intrinsically endowed with the ability to trigger ICD. These include a few chemotherapeutics that are routinely employed in the clinic, like doxorubicin, mitoxantrone, oxaliplatin and cyclophosphamide, as well as some agents that have not yet been approved for use in humans. Accumulating clinical data indicate that the activation of adaptive immune responses against dying cancer cells is associated with improved disease outcome in patients affected by various neoplasms. Thus, novel therapeutic regimens that trigger ICD are urgently awaited. Here, we discuss current combinatorial approaches to convert otherwise non-immunogenic instances of RCD into bona fide ICD.

  12. A Robust Parallel Algorithm for Combinatorial Compressed Sensing

    Science.gov (United States)

    Mendoza-Smith, Rodrigo; Tanner, Jared W.; Wechsung, Florian

    2018-04-01

    In previous work two of the authors have shown that a vector $x \\in \\mathbb{R}^n$ with at most $k Parallel-$\\ell_0$ decoding algorithm, where $\\mathrm{nnz}(A)$ denotes the number of nonzero entries in $A \\in \\mathbb{R}^{m \\times n}$. In this paper we present the Robust-$\\ell_0$ decoding algorithm, which robustifies Parallel-$\\ell_0$ when the sketch $Ax$ is corrupted by additive noise. This robustness is achieved by approximating the asymptotic posterior distribution of values in the sketch given its corrupted measurements. We provide analytic expressions that approximate these posteriors under the assumptions that the nonzero entries in the signal and the noise are drawn from continuous distributions. Numerical experiments presented show that Robust-$\\ell_0$ is superior to existing greedy and combinatorial compressed sensing algorithms in the presence of small to moderate signal-to-noise ratios in the setting of Gaussian signals and Gaussian additive noise.

  13. Combinatorial Method for Overexpression of Membrane Proteins in Escherichia coli*

    Science.gov (United States)

    Leviatan, Shani; Sawada, Keisuke; Moriyama, Yoshinori; Nelson, Nathan

    2010-01-01

    Membrane proteins constitute 20–30% of all proteins encoded by the genome of various organisms. Large amounts of purified proteins are required for activity and crystallization attempts. Thus, there is an unmet need for a heterologous membrane protein overexpression system for purification, crystallization, and activity determination. We developed a combinatorial method for overexpressing and purifying membrane proteins using Escherichia coli. This method utilizes short hydrophilic bacterial proteins, YaiN and YbeL, fused to the ends of the membrane proteins to serve as facilitating factors for expression and purification. Fourteen prokaryotic and mammalian membrane proteins were expressed using this system. Moderate to high expression was obtained for most proteins, and detergent solubilization combined with a short purification process produced stable, monodispersed membrane proteins. Five of the mammalian membrane proteins, overexpressed using our system, were reconstituted into liposomes and exhibited transport activity comparable with the native transporters. PMID:20525689

  14. Combinatorial method for overexpression of membrane proteins in Escherichia coli.

    Science.gov (United States)

    Leviatan, Shani; Sawada, Keisuke; Moriyama, Yoshinori; Nelson, Nathan

    2010-07-30

    Membrane proteins constitute 20-30% of all proteins encoded by the genome of various organisms. Large amounts of purified proteins are required for activity and crystallization attempts. Thus, there is an unmet need for a heterologous membrane protein overexpression system for purification, crystallization, and activity determination. We developed a combinatorial method for overexpressing and purifying membrane proteins using Escherichia coli. This method utilizes short hydrophilic bacterial proteins, YaiN and YbeL, fused to the ends of the membrane proteins to serve as facilitating factors for expression and purification. Fourteen prokaryotic and mammalian membrane proteins were expressed using this system. Moderate to high expression was obtained for most proteins, and detergent solubilization combined with a short purification process produced stable, monodispersed membrane proteins. Five of the mammalian membrane proteins, overexpressed using our system, were reconstituted into liposomes and exhibited transport activity comparable with the native transporters.

  15. Combinatorial polymer electrospun matrices promote physiologically-relevant cardiomyogenic stem cell differentiation.

    Directory of Open Access Journals (Sweden)

    Mukesh K Gupta

    Full Text Available Myocardial infarction results in extensive cardiomyocyte death which can lead to fatal arrhythmias or congestive heart failure. Delivery of stem cells to repopulate damaged cardiac tissue may be an attractive and innovative solution for repairing the damaged heart. Instructive polymer scaffolds with a wide range of properties have been used extensively to direct the differentiation of stem cells. In this study, we have optimized the chemical and mechanical properties of an electrospun polymer mesh for directed differentiation of embryonic stem cells (ESCs towards a cardiomyogenic lineage. A combinatorial polymer library was prepared by copolymerizing three distinct subunits at varying molar ratios to tune the physicochemical properties of the resulting polymer: hydrophilic polyethylene glycol (PEG, hydrophobic poly(ε-caprolactone (PCL, and negatively-charged, carboxylated PCL (CPCL. Murine ESCs were cultured on electrospun polymeric scaffolds and their differentiation to cardiomyocytes was assessed through measurements of viability, intracellular reactive oxygen species (ROS, α-myosin heavy chain expression (α-MHC, and intracellular Ca(2+ signaling dynamics. Interestingly, ESCs on the most compliant substrate, 4%PEG-86%PCL-10%CPCL, exhibited the highest α-MHC expression as well as the most mature Ca(2+ signaling dynamics. To investigate the role of scaffold modulus in ESC differentiation, the scaffold fiber density was reduced by altering the electrospinning parameters. The reduced modulus was found to enhance α-MHC gene expression, and promote maturation of myocyte Ca(2+ handling. These data indicate that ESC-derived cardiomyocyte differentiation and maturation can be promoted by tuning the mechanical and chemical properties of polymer scaffold via copolymerization and electrospinning techniques.

  16. Combinatorial transcriptional control of the lactose operon of Escherichia coli.

    Science.gov (United States)

    Kuhlman, Thomas; Zhang, Zhongge; Saier, Milton H; Hwa, Terence

    2007-04-03

    The goal of systems biology is to understand the behavior of the whole in terms of knowledge of the parts. This is hard to achieve in many cases due to the difficulty of characterizing the many constituents involved in a biological system and their complex web of interactions. The lac promoter of Escherichia coli offers the possibility of confronting "system-level" properties of transcriptional regulation with the known biochemistry of the molecular constituents and their mutual interactions. Such confrontations can reveal previously unknown constituents and interactions, as well as offer insight into how the components work together as a whole. Here we study the combinatorial control of the lac promoter by the regulators Lac repressor (LacR) and cAMP-receptor protein (CRP). A previous in vivo study [Setty Y, Mayo AE, Surette MG, Alon U (2003) Proc Natl Acad Sci USA 100:7702-7707] found gross disagreement between the observed promoter activities and the expected behavior based on the known molecular mechanisms. We repeated the study by identifying and removing several extraneous factors that significantly modulated the expression of the lac promoter. Through quantitative, systematic characterization of promoter activity for a number of key mutants and guided by the thermodynamic model of transcriptional regulation, we were able to account for the combinatorial control of the lac promoter quantitatively, in terms of a cooperative interaction between CRP and LacR-mediated DNA looping. Specifically, our analysis indicates that the sensitivity of the inducer response results from LacR-mediated DNA looping, which is significantly enhanced by CRP.

  17. Combinatorial and geometric aspects of Feynman graphs and Feynman integrals

    International Nuclear Information System (INIS)

    Bergbauer, Christoph

    2009-01-01

    The integrals associated to Feynman graphs must have been a source of frustration for particle physicists ever since. Indeed there is a delicate difference between being able to draw a Feynman graph and being able to compute the associated Feynman integral. Although perturbation theory has brought enormous breakthroughs, many physicists turned to more abstract developments in quantum field theory, looked for other ways to produce perturbational results, or left the field entirely. Nonetheless there is a significant number of physicists, computational and theoretical, who pursue the quest for concepts and algorithms to compute and understand those integrals to higher and higher orders. Their motivation is to help test the validity of the underlying physical theory. For a mathematician, Feynman graphs and their integrals provide a rich subject in their own right, independent of their computability. It was only recently though that the work of Bloch, Esnault and Kreimer has brought a growing interest of mathematicians from various disciplines to the subject. In fact it opened up a completely new direction of research: a motivic interpretation of Feynman graphs that unites their combinatorial, geometric and arithmetic aspects. This idea had been in the air for a while, based on computational results of Broadhurst and Kreimer, and on a theorem of Belkale and Brosnan related to a conjecture of Kontsevich about the generality of the underlying motives. A prerequisite for the motivic approach is a profound understanding of renormalization that was established less recently in a modern language by Connes and Kreimer. This dissertation studies the renormalization of Feynman graphs in position space using an adapted resolution of singularities, and makes two other contributions of mostly combinatorial nature to the subject. I hope this may serve as a reference for somebody who feels comfortable with the traditional position space literature and looks for a transition to the

  18. Library system of Italy

    Directory of Open Access Journals (Sweden)

    Nataša Gerbec

    2003-01-01

    Full Text Available In the European extent, Italy is the cradle of libraries and library sciences. In the past, Italian national public libraries played an important role through their vast book treasury. But only during the last thirty years have public libraries been developed following the Anglo-American public library model. Italy does not have any uniform or general legislation concerning libraries. On the state level, this area is regulated by some separate acts, while on the regional level there is a collection of various acts and regulations. Libraries are not strictly divided into general categories. It is required that the professionals engaged in Italian libraries should have secondary or university education. The level of their professional tasks depends on the type of library and its capacity. The competency for the development in the field of librarianship is assigned to The Ministry of Cultural and Environment Heritage as well as to its subordinate institutions (Central Institute for the Union catalogue of Italian Libraries and for Bibliographic Information, Central Institute for Book Pathology, Observatory for International Libraries Programmes.

  19. The participatory public library

    DEFF Research Database (Denmark)

    Rasmussen, Casper Hvenegaard

    2016-01-01

    Purpose From collection to connection has been a buzzword in the library world for more than a decade. This catchy phrase indicates that users are seen not only as borrowers, but as active participants. The aim of this paper is to investigate and analyse three questions in relation to user...... participation in public libraries in a Nordic perspective. How can participation in public libraries be characterised? Why should libraries deal with user participation? What kinds of different user participation can be identified in public libraries? Design/methodology/approach The paper uses a selection...... of theoretical approaches and practical examples to obtain a varied understanding of user participation in public libraries. Research fields outside library and information science have developed a wide range of theoretical approaches on user participation. Examples from cultural policy, museum studies...

  20. Combinatorial incorporation of fluoride and cobalt ions into calcium phosphates to stimulate osteogenesis and angiogenesis.

    Science.gov (United States)

    Birgani, Zeinab Tahmasebi; Gharraee, Nazli; Malhotra, Angad; van Blitterswijk, Clemens A; Habibovic, Pamela

    2016-02-29

    Bone healing requires two critical mechanisms, angiogenesis and osteogenesis. In order to improve bone graft substitutes, both mechanisms should be addressed simultaneously. While the individual effects of various bioinorganics have been studied, an understanding of the combinatorial effects is lacking. Cobalt and fluoride ions, in appropriate concentrations, are known to individually favor the vascularization and mineralization processes, respectively. This study investigated the potential of using a combination of fluoride and cobalt ions to simultaneously promote osteogenesis and angiogenesis in human mesenchymal stromal cells (hMSCs). Using a two-step biomimetic method, wells of tissue culture plates were coated with a calcium phosphate (CaP) layer without or with the incorporation of cobalt, fluoride, or both. In parallel, hMSCs were cultured on uncoated well plates, and cultured with cobalt and/or fluoride ions within the media. The results revealed that cobalt ions increased the expression of angiogenic markers, with the effects being stronger when the ions were added as a dissolved salt in cell medium as compared to incorporation into CaP. Cobalt ions generally suppressed the ALP activity, the expression of osteogenic genes, and the level of mineralization, regardless of delivery method. Fluoride ions, individually or in combination with cobalt, significantly increased the expression of many of the selected osteogenic markers, as well as mineral deposition. This study demonstrates an approach to simultaneously target the two essential mechanisms in bone healing: angiogenesis and osteogenesis. The incorporation of cobalt and fluoride into CaPs is a promising method to improve the biological performance of fully synthetic bone graft substitutes.

  1. Special Libraries and Multitype Networks.

    Science.gov (United States)

    Segal, JoAn S.

    1989-01-01

    Describes the history of multitype library networks; examines the reasons why special libraries and other network participants have resisted the inclusion of special libraries in these networks; and discusses the benefits to both special libraries and to other libraries in the network that would result from special library participation. (17…

  2. Synthetic biological networks

    International Nuclear Information System (INIS)

    Archer, Eric; Süel, Gürol M

    2013-01-01

    Despite their obvious relationship and overlap, the field of physics is blessed with many insightful laws, while such laws are sadly absent in biology. Here we aim to discuss how the rise of a more recent field known as synthetic biology may allow us to more directly test hypotheses regarding the possible design principles of natural biological networks and systems. In particular, this review focuses on synthetic gene regulatory networks engineered to perform specific functions or exhibit particular dynamic behaviors. Advances in synthetic biology may set the stage to uncover the relationship of potential biological principles to those developed in physics. (review article)

  3. Synthetic Base Fluids

    Science.gov (United States)

    Brown, M.; Fotheringham, J. D.; Hoyes, T. J.; Mortier, R. M.; Orszulik, S. T.; Randles, S. J.; Stroud, P. M.

    The chemical nature and technology of the main synthetic lubricant base fluids is described, covering polyalphaolefins, alkylated aromatics, gas-to-liquid (GTL) base fluids, polybutenes, aliphatic diesters, polyolesters, polyalkylene glycols or PAGs and phosphate esters.Other synthetic lubricant base oils such as the silicones, borate esters, perfluoroethers and polyphenylene ethers are considered to have restricted applications due to either high cost or performance limitations and are not considered here.Each of the main synthetic base fluids is described for their chemical and physical properties, manufacture and production, their chemistry, key properties, applications and their implications when used in the environment.

  4. Flight Software Math Library

    Science.gov (United States)

    McComas, David

    2013-01-01

    The flight software (FSW) math library is a collection of reusable math components that provides typical math utilities required by spacecraft flight software. These utilities are intended to increase flight software quality reusability and maintainability by providing a set of consistent, well-documented, and tested math utilities. This library only has dependencies on ANSI C, so it is easily ported. Prior to this library, each mission typically created its own math utilities using ideas/code from previous missions. Part of the reason for this is that math libraries can be written with different strategies in areas like error handling, parameters orders, naming conventions, etc. Changing the utilities for each mission introduces risks and costs. The obvious risks and costs are that the utilities must be coded and revalidated. The hidden risks and costs arise in miscommunication between engineers. These utilities must be understood by both the flight software engineers and other subsystem engineers (primarily guidance navigation and control). The FSW math library is part of a larger goal to produce a library of reusable Guidance Navigation and Control (GN&C) FSW components. A GN&C FSW library cannot be created unless a standardized math basis is created. This library solves the standardization problem by defining a common feature set and establishing policies for the library s design. This allows the libraries to be maintained with the same strategy used in its initial development, which supports a library of reusable GN&C FSW components. The FSW math library is written for an embedded software environment in C. This places restrictions on the language features that can be used by the library. Another advantage of the FSW math library is that it can be used in the FSW as well as other environments like the GN&C analyst s simulators. This helps communication between the teams because they can use the same utilities with the same feature set and syntax.

  5. Libraries and Accessibility: Istanbul Public Libraries Case

    OpenAIRE

    Yücel, Gül

    2016-01-01

    In the study; the assessment of accessibility has been conducted in Istanbul public libraries within the scope of public area. Public libraries commonly serve with its user of more than 20 million in total, spread to the general of Turkey, having more than one thousand branches in the centrums and having more than one million registered members. The building principles and standards covering the subjects such as the selection of place, historical and architectural specification of the region,...

  6. Synthetic Biological Membrane (SBM)

    Data.gov (United States)

    National Aeronautics and Space Administration — The ultimate goal of the Synthetic Biological Membrane project is to develop a new type of membrane that will enable the wastewater treatment system required on...

  7. Assessing Library Automation and Virtual Library Development in Four Academic Libraries in Oyo, Oyo State, Nigeria

    Science.gov (United States)

    Gbadamosi, Belau Olatunde

    2011-01-01

    The paper examines the level of library automation and virtual library development in four academic libraries. A validated questionnaire was used to capture the responses from academic librarians of the libraries under study. The paper discovers that none of the four academic libraries is fully automated. The libraries make use of librarians with…

  8. Wikis in Libraries

    Directory of Open Access Journals (Sweden)

    Matthew Bejune

    2007-09-01

    Full Text Available Wikis have recently been adopted to support a variety of collaborative activities within libraries. This article and its companion wiki, LibraryWikis (http://librarywikis.pbwiki.com/, seek to document the phenomenon of wikis in libraries. This subject is considered within the framework of computer-supported cooperative work (CSCW. The author identified thirty-three library wikis and developed a classification schema with four categories: (1 collaboration among libraries (45.7 percent; (2 collaboration among library staff (31.4 percent; (3 collaboration among library staff and patrons (14.3 percent; and (4 collaboration among patrons (8.6 percent. Examples of library wikis are presented within the article, as is a discussion for why wikis are primarily utilized within categories I and II and not within categories III and IV. It is clear that wikis have great utility within libraries, and the author urges further application of wikis in libraries.

  9. News from the Library

    CERN Multimedia

    CERN Library

    2010-01-01

    The LHC Library to be merged with the Central Library. Not everyone knows that CERN Scientific Information Service currently counts three physical libraries on site. The Central Library is located in Building 52 and there are two satellite libraries located respectively in building 30 (the LHC Library) and in building 864 on Prévessin site (the SPS Library). Moreover, the Legal Service Library is located in Building 60. In the past, there have been at CERN up to 6 satellite libraries; they were essential at a time when information was only in paper form and having multiple copies of documents located in several places at CERN was useful to facilitate scientific research. Today, this need is less critical as most of our resources are online. That is why, following a SIPB (Scientific Information Policy Board) decision, the collections of the LHC Library will be merged this summer with the Central collection. This reorganization and centralization of resources will improve loan services. The SP...

  10. Hybridization with synthetic oligonucleotides

    Energy Technology Data Exchange (ETDEWEB)

    Szostak, J.W.; Stiles, J.I.; Tye, B.K.; Sherman, F.; Wu, R.

    1978-01-01

    Procedures are described for the use of synthetic oligonucleotides for Southern blot experiments and gene bank screening, and the effect of various mismatches on the efficiency of hybridization is demonstrated. The following topics are discussed: sensitivity vs. specificity, hybridization of a 12-mer to the lambda endolysin gene; hybridization of oligonucleotide probes to the E. coli lac operator; hybridization of synthetic probes to the CYC1 gene of yeast; and cloning eucaryotic genes. (HLW)

  11. Mammalian Synthetic Biology

    OpenAIRE

    Martella, Andrea; Pollard, Steven M; Dai, Junbiao; Cai, Yizhi

    2016-01-01

    The enabling technologies of synthetic biology are opening up new opportunities for engineering and enhancement of mammalian cells. This will stimulate diverse applications in many life science sectors such as regenerative medicine, development of biosensing cell lines, therapeutic protein production, and generation of new synthetic genetic regulatory circuits. Harnessing the full potential of these new engineering-based approaches requires the design and assembly of large DNA constructs-pote...

  12. Construction of a human recombinant polyclonal Fab fragment antibody library using peripheral blood lymphocytes of snake bitten victims

    OpenAIRE

    Motedayen, M.H.; Nikbakht, G.; Rasaee, M.J.; Zare Mirakabadi, A.

    2015-01-01

    Human snake bitten poisoning is a serious threat in many tropical and subtropical countries such as Iran. The best acceptable treatment of envenomated humans is antivenoms; however they have a series of economic and medical problems and need more improvements. In this study a combinatorial human immunoglobulin gene library against some of Iranian snakes venoms was constructed. Total RNA prepared from peripheral blood lymphocytes of two recovered snake victims. RT-PCR was used for cDNA synthes...

  13. Human mammary progenitor cell fate decisions are productsof interactions with combinatorial microenvironments

    DEFF Research Database (Denmark)

    LaBarge, Mark A.; Nelson, Celeste M.; Villadsen, René

    2009-01-01

    factors, ECM, and other cells, as well as physical properties of the ECM. To understand regulation of fate decisions, therefore, would require a means of understanding carefully choreographed combinatorial interactions. Here we used microenvironment protein microarrays to functionally identify...

  14. Application of combinatorial biocatalysis for a unique ring expansion of dihydroxymethylzearalenone

    Science.gov (United States)

    Combinatorial biocatalysis was applied to generate a diverse set of dihydroxymethylzearalenone derivatives with modified ring structure. In one chemoenzymatic reaction sequence, dihydroxymethylzearalenone was first subjected to a unique enzyme-catalyzed oxidative ring opening reaction that creates ...

  15. Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila

    Science.gov (United States)

    Agrawal, Namita; Pallos, Judit; Slepko, Natalia; Apostol, Barbara L.; Bodai, Laszlo; Chang, Ling-Wen; Chiang, Ann-Shyn; Michels Thompson, Leslie; Marsh, J. Lawrence

    2005-03-01

    We explore the hypothesis that pathology of Huntington's disease involves multiple cellular mechanisms whose contributions to disease are incrementally additive or synergistic. We provide evidence that the photoreceptor neuron degeneration seen in flies expressing mutant human huntingtin correlates with widespread degenerative events in the Drosophila CNS. We use a Drosophila Huntington's disease model to establish dose regimens and protocols to assess the effectiveness of drug combinations used at low threshold concentrations. These proof of principle studies identify at least two potential combinatorial treatment options and illustrate a rapid and cost-effective paradigm for testing and optimizing combinatorial drug therapies while reducing side effects for patients with neurodegenerative disease. The potential for using prescreening in Drosophila to inform combinatorial therapies that are most likely to be effective for testing in mammals is discussed. combinatorial treatments | neurodegeneration

  16. Combinatorial thin film materials science: From alloy discovery and optimization to alloy design

    International Nuclear Information System (INIS)

    Gebhardt, Thomas; Music, Denis; Takahashi, Tetsuya; Schneider, Jochen M.

    2012-01-01

    This paper provides an overview of modern alloy development, from discovery and optimization towards alloy design, based on combinatorial thin film materials science. The combinatorial approach, combining combinatorial materials synthesis of thin film composition-spreads with high-throughput property characterization has proven to be a powerful tool to delineate composition–structure–property relationships, and hence to efficiently identify composition windows with enhanced properties. Furthermore, and most importantly for alloy design, theoretical models and hypotheses can be critically appraised. Examples for alloy discovery, optimization, and alloy design of functional as well as structural materials are presented. Using Fe-Mn based alloys as an example, we show that the combination of modern electronic-structure calculations with the highly efficient combinatorial thin film composition-spread method constitutes an effective tool for knowledge-based alloy design.

  17. Solidified self-nanoemulsifying formulation for oral delivery of combinatorial therapeutic regimen

    DEFF Research Database (Denmark)

    Jain, Amit K; Thanki, Kaushik; Jain, Sanyog

    2014-01-01

    PURPOSE: The present work reports rationalized development and characterization of solidified self-nanoemulsifying drug delivery system for oral delivery of combinatorial (tamoxifen and quercetin) therapeutic regimen. METHODS: Suitable oil for the preparation of liquid SNEDDS was selected based o...

  18. INdAM conference "CoMeTA 2013 - Combinatorial Methods in Topology and Algebra"

    CERN Document Server

    Delucchi, Emanuele; Moci, Luca

    2015-01-01

    Combinatorics plays a prominent role in contemporary mathematics, due to the vibrant development it has experienced in the last two decades and its many interactions with other subjects. This book arises from the INdAM conference "CoMeTA 2013 - Combinatorial Methods in Topology and Algebra,'' which was held in Cortona in September 2013. The event brought together emerging and leading researchers at the crossroads of Combinatorics, Topology and Algebra, with a particular focus on new trends in subjects such as: hyperplane arrangements; discrete geometry and combinatorial topology; polytope theory and triangulations of manifolds; combinatorial algebraic geometry and commutative algebra; algebraic combinatorics; and combinatorial representation theory. The book is divided into two parts. The first expands on the topics discussed at the conference by providing additional background and explanations, while the second presents original contributions on new trends in the topics addressed by the conference.

  19. Combinatorial Method/High Throughput Strategies for Hydrogel Optimization in Tissue Engineering Applications

    Directory of Open Access Journals (Sweden)

    Laura A. Smith Callahan

    2016-06-01

    Full Text Available Combinatorial method/high throughput strategies, which have long been used in the pharmaceutical industry, have recently been applied to hydrogel optimization for tissue engineering applications. Although many combinatorial methods have been developed, few are suitable for use in tissue engineering hydrogel optimization. Currently, only three approaches (design of experiment, arrays and continuous gradients have been utilized. This review highlights recent work with each approach. The benefits and disadvantages of design of experiment, array and continuous gradient approaches depending on study objectives and the general advantages of using combinatorial methods for hydrogel optimization over traditional optimization strategies will be discussed. Fabrication considerations for combinatorial method/high throughput samples will additionally be addressed to provide an assessment of the current state of the field, and potential future contributions to expedited material optimization and design.

  20. Perspectives on synthetic promoters for biocatalysis and biotransformation.

    Science.gov (United States)

    Ruth, Claudia; Glieder, Anton

    2010-04-12

    Acting on the transcriptional level, synthetic promoters have been useful tools for controlling gene expression and have applications in many fields. Here, we discuss synthetic promoters and libraries in regard to current and future applications in the field of biocatalysis or biotransformation. We also focus on synthetic promoter design principles and distinguish between prokaryotic and eukaryotic destinations. The natural toolboxes available for tuneable gene expression and the regulation of enzyme function are limited and primarily host specific. Synthetic biology offers generally applicable concepts and quick implementation. Smart alternatives to transcriptional regulation enrich the engineer's tool box for optimizing industrial enzyme production and host-cell physiology for whole-cell processes. Industrially applicable, tuneable enzyme cascades and artificial circuits for iterative up- and down-regulation will soon be achieved.

  1. The CERN Library

    CERN Multimedia

    Hester, Alec G

    1968-01-01

    Any advanced research centre needs a good Library. It can be regarded as a piece of equipment as vital as any machine. At the present time, the CERN Library is undergoing a number of modifications to adjust it to the changing scale of CERN's activities and to the ever increasing flood of information. This article, by A.G. Hester, former Editor of CERN COURIER who now works in the Scientific Information Service, describes the purposes, methods and future of the CERN Library.

  2. Fragment library design: using cheminformatics and expert chemists to fill gaps in existing fragment libraries.

    Science.gov (United States)

    Kutchukian, Peter S; So, Sung-Sau; Fischer, Christian; Waller, Chris L

    2015-01-01

    Fragment based screening (FBS) has emerged as a mainstream lead discovery strategy in academia, biotechnology start-ups, and large pharma. As a prerequisite of FBS, a structurally diverse library of fragments is desirable in order to identify chemical matter that will interact with the range of diverse target classes that are prosecuted in contemporary screening campaigns. In addition, it is also desirable to offer synthetically amenable starting points to increase the probability of a successful fragment evolution through medicinal chemistry. Herein we describe a method to identify biologically relevant chemical substructures that are missing from an existing fragment library (chemical gaps), and organize these chemical gaps hierarchically so that medicinal chemists can efficiently navigate the prioritized chemical space and subsequently select purchasable fragments for inclusion in an enhanced fragment library.

  3. Combinatorial solid-phase synthesis of hapalosin mimetics

    DEFF Research Database (Denmark)

    Olsen, Jacob A.; Jensen, Knud J.; Nielsen, John

    2000-01-01

    The solid-phase synthesis of a small library of mimetics of the cyclic depsipeptide hapalosin is described. 3-Amino-4-hydroxy-5-nitrobenzoic acid was anchored through the anilino moiety to a backbone amide linker (BAL) handle support. Using chemoselective reactions and without the need for protec......The solid-phase synthesis of a small library of mimetics of the cyclic depsipeptide hapalosin is described. 3-Amino-4-hydroxy-5-nitrobenzoic acid was anchored through the anilino moiety to a backbone amide linker (BAL) handle support. Using chemoselective reactions and without the need...

  4. High-throughput characterization of film thickness in thin film materials libraries by digital holographic microscopy

    Directory of Open Access Journals (Sweden)

    Yiu Wai Lai, Michael Krause, Alan Savan, Sigurd Thienhaus, Nektarios Koukourakis, Martin R Hofmann and Alfred Ludwig

    2011-01-01

    Full Text Available A high-throughput characterization technique based on digital holography for mapping film thickness in thin-film materials libraries was developed. Digital holographic microscopy is used for fully automatic measurements of the thickness of patterned films with nanometer resolution. The method has several significant advantages over conventional stylus profilometry: it is contactless and fast, substrate bending is compensated, and the experimental setup is simple. Patterned films prepared by different combinatorial thin-film approaches were characterized to investigate and demonstrate this method. The results show that this technique is valuable for the quick, reliable and high-throughput determination of the film thickness distribution in combinatorial materials research. Importantly, it can also be applied to thin films that have been structured by shadow masking.

  5. Resin Capsules: Permeable Containers for Parallel/Combinatorial Solid-Phase Organic Synthesis

    OpenAIRE

    Bouillon, Isabelle; Soural, Miroslav; Krchňák, Viktor

    2008-01-01

    A resin capsule is a permeable container for resin beads designed for multiple/combinatorial solid-phase organic synthesis. Resin capsules consist of a high density polyethylene ring sealed with peek mesh on both sides. The cylindrical shape of resin capsules enabled space-saving packing into plastic column-like reaction vessels commonly used for solid-phase organic synthesis. Resin capsules have been evaluated for their use in combinatorial synthesis, and a set of model compounds with excell...

  6. Combinatorial interpretations of particular evaluations of complete and elementary symmetric functions

    OpenAIRE

    Mongelli, Pietro

    2011-01-01

    The Jacobi-Stirling numbers and the Legendre-Stirling numbers of the first and second kind were first introduced in [6], [7]. In this paper we note that Jacobi-Stirling numbers and Legendre-Stirling numbers are specializations of elementary and complete symmetric functions. We then study combinatorial interpretations of this specialization and obtain new combinatorial interpretations of the Jacobi-Stirling and Legendre-Stirling numbers.

  7. NEIC Library Services

    Science.gov (United States)

    The National Enforcement Investigation Center (NEIC) Environmental Forensic Library partners with NEIC's forensic scientists to retrieve, validate and deliver information to develop methods, defensible regulations, and environmental measurements.

  8. Libraries and licensing

    Directory of Open Access Journals (Sweden)

    Maja Žumer

    2001-01-01

    Full Text Available In the mid 90s, the abundance of various electronic publications exposed libraries to the problems of licensing electronic content. Various licensing principles have been prepared recently to help libraries in the process; it can be said that in general, the knowledge of licensing issues has improved in libraries of all types. Libraries form consortia in order to gain stronger negotiating positions and obtain better conditions.In the article, new licensing principles are presented in more detail, as well as some domestic and foreign experiences with consortia forming.

  9. Combinatorial and off-shell effects in new physics cascades

    Energy Technology Data Exchange (ETDEWEB)

    Wiesler, Daniel

    2012-12-15

    Up to now, the Standard Model of elementary particle physics is in very good agreement with most data. However, it has various shortcomings which motivate the presence of new physics at the TeV scale. The first major step following a potential discovery of new particles at the Large Hadron Collider (LHC) is the determination of their intrinsic properties, foremost masses and spins. Event topologies of new physics signals with a conserved parity motivated by precision data and the dark matter paradigm require for sophisticated measurement procedures, which have been developed in recent years. These techniques often rely on simplifying assumptions, albeit they need not necessarily be fulfilled. In this thesis we investigate the impact of combinatorial and off-shell effects on new physics cascades in three different contexts. A detailed understanding of these effects is essential for the topic of model parameter determination of new physics signatures at the LHC. First, we study the non-resonant contributions of a broad gluino on mass and spin measurements as a prime example for the importance of off-shell effects. A phenomenological scan over the gluino's width-to-mass ratio yields a severe smearing of invariant mass distributions and as a consequence thereof drastically shifted endpoint positions. Spin determinations, on the other hand, are barely affected and a model discrimination of the two prime candidates SUSY and UED is not at risk. In the second part, we assess the feasibility of the gluino dijet endpoint measurement in three fully inclusive scenarios at the LHC to investigate the impact of combinatorial and SUSY backgrounds on its precise determination. We develop a method to disentangle two major signal contributions and extract their associated edges with good accuracy. For this we use existent kinematic variables and propose new ones to overcome the former's deficiencies. The last part governs the issue of so-called 'fake combinatorics

  10. Steps towards the synthetic biology of polyketide biosynthesis

    Science.gov (United States)

    Cummings, Matthew; Breitling, Rainer; Takano, Eriko

    2014-01-01

    Nature is providing a bountiful pool of valuable secondary metabolites, many of which possess therapeutic properties. However, the discovery of new bioactive secondary metabolites is slowing down, at a time when the rise of multidrug-resistant pathogens and the realization of acute and long-term side effects of widely used drugs lead to an urgent need for new therapeutic agents. Approaches such as synthetic biology are promising to deliver a much-needed boost to secondary metabolite drug development through plug-and-play optimized hosts and refactoring novel or cryptic bacterial gene clusters. Here, we discuss this prospect focusing on one comprehensively studied class of clinically relevant bioactive molecules, the polyketides. Extensive efforts towards optimization and derivatization of compounds via combinatorial biosynthesis and classical engineering have elucidated the modularity, flexibility and promiscuity of polyketide biosynthetic enzymes. Hence, a synthetic biology approach can build upon a solid basis of guidelines and principles, while providing a new perspective towards the discovery and generation of novel and new-to-nature compounds. We discuss the lessons learned from the classical engineering of polyketide synthases and indicate their importance when attempting to engineer biosynthetic pathways using synthetic biology approaches for the introduction of novelty and overexpression of products in a controllable manner. PMID:24372666

  11. Synthetic Biology Open Language (SBOL) Version 2.2.0

    KAUST Repository

    Cox, Robert Sidney

    2018-04-04

    Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems would be to improve the exchange of information about designed systems between laboratories. The synthetic biology open language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.2.0 of SBOL that builds upon version 2.1.0 published in last year\\'s JIB special issue. In particular, SBOL 2.2.0 includes improved description and validation rules for genetic design provenance, an extension to support combinatorial genetic designs, a new class to add non-SBOL data as attachments, a new class for genetic design implementations, and a description of a methodology to describe the entire design-build-test-learn cycle within the SBOL data model.

  12. New Library Buildings and Library Reconstructions

    Directory of Open Access Journals (Sweden)

    Steen Bille Larsen

    2002-07-01

    Full Text Available Visits to libraries have always been an important part of the LIBER Architecture Group Seminars, as they add practice, concrete examples of success and mistakes to the theory of the seminar presentations. The programme of the Leipzig seminar thus offered quite a few library visits: Universitätsbibliothek Leipzig, Thüringer Universitäts- und Landesbibliothek, Jena, Universitäts- und Forschungsbibliothek Erfurt, Herzogin-Anna-Amalia-Bibliothek, Weimar, Universitätsbibliothek der Bauhaus-Universität Weimar, Deutsche Bücherei, Leipzig and Sächsische Landesbibliothek – Staatsund Universitätsbibliothek, Dresden. The following is a short report about the libraries visited during the week. The reports are combined with quotations from the libraries’ presentation of their building projects and in some cases also with facts and figures.

  13. Trajectory and Population Metaheuristics applied to Combinatorial Optimization Problems

    Directory of Open Access Journals (Sweden)

    Natalia Alancay

    2016-04-01

    Full Text Available In the world there are a multitude of everyday problems that require a solution that meets a set of requirements in the most appropriate way maximizing or minimizing a certain value. However, finding an optimal solution for certain optimization problems can be an incredibly difficult or an impossible task. This is because when a problem becomes large enough, we have to look through a huge number of possible solutions, the most efficient solution, that is, the one that has the lower cost. The ways to treat feasible solutions for their practical application are varied. One of the strategy that has gained a great acceptance and that has been getting an important formal body are the metaheuristics since it is established strategies to cross and explore the space of solutions of the problem usually generated in a random and iterative way. The main advantage of this technique is their flexibility and robustness, which allows them to be applied to a wide range of problems. In this work we focus on a metaheuristic based on Simulated Annealing trajectory and a population - based Cellular Genetic Algorithm with the objective of carrying out a study and comparison of the results obtained in its application for the resolution of a set of academic problems of combinatorial optimization.

  14. Combinatorial approaches to evaluate nanodiamond uptake and induced cellular fate

    International Nuclear Information System (INIS)

    Eldawud, Reem; Dinu, Cerasela Zoica; Reitzig, Manuela; Opitz, Jörg; Rojansakul, Yon; Jiang, Wenjuan; Nangia, Shikha

    2016-01-01

    Nanodiamonds (NDs) are an emerging class of engineered nanomaterials that hold great promise for the next generation of bionanotechnological products to be used for drug and gene delivery, or for bio-imaging and biosensing. Previous studies have shown that upon their cellular uptake, NDs exhibit high biocompatibility in various in vitro and in vivo set-ups. Herein we hypothesized that the increased NDs biocompatibility is a result of minimum membrane perturbations and their reduced ability to induce disruption or damage during cellular translocation. Using multi-scale combinatorial approaches that simulate ND-membrane interactions, we correlated NDs real-time cellular uptake and kinetics with the ND-induced membrane fluctuations to derive energy requirements for the uptake to occur. Our discrete and real-time analyses showed that the majority of NDs internalization occurs within 2 h of cellular exposure, however, with no effects on cellular viability, proliferation or cellular behavior. Furthermore, our simulation analyses using coarse-grained models identified key changes in the energy profile, membrane deformation and recovery time, all functions of the average ND or ND-based agglomerate size. Understanding the mechanisms responsible for ND-cell membrane interactions could possibly advance their implementation in various biomedical applications. (paper)

  15. Geometric differential evolution for combinatorial and programs spaces.

    Science.gov (United States)

    Moraglio, A; Togelius, J; Silva, S

    2013-01-01

    Geometric differential evolution (GDE) is a recently introduced formal generalization of traditional differential evolution (DE) that can be used to derive specific differential evolution algorithms for both continuous and combinatorial spaces retaining the same geometric interpretation of the dynamics of the DE search across representations. In this article, we first review the theory behind the GDE algorithm, then, we use this framework to formally derive specific GDE for search spaces associated with binary strings, permutations, vectors of permutations and genetic programs. The resulting algorithms are representation-specific differential evolution algorithms searching the target spaces by acting directly on their underlying representations. We present experimental results for each of the new algorithms on a number of well-known problems comprising NK-landscapes, TSP, and Sudoku, for binary strings, permutations, and vectors of permutations. We also present results for the regression, artificial ant, parity, and multiplexer problems within the genetic programming domain. Experiments show that overall the new DE algorithms are competitive with well-tuned standard search algorithms.

  16. Quantum particle swarm approaches applied to combinatorial problems

    International Nuclear Information System (INIS)

    Nicolau, Andressa dos S.; Schirru, Roberto; Lima, Alan M.M. de

    2017-01-01

    Quantum Particle Swarm Optimization (QPSO) is a global convergence algorithm that combines the classical PSO philosophy and quantum mechanics to improve performance of PSO. Different from PSO it only has the 'measurement' of the position equation for all particles. The process of 'measurement' in quantum mechanics, obey classic laws while the particle itself follows the quantum rules. QPSO works like PSO in search ability but has fewer parameters control. In order to improve the QPSO performance, some strategies have been proposed in the literature. Weighted QPSO (WQPSO) is a version of QPSO, where weight parameter is insert in the calculation of the balance between the global and local searching of the algorithm. It has been shown to perform well in finding the optimal solutions for many optimization problems. In this article random confinement was introduced in WQPSO. The WQPSO with random confinement was tested in two combinatorial problems. First, we execute the model on Travelling Salesman Problem (TSP) to find the parameters' values resulting in good solutions in general. Finally, the model was tested on Nuclear Reactor Reload Problem, and the performance was compared with QPSO standard. (author)

  17. Combinatorial Labeling Method for Improving Peptide Fragmentation in Mass Spectrometry

    Science.gov (United States)

    Kuchibhotla, Bhanuramanand; Kola, Sankara Rao; Medicherla, Jagannadham V.; Cherukuvada, Swamy V.; Dhople, Vishnu M.; Nalam, Madhusudhana Rao

    2017-06-01

    Annotation of peptide sequence from tandem mass spectra constitutes the central step of mass spectrometry-based proteomics. Peptide mass spectra are obtained upon gas-phase fragmentation. Identification of the protein from a set of experimental peptide spectral matches is usually referred as protein inference. Occurrence and intensity of these fragment ions in the MS/MS spectra are dependent on many factors such as amino acid composition, peptide basicity, activation mode, protease, etc. Particularly, chemical derivatizations of peptides were known to alter their fragmentation. In this study, the influence of acetylation, guanidinylation, and their combination on peptide fragmentation was assessed initially on a lipase (LipA) from Bacillus subtilis followed by a bovine six protein mix digest. The dual modification resulted in improved fragment ion occurrence and intensity changes, and this resulted in the equivalent representation of b- and y-type fragment ions in an ion trap MS/MS spectrum. The improved representation has allowed us to accurately annotate the peptide sequences de novo. Dual labeling has significantly reduced the false positive protein identifications in standard bovine six peptide digest. Our study suggests that the combinatorial labeling of peptides is a useful method to validate protein identifications for high confidence protein inference. [Figure not available: see fulltext.

  18. Combinatorial set theory with a gentle introduction to forcing

    CERN Document Server

    Halbeisen, Lorenz J

    2017-01-01

    This book, now in a thoroughly revised second edition, provides a comprehensive and accessible introduction to modern set theory. Following an overview of basic notions in combinatorics and first-order logic, the author outlines the main topics of classical set theory in the second part, including Ramsey theory and the axiom of choice. The revised edition contains new permutation models and recent results in set theory without the axiom of choice. The third part explains the sophisticated technique of forcing in great detail, now including a separate chapter on Suslin’s problem. The technique is used to show that certain statements are neither provable nor disprovable from the axioms of set theory. In the final part, some topics of classical set theory are revisited and further developed in light of forcing, with new chapters on Sacks Forcing and Shelah’s astonishing construction of a model with finitely many Ramsey ultrafilters. Written for graduate students in axiomatic set theory, Combinatorial Set Th...

  19. HIV eradication: combinatorial approaches to activate latent viruses.

    Science.gov (United States)

    De Crignis, Elisa; Mahmoudi, Tokameh

    2014-11-21

    The concept of eradication of the Human Immune Deficiency Virus (HIV) from infected patients has gained much attention in the last few years. While combination Anti-Retroviral Therapy (c-ART) has been extremely effective in suppressing viral replication, it is not curative. This is due to the presence of a reservoir of latent HIV infected cells, which persist in the presence of c-ART. Recently, pharmaceutical approaches have focused on the development of molecules able to induce HIV-1 replication from latently infected cells in order to render them susceptible to viral cytopathic effects and host immune responses. Alternative pathways and transcription complexes function to regulate the activity of the HIV promoter and might serve as molecular targets for compounds to activate latent HIV. A combined therapy coupling various depressors and activators will likely be the most effective in promoting HIV replication while avoiding pleiotropic effects at the cellular level. Moreover, in light of differences among HIV subtypes and variability in integration sites, the combination of multiple agents targeting multiple pathways will increase likelihood of therapeutic effectiveness and prevent mutational escape. This review provides an overview of the mechanisms that can be targeted to induce HIV activation focusing on potential combinatorial approaches.

  20. Quantum particle swarm approaches applied to combinatorial problems

    Energy Technology Data Exchange (ETDEWEB)

    Nicolau, Andressa dos S.; Schirru, Roberto; Lima, Alan M.M. de, E-mail: andressa@lmp.ufrj.br [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Programa de Engenharia Nuclear

    2017-07-01

    Quantum Particle Swarm Optimization (QPSO) is a global convergence algorithm that combines the classical PSO philosophy and quantum mechanics to improve performance of PSO. Different from PSO it only has the 'measurement' of the position equation for all particles. The process of 'measurement' in quantum mechanics, obey classic laws while the particle itself follows the quantum rules. QPSO works like PSO in search ability but has fewer parameters control. In order to improve the QPSO performance, some strategies have been proposed in the literature. Weighted QPSO (WQPSO) is a version of QPSO, where weight parameter is insert in the calculation of the balance between the global and local searching of the algorithm. It has been shown to perform well in finding the optimal solutions for many optimization problems. In this article random confinement was introduced in WQPSO. The WQPSO with random confinement was tested in two combinatorial problems. First, we execute the model on Travelling Salesman Problem (TSP) to find the parameters' values resulting in good solutions in general. Finally, the model was tested on Nuclear Reactor Reload Problem, and the performance was compared with QPSO standard. (author)

  1. A Combinatorial Auction among Versatile Experts and Amateurs

    Science.gov (United States)

    Ito, Takayuki; Yokoo, Makoto; Matsubara, Shigeo

    Auctions have become an integral part of electronic commerce and a promising field for applying multi-agent technologies. Correctly judging the quality of auctioned goods is often difficult for amateurs, in particular, in Internet auctions. However, experts can correctly judge the quality of goods. In this situation, it is difficult to make experts tell the truth and attain an efficient allocation, since experts have a clear advantage over amateurs and they would not reveal their valuable information without some reward. In our previous work, we have succeeded in developing such auction protocols under the following two cases: (1) the case of a single-unit auction among experts and amateurs, and (2) the case of a combinatorial auction among single-skilled experts and amateurs. In this paper, we focus on versatile experts. Versatile experts have an interest in, and expert knowledge on the qualities of several goods. In the case of versatile experts, there would be several problems, e.g., free riding problems, if we simply extended the previous VCG-style auction protocol. Thus, in this paper, we employ PORF (price-oriented, rationing-free) protocol for designing our new protocol to realize a strategy-proof auction protocol for experts. In the protocol, the dominant strategy for experts is truth-telling. Also, for amateurs, truth-telling is the best response when two or more experts select the dominant strategy. Furthermore, the protocol is false-name-proof.

  2. Combinatorial approaches to evaluate nanodiamond uptake and induced cellular fate.

    Science.gov (United States)

    Eldawud, Reem; Reitzig, Manuela; Opitz, Jörg; Rojansakul, Yon; Jiang, Wenjuan; Nangia, Shikha; Dinu, Cerasela Zoica

    2016-02-26

    Nanodiamonds (NDs) are an emerging class of engineered nanomaterials that hold great promise for the next generation of bionanotechnological products to be used for drug and gene delivery, or for bio-imaging and biosensing. Previous studies have shown that upon their cellular uptake, NDs exhibit high biocompatibility in various in vitro and in vivo set-ups. Herein we hypothesized that the increased NDs biocompatibility is a result of minimum membrane perturbations and their reduced ability to induce disruption or damage during cellular translocation. Using multi-scale combinatorial approaches that simulate ND-membrane interactions, we correlated NDs real-time cellular uptake and kinetics with the ND-induced membrane fluctuations to derive energy requirements for the uptake to occur. Our discrete and real-time analyses showed that the majority of NDs internalization occurs within 2 h of cellular exposure, however, with no effects on cellular viability, proliferation or cellular behavior. Furthermore, our simulation analyses using coarse-grained models identified key changes in the energy profile, membrane deformation and recovery time, all functions of the average ND or ND-based agglomerate size. Understanding the mechanisms responsible for ND-cell membrane interactions could possibly advance their implementation in various biomedical applications.

  3. Library Systems: FY 2013 Public Libraries Survey (Administrative Entity)

    Data.gov (United States)

    Institute of Museum and Library Services — Find key information on library systems around the United States.These data include imputed values for libraries that did not submit information in the FY 2013 data...

  4. Library Systems: FY 2014 Public Libraries Survey (Administrative Entity Data)

    Data.gov (United States)

    Institute of Museum and Library Services — Find key information on library systems around the United States.These data include imputed values for libraries that did not submit information in the FY 2014 data...

  5. Library Systems: FY 2012 Public Libraries Survey (Administrative Entity)

    Data.gov (United States)

    Institute of Museum and Library Services — Find key information on library systems around the United States.These data include imputed values for libraries that did not submit information in the FY 2012 data...

  6. Merchandising Techniques and Libraries.

    Science.gov (United States)

    Green, Sylvie A.

    1981-01-01

    Proposes that libraries employ modern booksellers' merchandising techniques to improve circulation of library materials. Using displays in various ways, the methods and reasons for weeding out books, replacing worn book jackets, and selecting new books are discussed. Suggestions for learning how to market and 11 references are provided. (RBF)

  7. The Memory Library

    DEFF Research Database (Denmark)

    Olesen-Bagneux, Ole

    2014-01-01

    of classification and retrieval processes is presented. The key element is to understand the library both as a physical structure and as a structure in the memory of the Alexandrian scholars. In this article, these structures are put together so to propose a new interpretation of the library....

  8. School and Library Media.

    Science.gov (United States)

    Fitzgerald, Mary Ann; Lance, Keith Curry; Everhart, Nancy; Toor, Ruth; Weisburg, Hilda K.; Small, Ruth V.; Ohrazda, Celestia; Revercomb, Pamela; Spector, J. Michael; Hughes-Hassell, Sandra; Mancall, Jacqueline C.; Reid, Sarah; Deglin, Sarena; Haynes, Elizabeth

    2003-01-01

    Contains six articles that cover topics related to instructional technology in school library media centers, including: impact on student achievement; data collection for program evaluation; integrating national and state standards; library media specialist collaboration with educational technologists; a professional development model; and online…

  9. Small Public Library Management

    Science.gov (United States)

    Pearlmutter, Jane; Nelson, Paul

    2012-01-01

    Anyone at the helm of a small public library knows that every little detail counts. But juggling the responsibilities that are part and parcel of the job is far from easy. Finally, here's a handbook that includes everything administrators need to keep a handle on library operations, freeing them up to streamline and improve how the organization…

  10. Hospital Library Administration.

    Science.gov (United States)

    Cramer, Anne

    The objectives of a hospital are to improve patient care, while the objectives of a hospital library are to improve services to the staff which will support their efforts. This handbook dealing with hospital administration is designed to aid the librarian in either implementing a hospital library, or improving services in an existing medical…

  11. XML in Libraries.

    Science.gov (United States)

    Tennant, Roy, Ed.

    This book presents examples of how libraries are using XML (eXtensible Markup Language) to solve problems, expand services, and improve systems. Part I contains papers on using XML in library catalog records: "Updating MARC Records with XMLMARC" (Kevin S. Clarke, Stanford University) and "Searching and Retrieving XML Records via the…

  12. Iranian Library Update.

    Science.gov (United States)

    Harvey, John F.

    1979-01-01

    Discusses the state of Iranian libraries since the revolution: the printing industry flourishes because of obsolete copyright laws, and the government is attempting to dewesternize media and education. Also considered are budget cuts, the revolution's cost to libraries, and its effect on individual librarians. (SW)

  13. Increasing Library Effectiveness

    Science.gov (United States)

    Klement, Susan

    1977-01-01

    Libraries could benefit from the businesslike approach of an entrepreneur. Characteristics of entrepreneurial behavior of value to libraries include: moderate risk-taking as a function of skill, not chance; energetic instrumental activity; insistence upon individual responsibility; knowledge of results of decisions; anticipation of future…

  14. The academic library network

    Directory of Open Access Journals (Sweden)

    Jacek Wojciechowski

    2012-01-01

    Full Text Available The efficiency of libraries, academic libraries in particular, necessitates organizational changes facilitating or even imposing co-operation. Any structure of any university has to have an integrated network of libraries, with an appropriate division of work, and one that is consolidated as much as it is possible into medium-size or large libraries. Within thus created network, a chance arises to centralize the main library processes based on appropriate procedures in the main library, highly specialized, more effective and therefore cheaper in operation, including a co-ordination of all more important endeavours and tasks. Hierarchically subordinated libraries can be thus more focused on performing their routine service, more and more frequently providing for the whole of the university, and being able to adjust to changeable requirements and demands of patrons and of new tasks resulting from the new model of the university operation. Another necessary change seems to be a universal implementation of an ov rall programme framework that would include all services in the university’s library networks.

  15. Running the Library Race

    Directory of Open Access Journals (Sweden)

    Erica Jesonis

    2012-09-01

    Full Text Available In Brief: This article draws a parallel between fatigued runners and overworked librarians, proposing that libraries need to pace work more effectively to avoid burnout. Through an exploration of cognitive science, organizational psychology, and practical examples, guest author Erica Jesonis offers considerations for improving productivity and reducing stress within our fast-paced library culture. I recently [...

  16. Library Consortia in Hungary

    Science.gov (United States)

    Csajbok, Edit; Szluka, Peter; Vasas, Livia

    2012-01-01

    During the last two decades many Hungarian libraries have developed considerably, beyond what was considered possible prior to 1989 and the beginning of events signaling the end of Communism in the country. Some of the modernization of library services has been realized through participation in cooperative agreements. Many smaller and larger…

  17. Weeding Library Collections.

    Science.gov (United States)

    Slote, Stanley J.

    This work, based on two recent research projects in the weeding of library collections and the identification of core collections, provides a comprehensive summary of the literature and research on these topics. It also presents practical guidance in weeding for the professional librarian or for the library school student. The book is divided into…

  18. Library Automation Style Guide.

    Science.gov (United States)

    Gaylord Bros., Liverpool, NY.

    This library automation style guide lists specific terms and names often used in the library automation industry. The terms and/or acronyms are listed alphabetically and each is followed by a brief definition. The guide refers to the "Chicago Manual of Style" for general rules, and a notes section is included for the convenience of individual…

  19. Homelessness in Public Libraries

    Science.gov (United States)

    Wong, Yi Ling

    2009-01-01

    This paper takes a theoretical and practical approach in defining the "problem" of homelessness in libraries. The author examines three fundamental problems on homelessness. The three fundamental questions are: (a) Who are the homeless? (b) Why are they homeless? (c) What are their information needs in libraries? These questions are important in…

  20. Library Classification 2020

    Science.gov (United States)

    Harris, Christopher

    2013-01-01

    In this article the author explores how a new library classification system might be designed using some aspects of the Dewey Decimal Classification (DDC) and ideas from other systems to create something that works for school libraries in the year 2020. By examining what works well with the Dewey Decimal System, what features should be carried…