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Sample records for dynamic combinatorial libraries

  1. DNA-Encoded Dynamic Combinatorial Chemical Libraries.

    PubMed

    Reddavide, Francesco V; Lin, Weilin; Lehnert, Sarah; Zhang, Yixin

    2015-06-26

    Dynamic combinatorial chemistry (DCC) explores the thermodynamic equilibrium of reversible reactions. Its application in the discovery of protein binders is largely limited by difficulties in the analysis of complex reaction mixtures. DNA-encoded chemical library (DECL) technology allows the selection of binders from a mixture of up to billions of different compounds; however, experimental results often show low a signal-to-noise ratio and poor correlation between enrichment factor and binding affinity. Herein we describe the design and application of DNA-encoded dynamic combinatorial chemical libraries (EDCCLs). Our experiments have shown that the EDCCL approach can be used not only to convert monovalent binders into high-affinity bivalent binders, but also to cause remarkably enhanced enrichment of potent bivalent binders by driving their in situ synthesis. We also demonstrate the application of EDCCLs in DNA-templated chemical reactions. PMID:26014116

  2. Kinetically controlled phenomena in dynamic combinatorial libraries.

    PubMed

    Ji, Qing; Lirag, Rio Carlo; Miljanić, Ognjen Š

    2014-03-21

    Dynamic combinatorial libraries (DCLs) are collections of structurally related compounds that can interconvert through reversible chemical reaction(s). Such reversibility endows DCLs with adaptability to external stimuli, as rapid interconversion allows quick expression of those DCL components which best respond to the disturbing stimulus. This Tutorial Review focuses on the kinetically controlled phenomena that occur within DCLs. Specifically, it will describe dynamic chiral resolution of DCLs, their self-sorting under the influence of irreversible chemical and physical stimuli, and the autocatalytic behaviours within DCLs which can result in self-replicating systems. A brief discussion of precipitation-induced phenomena will follow and the review will conclude with the presentation of covalent organic frameworks (COFs)-porous materials whose synthesis critically depends on the fine tuning of the crystal growth and error correction rates within large DCLs. PMID:24445841

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

    PubMed Central

    Diemer, Sanna L.; Kristensen, Morten; Rasmussen, Brian; Beeren, Sophie R.; Pittelkow, Michael

    2015-01-01

    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. PMID:26378519

  4. Selection dynamic of Escherichia coli host in M13 combinatorial peptide phage display libraries.

    PubMed

    Zanconato, Stefano; Minervini, Giovanni; Poli, Irene; De Lucrezia, Davide

    2011-01-01

    Phage display relies on an iterative cycle of selection and amplification of random combinatorial libraries to enrich the initial population of those peptides that satisfy a priori chosen criteria. The effectiveness of any phage display protocol depends directly on library amino acid sequence diversity and the strength of the selection procedure. In this study we monitored the dynamics of the selective pressure exerted by the host organism on a random peptide library in the absence of any additional selection pressure. The results indicate that sequence censorship exerted by Escherichia coli dramatically reduces library diversity and can significantly impair phage display effectiveness. PMID:21512219

  5. Late stage modification of receptors identified from dynamic combinatorial libraries.

    PubMed

    Pinkin, Nicholas K; N Power, Amanie; Waters, Marcey L

    2015-11-28

    Small molecule receptors are attractive potential sensors of post-translational modifications, including methylated lysine and methylated arginine. Using dynamic combinatorial chemistry (DCC), our lab previously identified a suite of receptors that bind to Kme3 with a range of affinities ranging from low micromolar to high nanomolar, each with a unique selectivity for Kme3 over the lower methylation states. To enable these receptors to have broad application as Kme3 sensors, we have developed a method for their late-stage modification, which we used to synthesize biotinylated derivatives of A2B, A2D, and A2G in a single step. For our most attractive receptor for applications, A2N, we needed to develop an alternative method for its selective functionalization, which we achieved by "activating" the carboxylic acids on the constituent monomer A or N by pre-functionalizing them with glycine (Gly). Using the resulting Gly-A and Gly-N monomers, we synthesized the novel A2N variants A2Gly-N, Gly-A2N, and Gly-A2Gly-N, which enabled the late stage biotinylation of A2N wherever Gly was incorporated. Finally, we performed ITC and NMR binding experiments to study the effect that carboxylate spacing has on the affinity and selectivity of A2Gly-N and Gly-A2N for KmeX guests compared to A2N. These studies revealed the proximity of the carboxylates to play a complex role in the molecular recognition event, despite their positioning on the outside of the receptor. PMID:26384269

  6. Generation of a Multicomponent Library of Disulfide Donor-Acceptor Architectures Using Dynamic Combinatorial Chemistry

    PubMed Central

    Drożdż, Wojciech; Kołodziejski, Michał; Markiewicz, Grzegorz; Jenczak, Anna; Stefankiewicz, Artur R.

    2015-01-01

    We describe here the generation of new donor-acceptor disulfide architectures obtained in aqueous solution at physiological pH. The application of a dynamic combinatorial chemistry approach allowed us to generate a large number of new disulfide macrocyclic architectures together with a new type of [2]catenanes consisting of four distinct components. Up to fifteen types of structurally-distinct dynamic architectures have been generated through one-pot disulfide exchange reactions between four thiol-functionalized aqueous components. The distribution of disulfide products formed was found to be strongly dependent on the structural features of the thiol components employed. This work not only constitutes a success in the synthesis of topologically- and morphologically-complex targets, but it may also open new horizons for the use of this methodology in the construction of molecular machines. PMID:26193265

  7. Recursive deconvolution of combinatorial chemical libraries.

    PubMed

    Erb, E; Janda, K D; Brenner, S

    1994-11-22

    A recursive strategy that solves for the active members of a chemical library is presented. A pentapeptide library with an alphabet of Gly, Leu, Phe, and Tyr (1024 members) was constructed on a solid support by the method of split synthesis. One member of this library (NH2-Tyr-Gly-Gly-Phe-Leu) is a native binder to a beta-endorphin antibody. A variation of the split synthesis approach is used to build the combinatorial library. In four vials, a member of the library's alphabet is coupled to a solid support. After each coupling, a portion of the resin from each of the four reaction vials was set aside and catalogued. The solid support from each vial is then combined, mixed, and redivided. The steps of (i) coupling, (ii) saving and cataloging, and (iii) randomizing were repeated until a pentapeptide library was obtained. The four pentapeptide libraries where the N-terminal amino acid is defined were screened against the beta-endorphin antibody and quantitated via an ELISA. The amino acid of the four pools that demonstrated the most binding was then coupled to the four tetrapeptide partial libraries that had been set aside and catalogued during the split synthesis. This recursive deconvolution was repeated until the best binders were deduced. Besides the anticipated native binder, two other members of the library displayed significant binding. This recursive method of deconvolution does not use a molecular tag, requires only one split synthesis, and can be applied to the deconvolution of nonlinear small-molecule combinatorial libraries and linear oligomeric combinatorial libraries, since it is based only on the procedure of the synthesis. PMID:7972077

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

    ERIC Educational Resources Information Center

    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…

  9. Structure-based design of combinatorial mutagenesis libraries

    PubMed Central

    Verma, Deeptak; Grigoryan, Gevorg; Bailey-Kellogg, Chris

    2015-01-01

    The development of protein variants with improved properties (thermostability, binding affinity, catalytic activity, etc.) has greatly benefited from the application of high-throughput screens evaluating large, diverse combinatorial libraries. At the same time, since only a very limited portion of sequence space can be experimentally constructed and tested, an attractive possibility is to use computational protein design to focus libraries on a productive portion of the space. We present a general-purpose method, called “Structure-based Optimization of Combinatorial Mutagenesis” (SOCoM), which can optimize arbitrarily large combinatorial mutagenesis libraries directly based on structural energies of their constituents. SOCoM chooses both positions and substitutions, employing a combinatorial optimization framework based on library-averaged energy potentials in order to avoid explicitly modeling every variant in every possible library. In case study applications to green fluorescent protein, β-lactamase, and lipase A, SOCoM optimizes relatively small, focused libraries whose variants achieve energies comparable to or better than previous library design efforts, as well as larger libraries (previously not designable by structure-based methods) whose variants cover greater diversity while still maintaining substantially better energies than would be achieved by representative random library approaches. By allowing the creation of large-scale combinatorial libraries based on structural calculations, SOCoM promises to increase the scope of applicability of computational protein design and improve the hit rate of discovering beneficial variants. While designs presented here focus on variant stability (predicted by total energy), SOCoM can readily incorporate other structure-based assessments, such as the energy gap between alternative conformational or bound states. PMID:25611189

  10. Plasma sputtering system for deposition of thin film combinatorial libraries

    NASA Astrophysics Data System (ADS)

    Cooper, James S.; Zhang, Guanghai; McGinn, Paul J.

    2005-06-01

    The design of a plasma sputtering system for the deposition of combinatorial libraries is described. A rotating carousel is used to position shadow masks between the targets and the substrate. Multilayer films are built up by depositing sequentially through various masks. Postdeposition annealing is used to promote interdiffusion of the layered structures. Either discrete or compositional gradient libraries can be deposited in this system. Samples appropriate for characterization with a scanning electrochemical microscope or a multichannel microelectrode array system can be produced. The properties of some deposited Pt-Ru films for fuel cell applications are described.

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

    PubMed

    Jeschek, Markus; Gerngross, Daniel; Panke, Sven

    2016-01-01

    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. PMID:27029461

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

    PubMed Central

    Jeschek, Markus; Gerngross, Daniel; Panke, Sven

    2016-01-01

    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. PMID:27029461

  13. Asymmetric Proteome Equalization of the Skeletal Muscle Proteome Using a Combinatorial Hexapeptide Library

    PubMed Central

    Rivers, Jenny; Hughes, Chris; McKenna, Thérèse; Woolerton, Yvonne; Vissers, Johannes P. C.; Langridge, James I.; Beynon, Robert J.

    2011-01-01

    Immobilized combinatorial peptide libraries have been advocated as a strategy for equalization of the dynamic range of a typical proteome. The technology has been applied predominantly to blood plasma and other biological fluids such as urine, but has not been used extensively to address the issue of dynamic range in tissue samples. Here, we have applied the combinatorial library approach to the equalization of a tissue where there is also a dramatic asymmetry in the range of abundances of proteins; namely, the soluble fraction of skeletal muscle. We have applied QconCAT and label-free methodology to the quantification of the proteins that bind to the beads as the loading is progressively increased. Although some equalization is achieved, and the most abundant proteins no longer dominate the proteome analysis, at high protein loadings a new asymmetry of protein expression is reached, consistent with the formation of complex assembles of heat shock proteins, cytoskeletal elements and other proteins on the beads. Loading at different ionic strength values leads to capture of different subpopulations of proteins, but does not completely eliminate the bias in protein accumulation. These assemblies may impair the broader utility of combinatorial library approaches to the equalization of tissue proteomes. However, the asymmetry in equalization is manifest at either low and high ionic strength values but manipulation of the solvent conditions may extend the capacity of the method. PMID:22205978

  14. Direct selection for a catalytic mechanism from combinatorial antibody libraries.

    PubMed Central

    Janda, K D; Lo, C H; Li, T; Barbas, C F; Wirsching, P; Lerner, R A

    1994-01-01

    Semisynthetic combinatorial antibody library methodology in the phage-display format was used to select for a cysteine residue in complementarity-determining regions. Libraries were panned with an alpha-phenethyl pyridyl disulfide that undergoes disulfide interchange. Out of 10 randomly picked clones, two contained an unpaired cysteine, one of which was studied. The antibody catalyzed the hydrolysis of the corresponding thioester where the electrophilic carbonyl occupies the three-dimensional space that was defined by the reactive sulfur atom during selection. The reaction operates by covalent catalysis. Although the steady-state rate enhancement relative to the activated thiol ester substrate is modest, hydrolysis of the acylated cysteine intermediate is remarkably efficient with a catalytic advantage of about four orders of magnitude. The results suggest that iterative mechanism-based selection procedures can recapitulate the enzymatic mechanisms refined through evolution. Images PMID:8146149

  15. Device for preparing combinatorial libraries in powder metallurgy.

    PubMed

    Yang, Shoufeng; Evans, Julian R G

    2004-01-01

    This paper describes a powder-metering, -mixing, and -dispensing mechanism that can be used as a method for producing large numbers of samples for metallurgical evaluation or electrical or mechanical testing from multicomponent metal and cermet powder systems. It is designed to make use of the same commercial powders that are used in powder metallurgy and, therefore, to produce samples that are faithful to the microstructure of finished products. The particle assemblies produced by the device could be consolidated by die pressing, isostatic pressing, laser sintering, or direct melting. The powder metering valve provides both on/off and flow rate control of dry powders in open capillaries using acoustic vibration. The valve is simple and involves no relative movement, avoiding seizure with fine powders. An orchestra of such valves can be arranged on a building platform to prepare multicomponent combinatorial libraries. As with many combinatorial devices, identification and evaluation of sources of mixing error as a function of sample size is mandatory. Such an analysis is presented. PMID:15244416

  16. Selecting agonists from single cells infected with combinatorial antibody libraries.

    PubMed

    Zhang, Hongkai; Yea, Kyungmoo; Xie, Jia; Ruiz, Diana; Wilson, Ian A; Lerner, Richard A

    2013-05-23

    We describe a system for direct selection of antibodies that are receptor agonists. Combinatorial antibody libraries in lentiviruses are used to infect eukaryotic cells that contain a fluorescent reporter system coupled to the receptor for which receptor agonist antibodies are sought. In this embodiment of the method, very large numbers of candidate antibodies expressing lentivirus and eukaryotic reporter cells are packaged together in a format where each is capable of replication, thereby forging a direct link between genotype and phenotype. Following infection, cells that fluoresce are sorted and the integrated genes encoding the agonist antibodies recovered. We validated the system by illustrating its ability to generate rapidly potent antibody agonists that are complete thrombopoietin phenocopies. The system should be generalizable to any pathway where its activation can be linked to production of a selectable phenotype. PMID:23706638

  17. Protein-Directed Dynamic Combinatorial Chemistry: A Guide to Protein Ligand and Inhibitor Discovery.

    PubMed

    Huang, Renjie; Leung, Ivanhoe K H

    2016-01-01

    Protein-directed dynamic combinatorial chemistry is an emerging technique for efficient discovery of novel chemical structures for binding to a target protein. Typically, this method relies on a library of small molecules that react reversibly with each other to generate a combinatorial library. The components in the combinatorial library are at equilibrium with each other under thermodynamic control. When a protein is added to the equilibrium mixture, and if the protein interacts with any components of the combinatorial library, the position of the equilibrium will shift and those components that interact with the protein will be amplified, which can then be identified by a suitable biophysical technique. Such information is useful as a starting point to guide further organic synthesis of novel protein ligands and enzyme inhibitors. This review uses literature examples to discuss the practicalities of applying this method to inhibitor discovery, in particular, the set-up of the combinatorial library, the reversible reactions that may be employed, and the choice of detection methods to screen protein ligands from a mixture of reversibly forming molecules. PMID:27438816

  18. An Indexed Combinatorial Library: The Synthesis and Testing of Insect Repellents

    NASA Astrophysics Data System (ADS)

    Miles, William H.; Gelato, Kathy A.; Pompizzi, Kristen M.; Scarbinsky, Aislinn M.; Albrecht, Brian K.; Reynolds, Elaine R.

    2001-04-01

    An indexed combinatorial library of amides was prepared by the reaction of amines and acid chlorides. A simple test for insect repellency using fruit flies (Drosophila melanogaster) allowed the determination of the most repellent sublibraries. The student-generated data were collected and analyzed to determine the most active amide(s) in the library. This experiment illustrates the fundamentals of combinatorial chemistry, a field that has undergone explosive growth in the last decade.

  19. Combinatorial synthesis of thin film libraries for microwave dielectrics

    NASA Astrophysics Data System (ADS)

    Wessler, B.; Jéhanno, V.; Rossner, W.; Maier, W. F.

    2004-02-01

    The short innovation cycles in communication technology require the development and optimization of high-performance dielectrics for passive integration, utilized, e.g., in band pass filters, antennas, or dielectric resonators. Applying combinatorial methods offers the advantage to accelerate the discovery of more efficient microwave dielectrics and to investigate the effects of a variety of dopants on the dielectric properties. In the present study, libraries consisting of chemically diverse thin films are produced by chemical solution deposition. A sol-gel precursor set was developed consisting of precursor solutions for different elements, such as Ba, Ti, W, and Sr, which convert to the corresponding oxides by annealing. These precursor solutions are mixed in various ratios by pipetting robots and are then deposited on structured substrates followed by calcination and sintering. The influence of different parameters on the film quality such as the type of precursor used, their miscibility with each other, the thermal processing, and the technique used to pre-structure the wafer is discussed.

  20. Mimicking nature: Phosphopeptide enrichment using combinatorial libraries of affinity ligands.

    PubMed

    Batalha, Iris L; Zhou, Houjiang; Lilley, Kathryn; Lowe, Christopher R; Roque, Ana C A

    2016-07-29

    Phosphorylation is a reversible post-translational modification of proteins that controls a plethora of cellular processes and triggers specific physiological responses, for which there is a need to develop tools to characterize phosphorylated targets efficiently. Here, a combinatorial library of triazine-based synthetic ligands comprising 64 small molecules has been rationally designed, synthesized and screened for the enrichment of phosphorylated peptides. The lead candidate (coined A8A3), composed of histidine and phenylalanine mimetic components, showed high binding capacity and selectivity for binding mono- and multi-phosphorylated peptides at pH 3. Ligand A8A3 was coupled onto both cross-linked agarose and magnetic nanoparticles, presenting higher binding capacities (100-fold higher) when immobilized on the magnetic support. The magnetic adsorbent was further screened against a tryptic digest of two phosphorylated proteins (α- and β-caseins) and one non-phosphorylated protein (bovine serum albumin, BSA). The MALDI-TOF mass spectra of the eluted peptides allowed the identification of nine phosphopeptides, comprising both mono- and multi-phosphorylated peptides. PMID:27345211

  1. Combinatorial Library Screening Coupled to Mass Spectrometry to Identify Valuable Cyclic Peptides.

    PubMed

    Camperi, Silvia A; Giudicessi, Silvana L; Martínez-Ceron, María C; Gurevich-Messina, Juan M; Saavedra, Soledad L; Acosta, Gerardo; Cascone, Osvaldo; Erra-Balsells, Rosa; Albericio, Fernando

    2016-01-01

    Combinatorial library screening coupled to mass spectrometry (MS) analysis is a practical approach to identify useful peptides. Cyclic peptides can have high biological activity, selectivity, and affinity for target proteins, and high stability against proteolytic degradation. Here we describe two strategies to prepare combinatorial libraries suitable for MS analysis to accelerate the discovery of cyclic peptide structures. Both approaches use ChemMatrix resin and the linker 4-hydroxymethylbenzoic acid. One strategy involves the synthesis of a one-bead-two-peptides library in which each bead contains both the cyclic peptide and its linear counterpart to facilitate MS analysis. The other protocol is based on the synthesis of a cyclic depsipeptide library in which a glycolamidic ester group is incorporated by adding glycolic acid. After library screening, the ring is opened and the peptide is released simultaneously for subsequent MS analysis. © 2016 by John Wiley & Sons, Inc. PMID:27258690

  2. A Novel Human scFv Library with Non-Combinatorial Synthetic CDR Diversity

    PubMed Central

    Kang, Seungmin; Kim, Wankyu; Shim, Hyunbo

    2015-01-01

    The present work describes the construction and validation of a human scFv library with a novel design approach to synthetic complementarity determining region (CDR) diversification. The advantage of synthetic antibody libraries includes the possibility of exerting fine control over factors like framework sequences, amino acid and codon usage, and CDR diversity. However, random combinatorial synthesis of oligonucleotides for CDR sequence diversity also produces many clones with unnatural sequences and/or undesirable modification motifs. To alleviate these issues, we designed and constructed a novel semi-synthetic human scFv library with non-combinatorial, pre-designed CDR diversity and a single native human framework each for heavy, kappa, and lambda chain variable domains. Next-generation sequencing analysis indicated that the library consists of antibody clones with highly nature-like CDR sequences and the occurrence of the post-translational modification motifs is minimized. Multiple unique clones with nanomolar affinity could be isolated from the library against a number of target antigens, validating the library design strategy. The results demonstrate that it is possible to construct a functional antibody library using low, non-combinatorial synthetic CDR diversity, and provides a new strategy for the design of antibody libraries suitable for demanding applications. PMID:26484868

  3. Dynamic combinatorial synthesis of a catenane based on donor–acceptor interactions in water

    PubMed Central

    Au-Yeung, Ho Yu; Pantoş, G. Dan; Sanders, Jeremy K. M.

    2009-01-01

    A new type of neutral donor–acceptor [2]-catenane, containing both complementary units in the same ring was synthesized from a dynamic combinatorial library in water. The yield of the water soluble [2]-catenane is enhanced by increasing either building-block concentrations or ionic strength, or by the addition of an electron-rich template. NMR spectroscopy demonstrates that the template is intercalated between the 2 electron-deficient naphthalenediimide units of the catenane. PMID:19171892

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

    PubMed

    Pullar, Robert C

    2012-07-01

    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. PMID:22676556

  5. A Structure-Based Design Protocol for Optimizing Combinatorial Protein Libraries.

    PubMed

    Lunt, Mark W; Snow, Christopher D

    2016-01-01

    Protein variant libraries created via site-directed mutagenesis are a powerful approach to engineer improved proteins for numerous applications such as altering enzyme substrate specificity. Conventional libraries commonly use a brute force approach: saturation mutagenesis via degenerate codons that encode all 20 natural amino acids. In contrast, this chapter describes a protocol for designing "smarter" degenerate codon libraries via direct combinatorial optimization in "library space." Several case studies illustrate how it is possible to design degenerate codon libraries that are highly enriched for favorable, low-energy sequences as assessed using a standard all-atom scoring function. There is much to gain for experimental protein engineering laboratories willing to think beyond site saturation mutagenesis. In the common case that the exact experimental screening budget is not fixed, it is particularly helpful to perform a Pareto analysis to inspect favorable libraries at a range of possible library sizes. PMID:27094288

  6. Combinatorial synthesis and antibacterial evaluation of an indexed chalcone library.

    PubMed

    Ansari, Farzana Latif; Nazir, Samina; Noureen, Humaira; Mirza, Bushra

    2005-12-01

    A 120-membered chalcone library has been designed and prepared from six differently substituted acetophenones (A1-A6) and 20 benzaldehydes (B1-B20). The library was subjected to biological studies targeted against six bacterial strains. For the identification of the most-active member(s) of the library, the so-called indexed or positional-scanning method was applied. Six out of 26 sub-libraries, i.e., AL1-AL6, were synthesized by keeping the acetophenone moiety A fixed and using equimolar quantities of the 20 different benzaldehydes. The remaining 20 sub-libraries BL1-BL20 were prepared by keeping the benzaldehyde B component fixed and varying the six acetophenones (Table 1). The bactericidal activities of the resulting sub-libraries were tested and used as indices to the rows or columns of a two-dimensional matrix. Finally, parallel synthesis of 24 specific members with the highest-expected antibacterial activities, present in two sub-libraries, was carried out. These chalcones were screened again, and the results were exploited for establishing the structure-activity relationship (SAR) and the identification of the lead compound, which turned out to be 1,3-bis(2-hydroxyphenyl)prop-2-en-1-one (A2B2) in terms of activity towards Staphylococcus aureus and Bacillus subtilis (Tables 5-7). PMID:17191962

  7. Scanning electrochemical microscope characterization of thin film combinatorial libraries for fuel cell electrode applications

    NASA Astrophysics Data System (ADS)

    Black, M.; Cooper, J.; McGinn, P.

    2005-01-01

    Pt-Ru combinatorial libraries of potential fuel cell anode catalysts are formed by sequential sputter deposition through masks onto Si wafers. Scanning electrochemical microscopy (SECM) is employed for characterization of electrocatalytic activity. Aspects of using a scanning electrochemical microscope for characterization of an array of thin film fuel cell electrode materials are discussed. It is shown that in applying SECM to library characterization, careful attention must be paid to thin film annealing, specimen topography and tip degradation in order to realize meaningful results. Results from a Pt-Ru thin film library reveal the most active members near the 50 Pt/50 Ru composition.

  8. Combinatorial Libraries of Transition Metal Oxides Using an Ab Initio High Throughput Approach

    NASA Astrophysics Data System (ADS)

    Li, Guo; Yan, Qimin; Newhouse, Paul; Zhou, Lan; Gregoire, John; Neaton, Jeffrey

    2015-03-01

    Using the results of first-principles calculations and data from the Materials Project (materialsproject.org), we have developed a simple but efficient scheme to theoretically simulate phase coexistence in experimental combinatorial libraries as a function of composition and temperature. In our approach, each experimental sample in a combinatorial library at a fixed composition is considered as a mixture of all the known compounds; and the compound concentrations are determined from calculations of their compositions and relevant thermodynamic potentials. Consequently, multiple compounds can be identified in every sample. To test our approach, we studied the pseudobinary library MnxV(1-x)Oy, and found that, together with those stable compounds predicted in a phase diagram, some of the above-convex-hull compounds, which are viewed unstable, also play a significant role in the combinatorial library. We validated our approach via comparison of calculated X-ray diffraction spectra for multiple phases and recent measurements. This work supported by DOE (the JCAP under Award number DE-SC000499 and the Molecular Foundry of LBNL), and computational resources provided by NERSC.

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

    PubMed

    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. PMID:26371511

  10. Positional scanning substrate combinatorial library (PS-SCL) approach to define caspase substrate specificity.

    PubMed

    Poręba, Marcin; Szalek, Aleksandra; Kasperkiewicz, Paulina; Drąg, Marcin

    2014-01-01

    Positional scanning substrate combinatorial library (PS-SCL) is a powerful tool for studying substrate specificity of proteolytic enzymes. Here, we describe the protocol for analyzing S4-S2 pockets preferences of caspases using PS-SCL. Additionally, we describe procedures for the identification of optimal substrates sequence after PS-SCL, solid phase synthesis, and purification of selected fluorogenic substrates, as well as their kinetic analysis. PMID:24567093

  11. Direct screening of solution phase combinatorial libraries encoded with externally sensitized photolabile tags

    PubMed Central

    Kottani, Rudresha; Valiulin, Roman A.; Kutateladze, Andrei G.

    2006-01-01

    Solution phase combinatorial chemistry holds an enormous promise for modern drug discovery. Much needed are direct methods to assay such libraries for binding of biological targets. An approach to encoding and screening of solution phase libraries has been developed based on the conditional photorelease of externally sensitized photolabile tags. The encoding tags are released into solution only when a sought-for binding event occurs between the ligand and the receptor, outfitted with an electron-transfer sensitizer. The released tags are analyzed in solution revealing the identity of the lead ligand or narrowing the range of potential leads. PMID:16956977

  12. Selective Chromium(VI) Ligands Identified Using Combinatorial Peptoid Libraries

    PubMed Central

    Knight, Abigail S.; Zhou, Effie Y.; Pelton, Jeffrey G.; Francis, Matthew B.

    2013-01-01

    Hexavalent chromium (Cr(VI)) is a world-wide water contaminant that is currently without cost-effective and efficient remediation strategies. This is in part due to a lack of ligands that can bind it amid an excess of innocuous ions in aqueous solution. We present herein the design and application of a peptoid-based library of ligand candidates for toxic metal ions. A selective screening process was used to identify members of the library that can bind to Cr(VI) species at neutral pH and in the presence of a large excess of spectator ions. Eleven sequences were identified, and their affinities were compared using titrations monitored with UV-Vis spectroscopy. To identify the interactions involved in coordination and specificity, we evaluated the effects of sequence substitutions and backbone variation in the highest affinity structure. Additional characterization of the complex formed between this sequence and Cr(VI) was performed using NMR spectroscopy. To evaluate the ability of the developed sequences to remediate contaminated solutions, the structures were synthesized on a solid-phase resin and incubated with environmental water samples that contained simulated levels of chromium contamination. The synthetic structures demonstrated the ability to reduce the amount of toxic chromium to levels within the range of the EPA contamination guidelines. In addition to providing some of the first selective ligands for Cr(VI), these studies highlight the promise of peptoid sequences as easily-prepared components of environmental remediation materials. PMID:24195610

  13. Human Monoclonal Antibodies Against a Plethora of Viral Pathogens From Single Combinatorial Libraries

    NASA Astrophysics Data System (ADS)

    Williamson, R. Anthony; Burioni, Roberto; Sanna, Pietro P.; Partridge, Lynda J.; Barbas, Carlos F., III; Burton, Dennis R.

    1993-05-01

    Conventional antibody generation usually requires active immunization with antigen immediately prior to the preparation procedure. Combinatorial antibody library technology offers the possibility of cloning a range of antibody specificities at a single point in time and then accessing these specificities at will. Here we show that human monoclonal antibody Fab fragments against a plethora of infectious agents can be readily derived from a single library. Further examination of a number of libraries shows that whenever antibody against a pathogen can be detected in the serum of the donor, then specific antibodies can be derived from the corresponding library. We describe the generation of human Fab fragments against herpes simplex virus types 1 and 2, human cytomegalovirus, varicella zoster virus, rubella, human immunodeficiency virus type 1, and respiratory syncytial virus. The antibodies are shown to be highly specific and a number are effective in neutralizing virus in vitro.

  14. Human monoclonal antibodies against a plethora of viral pathogens from single combinatorial libraries.

    PubMed Central

    Williamson, R A; Burioni, R; Sanna, P P; Partridge, L J; Barbas, C F; Burton, D R

    1993-01-01

    Conventional antibody generation usually requires active immunization with antigen immediately prior to the preparation procedure. Combinatorial antibody library technology offers the possibility of cloning a range of antibody specificities at a single point in time and then accessing these specificities at will. Here we show that human monoclonal antibody Fab fragments against a plethora of infectious agents can be readily derived from a single library. Further examination of a number of libraries shows that whenever antibody against a pathogen can be detected in the serum of the donor, then specific antibodies can be derived from the corresponding library. We describe the generation of human Fab fragments against herpes simplex virus types 1 and 2, human cytomegalovirus, varicella zoster virus, rubella, human immunodeficiency virus type 1, and respiratory syncytial virus. The antibodies are shown to be highly specific and a number are effective in neutralizing virus in vitro. Images Fig. 1 Fig. 2 PMID:7683424

  15. Design, Synthesis, and Application of OB2C Combinatorial Peptide and Peptidomimetic Libraries

    PubMed Central

    Liu, Ruiwu; Shih, Tsung-Chieh; Deng, Xiaojun; Anwar, Lara; Ahadi, Sara; Kumaresan, Pappanaicken; Lam, Kit S.

    2015-01-01

    The “one-bead two-compound” (OB2C) combinatorial library is constructed on topologically segregated trifunctional bilayer beads such that each bead has a fixed cell-capturing ligand and a random library compound co-displayed on its surface and a chemical coding tag (bar code) inside the bead. An OB2C library containing thousands to millions of compounds can be synthesized and screened concurrently within a short period of time. When live cells are incubated with such OB2C libraries, every bead will be coated with a monolayer of cells. The cell membranes of the captured cells facing the bead surface are exposed to the library compounds tethered to each bead. A specific biochemical or cellular response can be detected with an appropriate reporter system. The OB2C method enables investigators to rapidly discover synthetic molecules that not only interact with cell-surface receptors but can also stimulate or inhibit downstream cell signaling. To demonstrate this powerful method, one OB2C peptide library and two OB2C peptidomimetic libraries were synthesized and screened against Molt-4 lymphoma cells to discover “death ligands.” Apoptosis of the bead-bound cells was detected with immunocytochemistry using horseradish peroxidase (HRP)-conjugated anti-cleaved caspase-3 antibody and 3,3′-diaminobenzidine as a substrate. Two novel synthetic “death ligands” against Molt-4 cells were discovered using this OB2C library approach. PMID:25616322

  16. Design, synthesis, and application of OB2C combinatorial peptide and peptidomimetic libraries.

    PubMed

    Liu, Ruiwu; Shih, Tsung-Chieh; Deng, Xiaojun; Anwar, Lara; Ahadi, Sara; Kumaresan, Pappanaicken; Lam, Kit S

    2015-01-01

    The "one-bead two-compound" (OB2C) combinatorial library is constructed on topologically segregated trifunctional bilayer beads such that each bead has a fixed cell-capturing ligand and a random library compound co-displayed on its surface and a chemical coding tag (bar code) inside the bead. An OB2C library containing thousands to millions of compounds can be synthesized and screened concurrently within a short period of time. When live cells are incubated with such OB2C libraries, every bead will be coated with a monolayer of cells. The cell membranes of the captured cells facing the bead surface are exposed to the library compounds tethered to each bead. A specific biochemical or cellular response can be detected with an appropriate reporter system. The OB2C method enables investigators to rapidly discover synthetic molecules that not only interact with cell-surface receptors but can also stimulate or inhibit downstream cell signaling. To demonstrate this powerful method, one OB2C peptide library and two OB2C peptidomimetic libraries were synthesized and screened against Molt-4 lymphoma cells to discover "death ligands." Apoptosis of the bead-bound cells was detected with immunocytochemistry using horseradish peroxidase (HRP)-conjugated anti-cleaved caspase-3 antibody and 3,3'-diaminobenzidine as a substrate. Two novel synthetic "death ligands" against Molt-4 cells were discovered using this OB2C library approach. PMID:25616322

  17. Template-based combinatorial enumeration of virtual compound libraries for lipids

    PubMed Central

    2012-01-01

    A variety of software packages are available for the combinatorial enumeration of virtual libraries for small molecules, starting from specifications of core scaffolds with attachments points and lists of R-groups as SMILES or SD files. Although SD files include atomic coordinates for core scaffolds and R-groups, it is not possible to control 2-dimensional (2D) layout of the enumerated structures generated for virtual compound libraries because different packages generate different 2D representations for the same structure. We have developed a software package called LipidMapsTools for the template-based combinatorial enumeration of virtual compound libraries for lipids. Virtual libraries are enumerated for the specified lipid abbreviations using matching lists of pre-defined templates and chain abbreviations, instead of core scaffolds and lists of R-groups provided by the user. 2D structures of the enumerated lipids are drawn in a specific and consistent fashion adhering to the framework for representing lipid structures proposed by the LIPID MAPS consortium. LipidMapsTools is lightweight, relatively fast and contains no external dependencies. It is an open source package and freely available under the terms of the modified BSD license. PMID:23006594

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

    SciTech Connect

    Evans, D.M.; Williams, K.P.; McGuinness, B.

    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.

  19. Composition-Dependent Phase Concentrations from First Principles: Simulating Combinatorial Libraries of Transition Metal Oxides

    NASA Astrophysics Data System (ADS)

    Li, Guo; Yan, Qimin; Zhou, Lan; Newhouse, Paul; Gregoire, John; Neaton, Jeffrey

    To identify material phases in experimental combinatorial libraries, we develop a theoretical model as a complementary approach to accelerate phase identification. In this approach, samples in a combinatorial library are simulated as mixtures in chemical equilibria. Each of these mixtures contains all the solid-state phases, which can possibly exist in the library. Using the total energies of these phases obtained in first-principle calculations, we calculate the Gibbs free energy changes in the corresponding chemical reactions, and subsequently evaluate the equilibrium concentrations of the phases in every sample according to the law of mass action. Furthermore, to test this approach, we simulate pseudobinary libraries MnxV1-xOy and CuxV1-xOy. Interestingly, we find that the composition-dependent phase concentrations calculated within our approach agree well with the experimental results measured with XRD spectroscopy. This work supported by DOE (the JCAP under Award Number DE-SC0004993 and the Molecular Foundry of LBNL), and computational resources provided by NERSC.

  20. A drop-on-demand ink-jet printer for combinatorial libraries and functionally graded ceramics.

    PubMed

    Mohebi, Mohammad Masoud; Evans, Julian R G

    2002-01-01

    A printer has been designed and built for the preparation of combinatorial libraries of ceramics and for solid freeforming of functionally graded ceramics with three-dimensionally programmable spatial variation in composition. Several ceramic suspensions (as inks) can be subjected to micromixing behind the nozzle and printed at precise positions. Both mixing and positioning are computer-controlled. The machine consists of an XY table to control the geometry, a set of electromagnetic valves that manage the mixing, a combined electromagnetic valve and sapphire nozzle that form the print head, and a computer that controls the whole system. The mixing valves can eject as little as 1 mg/s ink into the mixing chamber. The printer has been controlled, run, calibrated and tested; the composition and geometry of printed mixtures can be controlled precisely. This method for the controlled mixing of powders facilitates the advance of combinatorial methods within the materials sciences. PMID:12099843

  1. Generation of Synthetic Copolymer Libraries by Combinatorial Assembly on Nucleic Acid Templates.

    PubMed

    Kong, Dehui; Yeung, Wayland; Hili, Ryan

    2016-07-11

    Recent advances in nucleic acid-templated copolymerization have expanded the scope of sequence-controlled synthetic copolymers beyond the molecular architectures witnessed in nature. This has enabled the power of molecular evolution to be applied to synthetic copolymer libraries to evolve molecular function ranging from molecular recognition to catalysis. This Review seeks to summarize different approaches available to generate sequence-defined monodispersed synthetic copolymer libraries using nucleic acid-templated polymerization. Key concepts and principles governing nucleic acid-templated polymerization, as well as the fidelity of various copolymerization technologies, will be described. The Review will focus on methods that enable the combinatorial generation of copolymer libraries and their molecular evolution for desired function. PMID:27275512

  2. Decoding Split and Pool Combinatorial Libraries with Electron-Transfer Dissociation Tandem Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Sarkar, Mohosin; Pascal, Bruce D.; Steckler, Caitlin; Aquino, Claudio; Micalizio, Glenn C.; Kodadek, Thomas; Chalmers, Michael J.

    2013-07-01

    Screening of bead-based split and pool combinatorial chemistry libraries is a powerful approach to aid the discovery of new chemical compounds able to interact with, and modulate the activities of, protein targets of interest. Split and pool synthesis provides for large and well diversified chemical libraries, in this case comprised of oligomers generated from a well-defined starting set. At the end of the synthesis, each bead in the library displays many copies of a unique oligomer sequence. Because the sequence of the oligomer is not known at the time of screening, methods for decoding of the sequence of each screening "hit" are essential. Here we describe an electron-transfer dissociation (ETD) based tandem mass spectrometry approach for the decoding of mass-encoded split and pool libraries. We demonstrate that the newly described "chiral oligomers of pentenoic amides (COPAs)" yield non-sequence-specific product ions upon collisional activated dissociation; however, complete sequence information can be obtained with ETD. To aid in the decoding of libraries from MS and MS/MS data, we have incorporated 79Br/81Br isotope "tags" to differentiate N- and C-terminal product ions. In addition, we have created "Hit-Find," a software program that allows users to generate libraries in silico . The user can then search all possible members of the chemical library for those that fall within a user-defined mass error.

  3. Decoding Split and Pool Combinatorial Libraries with Electron Transfer Dissociation Tandem Mass Spectrometry

    PubMed Central

    Sarkar, Mohosin; Pascal, Bruce D.; Steckler, Caitlin; Aquino, Claudio; Micalizio, Glenn C.; Kodadek, Thomas; Chalmers, Michael J.

    2015-01-01

    Screening of bead-based split and pool combinatorial chemistry libraries is a powerful approach to aid the discovery of new chemical compounds able to interact with, and modulate the activities of, protein targets of interest. Split and pool synthesis provides for large and well diversified chemical libraries, in this case comprised of oligomers generated from a well-defined starting set. At the end of the synthesis, each bead in the library displays many copies of a unique oligomer sequence. Because the sequence of the oligomer is not known at the time of screening, methods for decoding of the sequence of each screening “hit” are essential. Here we describe an electron transfer dissociation (ETD) based tandem mass spectrometry approach for the decoding of mass-encoded split and pool libraries. We demonstrate that the newly described “chiral oligomers of pentenoic amides (COPAs)” yield non-sequence-specific product ions upon collisional activated dissociation; however, complete sequence information can be obtained with ETD. To aid in the decoding of libraries from MS and MS/MS data, we have incorporated 79Br/81Br isotope “tags” to differentiate N- and C-terminal product ions. In addition, we have created “Hit-Find,” a software program that allows users to generate libraries in silico. The user can then search all possible members of the chemical library for those that fall within a user-defined mass error. PMID:23636859

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

    PubMed Central

    Choi, Hye-Ji; Kim, Ye-Jin; Choi, Dong-Ki; Kim, Yong-Sung

    2015-01-01

    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. PMID:26675656

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

    PubMed

    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

  6. Distillative self-sorting of dynamic ester libraries.

    PubMed

    Ji, Qing; Miljanić, Ognjen Š

    2013-12-20

    Metal alkoxides, such as NaOt-Bu or Ti(OBu)4, can initiate acyl exchange within complex ester libraries. Reactive distillation of such dynamic combinatorial libraries (DCLs) isolates the most volatile ester at the expense of the less volatile library members that share a constituent with it. This process can be iteratively repeated to yield up to four industrially relevant esters as pure products from a single reaction setup. An algorithm has been developed to predict reactive distillation products in DCLs of as many as 121 members. PMID:24245808

  7. Biodegradable Fibrous Scaffolds with Diverse Properties by Electrospinning Candidates from a Combinatorial Macromer Library

    PubMed Central

    Metter, Robert B.; Ifkovits, Jamie L.; Hou, Kevin; Vincent, Ludovic; Hsu, Benjamin; Wang, Louis; Mauck, Robert L.; Burdick, Jason A.

    2009-01-01

    The properties of electrospun fibrous scaffolds, including degradation, mechanics and cellular interactions, are important for their use in tissue engineering applications. Although some diversity has been obtained previously in fibrous scaffolds, optimization of scaffold properties relies on iterative techniques in both polymer synthesis and processing. Here, we electrospun candidates from a combinatorial library of biodegradable and photopolymerizable poly(β-amino ester)s (PBAEs) to show that the diversity in properties found in this library is retained when processed into fibrous scaffolds. Specifically, three PBAE macromers were electrospun into scaffolds and possessed similar initial mechanical properties, but exhibited mass loss ranging from rapid (complete degradation within ∼2 weeks) to moderate (complete degradation within ∼ 3 months) to slow (only partial degradation after 3 months). These trends in mechanics and degradation mimicked what was previously observed in the bulk polymers. Although cellular adhesion was dependent on the polymer composition in films, adhesion to scaffolds that were electrospun with gelatin was similar on all formulations and controls. To further illustrate the diverse properties that are attainable in these systems, the fastest and slowest degrading polymers were electrospun together into one scaffold, but as distinct fiber populations. This dual-polymer scaffold exhibited behavior in mass loss and mechanics with time that fell between the single-polymer scaffolds. In general, this work indicates that combinatorial libraries may be an important source of information and specific polymer compositions for the fabrication of electrospun fibrous scaffolds with tunable properties. PMID:19853066

  8. Mapping protein-protein interactions with phage-displayed combinatorial peptide libraries and alanine scanning.

    PubMed

    Kokoszka, Malgorzata E; Kay, Brian K

    2015-01-01

    One avenue for inferring the function of a protein is to learn what proteins it may bind to in the cell. Among the various methodologies, one way for doing so is to affinity select peptide ligands from a phage-displayed combinatorial peptide library and then to examine if the proteins that carry such peptide sequences interact with the target protein in the cell. With the protocols described in this chapter, a laboratory with skills in microbiology, molecular biology, and protein biochemistry can readily identify peptides in the library that bind selectively, and with micromolar affinity, to a given target protein on the time scale of 2 months. To illustrate this approach, we use a library of bacteriophage M13 particles, which display 12-mer combinatorial peptides, to affinity select different peptide ligands for two different targets, the SH3 domain of the human Lyn protein tyrosine kinase and a segment of the yeast serine/threonine protein kinase Cbk1. The binding properties of the selected peptide ligands are then dissected by sequence alignment, Kunkel mutagenesis, and alanine scanning. Finally, the peptide ligands can be used to predict cellular interacting proteins and serve as the starting point for drug discovery. PMID:25616333

  9. Mapping protein-protein interactions with phage-displayed combinatorial peptide libraries.

    SciTech Connect

    Kay, B. K.; Castagnoli, L.; Biosciences Division; Univ. of Rome

    2003-01-01

    This unit describes the process and analysis of affinity selecting bacteriophage M13 from libraries displaying combinatorial peptides fused to either a minor or major capsid protein. Direct affinity selection uses target protein bound to a microtiter plate followed by purification of selected phage by ELISA. Alternatively, there is a bead-based affinity selection method. These methods allow one to readily isolate peptide ligands that bind to a protein target of interest and use the consensus sequence to search proteomic databases for putative interacting proteins.

  10. Dynamic combinatorial enrichment of polyconformational D-/L-peptide dimers.

    PubMed

    Jadhav, Kirtikumar B; Lichtenecker, Roman J; Bullach, Anke; Mandal, Bhubaneswar; Arndt, Hans-Dieter

    2015-04-01

    D-/L-peptides such as gramicidin A (gA) adopt unique dimeric β-helical structures of different topologies. To overcome their conformational promiscuity and enrich individual components, a dynamic combinatorial approach assisted by thiol tags was developed. This method led to identification of the preferential formation of antiparallel dimers under a broad range of conditions, which was independent of peptide side-chain polarity. Exclusive formation of an antiparallel cyclic dimer was achieved in the presence of cesium ions. PMID:25711604

  11. Comparative molecular surface analysis (CoMSA) for virtual combinatorial library screening of styrylquinoline HIV-1 blocking agents.

    PubMed

    Niedbala, Halina; Polanski, Jaroslaw; Gieleciak, Rafal; Musiol, Robert; Tabak, Dominik; Podeszwa, Barbara; Bak, Andrzej; Palka, Anna; Mouscadet, Jean-Francois; Gasteiger, Johann; Le Bret, Marc

    2006-12-01

    We used comparative molecular surface analysis to design molecules for the synthesis as part of the search for new HIV-1 integrase inhibitors. We analyzed the virtual combinatorial library (VCL) constituted from various moieties of styrylquinoline and styrylquinazoline inhibitors. Since imines can be applied in a strategy of dynamic combinatorial chemistry (DCC), we also tested similar compounds in which the -C=N- or -N=C- linker connected the heteroaromatic and aromatic moieties. We then used principal component analysis (PCA) or self-organizing maps (SOM), namely, the Kohonen neural networks to obtain a clustering plot analyzing the diversity of the VCL formed. Previously synthesized compounds of known activity, used as molecular probes, were projected onto this plot, which provided a set of promising virtual drugs. Moreover, we further modified the above mentioned VCL to include the single bond linker -C-N- or -N-C-. This allowed increasing compound stability but expanded also the diversity between the available molecular probes and virtual targets. The application of the CoMSA with SOM indicated important differences between such compounds and active molecular probes. We synthesized such compounds to verify the computational predictions. PMID:17168681

  12. Design of ultrasensitive probes for human neutrophil elastase through hybrid combinatorial substrate library profiling.

    PubMed

    Kasperkiewicz, Paulina; Poreba, Marcin; Snipas, Scott J; Parker, Heather; Winterbourn, Christine C; Salvesen, Guy S; Drag, Marcin

    2014-02-18

    The exploration of protease substrate specificity is generally restricted to naturally occurring amino acids, limiting the degree of conformational space that can be surveyed. We substantially enhanced this by incorporating 102 unnatural amino acids to explore the S1-S4 pockets of human neutrophil elastase. This approach provides hybrid natural and unnatural amino acid sequences, and thus we termed it the Hybrid Combinatorial Substrate Library. Library results were validated by the synthesis of individual tetrapeptide substrates, with the optimal substrate demonstrating more than three orders of magnitude higher catalytic efficiency than commonly used substrates of elastase. This optimal substrate was converted to an activity-based probe that demonstrated high selectivity and revealed the specific presence of active elastase during the process of neutrophil extracellular trap formation. We propose that this approach can be successfully used for any type of endopeptidase to deliver high activity and selectivity in substrates and probes. PMID:24550277

  13. Computational Fluid Dynamics Library

    Energy Science and Technology Software Center (ESTSC)

    2005-03-04

    CFDLib05 is the Los Alamos Computational Fluid Dynamics LIBrary. This is a collection of hydrocodes using a common data structure and a common numerical method, for problems ranging from single-field, incompressible flow, to multi-species, multi-field, compressible flow. The data structure is multi-block, with a so-called structured grid in each block. The numerical method is a Finite-Volume scheme employing a state vector that is fully cell-centered. This means that the integral form of the conservation lawsmore » is solved on the physical domain that is represented by a mesh of control volumes. The typical control volume is an arbitrary quadrilateral in 2D and an arbitrary hexahedron in 3D. The Finite-Volume scheme is for time-unsteady flow and remains well coupled by means of time and space centered fluxes; if a steady state solution is required, the problem is integrated forward in time until the user is satisfied that the state is stationary.« less

  14. A Robust and Versatile Method of Combinatorial Chemical Synthesis of Gene Libraries via Hierarchical Assembly of Partially Randomized Modules

    PubMed Central

    Popova, Blagovesta; Schubert, Steffen; Bulla, Ingo; Buchwald, Daniela; Kramer, Wilfried

    2015-01-01

    A major challenge in gene library generation is to guarantee a large functional size and diversity that significantly increases the chances of selecting different functional protein variants. The use of trinucleotides mixtures for controlled randomization results in superior library diversity and offers the ability to specify the type and distribution of the amino acids at each position. Here we describe the generation of a high diversity gene library using tHisF of the hyperthermophile Thermotoga maritima as a scaffold. Combining various rational criteria with contingency, we targeted 26 selected codons of the thisF gene sequence for randomization at a controlled level. We have developed a novel method of creating full-length gene libraries by combinatorial assembly of smaller sub-libraries. Full-length libraries of high diversity can easily be assembled on demand from smaller and much less diverse sub-libraries, which circumvent the notoriously troublesome long-term archivation and repeated proliferation of high diversity ensembles of phages or plasmids. We developed a generally applicable software tool for sequence analysis of mutated gene sequences that provides efficient assistance for analysis of library diversity. Finally, practical utility of the library was demonstrated in principle by assessment of the conformational stability of library members and isolating protein variants with HisF activity from it. Our approach integrates a number of features of nucleic acids synthetic chemistry, biochemistry and molecular genetics to a coherent, flexible and robust method of combinatorial gene synthesis. PMID:26355961

  15. Optical tools for high-throughput screening of abrasion resistance of combinatorial libraries of organic coatings

    NASA Astrophysics Data System (ADS)

    Potyrailo, Radislav A.; Chisholm, Bret J.; Olson, Daniel R.; Brennan, Michael J.; Molaison, Chris A.

    2002-02-01

    Design, validation, and implementation of an optical spectroscopic system for high-throughput analysis of combinatorially developed protective organic coatings are reported. Our approach replaces labor-intensive coating evaluation steps with an automated system that rapidly analyzes 8x6 arrays of coating elements that are deposited on a plastic substrate. Each coating element of the library is 10 mm in diameter and 2 to 5 micrometers thick. Performance of coatings is evaluated with respect to their resistance to wear abrasion because this parameter is one of the primary considerations in end-use applications. Upon testing, the organic coatings undergo changes that are impossible to quantitatively predict using existing knowledge. Coatings are abraded using industry-accepted abrasion test methods at single-or multiple-abrasion conditions, followed by high- throughput analysis of abrasion-induced light scatter. The developed automated system is optimized for the analysis of diffusively scattered light that corresponds to 0 to 30% haze. System precision of 0.1 to 2.5% relative standard deviation provides capability for the reliable ranking of coatings performance. While the system was implemented for high-throughput screening of combinatorially developed organic protective coatings for automotive applications, it can be applied to a variety of other applications where materials ranking can be achieved using optical spectroscopic tools.

  16. Characterization of new outer membrane proteins of Pseudomonas aeruginosa using a combinatorial peptide ligand library.

    PubMed

    Ben Mlouka, Mohamed Amine; Khemiri, Arbia; Seyer, Damien; Hardouin, Julie; Chan Tchi Song, Philippe; Dé, Emmanuelle; Jouenne, Thierry; Cosette, Pascal

    2015-02-01

    Most often, the use of ProteoMiner beads has been restricted to human serum proteins for the normalization of major proteins, such as albumin. However, there are other situations of interest in which the presence of major proteins would quench the signals of low abundance polypeptides. We propose the use of these beads for investigating the envelope of the gram-negative bacterium Pseudomonas aeruginosa. Initially, we performed comparative 2D electrophoresis to qualitatively evaluate the incidence of the normalization stage. This demonstrated a significant reduction of the major membrane proteins. Thereafter, using shotgun analysis, the same protein extract was targeted by using combinatorial peptide ligand library capture. This treatment yielded 154 additional outer membrane proteins (OMPs) uncovered by the study of the crude sample. PMID:25471289

  17. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates

    PubMed Central

    Vegas, Arturo J; Veiseh, Omid; Doloff, Joshua C; Ma, Minglin; Tam, Hok Hei; Bratlie, Kaitlin; Li, Jie; Bader, Andrew R; Langan, Erin; Olejnik, Karsten; Fenton, Patrick; Kang, Jeon Woong; Hollister-Locke, Jennifer; Bochenek, Matthew A; Chiu, Alan; Siebert, Sean; Tang, Katherine; Jhunjhunwala, Siddharth; Aresta-Dasilva, Stephanie; Dholakia, Nimit; Thakrar, Raj; Vietti, Thema; Chen, Michael; Cohen, Josh; Siniakowicz, Karolina; Qi, Meirigeng; McGarrigle, James; Graham, Adam C; Lyle, Stephen; Harlan, David M; Greiner, Dale L; Oberholzer, Jose; Weir, Gordon C; Langer, Robert; Anderson, Daniel G

    2016-01-01

    The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient1–6. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response. PMID:26807527

  18. HTS by NMR of Combinatorial Libraries: A Fragment-Based Approach to Ligand Discovery

    PubMed Central

    Wu, Bainan; Zhang, Ziming; Noberini, Roberta; Barile, Elisa; Giulianotti, Marc; Pinilla, Clemencia; Houghten, Richard A.; Pasquale, Elena B.; Pellecchia, Maurizio

    2014-01-01

    SUMMARY Fragment-based ligand design (FBLD) approaches have become more widely used in drug discovery projects from both academia and industry, and are even often preferred to traditional high-throughput screening (HTS) of large collection of compounds (>105). A key advantage of FBLD approaches is that these often rely on robust biophysical methods such as NMR spectroscopy for detection of ligand binding, hence are less prone to artifacts that too often plague the results from HTS campaigns. In this article, we introduce a screening strategy that takes advantage of both the robustness of protein NMR spectroscopy as the detection method, and the basic principles of combinatorial chemistry to enable the screening of large libraries of fragments (>105 compounds) preassembled on a common backbone. We used the method to identify compounds that target protein-protein interactions. PMID:23352136

  19. Utility of Redundant Combinatorial Libraries in Distinguishing High and Low Quality Screening Hits

    PubMed Central

    2014-01-01

    Large one-bead one-compound (OBOC) combinatorial libraries can be constructed relatively easily by solid-phase split and pool synthesis. The use of resins with hydrophilic surfaces, such as TentaGel, allows the beads to be used directly in screens for compounds that bind selectively to labeled proteins, nucleic acids, or other biomolecules. However, we have found that this method, while useful, has a high false positive rate. In other words, beads that are scored as hits often display compounds that prove to be poor ligands for the target of interest when they are resynthesized and carried through validation trials. This results in a significant waste of time and resources in cases where putative hits cannot be validated without resynthesis. Here, we report that this problem can be largely eliminated through the use of redundant OBOC libraries, where more than one bead displaying the same compound is present in the screen. We show that compounds isolated more than once are likely to be high quality ligands for the target of interest, whereas compounds isolated only once have a much higher likelihood of being poor ligands. While the use of redundant libraries does limit the number of unique compounds that can be screened at one time in this format, the overall savings in time, effort, and materials makes this a more efficient route to the isolation of useful ligands for biomolecules. PMID:24749624

  20. High-throughput flow cytometric screening of combinatorial chemistry bead libraries for proteomics and drug discovery

    NASA Astrophysics Data System (ADS)

    Leary, James F.; Reece, Lisa M.; Yang, Xian-Bin; Gorenstein, David

    2005-04-01

    For proteomics drug discovery applications, combinatorial microbead thioaptamer libraries (one thioaptamer sequence per bead) are being created by split synthesis method, creating a "proteomics library" of protein capture beads which can be analyzed by high-throughput screening methods in this case, flow cytometry and cell sorting. Thioaptamers, oligonucleotides with thiophosphate backbone substitutions, function like antibodies in terms of recognizing specific protein sequences but have a number of advantages over antibody libraries. These proteomics beads can then be analyzed by high-speed flow cytometry and sorted to single-bead level depending on relative fluorescence brightness of fluorescently-labeled proteins, or for a specific protein from all of the molecules of cell subpopulations being analyzed. The thioaptamer sequences on a given bead showing high affinity for that protein can then be sequenced. Alternatively, the protein-capturing beads can be analyzed by MALDI-TOF mass spectrometry for analysis of the bound proteins. The beads can be thought of as equivalent to single-element positions of a proteomics chip arrays but with the advantage of being able to much more rapidly analyze hundreds of millions of possible amino acid sequences/epitopes on the basis of thioaptamer sequence affinities to select single sequences of interest. Additionally, those beads can be manipulated and isolated at the single bead level by high-throughput flow cytometry/cell sorting for subsequent sequencing of the thioaptamer sequences.

  1. The pharmacological properties of a novel MCH1 receptor antagonist isolated from combinatorial libraries

    PubMed Central

    Nagasaki, Hiroshi; Chung, Shinjae; Dooley, Colette T.; Wang, Zhiwei; Li, Chunying; Saito, Yumiko; Clark, Stewart D; Houghten, Richard A.; Civelli, Olivier

    2009-01-01

    Melanin-concentrating hormone (MCH) is a neuropeptide that exhibits potent orexigenic activity. In rodents, it exerts its actions by interacting with one receptor, MCH1 receptor which is expressed in many parts of the central nervous system (CNS). To study the physiological implications of the MCH system, we need to be able to block it locally and acutely. This necessitates the use of MCH1 receptor antagonists. While MCH1 receptor antagonists have been previously reported, they are mainly not accessible to academic research. We apply here a strategy that leads to the isolation of a high affinity and selective MCH1 receptor antagonist amenable to in vivo analyses without further chemical modifications. This antagonist, TPI 1361-17, was identified through the screening of multiple non-peptide positional scanning synthetic combinatorial libraries (PS-SCL) totaling more than eight hundred thousand compounds in conditions that allow for the identification of only high-affinity compounds. TPI 1361-17 exhibited an IC50 value of 6.1 nM for inhibition of 1 nM MCH-induced Ca2+ mobilization and completely displaced the binding of [125I] MCH to rat MCH1 receptor. TPI 1361-17 was found specific, having no affinity for a variety of other G-protein coupled receptors and channels. TPI 1361-17 was found active in vivo since it blocked MCH-induced food intake by 75 %. Our results indicate that TPI 1361-17 is a novel and selective MCH1 receptor antagonist and is an effective tool to study the physiological functions of the MCH system. These results also illustrate the successful application of combinatorial library screening to identify specific surrogate antagonists in an academic setting. PMID:19041642

  2. Ligand-Based Peptide Design and Combinatorial Peptide Libraries to Target G Protein-Coupled Receptors

    PubMed Central

    Gruber, Christian W.; Muttenthaler, Markus; Freissmuth, Michael

    2016-01-01

    G protein-coupled receptors (GPCRs) are considered to represent the most promising drug targets; it has been repeatedly said that a large fraction of the currently marketed drugs elicit their actions by binding to GPCRs (with cited numbers varying from 30–50%). Closer scrutiny, however, shows that only a modest fraction of (~60) GPCRs are, in fact, exploited as drug targets, only ~20 of which are peptide-binding receptors. The vast majority of receptors in the humane genome have not yet been explored as sites of action for drugs. Given the drugability of this receptor class, it appears that opportunities for drug discovery abound. In addition, GPCRs provide for binding sites other than the ligand binding sites (referred to as the “orthosteric site”). These additional sites include (i) binding sites for ligands (referred to as “allosteric ligands”) that modulate the affinity and efficacy of orthosteric ligands, (ii) the interaction surface that recruits G proteins and arrestins, (iii) the interaction sites of additional proteins (GIPs, GPCR interacting proteins that regulate G protein signaling or give rise to G protein-independent signals). These sites can also be targeted by peptides. Combinatorial and natural peptide libraries are therefore likely to play a major role in identifying new GPCR ligands at each of these sites. In particular the diverse natural peptide libraries such as the venom peptides from marine cone-snails and plant cyclotides have been established as a rich source of drug leads. High-throughput screening and combinatorial chemistry approaches allow for progressing from these starting points to potential drug candidates. This will be illustrated by focusing on the ligand-based drug design of oxytocin (OT) and vasopressin (AVP) receptor ligands using natural peptide leads as starting points. PMID:20687879

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

    PubMed Central

    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

  4. Optimization of Combinatorial Mutagenesis

    NASA Astrophysics Data System (ADS)

    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

  5. A hybrid approach using chaotic dynamics and global search algorithms for combinatorial optimization problems

    NASA Astrophysics Data System (ADS)

    Igeta, Hideki; Hasegawa, Mikio

    Chaotic dynamics have been effectively applied to improve various heuristic algorithms for combinatorial optimization problems in many studies. Currently, the most used chaotic optimization scheme is to drive heuristic solution search algorithms applicable to large-scale problems by chaotic neurodynamics including the tabu effect of the tabu search. Alternatively, meta-heuristic algorithms are used for combinatorial optimization by combining a neighboring solution search algorithm, such as tabu, gradient, or other search method, with a global search algorithm, such as genetic algorithms (GA), ant colony optimization (ACO), or others. In these hybrid approaches, the ACO has effectively optimized the solution of many benchmark problems in the quadratic assignment problem library. In this paper, we propose a novel hybrid method that combines the effective chaotic search algorithm that has better performance than the tabu search and global search algorithms such as ACO and GA. Our results show that the proposed chaotic hybrid algorithm has better performance than the conventional chaotic search and conventional hybrid algorithms. In addition, we show that chaotic search algorithm combined with ACO has better performance than when combined with GA.

  6. Double Dutch: A Tool for Designing Combinatorial Libraries of Biological Systems.

    PubMed

    Roehner, Nicholas; Young, Eric M; Voigt, Christopher A; Gordon, D Benjamin; Densmore, Douglas

    2016-06-17

    Recently, semirational approaches that rely on combinatorial assembly of characterized DNA components have been used to engineer biosynthetic pathways. In practice, however, it is not practical to assemble and test millions of pathway variants in order to elucidate how different DNA components affect the behavior of a pathway. To address this challenge, we apply a rigorous mathematical approach known as design of experiments (DOE) that can be used to construct empirical models of system behavior without testing all variants. To support this approach, we have developed a tool named Double Dutch, which uses a formal grammar and heuristic algorithms to automate the process of DOE library design. Compared to designing by hand, Double Dutch enables users to more efficiently and scalably design libraries of pathway variants that can be used in a DOE framework and uniquely provides a means to flexibly balance design considerations of statistical analysis, construction cost, and risk of homologous recombination, thereby demonstrating the utility of automating decision making when faced with complex design trade-offs. PMID:27110633

  7. Inhibition of multidrug resistant Listeria monocytogenes by peptides isolated from combinatorial phage display libraries.

    PubMed

    Flachbartova, Z; Pulzova, L; Bencurova, E; Potocnakova, L; Comor, L; Bednarikova, Z; Bhide, M

    2016-01-01

    The aim of the study was to isolate and characterize novel antimicrobial peptides from peptide phage library with antimicrobial activity against multidrug resistant Listeria monocytogenes. Combinatorial phage-display library was used to affinity select peptides binding to the cell surface of multidrug resistant L. monocytogenes. After several rounds of affinity selection followed by sequencing, three peptides were revealed as the most promising candidates. Peptide L2 exhibited features common to antimicrobial peptides (AMPs), and was rich in Asp, His and Lys residues. Peptide L3 (NSWIQAPDTKSI), like peptide L2, inhibited bacterial growth in vitro, without any hemolytic or cytotoxic effects on eukaryotic cells. L1 peptide showed no inhibitory effect on Listeria. Structurally, peptides L2 and L3 formed random coils composed of α-helix and β-sheet units. Peptides L2 and L3 exhibited antimicrobial activity against multidrug resistant isolates of L. monocytogenes with no haemolytic or toxic effects. Both peptides identified in this study have the potential to be beneficial in human and veterinary medicine. PMID:27296960

  8. A combinatorial histidine scanning library approach to engineer highly pH-dependent protein switches

    SciTech Connect

    Murtaugh, Megan L.; Fanning, Sean W.; Sharma, Tressa M.; Terry, Alexandra M.; Horn, James R.

    2012-09-05

    There is growing interest in the development of protein switches, which are proteins whose function, such as binding a target molecule, can be modulated through environmental triggers. Efforts to engineer highly pH sensitive protein-protein interactions typically rely on the rational introduction of ionizable groups in the protein interface. Such experiments are typically time intensive and often sacrifice the protein's affinity at the permissive pH. The underlying thermodynamics of proton-linkage dictate that the presence of multiple ionizable groups, which undergo a pK{sub a} change on protein binding, are necessary to result in highly pH-dependent binding. To test this hypothesis, a novel combinatorial histidine library was developed where every possible combination of histidine and wild-type residue is sampled throughout the interface of a model anti-RNase A single domain VHH antibody. Antibodies were coselected for high-affinity binding and pH-sensitivity using an in vitro, dual-function selection strategy. The resulting antibodies retained near wild-type affinity yet became highly sensitive to small decreases in pH, drastically decreasing their binding affinity, due to the incorporation of multiple histidine groups. Several trends were observed, such as histidine 'hot-spots,' which will help enhance the development of pH switch proteins as well as increase our understanding of the role of ionizable residues in protein interfaces. Overall, the combinatorial approach is rapid, general, and robust and should be capable of producing highly pH-sensitive protein affinity reagents for a number of different applications.

  9. Identification of avocado (Persea americana) pulp proteins by nano-LC-MS/MS via combinatorial peptide ligand libraries.

    PubMed

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

    2012-09-01

    Avocado (Persea americana) proteins have been scarcely studied despite their importance, especially in food related allergies. The proteome of avocado pulp was explored in depth by extracting proteins with capture by combinatorial peptide ligand libraries at pH 7.4 and under conditions mimicking reverse-phase capture at pH 2.2. The total number of unique gene products identified amounts to 1012 proteins, of which 174 are in common with the control, untreated sample, 190 are present only in the control and 648 represent the new species detected via combinatorial peptide ligand libraries of all combined eluates and likely represent low-abundance proteins. Among the 1012 proteins, it was possible to identify the already known avocado allergen Pers a 1 and different proteins susceptible to be allergens such as a profilin, a polygalacturonase, a thaumatin-like protein, a glucanase, and an isoflavone reductase like protein. PMID:23019098

  10. Review of high-throughput techniques for detecting solid phase Transformation from material libraries produced by combinatorial methods

    NASA Technical Reports Server (NTRS)

    Lee, Jonathan A.

    2005-01-01

    High-throughput measurement techniques are reviewed for solid phase transformation from materials produced by combinatorial methods, which are highly efficient concepts to fabricate large variety of material libraries with different compositional gradients on a single wafer. Combinatorial methods hold high potential for reducing the time and costs associated with the development of new materials, as compared to time-consuming and labor-intensive conventional methods that test large batches of material, one- composition at a time. These high-throughput techniques can be automated to rapidly capture and analyze data, using the entire material library on a single wafer, thereby accelerating the pace of materials discovery and knowledge generation for solid phase transformations. The review covers experimental techniques that are applicable to inorganic materials such as shape memory alloys, graded materials, metal hydrides, ferric materials, semiconductors and industrial alloys.

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed

    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. PMID:23161558

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

    PubMed

    Rus, Eric D; Wang, Hongsen; Legard, Anna E; Ritzert, Nicole L; Van Dover, Robert Bruce; 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. PMID:23464226

  14. Combinatorial engineering to enhance amylosucrase performance: construction, selection, and screening of variant libraries for increased activity.

    PubMed

    van der Veen, Bart A; Potocki-Véronèse, Gabrielle; Albenne, Cécile; Joucla, Gilles; Monsan, Pierre; Remaud-Simeon, Magali

    2004-02-27

    Amylosucrase is a glucosyltransferase belonging to family 13 of glycoside hydrolases and catalyses the formation of an amylose-type polymer from sucrose. Its potential use as an industrial tool for the synthesis or the modification of polysaccharides, however, is limited by its low catalytic efficiency on sucrose alone, its low stability, and its side reactions resulting in sucrose isomer formation. Therefore, combinatorial engineering of the enzyme through random mutagenesis, gene shuffling, and selective screening (directed evolution) was started, in order to generate more efficient variants of the enzyme. A convenient zero background expression cloning strategy was developed. Mutant gene libraries were generated by error-prone polymerase chain reaction (PCR), using Taq polymerase with unbalanced dNTPs or Mutazyme trade mark, followed by recombination of the PCR products by DNA shuffling. A selection method was developed to allow only the growth of amylosucrase active clones on solid mineral medium containing sucrose as the sole carbon source. Automated protocols were designed to screen amylosucrase activity from mini-cultures using dinitrosalicylic acid staining of reducing sugars and iodine staining of amylose-like polymer. A pilot experiment using the described mutagenesis, selection, and screening methods yielded two variants with significantly increased activity (five-fold under the screening conditions). Sequence analysis of these variants revealed mutations in amino acid residues which would not be considered for rational design of improved amylosucrase variants. A method for the characterisation of amylosucrase action on sucrose, consisting of accurate measurement of glucose and fructose concentrations, was introduced. This allows discrimination between hydrolysis and transglucosylation, enabling a more detailed comparison between wild-type and mutant enzymes. PMID:14988004

  15. Laser direct writing of combinatorial libraries of idealized cellular constructs: Biomedical applications

    NASA Astrophysics Data System (ADS)

    Schiele, Nathan R.; Koppes, Ryan A.; Corr, David T.; Ellison, Karen S.; Thompson, Deanna M.; Ligon, Lee A.; Lippert, Thomas K. M.; Chrisey, Douglas B.

    2009-03-01

    The ability to control cell placement and to produce idealized cellular constructs is essential for understanding and controlling intercellular processes and ultimately for producing engineered tissue replacements. We have utilized a novel intra-cavity variable aperture excimer laser operated at 193 nm to reproducibly direct write mammalian cells with micrometer resolution to form a combinatorial array of idealized cellular constructs. We deposited patterns of human dermal fibroblasts, mouse myoblasts, rat neural stem cells, human breast cancer cells, and bovine pulmonary artery endothelial cells to study aspects of collagen network formation, breast cancer progression, and neural stem cell proliferation, respectively. Mammalian cells were deposited by matrix assisted pulsed laser evaporation direct write from ribbons comprised of a UV transparent quartz coated with either a thin layer of extracellular matrix or triazene as a dynamic release layer using CAD/CAM control. We demonstrate that through optical imaging and incorporation of a machine vision algorithm, specific cells on the ribbon can be laser deposited in spatial coherence with respect to geometrical arrays and existing cells on the receiving substrate. Having the ability to direct write cells into idealized cellular constructs can help to answer many biomedical questions and advance tissue engineering and cancer research.

  16. High-throughput measurements of thermochromic behavior in V(1-x)Nb(x)O(2) combinatorial thin film libraries.

    PubMed

    Barron, S C; Gorham, J M; Patel, M P; Green, M L

    2014-10-13

    We describe a high-throughput characterization of near-infrared thermochromism in V1-xNbxO2 combinatorial thin film libraries. The oxide thin film library was prepared with a VO2 crystal structure and a continuous gradient in composition with Nb concentrations in the range of less than 1% to 45%. The thermochromic phase transition from monoclinic to tetragonal was characterized by the accompanying change in near-infrared reflectance. With increasing Nb substitution, the transition temperature was depressed from 65 to 35 °C, as desirable for smart window applications. However, the magnitude of the reflectance change across the thermochromic transition was also reduced with increasing Nb film content. Data collection, handling, and analysis supporting thermochromic characterization were fully automated to achieve high throughput. Using this system, in 14 h, temperature-dependent infrared reflectances were measured at 165 arbitrary locations on a thin film combinatorial library; these measurements were analyzed for thermochromic transitions in minutes. PMID:25180465

  17. Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens.

    PubMed

    Fleeman, Renee; LaVoi, Travis M; Santos, Radleigh G; Morales, Angela; Nefzi, Adel; Welmaker, Gregory S; Medina-Franco, José L; Giulianotti, Marc A; Houghten, Richard A; Shaw, Lindsey N

    2015-04-23

    Mixture based synthetic combinatorial libraries offer a tremendous enhancement for the rate of drug discovery, allowing the activity of millions of compounds to be assessed through the testing of exponentially fewer samples. In this study, we used a scaffold-ranking library to screen 37 different libraries for antibacterial activity against the ESKAPE pathogens. Each library contained between 10000 and 750000 structural analogues for a total of >6 million compounds. From this, we identified a bis-cyclic guanidine library that displayed strong antibacterial activity. A positional scanning library for these compounds was developed and used to identify the most effective functional groups at each variant position. Individual compounds were synthesized that were broadly active against all ESKAPE organisms at concentrations <2 μM. In addition, these compounds were bactericidal, had antibiofilm effects, showed limited potential for the development of resistance, and displayed almost no toxicity when tested against human lung cells and erythrocytes. Using a murine model of peritonitis, we also demonstrate that these agents are highly efficacious in vivo. PMID:25780985

  18. Computational redesign of bacterial biotin carboxylase inhibitors using structure-based virtual screening of combinatorial libraries.

    PubMed

    Brylinski, Michal; Waldrop, Grover L

    2014-01-01

    As the spread of antibiotic resistant bacteria steadily increases, there is an urgent need for new antibacterial agents. Because fatty acid synthesis is only used for membrane biogenesis in bacteria, the enzymes in this pathway are attractive targets for antibacterial agent development. Acetyl-CoA carboxylase catalyzes the committed and regulated step in fatty acid synthesis. In bacteria, the enzyme is composed of three distinct protein components: biotin carboxylase, biotin carboxyl carrier protein, and carboxyltransferase. Fragment-based screening revealed that amino-oxazole inhibits biotin carboxylase activity and also exhibits antibacterial activity against Gram-negative organisms. In this report, we redesigned previously identified lead inhibitors to expand the spectrum of bacteria sensitive to the amino-oxazole derivatives by including Gram-positive species. Using 9,411 small organic building blocks, we constructed a diverse combinatorial library of 1.2×10⁸ amino-oxazole derivatives. A subset of 9×10⁶ of these compounds were subjected to structure-based virtual screening against seven biotin carboxylase isoforms using similarity-based docking by eSimDock. Potentially broad-spectrum antibiotic candidates were selected based on the consensus ranking by several scoring functions including non-linear statistical models implemented in eSimDock and traditional molecular mechanics force fields. The analysis of binding poses of the top-ranked compounds docked to biotin carboxylase isoforms suggests that: (1) binding of the amino-oxazole anchor is stabilized by a network of hydrogen bonds to residues 201, 202 and 204; (2) halogenated aromatic moieties attached to the amino-oxazole scaffold enhance interactions with a hydrophobic pocket formed by residues 157, 169, 171 and 203; and (3) larger substituents reach deeper into the binding pocket to form additional hydrogen bonds with the side chains of residues 209 and 233. These structural insights into drug

  19. Optimization of combinatorial mutagenesis.

    PubMed

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

    2011-11-01

    Protein engineering by combinatorial site-directed mutagenesis evaluates a portion of the sequence space near a target protein, seeking variants with improved properties (e.g., stability, activity, immunogenicity). 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

  20. Heuristic Implementation of Dynamic Programming for Matrix Permutation Problems in Combinatorial Data Analysis

    ERIC Educational Resources Information Center

    Brusco, Michael J.; Kohn, Hans-Friedrich; Stahl, Stephanie

    2008-01-01

    Dynamic programming methods for matrix permutation problems in combinatorial data analysis can produce globally-optimal solutions for matrices up to size 30x30, but are computationally infeasible for larger matrices because of enormous computer memory requirements. Branch-and-bound methods also guarantee globally-optimal solutions, but computation…

  1. Recombinant human antibodies: linkage of an Fab fragment from a combinatorial library to an Fc fragment for expression in mammalian cell culture.

    PubMed

    Bender, E; Woof, J M; Atkin, J D; Barker, M D; Bebbington, C R; Burton, D R

    1993-04-01

    The combinatorial phage library approach to immunoglobulin repertoire cloning recently made it possible to isolate gene fragments encoding human immunoglobulin G1 Fabs binding with high affinity to specific antigens. Here we describe the construction of genes encoding whole human anti-tetanus toxoid antibodies based on one of these gene fragments and the efficient expression of these constructs by co-transfection of separate heavy and light chain vectors into a Chinese hamster ovary cell line constitutively expressing a viral transactivator protein. This system will be generally useful for the rapid analysis of recombinant antibodies derived from combinatorial libraries. PMID:8518367

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

    PubMed

    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). PMID:22738629

  3. Development of combinatorial chemistry methods for coatings: high-throughput screening of abrasion resistance of coatings libraries.

    PubMed

    Potyrailo, Radislav A; Chisholm, Bret J; Olson, Daniel R; Brennan, Michael J; Molaison, Chris A

    2002-10-01

    Design, validation, and implementation of an optical spectroscopic system for high-throughput analysis of combinatorially developed protective organic coatings are reported. Our approach replaces labor-intensive coating evaluation steps with an automated system that rapidly analyzes 8 x 6 arrays of coating elements that are discretely deposited on a single plastic substrate. Each coating element of the library is 10 mm in diameter and 2-5 microm thick. Performance of coatings is evaluated with respect to their resistance to wear abrasion because this parameter is one of the primary considerations in end-use applications. Upon testing, the coating materials undergo changes that are impossible to quantitatively predict using existing knowledge. Coatings are abraded using industry-accepted abrasion test methods at a single or multiple abrasion conditions followed by the high-throughput analysis of abrasion-induced light scatter. The developed automated system is optimized for the analysis of diffusively scattered light that corresponds to 0-30% haze. System precision of 0.1-2.5% relative standard deviation provides capability for the reliable ranking of coatings performance. Although the system was implemented for high-throughput screening of combinatorially developed organic protective coatings for automotive applications, it can be applied for a variety of other applications for which materials ranking can be achieved using optical spectroscopic tools. PMID:12380837

  4. Combinatorial insulin secretion dynamics of recombinant hepatic and enteroendocrine cells.

    PubMed

    Durvasula, Kiranmai; Thulé, Peter M; Sambanis, Athanassios

    2012-04-01

    One of the most promising cell-based therapies for combating insulin-dependent diabetes entails the use of genetically engineered non-β cells that secrete insulin in response to physiologic stimuli. A normal pancreatic β cell secretes insulin in a biphasic manner in response to glucose. The first phase is characterized by a transient stimulation of insulin to rapidly lower the blood glucose levels, which is followed by a second phase of insulin secretion to sustain the lowered blood glucose levels over a longer period of time. Previous studies have demonstrated hepatic and enteroendocrine cells to be appropriate hosts for recombinant insulin expression. Due to different insulin secretion kinetics from these cells, we hypothesized that a combination of the two cell types would mimic the biphasic insulin secretion of normal β cells with higher fidelity than either cell type alone. In this study, insulin secretion experiments were conducted with two hepatic cell lines (HepG2 and H4IIE) transduced with 1 of 3 adenoviruses expressing the insulin transgene and with a stably transfected recombinant intestinal cell line (GLUTag-INS). Insulin secretion was stimulated by exposing the cells to glucose only (hepatic cells), meat hydrolysate only (GLUTag-INS), or to a cocktail of the two secretagogues. It was found experimentally that the recombinant hepatic cells secreted insulin in a more sustained manner, whereas the recombinant intestinal cell line exhibited rapid insulin secretion kinetics upon stimulation. The insulin secretion profiles were computationally combined at different cell ratios to arrive at the combinatorial kinetics. Results indicate that combinations of these two cell types allow for tuning the first and second phase of insulin secretion better than either cell type alone. This work provides the basic framework in understanding the secretion kinetics of the combined system and advances it towards preclinical studies. PMID:22094821

  5. Combinatorial Insulin Secretion Dynamics of Recombinant Hepatic and Enteroendocrine Cells

    PubMed Central

    Durvasula, Kiranmai; Thulé, Peter M.; Sambanis, Athanassios

    2012-01-01

    One of the more promising cell-based therapies for combating insulin-dependent diabetes entails the use of genetically engineered non-β cells that secrete insulin in response to physiologic stimuli. A normal pancreatic β cell secretes insulin in a biphasic manner in response to glucose. The first phase is characterized by a transient stimulation of insulin to rapidly lower the blood glucose levels, which is followed by a second phase of insulin secretion to sustain the lowered blood glucose levels over a longer period of time. Previous studies have demonstrated hepatic and enteroendocrine cells to be appropriate hosts for recombinant insulin expression. Due to different insulin secretion kinetics from these cells, we hypothesized that a combination of the two cell types would mimic the biphasic insulin secretion of normal β cells with higher fidelity than either cell type alone. In this study, insulin secretion experiments were conducted with two hepatic cell lines (HepG2 and H4IIE) transduced with one of three adenoviruses expressing the insulin transgene and with a stably transfected recombinant intestinal cell line (GLUTag-INS). Insulin secretion was stimulated by exposing the cells to glucose only (hepatic cells), meat hydrolysate only (GLUTag-INS), or to a cocktail of the two secretagogues. It was found experimentally that the recombinant hepatic cells secreted insulin in a more sustained manner, whereas the recombinant intestinal cell line exhibited rapid insulin secretion kinetics upon stimulation. The insulin secretion profiles were computationally combined at different cell ratios to arrive at the combinatorial kinetics. Results indicate that combinations of these two cell types allow for tuning the first and second phase of insulin secretion better than either cell type alone. This work provides the basic framework in understanding the secretion kinetics of the combined system and advances it towards pre-clinical studies. PMID:22094821

  6. An apparatus for spatially resolved, temperature dependent reflectance measurements for identifying thermochromism in combinatorial thin film libraries

    NASA Astrophysics Data System (ADS)

    Barron, S. C.; Patel, M. P.; Nguyen, Nam; Nguyen, N. V.; Green, M. L.

    2015-11-01

    A metrology and data analysis protocol is described for high throughput determination of thermochromic metal-insulator phase diagrams for lightly substituted VO2 thin films. The technique exploits the abrupt change in near infrared optical properties, measured in reflection, as an indicator of the temperature- or impurity-driven metal-insulator transition. Transition metal impurities were introduced in a complementary combinatorial synthesis process for producing thin film libraries with the general composition space V 1-x-yMxM'yO2, with M and M' being transition metals and x and y varying continuously across the library. The measurement apparatus acquires reflectance spectra in the visible or near infrared at arbitrarily many library locations, each with a unique film composition, at temperatures of 1 °C-85 °C. Data collection is rapid and automated; the measurement protocol is computer controlled to automate the collection of thousands of reflectance spectra, representing hundreds of film compositions at tens of different temperatures. A straightforward analysis algorithm is implemented to extract key information from the thousands of spectra such as near infrared thermochromic transition temperatures and regions of no thermochromic transition; similarly, reflectance to the visible spectrum generates key information for materials selection of smart window materials. The thermochromic transition for 160 unique compositions on a thin film library with the general formula V 1-x-yMxM'yO2 can be measured and described in a single 20 h experiment. The resulting impurity composition-temperature phase diagrams will contribute to the understanding of metal-insulator transitions in doped VO2 systems and to the development of thermochromic smart windows.

  7. An apparatus for spatially resolved, temperature dependent reflectance measurements for identifying thermochromism in combinatorial thin film libraries.

    PubMed

    Barron, S C; Patel, M P; Nguyen, Nam; Nguyen, N V; Green, M L

    2015-11-01

    A metrology and data analysis protocol is described for high throughput determination of thermochromic metal-insulator phase diagrams for lightly substituted VO2 thin films. The technique exploits the abrupt change in near infrared optical properties, measured in reflection, as an indicator of the temperature- or impurity-driven metal-insulator transition. Transition metal impurities were introduced in a complementary combinatorial synthesis process for producing thin film libraries with the general composition space V(1-x-y)M(x)M'(y)O2, with M and M' being transition metals and x and y varying continuously across the library. The measurement apparatus acquires reflectance spectra in the visible or near infrared at arbitrarily many library locations, each with a unique film composition, at temperatures of 1 °C-85 °C. Data collection is rapid and automated; the measurement protocol is computer controlled to automate the collection of thousands of reflectance spectra, representing hundreds of film compositions at tens of different temperatures. A straightforward analysis algorithm is implemented to extract key information from the thousands of spectra such as near infrared thermochromic transition temperatures and regions of no thermochromic transition; similarly, reflectance to the visible spectrum generates key information for materials selection of smart window materials. The thermochromic transition for 160 unique compositions on a thin film library with the general formula V(1-x-y)M(x)M'(y)O2 can be measured and described in a single 20 h experiment. The resulting impurity composition-temperature phase diagrams will contribute to the understanding of metal-insulator transitions in doped VO2 systems and to the development of thermochromic smart windows. PMID:26628147

  8. Cleavage of highly structured viral RNA molecules by combinatorial libraries of hairpin ribozymes. The most effective ribozymes are not predicted by substrate selection rules.

    PubMed

    Yu, Q; Pecchia, D B; Kingsley, S L; Heckman, J E; Burke, J M

    1998-09-01

    Combinatorial libraries of hairpin ribozymes representing all possible cleavage specificities (>10(5)) were used to evaluate all ribozyme cleavage sites within a large (4.2-kilobase) and highly structured viral mRNA, the 26 S subgenomic RNA of Sindbis virus. The combinatorial approach simultaneously accounts for target site structure and dynamics, together with ribozyme folding, and the sequences that result in a ribozyme-substrate complex with maximal activity. Primer extension was used to map and rank the relative activities of the ribozyme pool against individual sites and revealed two striking findings. First, only a small fraction of potential recognition sites are effectively cleaved (activity-selected sites). Second, nearly all of the most effectively cleaved sites deviated substantially from the established consensus selection rules for the hairpin ribozyme and were not predicted by examining the sequence, or through the use of computer-assisted predictions of RNA secondary structure. In vitro selection methods were used to isolate ribozymes with increased activity against substrates that deviate from the GUC consensus sequence. trans-Acting ribozymes targeting nine of the activity-selected sites were synthesized, together with ribozymes targeting four sites with a perfect match to the cleavage site consensus (sequence-selected sites). Activity-selected ribozymes have much higher cleavage activity against the long, structured RNA molecules than do sequence-selected ribozymes, although the latter are effective in cleaving oligoribonucleotides, as predicted. These results imply that, for Sindbis virus 26 S RNA, designing ribozymes based on matches to the consensus sequence may be an ineffective strategy. PMID:9722591

  9. Sequence-specific Ni(II)-dependent peptide bond hydrolysis for protein engineering. Combinatorial library determination of optimal sequences.

    PubMed

    Krezel, Artur; Kopera, Edyta; Protas, Anna Maria; Poznański, Jarosław; Wysłouch-Cieszyńska, Aleksandra; Bal, Wojciech

    2010-03-17

    Previously we demonstrated for several examples that peptides having a general internal sequence R(N)-Yaa-Ser/Thr-Xaa-His-Zaa-R(C) (Yaa = Glu or Ala, Xaa = Ala or His, Zaa = Lys, R(N) and R(C) = any N- and C-terminal amino acid sequence) were hydrolyzed specifically at the Yaa-Ser/Thr peptide bond in the presence of Ni(II) ions at alkaline pH (Krezel, A., Mylonas, M., Kopera, E. and Bal, E. Acta Biochim. Polon. 2006, 53, 721-727 and references therein). Hereby we report the synthesis of a combinatorial library of CH(3)CO-Gly-Ala-(Ser/Thr)-Xaa-His-Zaa-Lys-Phe-Leu-NH(2) peptides, where Xaa residues included 17 common alpha-amino acids (except Asp, Glu, and Cys) and Zaa residues included 19 common alpha-amino acids (except Cys). The Ni(II)-dependent hydrolysis at 37 and 45 degrees C of batches of combinatorial peptide mixtures randomized at Zaa was monitored by MALDI-TOF mass spectrometry. The correctness of library-based predictions was confirmed by accurate measurements of hydrolysis rates of seven selected peptides using HPLC. The hydrolysis was strictly limited to the Ala-Ser/Thr bond in all library and individual peptide experiments. The effects of individual residues on hydrolysis rates were quantified and correlated with physical properties of their side chains according to a model of independent contributions of Xaa and Zaa residues. The principal component analysis calculations demonstrated partial molar side chain volume and the free energy of amino acid vaporization for both Xaa and Zaa residues and the amine pK(a) for Zaa residues to be the most significant empirical parameters influencing the hydrolysis rate. Therefore, efficient hydrolysis required bulky and hydrophobic residues at both variable positions Xaa and Zaa, which contributed independently to the hydrolysis rate. This relationship between the peptide sequence and the hydrolysis rate provides a basis for further research, aimed at the elucidation of the reaction mechanism and biotechnological

  10. Preparation of pseudo-ternary library by combinatorial robot system based on wet and dry processes

    NASA Astrophysics Data System (ADS)

    Fujimoto, Kenjiro; Watanabe, Mamoru

    2005-01-01

    A fully automatic combinatorial robot system was developed for investigating inorganic materials. The system can prepare and characterize about 200 samples in 1 day. The phase relation of the pseudo-ternary LiO0.5-X-TiO2 (X: CrO1.5, FeO1.5 and NiO) system was investigated in order to determine the formation range of ramsdellite structures. A wider composition range was obtained for the ramsdellite-type compounds in the LiO0.5-CrO1.5-TiO2 system than for other compounds. It was found that the differences in the composition ranges for ramsdellite-type structures were caused by the different ionic radii of Cr3+, Fe3+ and Ni2+ in the octahedral site.

  11. A generic approach to engineer antibody pH-switches using combinatorial histidine scanning libraries and yeast display

    PubMed Central

    Schröter, Christian; Günther, Ralf; Rhiel, Laura; Becker, Stefan; Toleikis, Lars; Doerner, Achim; Becker, Janine; Schönemann, Andreas; Nasu, Daichi; Neuteboom, Berend; Kolmar, Harald; Hock, Björn

    2015-01-01

    There is growing interest in the fast and robust engineering of protein pH-sensitivity that aims to reduce binding at acidic pH, compared to neutral pH. Here, we describe a novel strategy for the incorporation of pH-sensitive antigen binding functions into antibody variable domains using combinatorial histidine scanning libraries and yeast surface display. The strategy allows simultaneous screening for both, high affinity binding at pH 7.4 and pH-sensitivity, and excludes conventional negative selection steps. As proof of concept, we applied this strategy to incorporate pH-dependent antigen binding into the complementary-determining regions of adalimumab. After 3 consecutive rounds of separate heavy and light chain library screening, pH-sensitive variants could be isolated. Heavy and light chain mutations were combined, resulting in 3 full-length antibody variants that revealed sharp, reversible pH-dependent binding profiles. Dissociation rate constants at pH 6.0 increased 230- to 780-fold, while high affinity binding at pH 7.4 in the sub-nanomolar range was retained. Furthermore, binding to huFcRn and thermal stability were not affected by histidine substitutions. Overall, this study emphasizes a generalizable strategy for engineering pH-switch functions potentially applicable to a variety of antibodies and further proteins-based therapeutics. PMID:25523975

  12. Discovery of a Direct Ras Inhibitor by Screening a Combinatorial Library of Cell-Permeable Bicyclic Peptides

    PubMed Central

    2015-01-01

    Cyclic peptides have great potential as therapeutic agents and research tools. However, their applications against intracellular targets have been limited, because cyclic peptides are generally impermeable to the cell membrane. It was previously shown that fusion of cyclic peptides with a cyclic cell-penetrating peptide resulted in cell-permeable bicyclic peptides that are proteolytically stable and biologically active in cellular assays. In this work, we tested the generality of the bicyclic approach by synthesizing a combinatorial library of 5.7 × 106 bicyclic peptides featuring a degenerate sequence in the first ring and an invariant cell-penetrating peptide in the second ring. Screening of the library against oncoprotein K-Ras G12V followed by hit optimization produced a moderately potent and cell-permeable K-Ras inhibitor, which physically blocks the Ras-effector interactions in vitro, inhibits the signaling events downstream of Ras in cancer cells, and induces apoptosis of the cancer cells. Our approach should be generally applicable to developing cell-permeable bicyclic peptide inhibitors against other intracellular proteins. PMID:26645887

  13. Enzyme-mediated spatial segregation on individual polymeric support beads: application to generation and screening of encoded combinatorial libraries.

    PubMed Central

    Vágner, J; Barany, G; Lam, K S; Krchnák, V; Sepetov, N F; Ostrem, J A; Strop, P; Lebl, M

    1996-01-01

    Proteolysis of short N alpha-protected peptide substrates bound to polyoxyethylene-polystyrene beads releases selectively free amino sites in the enzyme-accessible "surface" area. The substantial majority of functional sites in the "interior" of the polymeric support are not reached by the enzyme and remain uncleaved (protected). Subsequent synthesis with two classes of orthogonal protecting groups-N alpha-tert-butyloxycarbonyl (Boc) and N alpha-9-fluorenylmethyloxy-carbonyl (Fmoc)-allows generation of two structures on the same bead. The surface structure is available for receptor interactions, whereas the corresponding interior structure is used for coding. Coding structures are usually readily sequenceable peptides. This "shaving" methodology was illustrated by the preparation of a peptide-encoded model peptide combinatorial library containing 1.0 x 10(5) members at approximately 6-fold degeneracy. From this single library, good ligands were selected for three different receptors: anti-beta-endorphin anti-body, streptavidin, and thrombin, and the binding structures were deduced correctly by sequencing the coding peptides present on the same beads. PMID:8710846

  14. Combinatorial synthesis, lead identification, and antitumor study of a chalcone-based positional-scanning library.

    PubMed

    Ullah, Ahsan; Ansari, Farzana Latif; Nazir, Samina; Mirza, Bushra

    2007-02-01

    A 175-member chalcone library was designed and synthesized from seven differently substituted acetophenones (A(1)-A(7)) and 25 differently substituted aryl or heteroaryl aldehydes (B(1)-B(25)). Potential lead compounds were identified by deconvolution of a two-dimensional library matrix via positional scanning, and the members of the most-active sub-libraries were synthesized and screened against crown-gall tumors with the aid of the potato-disc assay. The resulting hits gave rise to significant antitumor activities, with no antibacterial effect on the tumor-producing bacterium Agrobacterium tumefaciens. Two identified lead structures, (2E)-3-(2-chlorophenyl)-1-phenylprop-2-en-1-one (A(1)B(9)) and the hydroxy analogue (2E)-3-(2-chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (A(2)B(9)), are promising candidates to be developed into highly effective anticancer chemotherapeutics. PMID:17311221

  15. Site-specific Labeling of a Protein Lysine Residue By Novel Kinetic Labeling Combinatorial Libraries

    PubMed Central

    Krantz, Allen; Hanel, Arthur M; Strug, Ivona; Wilczynski, Andrzej; Wolff, Jeremy J; Huang, Wolin; Huang, Linda H; Settineri, Tina; Holmes, Darren L; Hardy, Margaret C; Bridon, Dominique P

    2014-01-01

    The first example of a kinetic labeling library designed to enable the discovery of affinity labels is presented. Each library component (1) consists of a variable peptidyl component linked to a biotinyl moiety by a 4-mercaptobenzoyl linker in thioester format. We demonstrate that an affinity label can be uncovered by measuring reaction rates between library pools and the protein target, human serum albumin (HSA) and identifying significant outliers. By choosing peptide functionality compatible with a potentially reactive thioester labeling entity, libraries can be screened in pools. It is noteworthy that a limited subset of amino acids (R, S, E, F, Y, l, M, W, and Q) that compose the affinity moiety is sufficient to produce rate variances that guide the discovery process. After two rounds of deconvolution, J-FLYEE-NH2 (7-E) emerges as a bona fide affinity label of HSA. Unlike known affinity labels, the affinity moiety is not retained in the protein product, but is extruded upon acylation of the protein. This feature affords a method of introducing various payloads, without extraneous elements, onto protein frameworks. PMID:24757504

  16. Site-specific Labeling of a Protein Lysine Residue By Novel Kinetic Labeling Combinatorial Libraries.

    PubMed

    Krantz, Allen; Hanel, Arthur M; Strug, Ivona; Wilczynski, Andrzej; Wolff, Jeremy J; Huang, Wolin; Huang, Linda H; Settineri, Tina; Holmes, Darren L; Hardy, Margaret C; Bridon, Dominique P

    2014-01-01

    The first example of a kinetic labeling library designed to enable the discovery of affinity labels is presented. Each library component (1) consists of a variable peptidyl component linked to a biotinyl moiety by a 4-mercaptobenzoyl linker in thioester format. We demonstrate that an affinity label can be uncovered by measuring reaction rates between library pools and the protein target, human serum albumin (HSA) and identifying significant outliers. By choosing peptide functionality compatible with a potentially reactive thioester labeling entity, libraries can be screened in pools. It is noteworthy that a limited subset of amino acids (R, S, E, F, Y, l, M, W, and Q) that compose the affinity moiety is sufficient to produce rate variances that guide the discovery process. After two rounds of deconvolution, J-FLYEE-NH2 (7-E) emerges as a bona fide affinity label of HSA. Unlike known affinity labels, the affinity moiety is not retained in the protein product, but is extruded upon acylation of the protein. This feature affords a method of introducing various payloads, without extraneous elements, onto protein frameworks. PMID:24757504

  17. The combinatorial synthesis and chemical and biological evaluation of a 1,4-benzodiazepine library.

    PubMed Central

    Bunin, B A; Plunkett, M J; Ellman, J A

    1994-01-01

    A library of 192 structurally diverse 1,4-benzodiazepine derivatives containing a variety of chemical functionalities including amides, carboxylic acids, amines, phenols, and indoles was constructed from three components, 2-aminobenzophenones, amino acids, and alkylating agents, by employing Geysen's pin apparatus [Geysen, H. M., Rodda, S. J., Mason, T. J., Tribbick, G. & Schoofs, P. G. (1987) J. Immunol. Methods 102, 259-274]. Rigorous analytical verification of the chemical integrity and yield of a representative collection of the diverse derivatives was carried out. In addition, the library of derivatives was evaluated for binding to the cholecystokinin A receptor by employing a competitive radio-ligand binding assay. This provided detailed structure versus activity relationships that were confirmed by independent large-scale synthesis and evaluation of several of the 1,4-benzodiazepine derivatives. PMID:8197123

  18. Arabidopsis thaliana root cell wall proteomics: Increasing the proteome coverage using a combinatorial peptide ligand library and description of unexpected Hyp in peroxidase amino acid sequences.

    PubMed

    Nguyen-Kim, Huan; San Clemente, Hélène; Balliau, Thierry; Zivy, Michel; Dunand, Christophe; Albenne, Cécile; Jamet, Elisabeth

    2016-02-01

    Plant cell walls (CWs) contain a large proportion of polysaccharides (90-95% of CW mass) and proteins (5-10%) that play major roles in CW plasticity during development and in response to environmental cues. Here, we present CW proteomics data of Arabidopsis thaliana roots. Plants were cultivated in hydroponic conditions. CW protein (CWP) extracts were prepared and analyzed in two different ways in order to enlarge the coverage of the root CW proteome: proteins were analyzed either directly or following an affinity chromatography on a combinatorial peptide ligand library (CPLL) to reduce the concentration dynamic range. Proteins were identified by LC-MS/MS and bioinformatics. Altogether, 424 proteins having predicted signal peptides have been identified (CWPs). CPLL permitted to identify low-abundant CWPs never described before, thus enlarging the coverage of the root CW proteome. The number of oxidoreductases is particularly high and includes a large collection of class III peroxidases (CIII Prxs; 38 out of the 73 A. thaliana CIII Prxs). For the first time, hydroxyproline residues were localized at conserved positions in CIII Prx amino acid sequences. PMID:26572690

  19. MRNet-based Dynamic Probe Class Library

    Energy Science and Technology Software Center (ESTSC)

    2006-12-19

    The Dynamic Probe Class Library (DPCL) is an API that allows for the modification of running code, or dynamic instrumentation. Dynamic instruction is an attractive technique for implementing performance analysis tools, debugging, or process steering because this method doesn't require the modification of the application's source code and hence avoids recompiling, re-linking, and restarting the application. The DPCL API is machine independent; hence DPCL-based tools built on one platform will work on another platform

  20. Proteomic Analysis of Lonicera japonica Thunb. Immature Flower Buds Using Combinatorial Peptide Ligand Libraries and Polyethylene Glycol Fractionation.

    PubMed

    Zhu, Wei; Xu, Xiaobao; Tian, Jingkui; Zhang, Lin; Komatsu, Setsuko

    2016-01-01

    Lonicera japonica Thunb. flower is a well-known medicinal plant that has been widely used for the treatment of human disease. To explore the molecular mechanisms underlying the biological activities of L. japonica immature flower buds, a gel-free/label-free proteomic technique was used in combination with combinatorial peptide ligand libraries (CPLL) and polyethylene glycol (PEG) fractionation for the enrichment of low-abundance proteins and removal of high-abundance proteins, respectively. A total of 177, 614, and 529 proteins were identified in crude protein extraction, CPLL fractions, and PEG fractions, respectively. Among the identified proteins, 283 and 239 proteins were specifically identified by the CPLL and PEG methods, respectively. In particular, proteins related to the oxidative pentose phosphate pathway, signaling, hormone metabolism, and transport were highly enriched by CPLL and PEG fractionation compared to crude protein extraction. A total of 28 secondary metabolism-related proteins and 25 metabolites were identified in L. japonica immature flower buds. To determine the specificity of the identified proteins and metabolites for L. japonica immature flower buds, Cerasus flower buds were used, which resulted in the abundance of hydroxymethylbutenyl 4-diphosphate synthase in L. japonica immature flower buds being 10-fold higher than that in Cerasus flower buds. These results suggest that proteins related to secondary metabolism might be responsible for the biological activities of L. japonica immature flower buds. PMID:26573373

  1. Targeted Mutagenesis and Combinatorial Library Screening Enables Control of Protein Orientation on Surfaces and Increased Activity of Adsorbed Proteins.

    PubMed

    Cruz-Teran, Carlos A; Carlin, Kevin B; Efimenko, Kirill; Genzer, Jan; Rao, Balaji M

    2016-08-30

    While nonspecific adsorption is widely used for immobilizing proteins on solid surfaces, the random nature of protein adsorption may reduce the activity of immobilized proteins due to occlusion of the active site. We hypothesized that the orientation a protein assumes on a given surface can be controlled by systematically introducing mutations into a region distant from its active site, thereby retaining activity of the immobilized protein. To test this hypothesis, we generated a combinatorial protein library by randomizing six targeted residues in a binding protein derived from highly stable, nonimmunoglobulin Sso7d scaffold; mutations were targeted in a region that is distant from the binding site. This library was screened to isolate binders that retain binding to its cognate target (chicken immunoglobulin Y, cIgY) as well as exhibit adsorption on unmodified silica at pH 7.4 and high ionic strength conditions. A single mutant, Sso7d-2B5, was selected for further characterization. Sso7d-2B5 retained binding to cIgY with an apparent dissociation constant similar to that of the parent protein; both mutant and parent proteins saturated the surface of silica with similar densities. Strikingly, however, silica beads coated with Sso7d-2B5 could achieve up to 7-fold higher capture of cIgY than beads coated with the parent protein. These results strongly suggest that mutations introduced in Sso7d-2B5 alter its orientation relative to the parent protein, when adsorbed on silica surfaces. Our approach also provides a generalizable strategy for introducing mutations in proteins so as to improve their activity upon immobilization, and has direct relevance to development of protein-based biosensors and biocatalysts. PMID:27490089

  2. Autocrine-Based Selection of Drugs That Target Ion Channels from Combinatorial Venom Peptide Libraries.

    PubMed

    Zhang, Hongkai; Du, Mingjuan; Xie, Jia; Liu, Xiao; Sun, Jingying; Wang, Wei; Xin, Xiu; Possani, Lourival D; Yea, Kyungmoo; Lerner, Richard A

    2016-08-01

    Animal venoms represent a rich source of pharmacologically active peptides that interact with ion channels. However, a challenge to discovering drugs remains because of the slow pace at which venom peptides are discovered and refined. An efficient autocrine-based high-throughput selection system was developed to discover and refine venom peptides that target ion channels. The utility of this system was demonstrated by the discovery of novel Kv1.3 channel blockers from a natural venom peptide library that was formatted for autocrine-based selection. We also engineered a Kv1.3 blocker peptide (ShK) derived from sea anemone to generate a subtype-selective Kv1.3 blocker with a long half-life in vivo. PMID:27197631

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

    PubMed Central

    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

  4. Quantum efficiency and bandgap analysis for combinatorial photovoltaics: sorting activity of Cu-O compounds in all-oxide device libraries.

    PubMed

    Anderson, Assaf Y; Bouhadana, Yaniv; Barad, Hannah-Noa; Kupfer, Benjamin; Rosh-Hodesh, Eli; Aviv, Hagit; Tischler, Yaakov R; Rühle, Sven; Zaban, Arie

    2014-02-10

    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

  5. Targeting deeper the human serum fucome by a liquid-phase multicolumn platform in combination with combinatorial peptide ligand libraries.

    PubMed

    Selvaraju, Subhashini; El Rassi, Ziad

    2014-03-01

    Combinatorial peptide ligand library (CPLL) was evaluated as an off line step to narrow the differences of protein concentration in human serum prior to the capturing of human fucome from disease-free and breast cancer sera by a multicolumn platform via lectin affinity chromatography (LAC) followed by the fractionation of the captured glycoproteins by reversed phase chromatography (RPC). Two monolithic lectin columns specific to fucose, namely Aleuria aurantia lectin (AAL) and Lotus tetragonolobus agglutinin (LTA) columns were utilized to capture the fucome, which was subsequently fractionated by RPC yielding desalted fractions in volatile acetonitrile-rich mobile phase, which after vacuum evaporation were subjected to tryptic digestion prior to LC-MS/MS analysis. AAL has a strong affinity towards core fucosylated N-glycans and has a weak binding towards fucose in the outer arm while LTA can bind to glycans having fucose present in the outer arm. The combined strategy consisting of the CPLL, multicolumn platform and LC-MS/MS analysis permitted the identification of the differentially expressed proteins (DEPs) in breast cancer serum yielding 58 DEPs in both the LTA and AAL fractions with 6 DEPs common to both lectins. 17 DEPs were of the low abundance type, 16 DEPs of the borderline abundance type, 4 DEPs of the medium abundance type and 15 DEPs of the high abundance type. The remaining 6 DEPs are of unknown concentration. Only proteins exhibiting 99.9% protein identification probability, 95% peptide identification probability, and a minimum of 5 unique peptides were considered in finding the DEPs via scatterplots. PMID:24556279

  6. Targeting Deeper the Human Serum Fucome by a Liquid-phase Multicolumn Platform in Combination with Combinatorial Peptide Ligand Libraries

    PubMed Central

    Selvaraju, Subhashini; Rassi, Ziad El

    2014-01-01

    Combinatorial peptide ligand library (CPLL) was evaluated as an off line step to narrow the differences of protein concentration in human serum prior to the capturing of human fucome from disease-free and breast cancer sera by a multicolumn platform via lectin affinity chromatography (LAC) followed by the fractionation of the captured glycoproteins by reversed phase chromatography (RPC). Two monolithic lectin columns specific to fucose, namely Aleuria aurantia lectin (AAL) and Lotus tetragonolobus agglutinin (LTA) columns were utilized to capture the fucome, which was subsequently fractionated by RPC yielding desalted fractions in volatile acetonitrile-rich mobile phase, which after vacuum evaporation were subjected to tryptic digestion prior to LC-MS/MS analysis. AAL has a strong affinity towards core fucosylated N-glycans and has a weak binding towards fucose in the outer arm while LTA can bind to glycans having fucose present in the outer arm. The combined strategy consisting of the CPLL, multicolumn platform and LC-MS/MS analysis permitted the identification of the differentially expressed proteins (DEPs) in breast cancer serum yielding 58 DEPs in both the LTA and AAL fractions with 6 DEPs common to both lectins. 17 DEPs were of the low abundance type, 16 DEPs of the borderline abundance type, 4 DEPs of the medium abundance type and 15 DEPs of the high abundance type. The remaining 6 DEPs are of unknown concentration. Only proteins exhibiting 99.9% protein identification probability, 95% peptide identification probability, and a minimum of 5 unique peptides were considered in finding the DEPs via scatterplots. PMID:24556279

  7. Combinatorial support vector machines approach for virtual screening of selective multi-target serotonin reuptake inhibitors from large compound libraries.

    PubMed

    Shi, Z; Ma, X H; Qin, C; Jia, J; Jiang, Y Y; Tan, C Y; Chen, Y Z

    2012-02-01

    Selective multi-target serotonin reuptake inhibitors enhance antidepressant efficacy. Their discovery can be facilitated by multiple methods, including in silico ones. In this study, we developed and tested an in silico method, combinatorial support vector machines (COMBI-SVMs), for virtual screening (VS) multi-target serotonin reuptake inhibitors of seven target pairs (serotonin transporter paired with noradrenaline transporter, H(3) receptor, 5-HT(1A) receptor, 5-HT(1B) receptor, 5-HT(2C) receptor, melanocortin 4 receptor and neurokinin 1 receptor respectively) from large compound libraries. COMBI-SVMs trained with 917-1951 individual target inhibitors correctly identified 22-83.3% (majority >31.1%) of the 6-216 dual inhibitors collected from literature as independent testing sets. COMBI-SVMs showed moderate to good target selectivity in misclassifying as dual inhibitors 2.2-29.8% (majority <15.4%) of the individual target inhibitors of the same target pair and 0.58-7.1% of the other 6 targets outside the target pair. COMBI-SVMs showed low dual inhibitor false hit rates (0.006-0.056%, 0.042-0.21%, 0.2-4%) in screening 17 million PubChem compounds, 168,000 MDDR compounds, and 7-8181 MDDR compounds similar to the dual inhibitors. Compared with similarity searching, k-NN and PNN methods, COMBI-SVM produced comparable dual inhibitor yields, similar target selectivity, and lower false hit rate in screening 168,000 MDDR compounds. The annotated classes of many COMBI-SVMs identified MDDR virtual hits correlate with the reported effects of their predicted targets. COMBI-SVM is potentially useful for searching selective multi-target agents without explicit knowledge of these agents. PMID:22064367

  8. Targeting Leishmania major parasite with peptides derived from a combinatorial phage display library.

    PubMed

    Rhaiem, Rafik Ben; Houimel, Mehdi

    2016-07-01

    Cutaneous leishmaniasis (CL) is a global problem caused by intracellular protozoan pathogens of the genus Leishmania for which there are no suitable vaccine or chemotherapy options. Thus, de novo identification of small molecules binding to the Leishmania parasites by direct screening is a promising and appropriate alternative strategy for the development of new drugs. In this study, we used a random linear hexapeptide library fused to the gene III protein of M13 filamentous bacteriophage to select binding peptides to metacyclic promastigotes from a highly virulent strain of Leishmania major (Zymodeme MON-25; MHOM/TN/94/GLC94). After four rounds of stringent selection and amplification, polyclonal and monoclonal phage-peptides directed against L. major metacyclic promastigotes were assessed by ELISA, and the optimal phage-peptides were grown individually and characterized for binding to L. major by monoclonal phage ELISA. The DNA of 42 phage-peptides clones was amplified by PCR, sequenced, and their amino acid sequences deduced. Six different peptide sequences were obtained with frequencies of occurrence ranging from 2.3% to 85.7%. The biological effect of the peptides was assessed in vitro on human monocytes infected with L. major metacyclic promastigotes, and in vivo on susceptible parasite-infected BALB/c mice. The development of cutaneous lesions in the right hind footpads of infected mice after 13 weeks post-infection showed a protection rate of 81.94% with the injected peptide P2. Moreover, Western blots revealed that the P2 peptide interacted with the major surface protease gp63, a protein of 63kDa molecular weight. Moreover, bioinformatics were used to predict the interaction between peptides and the major surface molecule of the L. major. The molecular docking showed that the P2 peptide has the minimum interaction energy and maximum shape complimentarity with the L. major gp63 active site. Our study demonstrated that the P2 peptide occurs at high frequency

  9. CIDAR MoClo: Improved MoClo Assembly Standard and New E. coli Part Library Enable Rapid Combinatorial Design for Synthetic and Traditional Biology.

    PubMed

    Iverson, Sonya V; Haddock, Traci L; Beal, Jacob; Densmore, Douglas M

    2016-01-15

    Multipart and modular DNA part libraries and assembly standards have become common tools in synthetic biology since the publication of the Gibson and Golden Gate assembly methods, yet no multipart modular library exists for use in bacterial systems. Building upon the existing MoClo assembly framework, we have developed a publicly available collection of modular DNA parts and enhanced MoClo protocols to enable rapid one-pot, multipart assembly, combinatorial design, and expression tuning in Escherichia coli. The Cross-disciplinary Integration of Design Automation Research lab (CIDAR) MoClo Library is openly available and contains promoters, ribosomal binding sites, coding sequence, terminators, vectors, and a set of fluorescent control plasmids. Optimized protocols reduce reaction time and cost by >80% from that of previously published protocols. PMID:26479688

  10. Dynamic Mechanical and Nanofibrous Topological Combinatory Cues Designed for Periodontal Ligament Engineering

    PubMed Central

    Kim, Joong-Hyun; Kang, Min Sil; Eltohamy, Mohamed; Kim, Tae-Hyun; Kim, Hae-Won

    2016-01-01

    Complete reconstruction of damaged periodontal pockets, particularly regeneration of periodontal ligament (PDL) has been a significant challenge in dentistry. Tissue engineering approach utilizing PDL stem cells and scaffolding matrices offers great opportunity to this, and applying physical and mechanical cues mimicking native tissue conditions are of special importance. Here we approach to regenerate periodontal tissues by engineering PDL cells supported on a nanofibrous scaffold under a mechanical-stressed condition. PDL stem cells isolated from rats were seeded on an electrospun polycaprolactone/gelatin directionally-oriented nanofiber membrane and dynamic mechanical stress was applied to the cell/nanofiber construct, providing nanotopological and mechanical combined cues. Cells recognized the nanofiber orientation, aligning in parallel, and the mechanical stress increased the cell alignment. Importantly, the cells cultured on the oriented nanofiber combined with the mechanical stress produced significantly stimulated PDL specific markers, including periostin and tenascin with simultaneous down-regulation of osteogenesis, demonstrating the roles of topological and mechanical cues in altering phenotypic change in PDL cells. Tissue compatibility of the tissue-engineered constructs was confirmed in rat subcutaneous sites. Furthermore, in vivo regeneration of PDL and alveolar bone tissues was examined under the rat premaxillary periodontal defect models. The cell/nanofiber constructs engineered under mechanical stress showed sound integration into tissue defects and the regenerated bone volume and area were significantly improved. This study provides an effective tissue engineering approach for periodontal regeneration—culturing PDL stem cells with combinatory cues of oriented nanotopology and dynamic mechanical stretch. PMID:26989897

  11. Dynamic and Combinatorial Landscape of Histone Modifications during the Intraerythrocytic Developmental Cycle of the Malaria Parasite.

    PubMed

    Saraf, Anita; Cervantes, Serena; Bunnik, Evelien M; Ponts, Nadia; Sardiu, Mihaela E; Chung, Duk-Won D; Prudhomme, Jacques; Varberg, Joseph M; Wen, Zhihui; Washburn, Michael P; Florens, Laurence; Le Roch, Karine G

    2016-08-01

    A major obstacle in understanding the complex biology of the malaria parasite remains to discover how gene transcription is controlled during its life cycle. Accumulating evidence indicates that the parasite's epigenetic state plays a fundamental role in gene expression and virulence. Using a comprehensive and quantitative mass spectrometry approach, we determined the global and dynamic abundance of histones and their covalent post-transcriptional modifications throughout the intraerythrocytic developmental cycle of Plasmodium falciparum. We detected a total of 232 distinct modifications, of which 160 had never been detected in Plasmodium and 88 had never been identified in any other species. We further validated over 10% of the detected modifications and their expression patterns by multiple reaction monitoring assays. In addition, we uncovered an unusual chromatin organization with parasite-specific histone modifications and combinatorial dynamics that may be directly related to transcriptional activity, DNA replication, and cell cycle progression. Overall, our data suggest that the malaria parasite has a unique histone modification signature that correlates with parasite virulence. PMID:27291344

  12. Rainbow beads: a color coding method to facilitate high-throughput screening and optimization of one-bead one-compound combinatorial libraries.

    PubMed

    Luo, Juntao; Zhang, Hongyong; Xiao, Wenwu; Kumaresan, Pappanaicken R; Shi, Changying; Pan, Chong-Xian; Aina, Olulanu H; Lam, Kit S

    2008-01-01

    We have developed a new color-encoding method that facilitates high-throughput screening of one-bead one-compound (OBOC) combinatorial libraries. Polymer beads displaying chemical compounds or families of compounds are stained with oil-based organic dyes that are used as coding tags. The color dyes do not affect cell binding to the compounds displayed on the surface of the beads. We have applied such rainbow beads in a multiplex manner to discover and profile ligands against cell surface receptors. In the first application, a series of OBOC libraries with different scaffolds or motifs are each color-coded; small samples of each library are then combined and screened concurrently against live cells for cell attachment. Preferred libraries can be rapidly identified and selected for subsequent large-scale screenings for cell surface binding ligands. In a second application, beads with a series of peptide analogues (e.g., alanine scan) are color-coded, combined, and tested for binding against a specific cell line in a single-tissue culture well; the critical residues required for binding can be easily determined. In a third application, ligands reacting against a series of integrins are color-coded and used as a readily applied research tool to determine the integrin profile of any cell type. One major advantage of this straightforward and yet powerful method is that only an ordinary inverted microscope is needed for the analysis, instead of sophisticated (and expensive) fluorescent microscopes or flow cytometers. PMID:18558750

  13. Surface characteristics and protein adsorption on combinatorial binary Ti-M (Cr, Al, Ni) and Al-M (Ta, Zr) library films.

    PubMed

    Bai, Zhijun; Filiaggi, M J; Sanderson, R J; Lohstreter, L B; McArthur, M A; Dahn, J R

    2010-02-01

    Systematic studies of protein adsorption onto metallic biomaterial surfaces are generally lacking. Here, combinatorial binary library films with compositional gradients of Ti(1-x)Cr(x), Ti(1-x)Al(x), Ti(1-x)Ni(x) and Al(1-x)Ta(x), (0 library and an amorphous zone dominating along the gradient. These mirror-like films were generally found by atomic force microscopy to have a roughness of less than 8 nm, with any relative increases in roughness consistent with the development of crystalline phases. Surface chemistry by quantitative high-resolution X-ray photoelectron spectroscopy differed significantly from bulk film composition as measured by electron microprobe, with TiO(2) and Al(2)O(3) preferentially forming on the binary film surfaces. Correspondingly, protein adsorption onto these films closely correlated with their surface oxide fractions. Aluminum deposited as either a constant-composition film or as part of a binary library consistently adsorbed the least amount of albumin and fibrinogen, with alumina-enrichment of the surface oxide correlating with this adsorption. Overall, this combinatorial materials approach coupled with high-throughput surface analytical methods provides an efficient method of screening potential metallic biomaterials that may enable as well systematic studies of surface properties driving protein adsorption on these metal / metal oxide systems. PMID:19235218

  14. A dynamic multiarmed bandit-gene expression programming hyper-heuristic for combinatorial optimization problems.

    PubMed

    Sabar, Nasser R; Ayob, Masri; Kendall, Graham; Qu, Rong

    2015-02-01

    Hyper-heuristics are search methodologies that aim to provide high-quality solutions across a wide variety of problem domains, rather than developing tailor-made methodologies for each problem instance/domain. A traditional hyper-heuristic framework has two levels, namely, the high level strategy (heuristic selection mechanism and the acceptance criterion) and low level heuristics (a set of problem specific heuristics). Due to the different landscape structures of different problem instances, the high level strategy plays an important role in the design of a hyper-heuristic framework. In this paper, we propose a new high level strategy for a hyper-heuristic framework. The proposed high-level strategy utilizes a dynamic multiarmed bandit-extreme value-based reward as an online heuristic selection mechanism to select the appropriate heuristic to be applied at each iteration. In addition, we propose a gene expression programming framework to automatically generate the acceptance criterion for each problem instance, instead of using human-designed criteria. Two well-known, and very different, combinatorial optimization problems, one static (exam timetabling) and one dynamic (dynamic vehicle routing) are used to demonstrate the generality of the proposed framework. Compared with state-of-the-art hyper-heuristics and other bespoke methods, empirical results demonstrate that the proposed framework is able to generalize well across both domains. We obtain competitive, if not better results, when compared to the best known results obtained from other methods that have been presented in the scientific literature. We also compare our approach against the recently released hyper-heuristic competition test suite. We again demonstrate the generality of our approach when we compare against other methods that have utilized the same six benchmark datasets from this test suite. PMID:24951713

  15. Multiplexed tracking of combinatorial genomic mutations in engineered cell populations.

    PubMed

    Zeitoun, Ramsey I; Garst, Andrew D; Degen, George D; Pines, Gur; Mansell, Thomas J; Glebes, Tirzah Y; Boyle, Nanette R; Gill, Ryan T

    2015-06-01

    Multiplexed genome engineering approaches can be used to generate targeted genetic diversity in cell populations on laboratory timescales, but methods to track mutations and link them to phenotypes have been lacking. We present an approach for tracking combinatorial engineered libraries (TRACE) through the simultaneous mapping of millions of combinatorially engineered genomes at single-cell resolution. Distal genomic sites are assembled into individual DNA constructs that are compatible with next-generation sequencing strategies. We used TRACE to map growth selection dynamics for Escherichia coli combinatorial libraries created by recursive multiplex recombineering at a depth 10(4)-fold greater than before. TRACE was used to identify genotype-to-phenotype correlations and to map the evolutionary trajectory of two individual combinatorial mutants in E. coli. Combinatorial mutations in the human ES2 ovarian carcinoma cell line were also assessed with TRACE. TRACE completes the combinatorial engineering cycle and enables more sophisticated approaches to genome engineering in both bacteria and eukaryotic cells than are currently possible. PMID:25798935

  16. High-performance combinatorial algorithms

    SciTech Connect

    Pinar, Ali

    2003-10-31

    Combinatorial algorithms have long played an important role in many applications of scientific computing such as sparse matrix computations and parallel computing. The growing importance of combinatorial algorithms in emerging applications like computational biology and scientific data mining calls for development of a high performance library for combinatorial algorithms. Building such a library requires a new structure for combinatorial algorithms research that enables fast implementation of new algorithms. We propose a structure for combinatorial algorithms research that mimics the research structure of numerical algorithms. Numerical algorithms research is nicely complemented with high performance libraries, and this can be attributed to the fact that there are only a small number of fundamental problems that underlie numerical solvers. Furthermore there are only a handful of kernels that enable implementation of algorithms for these fundamental problems. Building a similar structure for combinatorial algorithms will enable efficient implementations for existing algorithms and fast implementation of new algorithms. Our results will promote utilization of combinatorial techniques and will impact research in many scientific computing applications, some of which are listed.

  17. Synthesis of solution-phase combinatorial library of 4,6-diamino-1,2-dihydro-1,3,5-triazine and identification of new leads against A16V+S108T mutant dihydrofolate reductase of Plasmodium falciparum.

    PubMed

    Vilaivan, Tirayut; Saesaengseerung, Neungruthai; Jarprung, Deanpen; Kamchonwongpaisan, Sumalee; Sirawaraporn, Worachart; Yuthavong, Yongyuth

    2003-01-17

    An efficient method to synthesize solution-phase combinatorial library of 1-aryl-4,6-diamino-1,2-dihydro-1,3,5-triazine was developed. The strategy involved an acid-catalyzed cyclocondensation between arylbiguanide hydrochlorides and carbonyl compounds in the presence of triethyl orthoacetate as water scavenger. A 96-membered combinatorial library was constructed from 6 aryl biguanides and 16 carbonyl compounds. Screening of the library by iterative deconvolution method revealed two candidate leads which are equally active against wild-type Plasmodium falciparum dihydrofolate reductase, but are about 100-fold more effective against the A16V+S108T mutant enzyme as compared to cycloguanil. PMID:12470716

  18. Identification of a potent and selective oxytocin antagonist, from screening a fully encoded differential release combinatorial chemical library.

    PubMed

    Evans, B; Pipe, A; Clark, L; Banks, M

    2001-05-21

    A library of 1,296 1,4-benzodiazepines was prepared on 160 microM Tentagel beads. Compounds are attached to the beads using orthogonally cleavable linkers. The library was first screened as pools of 30 beads where 50% of the material is released and screened. GW405212X, a selective oxytocin antagonist, was identified by picking single beads from active pools. PMID:11392541

  19. Algorithmic Strategies in Combinatorial Chemistry

    SciTech Connect

    GOLDMAN,DEBORAH; ISTRAIL,SORIN; LANCIA,GIUSEPPE; PICCOLBONI,ANTONIO; WALENZ,BRIAN

    2000-08-01

    Combinatorial Chemistry is a powerful new technology in drug design and molecular recognition. It is a wet-laboratory methodology aimed at ``massively parallel'' screening of chemical compounds for the discovery of compounds that have a certain biological activity. The power of the method comes from the interaction between experimental design and computational modeling. Principles of ``rational'' drug design are used in the construction of combinatorial libraries to speed up the discovery of lead compounds with the desired biological activity. This paper presents algorithms, software development and computational complexity analysis for problems arising in the design of combinatorial libraries for drug discovery. The authors provide exact polynomial time algorithms and intractability results for several Inverse Problems-formulated as (chemical) graph reconstruction problems-related to the design of combinatorial libraries. These are the first rigorous algorithmic results in the literature. The authors also present results provided by the combinatorial chemistry software package OCOTILLO for combinatorial peptide design using real data libraries. The package provides exact solutions for general inverse problems based on shortest-path topological indices. The results are superior both in accuracy and computing time to the best software reports published in the literature. For 5-peptoid design, the computation is rigorously reduced to an exhaustive search of about 2% of the search space; the exact solutions are found in a few minutes.

  20. Dynamic combinatorial/covalent chemistry: a tool to read, generate and modulate the bioactivity of compounds and compound mixtures.

    PubMed

    Herrmann, Andreas

    2014-03-21

    Reversible covalent bond formation under thermodynamic control adds reactivity to self-assembled supramolecular systems, and is therefore an ideal tool to assess complexity of chemical and biological systems. Dynamic combinatorial/covalent chemistry (DCC) has been used to read structural information by selectively assembling receptors with the optimum molecular fit around a given template from a mixture of reversibly reacting building blocks. This technique allows access to efficient sensing devices and the generation of new biomolecules, such as small molecule receptor binders for drug discovery, but also larger biomimetic polymers and macromolecules with particular three-dimensional structural architectures. Adding a kinetic factor to a thermodynamically controlled equilibrium results in dynamic resolution and in self-sorting and self-replicating systems, all of which are of major importance in biological systems. Furthermore, the temporary modification of bioactive compounds by reversible combinatorial/covalent derivatisation allows control of their release and facilitates their transport across amphiphilic self-assembled systems such as artificial membranes or cell walls. The goal of this review is to give a conceptual overview of how the impact of DCC on supramolecular assemblies at different levels can allow us to understand, predict and modulate the complexity of biological systems. PMID:24296754

  1. Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry.

    PubMed

    Mondal, Milon; Radeva, Nedyalka; Fanlo-Virgós, Hugo; Otto, Sijbren; Klebe, Gerhard; Hirsch, Anna K H

    2016-08-01

    Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization. PMID:27400756

  2. Design, synthesis, and biological evaluation of the combinatorial library with a new spirodiketopiperazine scaffold. Discovery of novel potent and selective low-molecular-weight CCR5 antagonists.

    PubMed

    Habashita, Hiromu; Kokubo, Masaya; Hamano, Shin-ichi; Hamanaka, Nobuyuki; Toda, Masaaki; Shibayama, Shiro; Tada, Hideaki; Sagawa, Kenji; Fukushima, Daikichi; Maeda, Kenji; Mitsuya, Hiroaki

    2006-07-13

    We previously reported the discovery of several spirodiketopiperazine derivatives as potent CCR5 antagonists with anti-HIV activity. Herein, we describe in detail the identification of these lead compounds using a combinatorial chemistry approach. A novel spirodiketopiperazine scaffold was designed on the basis of the concept of the privileged structure of G-protein-coupled receptors (GPCRs). This new framework was obtained in acceptable yield with high purity from the readily prepared isonitrile resin through the Ugi reaction, sequential transformations, and cyclative cleavage. By measuring the inhibitory activity of each compound in the initial library against the intracellular calcium mobilization stimulated by MIP-1alpha, several compounds were found to show modest but selective CCR5 antagonistic activity. After the rapid evaluation of these hit compounds, several single-digit nanomolar, low-molecular-weight CCR5 antagonists that can potently block the infectivity and replication of laboratory and clinical strains of HIV as well as those of highly drug-resistant HIV variants with minimal cytotoxicity have been identified. PMID:16821774

  3. Combinatorial peptide ligand libraries for the analysis of low-expression proteins: Validation for normal urine and definition of a first protein MAP.

    PubMed

    Santucci, Laura; Candiano, Giovanni; Bruschi, Maurizio; D'Ambrosio, Chiara; Petretto, Andrea; Scaloni, Andrea; Urbani, Andrea; Righetti, Pier G; Ghiggeri, Gian M

    2012-02-01

    In this review, we report the evolution on experimental conditions for the analysis of normal urine based on combinatorial peptide ligand library (CPLL) treatment and successive 2-DE and 2-DE/MS analysis. The main topics are (i) definition of the urine sample requirements, (ii) optimization of the urine/ligand ratio, (iii) essay conditions, (iv) en bloc elution. Overall, normal urine protein composition as studied by 2-DE includes over 2600 spots. Relevant data on inter and intraessay reproducibility obtained by the analysis of different normal urines repeated several times are also here presented. We found a 73% reproducibility upon analysis of the same sample and 68% correspondence of protein composition among different normal urine samples. Based on the above results, we are completing the characterization with LC-MS of 249 spots. The composition of normal urine proteins after CPLLs is finally shown with the indication of those spots which are currently under identification. This map will be completed in a near future; in the meantime this would represent the basic reference sample for newly developed studies on human diseases. PMID:22246922

  4. Combinatorial approach to flavor analysis. 2. Olfactory investigation of a library of S-methyl thioesters and sensory evaluation of selected components.

    PubMed

    Berger, C; Martin, N; Collin, S; Gijs, L; Khan, J A; Piraprez, G; Spinnler, H E; Vulfson, E N

    1999-08-01

    The odor characteristics of individual components present in a library comprised of S-methyl thioesters were determined independently by two laboratories using similar but not identical techniques. The odor potency was assessed by values of best estimate-GC-lower amount detected by sniffing (BE-GC-LOADS). For small and medium chain S-methyl thioesters, these values were found to increase from 6 ng for S-methyl thiobutanoate to 90 ng for S-methyl thiostearate. All assessors detected a "green", "floral", or "pineapple" odor for S-methyl thiohexanoate and described thioesters containing a 2-6 carbon chain length as "cheesy". The results of this preliminary analysis were confirmed by a more extensive study of selected compounds, namely S-methyl thioacetate, S-methyl thiopropionate, S-methyl thiobutanoate, and S-methyl thiohexanoate, using a trained panel of 18 subjects. The subjects confirmed the presence of the "green" and "fruity" notes in the odor of S-methyl thiohexanoate. The analysis also revealed a significant difference in the odor of S-methyl thiopropionate relative to that of S-methyl thioacetate and S-methyl thiobutanoate. When "cheesy" characteristics were mentioned, the majority of panelists clearly associated the flavor of S-methyl thiopropionate with Camembert with almost 20% of all the descriptors given referring specifically to this cheese variety as compared to about 2 and 5% in the case of S-methyl thioacetate and thiobutanoate, respectively. Prompted by this observation, two samples of Camembert prepared from unpasteurized and pasteurized milk were analyzed and relatively large amounts of S-methyl thiopropionate were found in the former but not in the latter cheese. The results obtained in the course of this work suggest that the sensory analysis of combinatorial libraries is a useful new approach in the search for new commercial flavors and/or identification of characteristic flavors in foods. PMID:10552644

  5. Discovery of small peptide antagonists of PED/PEA15-D4α interaction from simplified combinatorial libraries.

    PubMed

    Scognamiglio, Pasqualina Liana; Doti, Nunzianna; Grieco, Paolo; Pedone, Carlo; Ruvo, Menotti; Marasco, Daniela

    2011-05-01

    Most biological processes involve permanent and temporary interactions between different proteins: protein complexes often play key roles in human diseases and, as a consequence, molecules that prevent protein-protein interactions can be potential new therapeutic agents to treat diseases. Here, we describe a simplified approach by which small synthetic peptide libraries were screened to identify the inhibitors of the complex between phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes15 (PED/PEA15) and D4α, a functional domain of the phospholipase D1, that is involved in the molecular mechanisms of insulin resistance occurring in type 2 diabetes. By using an enzyme-linked immunosorbent assay (ELISA)-based screening, performed on a fully automated platform, we analyzed two simplified peptide libraries in a positional scanning format. This screening led to the identification of small peptides able to inhibit PED/PEA15-D4α interaction. The selection of inhibitors was carried out employing combined competitive and direct experiments, through ELISA and surface plasmon resonance techniques, providing peptides with IC(50) values in the micromolar range. Our results showed that the protein complex PED/PEA15-D4α is susceptible to peptides having H-donor groups and aromatic rings on specific positions. These small sequences can be considered as promising scaffolds that could be converted into higher-affinity inhibitor compounds. PMID:21294846

  6. Probing a 2-Aminobenzimidazole Library for Binding to RNA Internal Loops via Two-Dimensional Combinatorial Screening

    PubMed Central

    Velegapudi, Sai Pradeep; Pushechnikov, Alexei; Labuda, Lucas P.; French, Jonathan M.; Disney, Matthew D.

    2012-01-01

    There are many potential RNA drug targets in bacterial, viral, and the human transcriptomes. However, there are few small molecules that modulate RNA function. This is due, in part, to a lack of fundamental understanding about RNA-ligand interactions including the types of small molecules that bind to RNA structural elements and the RNA structural elements that bind to small molecules. In an effort to better understand RNA-ligand interactions, we diversified the 2-aminobenzimidazole core (2AB) and probed the resulting library for binding to a library of RNA internal loops. We chose the 2AB core for these studies because it is a privileged scaffold for binding RNA based on previous reports. These studies identified that N-methyl pyrrolidine, imidazole, and propylamine diversity elements at the R1 position increase binding to internal loops; variability at the R2 position is well tolerated. The preferred RNA loop space was also determined for five ligands using a statistical approach and identified trends that lead to selective recognition. PMID:22958065

  7. Probing a 2-aminobenzimidazole library for binding to RNA internal loops via two-dimensional combinatorial screening.

    PubMed

    Velagapudi, Sai Pradeep; Pushechnikov, Alexei; Labuda, Lucas P; French, Jonathan M; Disney, Matthew D

    2012-11-16

    There are many potential RNA drug targets in bacterial, viral, and human transcriptomes. However, there are few small molecules that modulate RNA function. This is due, in part, to a lack of fundamental understanding about RNA-ligand interactions including the types of small molecules that bind to RNA structural elements and the RNA structural elements that bind to small molecules. In an effort to better understand RNA-ligand interactions, we diversified the 2-aminobenzimidazole core (2AB) and probed the resulting library for binding to a library of RNA internal loops. We chose the 2AB core for these studies because it is a privileged scaffold for binding RNA based on previous reports. These studies identified that N-methyl pyrrolidine, imidazole, and propylamine diversity elements at the R1 position increase binding to internal loops; variability at the R2 position is well tolerated. The preferred RNA loop space was also determined for five ligands using a statistical approach and identified trends that lead to selective recognition. PMID:22958065

  8. Two-Dimensional Combinatorial Screening (2DCS) of a Bacterial rRNA A-site-like Motif Library: Defining Privileged Asymmetric Internal Loops that Bind Aminoglycosides

    PubMed Central

    Tran, Tuan; Disney, Matthew D.

    2010-01-01

    RNAs have diverse structures that are important for biological function. These structures include bulges and internal loops that can form tertiary contacts or serve as ligand binding sites. The most commonly exploited RNA drug target for small molecule intervention is the bacterial ribosome, more specifically the ribosomal RNA aminoacyl-tRNA site (rRNA A-site) which is a major target for the aminoglycoside class of antibiotics. The bacterial A-site is composed of a 1×1 nucleotide all-U internal loop and a 2×1 nucleotide all-A internal loop separated by a single GC base pair. Therefore, we probed the molecular recognition of a small library of four aminoglycosides for binding a 16384-member bacterial rRNA A-site-like internal loop library using Two-Dimensional Combinatorial Screening (2DCS). 2DCS is a microarray-based method that probes RNA and chemical spaces simultaneously. These studies sought to determine if aminoglycosides select their therapeutic target if given a choice of binding all possible internal loops derived from an A-site-like library. Results show that the bacterial rRNA A-site was not selected by any aminoglycoside. Analyses of selected sequences using the RNA Privileged Space Predictor (RNA-PSP) program show that each aminoglycoside preferentially binds different types of internal loops. For three of the aminoglycosides, 6″-azido-kanamycin A, 5-O-(2-azidoethyl) neamine, and 6″-azido-tobramycin, the selected internal loops bind with ~10-fold higher affinity than the bacterial rRNA A-site. The internal loops selected to bind 5″-azido-neomycin B bind with similar affinity as the therapeutic target. Selected internal loops that are unique for each aminoglycoside have dissociation constants ranging from 25 to 270 nM and are specific for the aminoglycoside they were selected to bind compared to the other arrayed aminoglycosides. These studies further establish a database of RNA motifs that are recognized by small molecules that could be used to

  9. Combinatorial Optimization Algorithms for Dynamic Multiple Fault Diagnosis in Automotive and Aerospace Applications

    NASA Astrophysics Data System (ADS)

    Kodali, Anuradha

    facility, respectively. The set-covering matrix encapsulates the relationship among the rows (tests or demand points) and columns (faults or locations) of the system at each time. By relaxing the coupling constraints using Lagrange multipliers, the DSC problem can be decoupled into independent subproblems, one for each column. Each subproblem is solved using the Viterbi decoding algorithm, and a primal feasible solution is constructed by modifying the Viterbi solutions via a heuristic. The proposed Viterbi-Lagrangian relaxation algorithm (VLRA) provides a measure of suboptimality via an approximate duality gap. As a major practical extension of the above problem, we also consider the problem of diagnosing faults with delayed test outcomes, termed delay-dynamic set-covering (DDSC), and experiment with real-world problems that exhibit masking faults. Also, we present simulation results on OR-library datasets (set-covering formulations are predominantly validated on these matrices in the literature), posed as facility location problems. Finally, we implement these algorithms to solve problems in aerospace and automotive applications. Firstly, we address the diagnostic ambiguity problem in aerospace and automotive applications by developing a dynamic fusion framework that includes dynamic multiple fault diagnosis algorithms. This improves the correct fault isolation rate, while minimizing the false alarm rates, by considering multiple faults instead of the traditional data-driven techniques based on single fault (class)-single epoch (static) assumption. The dynamic fusion problem is formulated as a maximum a posteriori decision problem of inferring the fault sequence based on uncertain outcomes of multiple binary classifiers over time. The fusion process involves three steps: the first step transforms the multi-class problem into dichotomies using error correcting output codes (ECOC), thereby solving the concomitant binary classification problems; the second step fuses the

  10. High throughput assay for cytochrome P450 BM3 for screening libraries of substrates and combinatorial mutants.

    PubMed

    Tsotsou, Georgia Eleni; Cass, Anthony Edward George; Gilardi, Gianfranco

    2002-01-01

    A rapid method for identifying compounds that are potential substrates for the drug metabolising enzyme cytochrome P450 is described. The strategy is based on the detection of a degradation product of NAD(P)H oxidation during substrate turnover by the enzyme expressed in Escherichia coli cells spontaneously lysed under the experimental conditions. The performance of the method has been tested on two known substrates of the wild-type cytochrome P450 BM3, arachidonic (AA) and lauric (LA) acids, and two substrates with environmental significance, the anionic surfactant sodium dodecyl sulfate (SDS), and the solvent 1,1,2,2-tetrachloroethane (TCE). The minimal background signal given from cells expressing cytochrome P450 BM3 in the absence of added substrate is only 3% of the signal in the presence of saturating substrate. Control experiments have proven that this method is specifically detecting NADPH oxidation by catalytic turnover of P450 BM3. The assay has been adapted to a microtitre plate format and used to screen a series of furazan derivatives as potential substrates. Three derivatives were identified as substrates. The method gave a significant different signal for two isomeric furazan derivatives. All results found on the cell lysate were verified and confirmed with the purified enzyme. This strategy opens the way to automated high throughput screening of NAD(P)H-linked enzymatic activity of molecules of pharmacological and biotechnological interest and libraries of random mutants of NAD(P)H-dependent biocatalysts. PMID:11742743

  11. Towards an animal model of ovarian cancer: cataloging chicken blood proteins using combinatorial peptide ligand libraries coupled with shotgun proteomic analysis for translational research.

    PubMed

    Ma, Yingying; Sun, Zeyu; de Matos, Ricardo; Zhang, Jing; Odunsi, Kunle; Lin, Biaoyang

    2014-05-01

    Epithelial ovarian cancer is the most deadly gynecological cancer around the world, with high morbidity in industrialized countries. Early diagnosis is key in reducing its morbidity rate. Yet, robust biomarkers, diagnostics, and animal models are still limited for ovarian cancer. This calls for broader omics and systems science oriented diagnostics strategies. In this vein, the domestic chicken has been used as an ovarian cancer animal model, owing to its high rate of developing spontaneous epithelial ovarian tumors. Chicken blood has thus been considered a surrogate reservoir from which cancer biomarkers can be identified. However, the presence of highly abundant proteins in chicken blood has compromised the applicability of proteomics tools to study chicken blood owing to a lack of immunodepletion methods. Here, we demonstrate that a combinatorial peptide ligand library (CPLL) can efficiently remove highly abundant proteins from chicken blood samples, consequently doubling the number of identified proteins. Using an integrated CPLL-1DGE-LC-MSMS workflow, we identified a catalog of 264 unique proteins. Functional analyses further suggested that most proteins were coagulation and complement factors, blood transport and binding proteins, immune- and defense-related proteins, proteases, protease inhibitors, cellular enzymes, or cell structure and adhesion proteins. Semiquantitative spectral counting analysis identified 10 potential biomarkers from the present chicken ovarian cancer model. Additionally, many human homologs of chicken blood proteins we have identified have been independently suggested as diagnostic biomarkers for ovarian cancer, further triangulating our novel observations reported here. In conclusion, the CPLL-assisted proteomic workflow using the chicken ovarian cancer model provides a feasible platform for translational research to identify ovarian cancer biomarkers and understand ovarian cancer biology. To the best of our knowledge, we report here

  12. Combinatorial synthesis of ceramic materials

    DOEpatents

    Lauf, Robert J [Oak Ridge, TN; Walls, Claudia A [Oak Ridge, TN; Boatner, Lynn A [Oak Ridge, TN

    2010-02-23

    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. Combinatorial synthesis of ceramic materials

    DOEpatents

    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.

  14. Combinatorial Chemistry for Optical Sensing Applications

    NASA Astrophysics Data System (ADS)

    Díaz-García, M. E.; Luis, G. Pina; Rivero-Espejel, I. A.

    The recent interest in combinatorial chemistry for the synthesis of selective recognition materials for optical sensing applications is presented. The preparation, screening, and applications of libraries of ligands and chemosensors against molecular species and metal ions are first considered. Included in this chapter are also the developments involving applications of combinatorial approaches to the discovery of sol-gel and acrylic-based imprinted materials for optical sensing of antibiotics and pesticides, as well as libraries of doped sol-gels for high-throughput optical sensing of oxygen. The potential of combinatorial chemistry applied to the discovery of new sensing materials is highlighted.

  15. galpy: A python LIBRARY FOR GALACTIC DYNAMICS

    SciTech Connect

    Bovy, Jo

    2015-02-01

    I describe the design, implementation, and usage of galpy, a python package for galactic-dynamics calculations. At its core, galpy consists of a general framework for representing galactic potentials both in python and in C (for accelerated computations); galpy functions, objects, and methods can generally take arbitrary combinations of these as arguments. Numerical orbit integration is supported with a variety of Runge-Kutta-type and symplectic integrators. For planar orbits, integration of the phase-space volume is also possible. galpy supports the calculation of action-angle coordinates and orbital frequencies for a given phase-space point for general spherical potentials, using state-of-the-art numerical approximations for axisymmetric potentials, and making use of a recent general approximation for any static potential. A number of different distribution functions (DFs) are also included in the current release; currently, these consist of two-dimensional axisymmetric and non-axisymmetric disk DFs, a three-dimensional disk DF, and a DF framework for tidal streams. I provide several examples to illustrate the use of the code. I present a simple model for the Milky Way's gravitational potential consistent with the latest observations. I also numerically calculate the Oort functions for different tracer populations of stars and compare them to a new analytical approximation. Additionally, I characterize the response of a kinematically warm disk to an elliptical m = 2 perturbation in detail. Overall, galpy consists of about 54,000 lines, including 23,000 lines of code in the module, 11,000 lines of test code, and about 20,000 lines of documentation. The test suite covers 99.6% of the code. galpy is available at http://github.com/jobovy/galpy with extensive documentation available at http://galpy.readthedocs.org/en/latest.

  16. galpy: A python Library for Galactic Dynamics

    NASA Astrophysics Data System (ADS)

    Bovy, Jo

    2015-02-01

    I describe the design, implementation, and usage of galpy, a python package for galactic-dynamics calculations. At its core, galpy consists of a general framework for representing galactic potentials both in python and in C (for accelerated computations); galpy functions, objects, and methods can generally take arbitrary combinations of these as arguments. Numerical orbit integration is supported with a variety of Runge-Kutta-type and symplectic integrators. For planar orbits, integration of the phase-space volume is also possible. galpy supports the calculation of action-angle coordinates and orbital frequencies for a given phase-space point for general spherical potentials, using state-of-the-art numerical approximations for axisymmetric potentials, and making use of a recent general approximation for any static potential. A number of different distribution functions (DFs) are also included in the current release; currently, these consist of two-dimensional axisymmetric and non-axisymmetric disk DFs, a three-dimensional disk DF, and a DF framework for tidal streams. I provide several examples to illustrate the use of the code. I present a simple model for the Milky Way's gravitational potential consistent with the latest observations. I also numerically calculate the Oort functions for different tracer populations of stars and compare them to a new analytical approximation. Additionally, I characterize the response of a kinematically warm disk to an elliptical m = 2 perturbation in detail. Overall, galpy consists of about 54,000 lines, including 23,000 lines of code in the module, 11,000 lines of test code, and about 20,000 lines of documentation. The test suite covers 99.6% of the code. galpy is available at http://github.com/jobovy/galpy with extensive documentation available at http://galpy.readthedocs.org/en/latest.

  17. Developing New Tools for the in vivo Generation/Screening of Cyclic Peptide Libraries. A New Combinatorial Approach for the Detection of Bacterial Toxin Inhibitors

    SciTech Connect

    Camarero, J A

    2006-11-28

    A new combinatorial approach for the biosynthesis and screening of small drug-like toxin inhibitors inside living cells is presented. This approach has been initially used as proof of principle for finding inhibitors against the LF factor from Bacillus anthracis. Key to our ''living combinatorial'' approach is the use of a living cell as a micro-chemical factory for both synthesis and screening of potential inhibitors for a given molecular recognition event (see Scheme 1). This powerful technique posses the advantage that both processes synthesis and screening happen inside the cell thus accelerating the whole screening/selection process.

  18. Molecular insights of protein contour recognition with ligand pharmacophoric sites through combinatorial library design and MD simulation in validating HTLV-1 PR inhibitors.

    PubMed

    Selvaraj, Chandrabose; Omer, Ankur; Singh, Poonam; Singh, Sanjeev Kumar

    2015-01-01

    Retroviruses HIV-1 and HTLV-1 are chiefly considered to be the most dangerous pathogens in Homo sapiens. These two viruses have structurally unique protease (PR) enzymes, which are having common function of its replication mechanism. Though HIV PR drugs failed to inhibit HTLV-1 infections, they emphatically emphasise the need for designing new lead compounds against HTLV-1 PR. Therefore, we tried to understand the binding level interactions through the charge environment present in both ligand and protein active sites. The domino effect illustrates that libraries of purvalanol-A are attuned to fill allosteric binding site of HTLV-1 PR through molecular recognition and shows proper binding of ligand pharmacophoric features in receptor contours. Our screening evaluates seven compounds from purvalanol-A libraries, and these compounds' pharmacophore searches for an appropriate place in the binding site and it places well according to respective receptor contour surfaces. Thus our result provides a platform for the progress of more effective compounds, which are better in free energy calculation, molecular docking, ADME and molecular dynamics studies. Finally, this research provided novel chemical scaffolds for HTLV-1 drug discovery. PMID:25335799

  19. Library+

    ERIC Educational Resources Information Center

    Merrill, Alex

    2011-01-01

    This article discusses possible future directions for academic libraries in the post Web/Library 2.0 world. These possible directions include areas such as data literacy, linked data sets, and opportunities for libraries in support of digital humanities. The author provides a brief sketch of the background information regarding the topics and…

  20. Selection of functional tRNA primers and primer binding site sequences from a retroviral combinatorial library: identification of new functional tRNA primers in murine leukemia virus replication

    PubMed Central

    Lund, Anders H.; Duch, Mogens; Pedersen, Finn Skou

    2000-01-01

    Retroviral reverse transcription is initiated from a cellular tRNA molecule and all known exogenous isolates of murine leukemia virus utilise a tRNAPro molecule. While several studies suggest flexibility in murine leukemia virus primer utilisation, studies on human immunodeficiency virus and avian retroviruses have revealed evidence of molecular adaptation towards the specific tRNA isoacceptor used as replication primer. In this study, murine leukemia virus tRNA utilisation is investigated by in vivo screening of a retroviral vector combinatorial library with randomised primer binding sites. While most of the selected primer binding sites are complementary to the 3′-end of tRNAPro, we also retrieved PBS sequences matching four other tRNA molecules and demonstrate that Akv murine leukemia virus vectors may efficiently replicate using tRNAArg(CCU), tRNAPhe(GAA) and a hitherto unknown human tRNASer(CGA). PMID:10637332

  1. An affinity selection-mass spectrometry method for the identification of small molecule ligands from self-encoded combinatorial libraries: Discovery of a novel antagonist of E. coli dihydrofolate reductase

    NASA Astrophysics Data System (ADS)

    Annis, D. Allen; Athanasopoulos, John; Curran, Patrick J.; Felsch, Jason S.; Kalghatgi, Krishna; Lee, William H.; Nash, Huw M.; Orminati, Jean-Paul A.; Rosner, Kristin E.; Shipps, Gerald W., Jr.; Thaddupathy, G. R. A.; Tyler, Andrew N.; Vilenchik, Lev; Wagner, Carston R.; Wintner, Edward A.

    2004-11-01

    The NeoGenesis Automated Ligand Identification System (ALIS), an affinity selection-mass spectrometry (AS-MS) process consisting of a rapid size-exclusion chromatography stage integrated with reverse-phase chromatography, electrospray mass spectrometry, and novel data searching algorithms, was used to screen mass-encoded, 2500-member combinatorial libraries, leading to the discovery of a novel, bioactive ligand for the anti-infective target Escherichia coli dihydrofolate reductase (DHFR). Synthesis of the mass-encoded, ligand-containing library, discussion of the deconvolution process for verifying the structure of the ligand through independent synthesis and screening in a small mixture (sub-library) format, and ALIS-MS/MS techniques to assign its regioisomeric connectivity are presented. ALIS-based competition experiments between the newly discovered ligand and other, known DHFR ligands, and biological activity assessments with stereo- and regioisomers of the hit compound confirm its DHFR-specific biological activity. The method described requires no foreknowledge of the structure or biochemistry of the protein target, consumes less than 1 [mu]g protein to screen >2500 compounds in a single experiment, and enables screening of >250,000 compounds per system per day. These advantages highlight the potential of the ALIS method for drug discovery against genomic targets with unknown biological function, as well as validated targets for which traditional discovery efforts have failed.

  2. Dynamic Peptide Library for the Discovery of Charge Transfer Hydrogels.

    PubMed

    Berdugo, Cristina; Nalluri, Siva Krishna Mohan; Javid, Nadeem; Escuder, Beatriu; Miravet, Juan F; Ulijn, Rein V

    2015-11-25

    Coupling of peptide self-assembly to dynamic sequence exchange provides a useful approach for the discovery of self-assembling materials. In here, we demonstrate the discovery and optimization of aqueous, gel-phase nanostructures based on dynamically exchanging peptide sequences that self-select to maximize charge transfer of n-type semiconducting naphthalenediimide (NDI)-dipeptide bioconjugates with various π-electron-rich donors (dialkoxy/hydroxy/amino-naphthalene or pyrene derivatives). These gel-phase peptide libraries are characterized by spectroscopy (UV-vis and fluorescence), microscopy (TEM), HPLC, and oscillatory rheology and it is found that, of the various peptide sequences explored (tyrosine Y-NDI with tyrosine Y, phenylalanine F, leucine L, valine V, alanine A or glycine G-NH2), the optimum sequence is tyrosine-phenylalanine in each case; however, both its absolute and relative yield amplification is dictated by the properties of the donor component, indicating cooperativity of peptide sequence and donor/acceptor pairs in assembly. The methodology provides an in situ discovery tool for nanostructures that enable dynamic interfacing of supramolecular electronics with aqueous (biological) systems. PMID:26540455

  3. Discovery of active proteins directly from combinatorial randomized protein libraries without display, purification or sequencing: identification of novel zinc finger proteins

    PubMed Central

    Hughes, Marcus D.; Zhang, Zhan-Ren; Sutherland, Andrew J.; Santos, Albert F.; Hine, Anna V.

    2005-01-01

    We have successfully linked protein library screening directly with the identification of active proteins, without the need for individual purification, display technologies or physical linkage between the protein and its encoding sequence. By using ‘MAX’ randomization we have rapidly constructed 60 overlapping gene libraries that encode zinc finger proteins, randomized variously at the three principal DNA-contacting residues. Expression and screening of the libraries against five possible target DNA sequences generated data points covering a potential 40 000 individual interactions. Comparative analysis of the resulting data enabled direct identification of active proteins. Accuracy of this library analysis methodology was confirmed by both in vitro and in vivo analyses of identified proteins to yield novel zinc finger proteins that bind to their target sequences with high affinity, as indicated by low nanomolar apparent dissociation constants. PMID:15722478

  4. Jeffamine Derivatized TentaGel Beads and PDMS Microbead Cassettes for Ultra-high Throughput in situ Releasable Solution-Phase Cell-based Screening of OBOC Combinatorial Small Molecule Libraries

    PubMed Central

    Townsend, Jared B.; Shaheen, Farzana; Liu, Ruiwu; Lam, Kit S.

    2011-01-01

    A method to efficiently immobilize and partition large quantities of microbeads in an array format in microfabricated polydimethylsiloxane (PDMS) cassette for high-throughput in situ releasable solution-phase cell-based screening of one-bead-one-compound (OBOC) combinatorial libraries is described. Commercially available Jeffamine triamine T-403 (∼440 Da) was derivatized such that two of its amino groups were protected by Fmoc and the remaining amino group capped with succinic anhydride to generate a carboxyl group. This resulting tri-functional hydrophilic polymer was then sequentially coupled two times to the outer layer of topologically segregated bilayer TentaGel (TG) beads with solid phase peptide synthesis chemistry, resulting in beads with increased loading capacity, hydrophilicity and porosity at the outer layer. We have found that such bead configuration can facilitate ultra high-throughput in situ releasable solution-phase screening of OBOC libraries. An encoded releasable OBOC small molecule library was constructed on Jeffamine derivatized TG beads with library compounds tethered to the outer layer via a disulfide linker and coding tags in the interior of the beads. Compound-beads could be efficiently loaded (5-10 minutes) into a 5 cm diameter Petri dish containing a 10,000-well PDMS microbead cassette, such that over 90% of the microwells were each filled with only one compound-bead. Jurkat T-lymphoid cancer cells suspended in Matrigel® were then layered over the microbead cassette to immobilize the compound-beads. After 24 hours of incubation at 37°C, dithiothreitol was added to trigger the release of library compounds. Forty-eight hours later, MTT reporter assay was used to identify regions of reduced cell viability surrounding each positive bead. From a total of about 20,000 beads screened, 3 positive beads were detected and physically isolated for decoding. A strong consensus motif was identified for these three positive compounds. These

  5. Fractal analysis on human dynamics of library loans

    NASA Astrophysics Data System (ADS)

    Fan, Chao; Guo, Jin-Li; Zha, Yi-Long

    2012-12-01

    In this paper, the fractal characteristic of human behaviors is investigated from the perspective of time series constructed with the amount of library loans. The values of the Hurst exponent and length of non-periodic cycle calculated through rescaled range analysis indicate that the time series of human behaviors and their sub-series are fractal with self-similarity and long-range dependence. Then the time series are converted into complex networks by the visibility algorithm. The topological properties of the networks such as scale-free property and small-world effect imply that there is a close relationship among the numbers of repetitious behaviors performed by people during certain periods of time. Our work implies that there is intrinsic regularity in the human collective repetitious behaviors. The conclusions may be helpful to develop some new approaches to investigate the fractal feature and mechanism of human dynamics, and provide some references for the management and forecast of human collective behaviors.

  6. New Electrocatalysts by Combinatorial Methods

    NASA Astrophysics Data System (ADS)

    Smotkin, Eugene S.; Diaz-Morales, Robert R.

    2003-08-01

    Combinatorial methods provide a means for accelerating the discovery of fuel cell catalysts. The first example of parallel fuel cell catalysts screening was an indirect method that used fluorescent chemosensors to detect changes in pH in proximity to electrocatalyst spots. Serial direct electrochemical methods have been developed that use voltammetry, chronoamperometry, and scanning electrochemical microscopy. An array fuel cell screens catalysts simultaneously, using high-performance fuel cell components. Heuristic models based on mechanistic and spectroscopic studies provide guidance for library development, and detailed studies of discovered catalysts can help to refine these models. The remaining challenges are the development of high throughput synthetic methods that can enable the use of discovery level and focus level screening. Until these synthetic methods are developed, a greater emphasis should be placed on smaller libraries with design of experiment strategies leveraged with informatics and data mining.

  7. SECM characterization of Pt-Ru-WC and Pt-Ru-Co ternary thin film combinatorial libraries as anode electrocatalysts for PEMFC

    NASA Astrophysics Data System (ADS)

    Lu, Guojin; Cooper, James S.; McGinn, Paul J.

    Rapid screening of electrocatalytic activity of ternary Pt-Ru-WC and Pt-Ru-Co thin film gradient material libraries towards hydrogen oxidation in the presence or absence of CO adsorption was performed by scanning electrochemical microscopy. It was observed that the addition of WC or Co to Pt or Pt-Ru catalysts can improve their hydrogen oxidation reaction activity and CO tolerance, making them suitable as potential electrocatalysts for polymer electrolyte membrane fuel cells. The stability of WC and Co in the acidic electrolyte were enhanced by alloying with Pt. SECM offers the capability for both qualitative and quantitative characterization of electrocatalytic activity of thin films of potential fuel cell electrode material candidates. However, promising electrode compositions identified by this technique need to be verified by traditional electrode preparation and characterization techniques.

  8. Liquid-phase combinatorial synthesis.

    PubMed Central

    Han, H; Wolfe, M M; Brenner, S; Janda, K D

    1995-01-01

    A concept termed liquid-phase combinatorial synthesis (LPCS) is described. The central feature of this methodology is that it combines the advantages that classic organic synthesis in solution offers with those that solid-phase synthesis can provide, through the application of a linear homogeneous polymer. To validate this concept two libraries were prepared, one of peptide and the second of nonpeptide origin. The peptide-based library was synthesized by a recursive deconvolution strategy [Erb, E., Janda, K. D. & Brenner, S. (1994) Proc. Natl. Acad. Sci. USA 91, 11422-11426] and several ligands were found within this library to bind a monoclonal antibody elicited against beta-endorphin. The non-peptide molecules synthesized were arylsulfonamides, a class of compounds of known clinical bactericidal efficacy. The results indicate that the reaction scope of LPCS should be general, and its value to multiple, high-throughput screening assays could be of particular merit, since multimilligram quantities of each library member can readily be attained. PMID:7541541

  9. Selection of a high-affinity WW domain against the extracellular region of VEGF receptor isoform-2 from a combinatorial library using CIS display.

    PubMed

    Patel, Seema; Mathonet, Pascale; Jaulent, Agnes M; Ullman, Christopher G

    2013-04-01

    WW domains are small β-sheet motifs that are involved in intracellular signalling through the recognition of proline-rich or phosphorylated linear peptide sequences. Here, we describe modification of this motif to provide a framework for engineering the side chains exposed on its concave surface. This non-natural scaffold incorporates an additional tryptophan, has a shorter loop 1 and supports modification of 25% of the natural protein to form a novel affinity reagent. We demonstrate the utility of this structure by selecting a high-affinity binder to the extracellular region of human vascular endothelial growth factor receptor isoform 2 (VEGFR-2) from a library of modifications, using a cell-free molecular display platform, CIS display. The isolate has low nanomolar affinity to VEGFR-2 and inhibits binding of human VEGF to its receptor with nanomolar activity. The structure is amenable to cyclisation to improve its proteolytic stability and has advantages over larger protein scaffolds in that it can be synthesised chemically to high yields offering potential for therapeutic and non-therapeutic applications. PMID:23378640

  10. Available pathways database (APD): an essential resource for combinatorial biology.

    PubMed

    Pirrung, M C; Silva, C M; Jaeger, J

    2000-10-01

    A relational database, the Available Pathways Database (APD), has been constructed of microbial natural products, their producing strains, and their biosynthetic pathways. The database allows the ready selection of donor strains for combinatorial biology experiments. It provides the same type of resource for combinatorial biology as the Available Chemicals Directory (ACD) does for combinatorial chemical library generation. Its cataloging ability can also provide insight into novel aspects of biosynthetic routes. In particular, no 10-unit Type I polyketides were found in the compilation of this edition of the APD (Version I). PMID:11076562

  11. Combinatorial protein design strategies using computational methods.

    PubMed

    Kono, Hidetoshi; Wang, Wei; Saven, Jeffery G

    2007-01-01

    Computational methods continue to facilitate efforts in protein design. Most of this work has focused on searching sequence space to identify one or a few sequences compatible with a given structure and functionality. Probabilistic computational methods provide information regarding the range of amino acid variability permitted by desired functional and structural constraints. Such methods may be used to guide the construction of both individual sequences and combinatorial libraries of proteins. PMID:17041256

  12. Combinatorial Geometry Printer Plotting.

    Energy Science and Technology Software Center (ESTSC)

    1987-01-05

    Picture generates plots of two-dimensional slices through the three-dimensional geometry described by the combinatorial geometry (CG) package used in such codes as MORSE and QAD-CG. These plots are printed on a standard line printer.

  13. Combinatorial Interdependence in Lottery

    ERIC Educational Resources Information Center

    Helman, Danny

    2005-01-01

    This paper examines a real life question of gamble facing lottery players. Combinatorial dependence plays a central role in shaping the game probabilistic structure, but might not carry the merited weight in punters' considerations.

  14. From dynamic combinatorial ‘hit’ to lead: in vitro and in vivo activity of compounds targeting the pathogenic RNAs that cause myotonic dystrophy

    PubMed Central

    Ofori, Leslie O.; Hoskins, Jason; Nakamori, Masayuki; Thornton, Charles A.; Miller, Benjamin L.

    2012-01-01

    The myotonic dystrophies (DM) are human diseases in which the accumulation of toxic RNA (CUG or CCUG) repeats in the cell causes sequestration of splicing factors, including MBNL1, leading to clinical symptoms such as muscle wasting and myotonia. We previously used Dynamic Combinatorial Chemistry to identify the first compounds known to inhibit (CUG)-MBNL1 binding in vitro. We now report transformation of those compounds into structures with activity in vivo. Introduction of a benzo[g]quinoline substructure previously unknown in the context of RNA recognition, as well as other modifications, provided several molecules with enhanced binding properties, including compounds with strong selectivity for CUG repeats over CAG repeats or CAG–CUG duplex RNA. Compounds readily penetrate cells, and improve luciferase activity in a mouse myoblast assay in which enzyme function is coupled to a release of nuclear CUG–RNA retention. Most importantly, two compounds are able to partially restore splicing in a mouse model of DM1. PMID:22492623

  15. SwiftLib: rapid degenerate-codon-library optimization through dynamic programming

    PubMed Central

    Jacobs, Timothy M.; Yumerefendi, Hayretin; Kuhlman, Brian; Leaver-Fay, Andrew

    2015-01-01

    Degenerate codon (DC) libraries efficiently address the experimental library-size limitations of directed evolution by focusing diversity toward the positions and toward the amino acids (AAs) that are most likely to generate hits; however, manually constructing DC libraries is challenging, error prone and time consuming. This paper provides a dynamic programming solution to the task of finding the best DCs while keeping the size of the library beneath some given limit, improving on the existing integer-linear programming formulation. It then extends the algorithm to consider multiple DCs at each position, a heretofore unsolved problem, while adhering to a constraint on the number of primers needed to synthesize the library. In the two library-design problems examined here, the use of multiple DCs produces libraries that very nearly cover the set of desired AAs while still staying within the experimental size limits. Surprisingly, the algorithm is able to find near-perfect libraries where the ratio of amino-acid sequences to nucleic-acid sequences approaches 1; it effectively side-steps the degeneracy of the genetic code. Our algorithm is freely available through our web server and solves most design problems in about a second. PMID:25539925

  16. Combinatorial stresses kill pathogenic Candida species.

    PubMed

    Kaloriti, Despoina; Tillmann, Anna; Cook, Emily; Jacobsen, Mette; You, Tao; Lenardon, Megan; Ames, Lauren; Barahona, Mauricio; Chandrasekaran, Komelapriya; Coghill, George; Goodman, Daniel; Gow, Neil A R; Grebogi, Celso; Ho, Hsueh-Lui; Ingram, Piers; McDonagh, Andrew; de Moura, Alessandro P S; Pang, Wei; Puttnam, Melanie; Radmaneshfar, Elahe; Romano, Maria Carmen; Silk, Daniel; Stark, Jaroslav; Stumpf, Michael; Thiel, Marco; Thorne, Thomas; Usher, Jane; Yin, Zhikang; Haynes, Ken; Brown, Alistair J P

    2012-10-01

    Pathogenic microbes exist in dynamic niches and have evolved robust adaptive responses to promote survival in their hosts. The major fungal pathogens of humans, Candida albicans and Candida glabrata, are exposed to a range of environmental stresses in their hosts including osmotic, oxidative and nitrosative stresses. Significant efforts have been devoted to the characterization of the adaptive responses to each of these stresses. In the wild, cells are frequently exposed simultaneously to combinations of these stresses and yet the effects of such combinatorial stresses have not been explored. We have developed a common experimental platform to facilitate the comparison of combinatorial stress responses in C. glabrata and C. albicans. This platform is based on the growth of cells in buffered rich medium at 30°C, and was used to define relatively low, medium and high doses of osmotic (NaCl), oxidative (H(2)O(2)) and nitrosative stresses (e.g., dipropylenetriamine (DPTA)-NONOate). The effects of combinatorial stresses were compared with the corresponding individual stresses under these growth conditions. We show for the first time that certain combinations of combinatorial stress are especially potent in terms of their ability to kill C. albicans and C. glabrata and/or inhibit their growth. This was the case for combinations of osmotic plus oxidative stress and for oxidative plus nitrosative stress. We predict that combinatorial stresses may be highly significant in host defences against these pathogenic yeasts. PMID:22463109

  17. Application of computer assisted combinatorial chemistry in antivirial, antimalarial and anticancer agents design

    NASA Astrophysics Data System (ADS)

    Burello, E.; Bologa, C.; Frecer, V.; Miertus, S.

    Combinatorial chemistry and technologies have been developed to a stage where synthetic schemes are available for generation of a large variety of organic molecules. The innovative concept of combinatorial design assumes that screening of a large and diverse library of compounds will increase the probability of finding an active analogue among the compounds tested. Since the rate at which libraries are screened for activity currently constitutes a limitation to the use of combinatorial technologies, it is important to be selective about the number of compounds to be synthesized. Early experience with combinatorial chemistry indicated that chemical diversity alone did not result in a significant increase in the number of generated lead compounds. Emphasis has therefore been increasingly put on the use of computer assisted combinatorial chemical techniques. Computational methods are valuable in the design of virtual libraries of molecular models. Selection strategies based on computed physicochemical properties of the models or of a target compound are introduced to reduce the time and costs of library synthesis and screening. In addition, computational structure-based library focusing methods can be used to perform in silico screening of the activity of compounds against a target receptor by docking the ligands into the receptor model. Three case studies are discussed dealing with the design of targeted combinatorial libraries of inhibitors of HIV-1 protease, P. falciparum plasmepsin and human urokinase as potential antivirial, antimalarial and anticancer drugs. These illustrate library focusing strategies.

  18. Manipulating Combinatorial Structures.

    ERIC Educational Resources Information Center

    Labelle, Gilbert

    This set of transparencies shows how the manipulation of combinatorial structures in the context of modern combinatorics can easily lead to interesting teaching and learning activities at every level of education from elementary school to university. The transparencies describe: (1) the importance and relations of combinatorics to science and…

  19. Increasing the dynamic control space of mammalian transcription devices by combinatorial assembly of homologous regulatory elements from different bacterial species.

    PubMed

    Bacchus, William; Weber, Wilfried; Fussenegger, Martin

    2013-01-01

    Prokaryotic transcriptional regulatory elements are widely utilized building blocks for constructing regulatory genetic circuits adapted for mammalian cells and have found their way into a broad range of biotechnological applications. Prokaryotic transcriptional repressors, fused to eukaryotic transactivation or repression domains, compose the transcription factor, which binds and adjusts transcription from chimeric promoters containing the repressor-specific operator sequence. Escherichia coli and Chlamydia trachomatis share common features in the regulatory mechanism of the biosynthesis of l-tryptophan. The repressor protein TrpR of C. trachomatis regulates the trpRBA operon and the TrpR of E. coli regulates the trpEDCBA operon, both requiring l-tryptophan as a co-repressor. Fusion of these bacterial repressors to the VP16 transactivation domain of Herpes simplex virus creates synthetic transactivators that could bind and activate chimeric promoters, assembled by placing repressor-specific operator modules adjacent to a minimal promoter, in an l-tryptophan-adjustable manner. Combinations of different transactivator and promoter variants from the same or different bacterial species resulted in a multitude of regulatory systems where l-tryptophan regulation properties, background noise, and maximal gene expression levels were significantly diverse. Different l-tryptophan analogues showed diverse regulatory capacity depending on the promoter/transactivator combination. We believe the systems approach to rationally choose promoters, transactivators and inducer molecules, to obtain desired and predefined genetic expression dynamics and control profiles, will significantly advance the design of new regulatory circuits as well as improving already existing ones. PMID:23178502

  20. Massively parallel high-order combinatorial genetics in human cells

    PubMed Central

    Wong, Alan S L; Choi, Gigi C G; Cheng, Allen A; Purcell, Oliver; Lu, Timothy K

    2016-01-01

    The systematic functional analysis of combinatorial genetics has been limited by the throughput that can be achieved and the order of complexity that can be studied. To enable massively parallel characterization of genetic combinations in human cells, we developed a technology for rapid, scalable assembly of high-order barcoded combinatorial genetic libraries that can be quantified with high-throughput sequencing. We applied this technology, combinatorial genetics en masse (CombiGEM), to create high-coverage libraries of 1,521 two-wise and 51,770 three-wise barcoded combinations of 39 human microRNA (miRNA) precursors. We identified miRNA combinations that synergistically sensitize drug-resistant cancer cells to chemotherapy and/or inhibit cancer cell proliferation, providing insights into complex miRNA networks. More broadly, our method will enable high-throughput profiling of multifactorial genetic combinations that regulate phenotypes of relevance to biomedicine, biotechnology and basic science. PMID:26280411

  1. Research on Universal Combinatorial Coding

    PubMed Central

    Lu, Jun; Zhang, Zhuo; Mo, Juan

    2014-01-01

    The conception of universal combinatorial coding is proposed. Relations exist more or less in many coding methods. It means that a kind of universal coding method is objectively existent. It can be a bridge connecting many coding methods. Universal combinatorial coding is lossless and it is based on the combinatorics theory. The combinational and exhaustive property make it closely related with the existing code methods. Universal combinatorial coding does not depend on the probability statistic characteristic of information source, and it has the characteristics across three coding branches. It has analyzed the relationship between the universal combinatorial coding and the variety of coding method and has researched many applications technologies of this coding method. In addition, the efficiency of universal combinatorial coding is analyzed theoretically. The multicharacteristic and multiapplication of universal combinatorial coding are unique in the existing coding methods. Universal combinatorial coding has theoretical research and practical application value. PMID:24772019

  2. Research on universal combinatorial coding.

    PubMed

    Lu, Jun; Zhang, Zhuo; Mo, Juan

    2014-01-01

    The conception of universal combinatorial coding is proposed. Relations exist more or less in many coding methods. It means that a kind of universal coding method is objectively existent. It can be a bridge connecting many coding methods. Universal combinatorial coding is lossless and it is based on the combinatorics theory. The combinational and exhaustive property make it closely related with the existing code methods. Universal combinatorial coding does not depend on the probability statistic characteristic of information source, and it has the characteristics across three coding branches. It has analyzed the relationship between the universal combinatorial coding and the variety of coding method and has researched many applications technologies of this coding method. In addition, the efficiency of universal combinatorial coding is analyzed theoretically. The multicharacteristic and multiapplication of universal combinatorial coding are unique in the existing coding methods. Universal combinatorial coding has theoretical research and practical application value. PMID:24772019

  3. Libra: An open-Source "methodology discovery" library for quantum and classical dynamics simulations.

    PubMed

    Akimov, Alexey V

    2016-06-30

    The "methodology discovery" library for quantum and classical dynamics simulations is presented. One of the major foci of the code is on nonadiabatic molecular dynamics simulations with model and atomistic Hamiltonians treated on the same footing. The essential aspects of the methodology, design philosophy, and implementation are discussed. The code capabilities are demonstrated on a number of model and atomistic test cases. It is demonstrated how the library can be used to study methodologies for quantum and classical dynamics, as well as a tool for performing detailed atomistic studies of nonadiabatic processes in molecular systems. The source code and additional information are available on the Web at http://www.acsu.buffalo.edu/~alexeyak/libra/index.html. © 2016 Wiley Periodicals, Inc. PMID:27016373

  4. Automated Combinatorial Chemistry in the Organic Chemistry Majors Laboratory

    ERIC Educational Resources Information Center

    Nichols, Christopher J.; Hanne, Larry F.

    2010-01-01

    A multidisciplinary experiment has been developed in which students each synthesize a combinatorial library of 48 hydrazones with the aid of a liquid-handling robot. Each product is then subjected to a Kirby-Bauer disk diffusion assay to assess its antibacterial activity. Students gain experience working with automation and at the…

  5. A combinatorial approach to the discovery of advanced materials

    NASA Astrophysics Data System (ADS)

    Sun, Xiao-Dong

    This thesis discusses the application of combinatorial methods to the search of advanced materials. The goal of this research is to develop a "parallel" or "fast sequential" methodology for both the synthesis and characterization of materials with novel electronic, magnetic and optical properties. Our hope is to dramatically accelerate the rate at which materials are generated and studied. We have developed two major combinatorial methodologies to this end. One involves generating thin film materials libraries using a combination of various thin film deposition and masking strategies with multi-layer thin film precursors. The second approach is to generate powder materials libraries with solution precursors delivered with a multi-nozzle inkjet system. The first step in this multistep combinatorial process involves the design and synthesis of high density libraries of diverse materials aimed at exploring a large segment of the compositional space of interest based on our understanding of the physical and structural properties of a particular class of materials. Rapid, sensitive measurements of one or more relevant physical properties of each library member result in the identification of a family of "lead" compositions with a desired property. These compositions are then optimized by continuously varying the stoichiometries of a more focused set of precursors. Materials with the optimal composition are then synthesized in quantities sufficient for detailed characterization of their structural and physical properties. Finally, the information obtained from this process should enhance our predictive ability in subsequent experiments. Combinatorial methods have been successfully used in the synthesis and discovery of materials with novel properties. For example, a class of cobaltite based giant magnetoresistance (GMR) ceramics was discovered; Application of this method to luminescence materials has resulted in the discovery of a few highly efficient tricolor

  6. Nonlinear model reduction for dynamical systems using sparse sensor locations from learned libraries

    NASA Astrophysics Data System (ADS)

    Sargsyan, Syuzanna; Brunton, Steven L.; Kutz, J. Nathan

    2015-09-01

    We demonstrate the synthesis of sparse sampling and dimensionality reduction to characterize and model nonlinear dynamical systems over a range of bifurcation parameters. First, we construct modal libraries using the classical proper orthogonal decomposition in order to expose the dominant low-rank coherent structures. Here, libraries of the nonlinear terms are also constructed in order to take advantage of the discrete empirical interpolation method and projection that allows for the approximation of nonlinear terms from a sparse number of grid points. The selected grid points are shown to be effective sensing and measurement locations for characterizing the underlying dynamics, stability, and bifurcations of nonlinear dynamical systems. The use of empirical interpolation points and sparse representation facilitates a family of local reduced-order models for each physical regime, rather than a higher-order global model, which has the benefit of physical interpretability of energy transfer between coherent structures. The method advocated also allows for orders-of-magnitude improvement in computational speed and memory requirements. To illustrate the method, the discrete interpolation points and nonlinear modal libraries are used for sparse representation in order to classify and reconstruct the dynamic bifurcation regimes in the complex Ginzburg-Landau equation. It is also shown that point measurements of the nonlinearity are more effective than linear measurements when sensor noise is present.

  7. Nonlinear model reduction for dynamical systems using sparse sensor locations from learned libraries.

    PubMed

    Sargsyan, Syuzanna; Brunton, Steven L; Kutz, J Nathan

    2015-09-01

    We demonstrate the synthesis of sparse sampling and dimensionality reduction to characterize and model nonlinear dynamical systems over a range of bifurcation parameters. First, we construct modal libraries using the classical proper orthogonal decomposition in order to expose the dominant low-rank coherent structures. Here, libraries of the nonlinear terms are also constructed in order to take advantage of the discrete empirical interpolation method and projection that allows for the approximation of nonlinear terms from a sparse number of grid points. The selected grid points are shown to be effective sensing and measurement locations for characterizing the underlying dynamics, stability, and bifurcations of nonlinear dynamical systems. The use of empirical interpolation points and sparse representation facilitates a family of local reduced-order models for each physical regime, rather than a higher-order global model, which has the benefit of physical interpretability of energy transfer between coherent structures. The method advocated also allows for orders-of-magnitude improvement in computational speed and memory requirements. To illustrate the method, the discrete interpolation points and nonlinear modal libraries are used for sparse representation in order to classify and reconstruct the dynamic bifurcation regimes in the complex Ginzburg-Landau equation. It is also shown that point measurements of the nonlinearity are more effective than linear measurements when sensor noise is present. PMID:26465583

  8. Combinatorial Engineering of Dextransucrase Specificity

    PubMed Central

    Irague, Romain; Tarquis, Laurence; André, Isabelle; Moulis, Claire; Morel, Sandrine; Monsan, Pierre; Potocki-Véronèse, Gabrielle; Remaud-Siméon, Magali

    2013-01-01

    We used combinatorial engineering to investigate the relationships between structure and linkage specificity of the dextransucrase DSR-S from Leuconostoc mesenteroides NRRL B-512F, and to generate variants with altered specificity. Sequence and structural analysis of glycoside-hydrolase family 70 enzymes led to eight amino acids (D306, F353, N404, W440, D460, H463, T464 and S512) being targeted, randomized by saturation mutagenesis and simultaneously recombined. Screening of two libraries totaling 3.6.104 clones allowed the isolation of a toolbox comprising 81 variants which synthesize high molecular weight α-glucans with different proportions of α(1→3) linkages ranging from 3 to 20 %. Mutant sequence analysis, biochemical characterization and molecular modelling studies revealed the previously unknown role of peptide 460DYVHT464 in DSR-S linkage specificity. This peptide sequence together with residue S512 contribute to defining +2 subsite topology, which may be critical for the enzyme regiospecificity. PMID:24204991

  9. Combinatorial measurements of Hall effect and resistivity in oxide films.

    PubMed

    Clayhold, J A; Kerns, B M; Schroer, M D; Rench, D W; Logvenov, G; Bollinger, A T; Bozovic, I

    2008-03-01

    A system for the simultaneous measurement of the Hall effect in 31 different locations as well as the measurement of the resistivity in 30 different locations on a single oxide thin film grown with a composition gradient is described. Considerations for designing and operating a high-throughput system for characterizing highly conductive oxides with Hall coefficients as small as 10(-10) m3/C are discussed. Results from measurements on films grown using combinatorial molecular beam epitaxy show the usefulness of characterizing combinatorial libraries via both the resistivity and the Hall effect. PMID:18377026

  10. Combinatorial Mechanical Metamaterials

    NASA Astrophysics Data System (ADS)

    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.

  11. Development of a combinatorial atmospheric pressure cold plasma processor

    NASA Astrophysics Data System (ADS)

    Terajima, Takeshi; Koinuma, Hideomi

    2004-02-01

    Low-temperature plasma can be generated under atmospheric pressure by applying an RF (13.56 MHz) voltage between parallel electrodes, the surfaces of which are preferably covered with an insulator. Applications of this atmospheric pressure cold plasma include thin film deposition, chemical synthesis, etching, resist-ashing, surface treatment, and sterilization. For seeking further improvement of the system and more applications, we have developed a combinatorial atmospheric pressure cold plasma generator to fabricate composition spread thin films by synchronizing the variation of feeding gas ratio with the substrate stage motion. This system can be extended to fabricating a variety of combinatorial libraries by controlling other parameters in the operation such as the gas flow rate, the RF power, substrate temperature, and the treatment time. The utility of this combinatorial plasma process has been demonstrated with the plasma copolymerization of CO 2 with ethylene to fix CO 2 into the plasma polymerized film in the form of ester linkage.

  12. Cryptographic Combinatorial Securities Exchanges

    NASA Astrophysics Data System (ADS)

    Thorpe, Christopher; Parkes, David C.

    We present a useful new mechanism that facilitates the atomic exchange of many large baskets of securities in a combinatorial exchange. Cryptography prevents information about the securities in the baskets from being exploited, enhancing trust. Our exchange offers institutions who wish to trade large positions a new alternative to existing methods of block trading: they can reduce transaction costs by taking advantage of other institutions’ available liquidity, while third party liquidity providers guarantee execution—preserving their desired portfolio composition at all times. In our exchange, institutions submit encrypted orders which are crossed, leaving a “remainder”. The exchange proves facts about the portfolio risk of this remainder to third party liquidity providers without revealing the securities in the remainder, the knowledge of which could also be exploited. The third parties learn either (depending on the setting) the portfolio risk parameters of the remainder itself, or how their own portfolio risk would change if they were to incorporate the remainder into a portfolio they submit. In one setting, these third parties submit bids on the commission, and the winner supplies necessary liquidity for the entire exchange to clear. This guaranteed clearing, coupled with external price discovery from the primary markets for the securities, sidesteps difficult combinatorial optimization problems. This latter method of proving how taking on the remainder would change risk parameters of one’s own portfolio, without revealing the remainder’s contents or its own risk parameters, is a useful protocol of independent interest.

  13. Combinatorial investigation of ferromagnetic shape memory materials

    NASA Astrophysics Data System (ADS)

    Famodu, Olugbenga O.

    2005-07-01

    Combinatorial synthesis is research methodology which allows one to systemically study a large number of compositionally varying samples simultaneously. We apply this technique to the investigation of multifunctional materials. Different designs of combinatorial libraries and various characterization tools are implemented in order to rapidly map composition-structure-property relationships in a variety of materials systems. In this thesis, I will discuss combinatorial investigation of various shape memory alloys. We have utilized the combinatorial magnetron co-sputtering deposition technique for fabricating composition spreads of ternary alloy systems containing ferromagnetic shape memory alloys (FSMAs) and thermoelastic shape memory alloys (SMAs). Magnetic properties of the composition spreads were rapidly characterized using a room temperature scanning semiconducting quantum interference device (SQUID) microscope which provides mapping of the magnetic field emanating from different parts of the composition spreads. By applying the inversion technique to the mapping of the magnetic field distribution, we have mapped the magnetic phase diagram of the Ni-Mn-Ga and Ni-Mn-Al systems whose Heusler compositions Ni2MnGa and Ni2MnAl are well known ferromagnetic shape memory alloys (FSMAs). In addition, a rapid visual inspection technique was developed for detection of reversible martensites using arrays of micromachined cantilevers. A large, previously unexplored compositional region of FSMAs outside the Heusler composition was found. In search of novel FSMAs, we have also investigated a number of other ternary alloys systems. These systems included Ni-Mn-In, Gd-Ge-Si, Co-Mn-Ga, Ni-Fe-Al, and Co-Ni-Ga. A summary of the results from the investigation of these systems is presented. We have used the combinatorial technique to search for "ideal" SMAs with minimal hysteresis. For pursuing this, we had first set out to verify the geometric non-linear theory of martensites which

  14. Combinatorial thin film composition mapping using three dimensional deposition profiles.

    PubMed

    Suram, Santosh K; Zhou, Lan; Becerra-Stasiewicz, Natalie; Kan, Kevin; Jones, Ryan J R; Kendrick, Brian M; Gregoire, John M

    2015-03-01

    Many next-generation technologies are limited by material performance, leading to increased interest in the discovery of advanced materials using combinatorial synthesis, characterization, and screening. Several combinatorial synthesis techniques, such as solution based methods, advanced manufacturing, and physical vapor deposition, are currently being employed for various applications. In particular, combinatorial magnetron sputtering is a versatile technique that provides synthesis of high-quality thin film composition libraries. Spatially addressing the composition of these thin films generally requires elemental quantification measurements using techniques such as energy-dispersive X-ray spectroscopy or X-ray fluorescence spectroscopy. Since these measurements are performed ex-situ and post-deposition, they are unable to provide real-time design of experiments, a capability that is required for rapid synthesis of a specific composition library. By using three quartz crystal monitors attached to a stage with translational and rotational degrees of freedom, we measure three-dimensional deposition profiles of deposition sources whose tilt with respect to the substrate is robotically controlled. We exhibit the utility of deposition profiles and tilt control to optimize the deposition geometry for specific combinatorial synthesis experiments. PMID:25832242

  15. Combinatorial thin film composition mapping using three dimensional deposition profiles

    NASA Astrophysics Data System (ADS)

    Suram, Santosh K.; Zhou, Lan; Becerra-Stasiewicz, Natalie; Kan, Kevin; Jones, Ryan J. R.; Kendrick, Brian M.; Gregoire, John M.

    2015-03-01

    Many next-generation technologies are limited by material performance, leading to increased interest in the discovery of advanced materials using combinatorial synthesis, characterization, and screening. Several combinatorial synthesis techniques, such as solution based methods, advanced manufacturing, and physical vapor deposition, are currently being employed for various applications. In particular, combinatorial magnetron sputtering is a versatile technique that provides synthesis of high-quality thin film composition libraries. Spatially addressing the composition of these thin films generally requires elemental quantification measurements using techniques such as energy-dispersive X-ray spectroscopy or X-ray fluorescence spectroscopy. Since these measurements are performed ex-situ and post-deposition, they are unable to provide real-time design of experiments, a capability that is required for rapid synthesis of a specific composition library. By using three quartz crystal monitors attached to a stage with translational and rotational degrees of freedom, we measure three-dimensional deposition profiles of deposition sources whose tilt with respect to the substrate is robotically controlled. We exhibit the utility of deposition profiles and tilt control to optimize the deposition geometry for specific combinatorial synthesis experiments.

  16. Combinatorial optimization games

    SciTech Connect

    Deng, X.; Ibaraki, Toshihide; Nagamochi, Hiroshi

    1997-06-01

    We introduce a general integer programming formulation for a class of combinatorial optimization games, which immediately allows us to improve the algorithmic result for finding amputations in the core (an important solution concept in cooperative game theory) of the network flow game on simple networks by Kalai and Zemel. An interesting result is a general theorem that the core for this class of games is nonempty if and only if a related linear program has an integer optimal solution. We study the properties for this mathematical condition to hold for several interesting problems, and apply them to resolve algorithmic and complexity issues for their cores along the line as put forward in: decide whether the core is empty; if the core is empty, find an imputation in the core; given an imputation x, test whether x is in the core. We also explore the properties of totally balanced games in this succinct formulation of cooperative games.

  17. BAL: A library for the brute-force analysis of dynamical systems

    NASA Astrophysics Data System (ADS)

    Linaro, Daniele; Storace, Marco

    2016-04-01

    This paper describes the functionality and usage of BAL, a C/C++ library with a Python front-end for the brute-force analysis of continuous-time dynamical systems described by ordinary differential equations (ODEs). BAL provides an easy-to-use wrapper for the efficient numerical integration of ODEs and, by detecting intersections of the trajectory with appropriate Poincaré sections, allows to classify the asymptotic trajectory of a dynamical system for bifurcation analysis. Some examples of application are discussed, concerning two-dimensional bifurcation diagrams, Lyapunov exponents and finite-time Lyapunov exponents, basins of attraction, simulation of switching ODE systems, and integration with AUTO, a software package for continuation analysis.

  18. Combinatorial synthesis of deuterium-enriched (S)-oxybutynin.

    PubMed

    Li, Feng; Jiang, Wenfeng; Czarnik, Anthony W; Li, Wenbao

    2016-08-01

    The concept of deuterium enrichment has gained more attention due to its advantages in the studies of clinical pharmacokinetics and metabolic profiles. In addition, it is cost and time efficient to develop deuterium-enriched drugs. Herein we built a combinatorial library of deuterated (S)-oxybutynins which all 8 D-compounds were characterized by MS, [Formula: see text] NMR and [Formula: see text]C NMR. PMID:26852022

  19. Quantum supercharger library: hyper-parallel integral derivatives algorithms for ab initio QM/MM dynamics.

    PubMed

    Renison, C Alicia; Fernandes, Kyle D; Naidoo, Kevin J

    2015-07-01

    This article describes an extension of the quantum supercharger library (QSL) to perform quantum mechanical (QM) gradient and optimization calculations as well as hybrid QM and molecular mechanical (QM/MM) molecular dynamics simulations. The integral derivatives are, after the two-electron integrals, the most computationally expensive part of the aforementioned calculations/simulations. Algorithms are presented for accelerating the one- and two-electron integral derivatives on a graphical processing unit (GPU). It is shown that a Hartree-Fock ab initio gradient calculation is up to 9.3X faster on a single GPU compared with a single central processing unit running an optimized serial version of GAMESS-UK, which uses the efficient Schlegel method for s- and l-orbitals. Benchmark QM and QM/MM molecular dynamics simulations are performed on cellobiose in vacuo and in a 39 Å water sphere (45 QM atoms and 24843 point charges, respectively) using the 6-31G basis set. The QSL can perform 9.7 ps/day of ab initio QM dynamics and 6.4 ps/day of QM/MM dynamics on a single GPU in full double precision. © 2015 Wiley Periodicals, Inc. PMID:25975864

  20. Development of Combinatorial Methods for Alloy Design and Optimization

    SciTech Connect

    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 powerful technique for

  1. SMMH - A Parallel Heuristic for Combinatorial Optimization Problems

    SciTech Connect

    Domingues, Guilherme; Morie, Yoshiyuki; Gu, Feng Long; Nanri, Takeshi; Murakami, Kazuaki

    2007-12-26

    The process of finding one or more optimal solutions for answering combinatorial optimization problems bases itself on the use of algorithms instances. Those instances usually have to explore a very large search spaces. Heuristics search focusing on the use of High-Order Hopfield neural networks is a largely deployed technique for very large search space. It can be established a very powerful analogy towards the dynamics evolution of a physics spin-glass system while minimizing its own energy and the energy function of the network. This paper presents a new approach for solving combinatorial optimization problems through parallel simulations, based on a High-Order Hopfield neural network using MPI specification.

  2. SMMH--A Parallel Heuristic for Combinatorial Optimization Problems

    SciTech Connect

    Domingues, Guilherme; Morie, Yoshiyuki; Gu, Feng Long; Nanri, Takeshi; Murakami, Kazuaki

    2007-12-26

    The process of finding one or more optimal solutions for answering combinatorial optimization problems bases itself on the use of algorithms instances. Those instances usually have to explore a very large search spaces. Heuristics search focusing on the use of High-Order Hopfield neural networks is a largely deployed technique for very large search space. It can be established a very powerful analogy towards the dynamics evolution of a physics spin-glass system while minimizing its own energy and the energy function of the network. This paper presents a new approach for solving combinatorial optimization problems through parallel simulations, based on a High-Order Hopfield neural network using MPI specification.

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

    PubMed

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

    2015-05-01

    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. PMID:25904530

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

    PubMed Central

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

    2015-01-01

    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. PMID:25904530

  5. EDITORIAL: Combinatorial and High-Throughput Materials Research

    NASA Astrophysics Data System (ADS)

    Potyrailo, Radislav A.; Takeuchi, Ichiro

    2005-01-01

    The success of combinatorial and high-throughput methodologies relies greatly on the availability of various characterization tools with new and improved capabilities [1]. Indeed, how useful can a combinatorial library of 250, 400, 25 000 or 2 000 000 compounds be [2-5] if one is unable to characterize its properties of interest fairly quickly? How useful can a set of thousands of spectra or chromatograms be if one is unable to analyse them in a timely manner? For these reasons, the development of new approaches for materials characterization is one of the most active areas in combinatorial materials science. The importance of this aspect of research in the field has been discussed in numerous conferences including the Pittsburgh Conferences, the American Chemical Society Meetings, the American Physical Society Meetings, the Materials Research Society Symposia and various Gordon Research Conferences. Naturally, the development of new measurement instrumentation attracts the attention not only of practitioners of combinatorial materials science but also of those who design new software for data manipulation and mining. Experimental designs of combinatorial libraries are pursued with available and realistic synthetic and characterization capabilities in mind. It is becoming increasingly critical to link the design of new equipment for high-throughput parallel materials synthesis with integrated measurement tools in order to enhance the efficacy of the overall experimental strategy. We have received an overwhelming response to our proposal and call for papers for this Special Issue on Combinatorial Materials Science. The papers in this issue of Measurement Science and Technology are a very timely collection that captures the state of modern combinatorial materials science. They demonstrate the significant advances that are taking place in the field. In some cases, characterization tools are now being operated in the factory mode. At the same time, major challenges

  6. Combinatorial synthesis and screening of fuel cell catalysts

    NASA Astrophysics Data System (ADS)

    Jayaraman, Shrisudersan

    Polymer electrolyte membrane fuel cells (PEMFCs) are compact power sources that can operate with high efficiencies and low emission of environmentally harmful gases. One of the major barriers impeding the development of PEMFCs as a competitive energy source is the inability of existing anode catalysts to oxidize fuels other than hydrogen at sufficient levels due to catalyst deactivation by carbon monoxide (CO) and other partial oxidation products. The focus of this research is the development and application of combinatorial strategies to construct and interrogate electrooxidation (anode) catalysts pertaining to PEMFCs to discover catalysts with enhanced performance in catalyst deactivating environments. A novel method (known as the "gel-transfer" method) for synthesizing catalyst composition gradient libraries for combinatorial catalyst discovery was developed. This method involved transferring a spatial concentration gradient of precursor metal salts created within a polymer gel on to a solid conducting substrate by electrochemical reduction. Chemically sensitive surface-imaging techniques, namely, scanning electrochemical microscopy (SECM) and optical screening with a pH-dependent fluorescence probe were used to characterize the combinatorial catalyst samples. The utility of SECM as a screening tool to measure the activity of multicomponent catalyst libraries towards fuel cell electrooxidation reactions was established with simple catalyst libraries including a platinum coverage gradient and platinum-ruthenium and platinum-ruthenium-molybdenum arrays. A platinum-ruthenium surface composition gradient was constructed through the gel-transfer method and its reactivity towards hydrogen oxidation in the presence of a catalyst poison (CO) was mapped using the SECM. Ruthenium composition between 20 and 30% exhibited superior performance than the rest of the binary. The gel-transfer method was extended to construct a ternary platinum-ruthenium-rhodium catalyst library

  7. Combinatorial Synthesis and Discovery of an Antibiotic Compound. An Experiment Suitable for High School and Undergraduate Laboratories

    NASA Astrophysics Data System (ADS)

    Wolkenberg, Scott E.; Su, Andrew I.

    2001-06-01

    An exercise demonstrating solution-phase combinatorial chemistry and its application to drug discovery is described. The experiment involves the synthesis of six libraries of three hydrazones, screening the libraries for antibiotic activity, and deconvolution to determine the active individual compound. The laboratory was designed for a high school classroom, though it can easily be expanded to suit a college introductory organic laboratory course.

  8. Mesofluidic Devices for DNA-Programmed Combinatorial Chemistry

    PubMed Central

    Weisinger, Rebecca M.; Marinelli, Robert J.; Wrenn, S. Jarrett; Harbury, Pehr B.

    2012-01-01

    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. PMID:22479318

  9. Logical Structures Underlying Combinatorial Reasoning.

    ERIC Educational Resources Information Center

    Glick, Rochelle; Martorano, Suzanne

    This study was designed to examine the processes underlying developmental changes in children's (1) use of combinatorial strategy, and (2) comprehension of conjunctive and disjunctive propositional relationships. A total of 108 children from third, sixth and eighth grades participated in this study. Each child was administered three tasks…

  10. Combinatorial Evolution of Enzymes and Synthetic Pathways Using One-Step PCR.

    PubMed

    Jin, Peng; Kang, Zhen; Zhang, Junli; Zhang, Linpei; Du, Guocheng; Chen, Jian

    2016-03-18

    DNA engineering is the fundamental motive driving the rapid development of modern biotechnology. Here, we present a versatile evolution method termed "rapidly efficient combinatorial oligonucleotides for directed evolution" (RECODE) for rapidly introducing multiple combinatorial mutations to the target DNA by combined action of a thermostable high-fidelity DNA polymerase and a thermostable DNA Ligase in one reaction system. By applying this method, we rapidly constructed a variant library of the rpoS promoters (with activity of 8-460%), generated a novel heparinase from the highly specific leech hyaluronidase (with more than 30 mutant residues) and optimized the heme biosynthetic pathway by combinatorial evolution of regulatory elements and pathway enzymes (2500 ± 120 mg L(-1) with 20-fold increase). The simple RECODE method enabled researchers the unparalleled ability to efficiently create diverse mutant libraries for rapid evolution and optimization of enzymes and synthetic pathways. PMID:26751617

  11. Why is combinatorial communication rare in the natural world, and why is language an exception to this trend?

    PubMed Central

    Scott-Phillips, Thomas C.; Blythe, Richard A.

    2013-01-01

    In a combinatorial communication system, some signals consist of the combinations of other signals. Such systems are more efficient than equivalent, non-combinatorial systems, yet despite this they are rare in nature. Why? Previous explanations have focused on the adaptive limits of combinatorial communication, or on its purported cognitive difficulties, but neither of these explains the full distribution of combinatorial communication in the natural world. Here, we present a nonlinear dynamical model of the emergence of combinatorial communication that, unlike previous models, considers how initially non-communicative behaviour evolves to take on a communicative function. We derive three basic principles about the emergence of combinatorial communication. We hence show that the interdependence of signals and responses places significant constraints on the historical pathways by which combinatorial signals might emerge, to the extent that anything other than the most simple form of combinatorial communication is extremely unlikely. We also argue that these constraints can be bypassed if individuals have the socio-cognitive capacity to engage in ostensive communication. Humans, but probably no other species, have this ability. This may explain why language, which is massively combinatorial, is such an extreme exception to nature's general trend for non-combinatorial communication. PMID:24047871

  12. Using Web Services and XML Harvesting to Achieve a Dynamic Web Site. Computers in Small Libraries

    ERIC Educational Resources Information Center

    Roberts, Gary

    2005-01-01

    Exploiting and contextualizing free information is a natural part of library culture. In this column, Gary Roberts, the information systems and reference librarian at Herrick Library, Alfred University in Alfred, NY, describes how to use XML content on a Web site to link to hundreds of free and useful resources. He gives a general overview of the…

  13. Deciphering the Structural Requirements of Nucleoside Bisubstrate Analogues for Inhibition of MbtA in Mycobacterium tuberculosis: A FB-QSAR Study and Combinatorial Library Generation for Identifying Potential Hits.

    PubMed

    Maganti, Lakshmi; Das, Sanjit Kumar; Mascarenhas, Nahren Manuel; Ghoshal, Nanda

    2011-10-01

    The re-emergence of tuberculosis infections, which are resistant to conventional drug therapy, has steadily risen in the last decade. Inhibitors of aryl acid adenylating enzyme known as MbtA, involved in siderophore biosynthesis in Mycobacterium tuberculosis, are being explored as potential antitubercular agents. The ability to identify fragments that interact with a biological target is a key step in fragment based drug design (FBDD). To expand the boundaries of quantitative structure activity relationship (QSAR) paradigm, we have proposed a Fragment Based QSAR methodology, referred here in as FB-QSAR, for deciphering the structural requirements of a series of nucleoside bisubstrate analogs for inhibition of MbtA, a key enzyme involved in siderophore biosynthetic pathway. For the development of FB-QSAR models, statistical techniques such as stepwise multiple linear regression (SMLR), genetic function approximation (GFA) and GFAspline were used. The predictive ability of the generated models was validated using different statistical metrics, and similarity-based coverage estimation was carried out to define applicability boundaries. To aid the creation of novel antituberculosis compounds, a bioisosteric database was enumerated using the combichem approach endorsed mining in a lead-like chemical space. The generated library was screened using an integrated in-silico approach and potential hits identified. PMID:27468106

  14. Chaotic itinerancy, temporal segmentation and spatio-temporal combinatorial codes

    NASA Astrophysics Data System (ADS)

    Dias, Juliana R.; Oliveira, Rodrigo F.; Kinouchi, Osame

    2008-01-01

    We study a deterministic dynamics with two time scales in a continuous state attractor network. To the usual (fast) relaxation dynamics towards point attractors (“patterns”) we add a slow coupling dynamics that makes the visited patterns lose stability, leading to an itinerant behavior in the form of punctuated equilibria. One finds that the transition frequency matrix for transitions between patterns shows non-trivial statistical properties in the chaotic itinerant regime. We show that mixture input patterns can be temporally segmented by the itinerant dynamics. The viability of a combinatorial spatio-temporal neural code is also demonstrated.

  15. Combinatorial 3D Mechanical Metamaterials

    NASA Astrophysics Data System (ADS)

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

    2015-03-01

    We present a class of elastic structures which exhibit 3D-folding motion. Our structures consist of cubic lattices of anisotropic unit cells that can be tiled in a complex combinatorial fashion. We design and 3d-print this complex ordered mechanism, in which we combine elastic hinges and defects to tailor the mechanics of the material. Finally, we use this large design space to encode smart functionalities such as surface patterning and multistability.

  16. YCRD: Yeast Combinatorial Regulation Database

    PubMed Central

    Wu, Wei-Sheng; Hsieh, Yen-Chen; Lai, Fu-Jou

    2016-01-01

    In eukaryotes, the precise transcriptional control of gene expression is typically achieved through combinatorial regulation using cooperative transcription factors (TFs). Therefore, a database which provides regulatory associations between cooperative TFs and their target genes is helpful for biologists to study the molecular mechanisms of transcriptional regulation of gene expression. Because there is no such kind of databases in the public domain, this prompts us to construct a database, called Yeast Combinatorial Regulation Database (YCRD), which deposits 434,197 regulatory associations between 2535 cooperative TF pairs and 6243 genes. The comprehensive collection of more than 2500 cooperative TF pairs was retrieved from 17 existing algorithms in the literature. The target genes of a cooperative TF pair (e.g. TF1-TF2) are defined as the common target genes of TF1 and TF2, where a TF’s experimentally validated target genes were downloaded from YEASTRACT database. In YCRD, users can (i) search the target genes of a cooperative TF pair of interest, (ii) search the cooperative TF pairs which regulate a gene of interest and (iii) identify important cooperative TF pairs which regulate a given set of genes. We believe that YCRD will be a valuable resource for yeast biologists to study combinatorial regulation of gene expression. YCRD is available at http://cosbi.ee.ncku.edu.tw/YCRD/ or http://cosbi2.ee.ncku.edu.tw/YCRD/. PMID:27392072

  17. RosettaEPR: Rotamer Library for Spin Label Structure and Dynamics

    PubMed Central

    Alexander, Nathan S.; Stein, Richard A.; Koteiche, Hanane A.; Kaufmann, Kristian W.; Mchaourab, Hassane S.; Meiler, Jens

    2013-01-01

    An increasingly used parameter in structural biology is the measurement of distances between spin labels bound to a protein. One limitation to these measurements is the unknown position of the spin label relative to the protein backbone. To overcome this drawback, we introduce a rotamer library of the methanethiosulfonate spin label (MTSSL) into the protein modeling program Rosetta. Spin label rotamers were derived from conformations observed in crystal structures of spin labeled T4 lysozyme and previously published molecular dynamics simulations. Rosetta’s ability to accurately recover spin label conformations and EPR measured distance distributions was evaluated against 19 experimentally determined MTSSL labeled structures of T4 lysozyme and the membrane protein LeuT and 73 distance distributions from T4 lysozyme and the membrane protein MsbA. For a site in the core of T4 lysozyme, the correct spin label conformation (Χ1 and Χ2) is recovered in 99.8% of trials. In surface positions 53% of the trajectories agree with crystallized conformations in Χ1 and Χ2. This level of recovery is on par with Rosetta performance for the 20 natural amino acids. In addition, Rosetta predicts the distance between two spin labels with a mean error of 4.4 Å. The width of the experimental distance distribution, which reflects the flexibility of the two spin labels, is predicted with a mean error of 1.3 Å. RosettaEPR makes full-atom spin label modeling available to a wide scientific community in conjunction with the powerful suite of modeling methods within Rosetta. PMID:24039810

  18. Do-It-Yourself: A Special Library's Approach to Creating Dynamic Web Pages Using Commercial Off-The-Shelf Applications

    NASA Technical Reports Server (NTRS)

    Steeman, Gerald; Connell, Christopher

    2000-01-01

    Many librarians may feel that dynamic Web pages are out of their reach, financially and technically. Yet we are reminded in library and Web design literature that static home pages are a thing of the past. This paper describes how librarians at the Institute for Defense Analyses (IDA) library developed a database-driven, dynamic intranet site using commercial off-the-shelf applications. Administrative issues include surveying a library users group for interest and needs evaluation; outlining metadata elements; and, committing resources from managing time to populate the database and training in Microsoft FrontPage and Web-to-database design. Technical issues covered include Microsoft Access database fundamentals, lessons learned in the Web-to-database process (including setting up Database Source Names (DSNs), redesigning queries to accommodate the Web interface, and understanding Access 97 query language vs. Standard Query Language (SQL)). This paper also offers tips on editing Active Server Pages (ASP) scripting to create desired results. A how-to annotated resource list closes out the paper.

  19. Dynamic Regulation of a Cell Adhesion Protein Complex Including CADM1 by Combinatorial Analysis of FRAP with Exponential Curve-Fitting

    PubMed Central

    Sakurai-Yageta, Mika; Maruyama, Tomoko; Suzuki, Takashi; Ichikawa, Kazuhisa; Murakami, Yoshinori

    2015-01-01

    Protein components of cell adhesion machinery show continuous renewal even in the static state of epithelial cells and participate in the formation and maintenance of normal epithelial architecture and tumor suppression. CADM1 is a tumor suppressor belonging to the immunoglobulin superfamily of cell adhesion molecule and forms a cell adhesion complex with an actin-binding protein, 4.1B, and a scaffold protein, MPP3, in the cytoplasm. Here, we investigate dynamic regulation of the CADM1-4.1B-MPP3 complex in mature cell adhesion by fluorescence recovery after photobleaching (FRAP) analysis. Traditional FRAP analysis were performed for relatively short period of around 10min. Here, thanks to recent advances in the sensitive laser detector systems, we examine FRAP of CADM1 complex for longer period of 60 min and analyze the recovery with exponential curve-fitting to distinguish the fractions with different diffusion constants. This approach reveals that the fluorescence recovery of CADM1 is fitted to a single exponential function with a time constant (τ) of approximately 16 min, whereas 4.1B and MPP3 are fitted to a double exponential function with two τs of approximately 40-60 sec and 16 min. The longer τ is similar to that of CADM1, suggesting that 4.1B and MPP3 have two distinct fractions, one forming a complex with CADM1 and the other present as a free pool. Fluorescence loss in photobleaching analysis supports the presence of a free pool of these proteins near the plasma membrane. Furthermore, double exponential fitting makes it possible to estimate the ratio of 4.1B and MPP3 present as a free pool and as a complex with CADM1 as approximately 3:2 and 3:1, respectively. Our analyses reveal a central role of CADM1 in stabilizing the complex with 4.1B and MPP3 and provide insight in the dynamics of adhesion complex formation. PMID:25780926

  20. Analysis of Combinatorial Epigenomic States.

    PubMed

    Soloway, Paul D

    2016-03-18

    Hundreds of distinct chemical modifications to DNA and histone amino acids have been described. Regulation exerted by these so-called epigenetic marks is vital to normal development, stability of cell identity through mitosis, and nongenetic transmission of traits between generations through meiosis. Loss of this regulation contributes to many diseases. Evidence indicates epigenetic marks function in combinations, whereby a given modification has distinct effects on local genome control, depending on which additional modifications are locally present. This review summarizes emerging methods for assessing combinatorial epigenomic states, as well as challenges and opportunities for their refinement. PMID:26555135

  1. Multispecies TASEP and combinatorial R

    NASA Astrophysics Data System (ADS)

    Kuniba, Atsuo; Maruyama, Shouya; Okado, Masato

    2015-08-01

    We identify the algorithm for constructing steady states of the n-species totally asymmetric simple exclusion process (TASEP) on an L site periodic chain by Ferrari and Martin with a composition of combinatorial R for the quantum affine algebra {U}q({\\widehat{{sl}}}L) in crystal base theory. Based on this connection and the factorized form of the R matrix derived recently from the tetrahedron equation, we establish a new matrix product formula for the steady state of the TASEP, which is expressed in terms of corner transfer matrices of the q-oscillator valued five-vertex model at q = 0. Dedicated to the memory of Professor Ryogo Hirota.

  2. Combinatorial Strategies for the Development of Bulk Metallic Glasses

    NASA Astrophysics Data System (ADS)

    Ding, Shiyan

    The systematic identification of multi-component alloys out of the vast composition space is still a daunting task, especially in the development of bulk metallic glasses that are typically based on three or more elements. In order to address this challenge, combinatorial approaches have been proposed. However, previous attempts have not successfully coupled the synthesis of combinatorial libraries with high-throughput characterization methods. The goal of my dissertation is to develop efficient high-throughput characterization methods, optimized to identify glass formers systematically. Here, two innovative approaches have been invented. One is to measure the nucleation temperature in parallel for up-to 800 compositions. The composition with the lowest nucleation temperature has a reasonable agreement with the best-known glass forming composition. In addition, the thermoplastic formability of a metallic glass forming system is determined through blow molding a compositional library. Our results reveal that the composition with the largest thermoplastic deformation correlates well with the best-known formability composition. I have demonstrated both methods as powerful tools to develop new bulk metallic glasses.

  3. DNA Assembly Techniques for Next Generation Combinatorial Biosynthesis of Natural Products

    PubMed Central

    Cobb, Ryan E.; Ning, Jonathan C.; Zhao, Huimin

    2013-01-01

    Natural product scaffolds remain important leads for pharmaceutical development. However, transforming a natural product into a drug entity often requires derivatization to enhance the compound’s therapeutic properties. A powerful method by which to perform this derivatization is combinatorial biosynthesis, the manipulation of the genes in the corresponding pathway to divert synthesis towards novel derivatives. While these manipulations have traditionally been carried out via restriction digestion/ligation-based cloning, the shortcomings of such techniques limit their throughput and thus the scope of corresponding combinatorial biosynthesis experiments. In the burgeoning field of synthetic biology, the demand for facile DNA assembly techniques has promoted the development of a host of novel DNA assembly strategies. Here we describe the advantages of these recently-developed tools for rapid, efficient synthesis of large DNA constructs. We also discuss their potential to facilitate the simultaneous assembly of complete libraries of natural product biosynthetic pathways, ushering in the next generation of combinatorial biosynthesis. PMID:24127070

  4. Developmental Relationships in the Dynamic Library Environment: Re-Conceptualizing Mentoring for the Future

    ERIC Educational Resources Information Center

    Murphy, Sarah Anne

    2008-01-01

    This article examines the current conceptualization of mentoring in academic libraries and argues that traditional hierarchical mentoring relationships are no longer sufficient for developing tomorrow's leaders. Drawing insights from the management and human resources development literature, it concludes that an expanded understanding of…

  5. Education Library 2.0: The Establishment of a Dynamic Multi-Site Liaison Program

    ERIC Educational Resources Information Center

    Dutton Ewbank, Ann

    2009-01-01

    Using a combination of marketing, Web 2.0 tools, videoconferencing, face-to-face instruction and site visits, a library presence including systematic information literacy instruction is embedded into multiple programs at sixteen sites in a growing college of education with nearly 6000 students and over 115 full-time faculty members. As the needs…

  6. A Complex Systems Framework for Research on Leadership and Organizational Dynamics in Academic Libraries

    ERIC Educational Resources Information Center

    Gilstrap, Donald L.

    2009-01-01

    This article provides a historiographical analysis of major leadership and organizational development theories that have shaped our thinking about how we lead and administrate academic libraries. Drawing from behavioral, cognitive, systems, and complexity theories, this article discusses major theorists and research studies appearing over the past…

  7. Institutional, Public and Individual Learning Dynamics of the Andy Holt Virtual Library.

    ERIC Educational Resources Information Center

    Peckham, Robert

    The Andy Holt Virtual Library, with a focus on the Humanities and Fine Arts, is free and open to the public, though designed to serve the learning communities within the College of Humanities and Fine Arts at the University of Tennessee-Martin (UT). It also plays a resource role in UT's New College and the Tennessee Governors School for the…

  8. A web based Radiation Oncology Dose Manager with a rich User Interface developed using AJAX, ruby, dynamic XHTML and the new Yahoo/EXT User Interface Library.

    PubMed

    Vali, Faisal; Hong, Robert

    2007-01-01

    With the evolution of AJAX, ruby on rails, advanced dynamic XHTML technologies and the advent of powerful user interface libraries for javascript (EXT, Yahoo User Interface Library), developers now have the ability to provide truly rich interfaces within web browsers, with reasonable effort and without third-party plugins. We designed and developed an example of such a solution. The User Interface allows radiation oncology practices to intuitively manage different dose fractionation schemes by helping estimate total dose to irradiated organs. PMID:18694240

  9. Spinach - A software library for simulation of spin dynamics in large spin systems

    NASA Astrophysics Data System (ADS)

    Hogben, H. J.; Krzystyniak, M.; Charnock, G. T. P.; Hore, P. J.; Kuprov, Ilya

    2011-02-01

    We introduce a software library incorporating our recent research into efficient simulation algorithms for large spin systems. Liouville space simulations (including symmetry, relaxation and chemical kinetics) of most liquid-state NMR experiments on 40+ spin systems can now be performed without effort on a desktop workstation. Much progress has also been made with improving the efficiency of ESR, solid state NMR and Spin Chemistry simulations. Spinach is available for download at http://spindynamics.org.

  10. From combinatorial chemistry to cancer targeting nanotherapeutics

    NASA Astrophysics Data System (ADS)

    Xiao, Kai; Luo, Juntao; Li, Yuanpei; Xiao, Wenwu; Lee, Joyce S.; Gonik, Abby M.; Lam, Kit S.

    2010-04-01

    We have developed a number of amphiphilic polymers, comprised of a cluster of cholic acids (4 to 10) linked by a series of lysines and attached to one end of a linear polyethylene glycol chain (PEG, 2000-5000 Dalton). Under aqueous condition, such telodendrimers can self-assemble together with hydrophobic payloads to form highly stable micelles (15-150 nm diameter, size tunable). We used near infrared fluorescence (NIRF) optical imaging technique to study the in vivo passive accumulation of our nanocarriers (via EPR effect) in different types and stages of tumors. The results demonstrated that the micelle could preferentially accumulate in many types of tumor xenografts or synografts implanted in mice. Nanoparticle uptake in solid tumors was found to be much higher than that of lymphoma, which could be attributed to the relatively low microvascular density in the latter. We have also demonstrated that micelles smaller than 64 nm preferentially targeted xenografts with high efficiency and with low liver and lung uptake, whereas those micelles at 154 nm targeted the tumor poorly but with very high liver and lung uptake. Telodendrimers decorated with oligolysine or oligoaspartic acid resulted in high uptake of the nanoparticles into the liver. When decorated with cancer targeting ligands identified from the one-bead-one-compound (OBOC) combinatorial library methods, the drug-loaded nanoparticles were rapidly taken up by the target cultured tumor cells causing cell death. In vivo near infra-red optical imaging studies with hydrophobic fluorescent dye demonstrated that xenograft uptake of the micelles was greatly enhanced by the cancer targeting peptide.

  11. Losing Libraries, Saving Libraries

    ERIC Educational Resources Information Center

    Miller, Rebecca

    2010-01-01

    This summer, as public libraries continued to get budget hit after budget hit across the country, several readers asked for a comprehensive picture of the ravages of the recession on library service. In partnership with 2010 Movers & Shakers Laura Solomon and Mandy Knapp, Ohio librarians who bought the Losing Libraries domain name, "LJ" launched…

  12. Accelerated luminophore discovery through combinatorial synthesis.

    PubMed

    Lowry, Michael S; Hudson, William R; Pascal, Robert A; Bernhard, Stefan

    2004-11-01

    A method for accelerating the discovery of ionic luminophores using combinatorial techniques is reported. The photophysical properties of the resulting transition-metal-based chromophores were compared against a series of analogous, traditionally prepared species. The strong overlap between these two sets confirms the identity of the parallel synthesis products and supports the truthfulness of the combinatorial results. Further support for the combinatorial method comes from the adherence of these complexes to the energy gap law. The relationship between the structure of a complex and its photophysical properties was also considered, and static DFT calculations were used to assess whether it is feasible to predict the luminescent behavior of novel materials. PMID:15506778

  13. Combinatorial Optimization of Heterogeneous Catalysts Used in the Growth of Carbon Nanotubes

    NASA Technical Reports Server (NTRS)

    Cassell, Alan M.; Verma, Sunita; Delzeit, Lance; Meyyappan, M.; Han, Jie

    2000-01-01

    Libraries of liquid-phase catalyst precursor solutions were printed onto iridium-coated silicon substrates and evaluated for their effectiveness in catalyzing the growth of multi-walled carbon nanotubes (MWNTs) by chemical vapor deposition (CVD). The catalyst precursor solutions were composed of inorganic salts and a removable tri-block copolymer (EO)20(PO)70(EO)20 (EO = ethylene oxide, PO = propylene oxide) structure-directing agent (SDA), dissolved in ethanol/methanol mixtures. Sample libraries were quickly assayed using scanning electron microscopy after CVD growth to identify active catalysts and CVD conditions. Composition libraries and focus libraries were then constructed around the active spots identified in the discovery libraries to understand how catalyst precursor composition affects the yield, density, and quality of the nanotubes. Successful implementation of combinatorial optimization methods in the development of highly active, carbon nanotube catalysts is demonstrated, as well as the identification of catalyst formulations that lead to varying densities and shapes of aligned nanotube towers.

  14. High Divergence of the Precursor Peptides in Combinatorial Lanthipeptide Biosynthesis

    PubMed Central

    2015-01-01

    Lanthionine-containing peptides (lanthipeptides) are a rapidly growing family of polycyclic peptide natural products belonging to the large class of ribosomally synthesized and post-translationally modified peptides (RiPPs). These compounds are widely distributed in taxonomically distant species, and their biosynthetic systems and biological activities are diverse. A unique example of lanthipeptide biosynthesis is the prochlorosin synthetase ProcM from the marine cyanobacterium Prochlorococcus MIT9313, which transforms up to 29 different precursor peptides (ProcAs) into a library of lanthipeptides called prochlorosins (Pcns) with highly diverse sequences and ring topologies. Here, we show that many ProcM-like enzymes from a variety of bacteria have the capacity to carry out post-translational modifications on highly diverse precursor peptides, providing new examples of natural combinatorial biosynthesis. We also demonstrate that the leader peptides come from different evolutionary origins, suggesting that the combinatorial biosynthesis is tied to the enzyme and not a specific type of leader peptide. For some precursor peptides encoded in the genomes, the leader peptides apparently have been truncated at the N-termini, and we show that these N-terminally truncated peptides are still substrates of the enzymes. Consistent with this hypothesis, we demonstrate that about two-thirds of the ProcA N-terminal sequence is not essential for ProcM activity. Our results also highlight the potential of exploring this class of natural products by genome mining and bioengineering. PMID:25244001

  15. Combinatorial metabolic pathway assembly in the yeast genome with RNA-guided Cas9.

    PubMed

    EauClaire, Steve F; Zhang, Jianzhong; Rivera, Corban Gregory; Huang, Lixuan L

    2016-07-01

    The yeast Saccharomyces cerevisiae is an important industrial platform for the production of grain and cellulosic ethanol, isobutanol, butanediol, isoprenoids, and other chemicals. The construction of a successful production strain usually involves multiple gene knockouts and chromosomal integration of expression cassettes to redirect the metabolic fluxes for the conversion of sugars and other feed stocks into the desired product. RNA-guided Cas9 based genome editing has been demonstrated in many prokaryotic and eukaryotic hosts including S. cerevisiae, in which it has been additionally exploited as a tool for metabolic engineering. To extend the utilization of RNA-guided Cas9 as a metabolic pathway building tool, we demonstrated the direct assembly and chromosomal integration of up to 17 overlapping DNA fragments encoding the beta-carotene biosynthetic pathway. Furthermore, we generated a combinatorial strain library for the beta-carotene biosynthetic pathway, directly integrated into the yeast genome to create a diverse library of strains. This enabled the screening of combinatorial libraries in stable chromosomally integrated strains for rapid improvements of product titers. This combinatorial approach for pathway assembly will significantly accelerate the current speed of metabolic engineering for S. cerevisiae as an industrial platform, and increase the number of strains that can be simultaneously evaluated for enzyme screening, expression optimization and protein engineering to achieve the titer, rate and yield necessary for the commercialization of new industrial fermentation products. PMID:27138038

  16. Applications of high throughput (combinatorial) methodologies to electronic, magnetic, optical, and energy-related materials

    NASA Astrophysics Data System (ADS)

    Green, Martin L.; Takeuchi, Ichiro; Hattrick-Simpers, Jason R.

    2013-06-01

    High throughput (combinatorial) materials science methodology is a relatively new research paradigm that offers the promise of rapid and efficient materials screening, optimization, and discovery. The paradigm started in the pharmaceutical industry but was rapidly adopted to accelerate materials research in a wide variety of areas. High throughput experiments are characterized by synthesis of a "library" sample that contains the materials variation of interest (typically composition), and rapid and localized measurement schemes that result in massive data sets. Because the data are collected at the same time on the same "library" sample, they can be highly uniform with respect to fixed processing parameters. This article critically reviews the literature pertaining to applications of combinatorial materials science for electronic, magnetic, optical, and energy-related materials. It is expected that high throughput methodologies will facilitate commercialization of novel materials for these critically important applications. Despite the overwhelming evidence presented in this paper that high throughput studies can effectively inform commercial practice, in our perception, it remains an underutilized research and development tool. Part of this perception may be due to the inaccessibility of proprietary industrial research and development practices, but clearly the initial cost and availability of high throughput laboratory equipment plays a role. Combinatorial materials science has traditionally been focused on materials discovery, screening, and optimization to combat the extremely high cost and long development times for new materials and their introduction into commerce. Going forward, combinatorial materials science will also be driven by other needs such as materials substitution and experimental verification of materials properties predicted by modeling and simulation, which have recently received much attention with the advent of the Materials Genome

  17. High-pressure combinatorial process integrating hot isostatic pressing.

    PubMed

    Fujimoto, Kenjiro; Morita, Hiroki; Goshima, Yuji; Ito, Shigeru

    2013-12-01

    A high-pressure combinatorial process integrating hot isostatic pressing (HIP) was developed by providing a reaction vessel with a high-pressure tightness based on a commercial flange. The reaction vessel can be used up to 200 MPa and 500 °C under HIP processing condition. Preparation of spinel-type MgAl2O4 from Mg(OH)2, Al(OH)3 and AlOOH was performed using the reaction vessel under 200 MPa and 500 °C as demonstration. The entire powder library was characterized using powder X-ray diffraction patterns, and the single phase of spinel-type MgAl2O4 was obtained from Mg(OH)2+Al(OH)3. These assessments corresponded with previously published data. PMID:24168067

  18. Combinatorial discovery of two-photon photoremovable protecting groups.

    PubMed

    Pirrung, Michael C; Pieper, Wolfgang H; Kaliappan, Krishna P; Dhananjeyan, Mugunthu R

    2003-10-28

    A design principle for a two-photon photochemically removable protecting group based on sequential one-photon processes has been established. The expected performance of such groups in spatially directed photoactivation/photodeprotection has been shown by a kinetic analysis. One particular molecular class fitting into this design, the nitrobenzyl ethers of o-hydroxycinnamates, has been presented. An initial demonstration of two-photon deprotection of one such group prompted further optimization with respect to photochemical deprotection rate. This was accomplished by the preparation and screening of a 135-member indexed combinatorial library. Optimum performance for lambda >350 nm deprotection in organic solvent was found with 4,5-dialkoxy and -cyano substitution in the nitrobenzyl group and 4-methoxy substitution in the cinnamate. PMID:14557545

  19. Inducible and combinatorial gene manipulation in mouse brain

    PubMed Central

    Dogbevia, Godwin K.; Marticorena-Alvarez, Ricardo; Bausen, Melanie; Sprengel, Rolf; Hasan, Mazahir T.

    2015-01-01

    We have deployed recombinant adeno-associated viruses equipped with tetracycline-controlled genetic switches to manipulate gene expression in mouse brain. Here, we show a combinatorial genetic approach for inducible, cell type-specific gene expression and Cre/loxP mediated gene recombination in different brain regions. Our chemical-genetic approach will help to investigate ‘when’, ‘where’, and ‘how’ gene(s) control neuronal circuit dynamics, and organize, for example, sensory signal processing, learning and memory, and behavior. PMID:25954155

  20. Affinity chromatography based on a combinatorial strategy for rerythropoietin purification.

    PubMed

    Martínez-Ceron, María C; Marani, Mariela M; Taulés, Marta; Etcheverrigaray, Marina; Albericio, Fernando; Cascone, Osvaldo; Camperi, Silvia A

    2011-05-01

    Small peptides containing fewer than 10 amino acids are promising ligand candidates with which to build affinity chromatographic systems for industrial protein purification. The application of combinatorial peptide synthesis strategies greatly facilitates the discovery of suitable ligands for any given protein of interest. Here we sought to identify peptide ligands with affinity for recombinant human erythropoietin (rhEPO), which is used for the treatment of anemia. A combinatorial library containing the octapeptides X-X-X-Phe-X-X-Ala-Gly, where X = Ala, Asp, Glu, Phe, His, Leu, Asn, Pro, Ser, or Thr, was synthesized on HMBA-ChemMatrix resin by the divide-couple-recombine method. For the library screening, rhEPO was coupled to either Texas Red or biotin. Fluorescent beads or beads showing a positive reaction with streptavidin-peroxidase were isolated. After cleavage, peptides were sequenced by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Fifty-seven beads showed a positive reaction. Peptides showing more consensuses were synthesized, and their affinity to rhEPO was assessed using a plasma resonance biosensor. Dissociation constant values in the range of 1-18 μM were obtained. The best two peptides were immobilized on Sepharose, and the resultant chromatographic matrixes showed affinity for rhEPO with dissociation constant values between 1.8 and 2.7 μM. Chinese hamster ovary (CHO) cell culture supernatant was spiked with rhEPO, and the artificial mixture was loaded on Peptide-Sepharose columns. The rhEPO was recovered in the elution fraction with a yield of 90% and a purity of 95% and 97% for P1-Sepharose and P2-Sepharose, respectively. PMID:21495625

  1. Combinatorial Pooling Enables Selective Sequencing of the Barley Gene Space

    PubMed Central

    Lonardi, Stefano; Duma, Denisa; Alpert, Matthew; Cordero, Francesca; Beccuti, Marco; Bhat, Prasanna R.; Wu, Yonghui; Ciardo, Gianfranco; Alsaihati, Burair; Ma, Yaqin; Wanamaker, Steve; Resnik, Josh; Bozdag, Serdar; Luo, Ming-Cheng; Close, Timothy J.

    2013-01-01

    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. PMID:23592960

  2. Library Cooperation.

    ERIC Educational Resources Information Center

    Lund, Patricia; And Others

    1993-01-01

    Includes nine articles that discuss cooperative library networking in Illinois. Highlights include library systems as cooperative agencies; PALI (Private Academic Libraries of Illinois); rural school and public library development; systemwide users; regional medical libraries; virtual libraries and the Coalition for Networked Information; a…

  3. A 3-D microfluidic combinatorial cell array.

    PubMed

    Liu, Mike C; Tai, Yu-Chong

    2011-02-01

    We present the development of a three-dimensional (3-D) combinatorial cell culture array device featured with integrated three-input, eight-output combinatorial mixer and cell culture chambers. The device is designed for cell-based screening of multiple compounds simultaneously on a microfluidic platform. The final assembled device is composed of a porous membrane integrated in between a Parylene 3-D microfluidic chip and a PDMS microfluidic chip. The membrane turned the cell culture chambers into two-level configuration to facilitate cell loading and to maintain cells in a diffusion dominated space during device operation. Experimentally, we first characterized the combined compound concentration profile at each chamber using a fluorescence method. We then successfully demonstrated the functionality of the quantitative cell-based assay by culturing B35 rat neuronal cells on this device and screening the ability of three compounds (1,5-dihydroxyisoquinoline, deferoxamine, and 3-aminobenzoic acid) to attenuate cell death caused by cytotoxic hydrogen peroxide. In another experiment, we assayed for the combinatorial effects of three chemotherapeutic compound exposures (vinorelbine, paclitaxel, and γ-linolenic acid) on human breast cancer cells, MDA-MB-231. The same technology will enable the construction of inexpensive lab-on-a-chip devices with high-input combinatorial mixer for performing high-throughput cell-based assay and highly parallel and combinatorial chemical or biochemical reactions. PMID:21063783

  4. Bulk Combinatorial Synthesis and High Throughput Characterization for Rapid Assessment of Magnetic Materials: Application of Laser Engineered Net Shaping (LENS™)

    NASA Astrophysics Data System (ADS)

    Geng, J.; Nlebedim, I. C.; Besser, M. F.; Simsek, E.; Ott, R. T.

    2016-07-01

    A bulk combinatorial approach for synthesizing alloy libraries using laser engineered net shaping (LENS™; i.e., 3D printing) was utilized to rapidly assess material systems for magnetic applications. The LENS™ system feeds powders in different ratios into a melt pool created by a laser to synthesize samples with bulk (millimeters) dimensions. By analyzing these libraries with autosampler differential scanning calorimeter/thermal gravimetric analysis and vibrating sample magnetometry, we are able to rapidly characterize the thermodynamic and magnetic properties of the libraries. The Fe-Co binary alloy was used as a model system and the results were compared with data in the literature.

  5. Bulk Combinatorial Synthesis and High Throughput Characterization for Rapid Assessment of Magnetic Materials: Application of Laser Engineered Net Shaping (LENS™)

    NASA Astrophysics Data System (ADS)

    Geng, J.; Nlebedim, I. C.; Besser, M. F.; Simsek, E.; Ott, R. T.

    2016-04-01

    A bulk combinatorial approach for synthesizing alloy libraries using laser engineered net shaping (LENS™; i.e., 3D printing) was utilized to rapidly assess material systems for magnetic applications. The LENS™ system feeds powders in different ratios into a melt pool created by a laser to synthesize samples with bulk (millimeters) dimensions. By analyzing these libraries with autosampler differential scanning calorimeter/thermal gravimetric analysis and vibrating sample magnetometry, we are able to rapidly characterize the thermodynamic and magnetic properties of the libraries. The Fe-Co binary alloy was used as a model system and the results were compared with data in the literature.

  6. Combinatorial gene regulation by modulation of relative pulse timing

    PubMed Central

    Lin, Yihan; Sohn, Chang Ho; Dalal, Chiraj K.; Cai, Long; Elowitz, Michael B.

    2015-01-01

    Studies of individual living cells have revealed that many transcription factors activate in dynamic, and often stochastic, pulses within the same cell. However, it has remained unclear whether cells might modulate the relative timing of these pulses to control gene expression. Here, using quantitative single-cell time-lapse imaging of Saccharomyces cerevisiae, we show that the pulsatile transcription factors Msn2 and Mig1 combinatorially regulate their target genes through modulation of their relative pulse timing. The activator Msn2 and repressor Mig1 pulsed in either a temporally overlapping or non-overlapping manner during their transient response to different inputs, with only the non-overlapping dynamics efficiently activating target gene expression. Similarly, under constant environmental conditions, where Msn2 and Mig1 exhibit sporadic pulsing, glucose concentration modulated the temporal overlap between pulses of the two factors. Together, these results reveal a time-based mode of combinatorial gene regulation. Regulation through relative signal timing is common in engineering and neurobiology, and these results suggest that it could also function broadly within the signaling and regulatory systems of the cell. PMID:26466562

  7. Combinatorial polymer electrospun matrices promote physiologically-relevant cardiomyogenic stem cell differentiation.

    PubMed

    Gupta, Mukesh K; Walthall, Joel M; Venkataraman, Raghav; Crowder, Spencer W; Jung, Dae Kwang; Yu, Shann S; Feaster, Tromondae K; Wang, Xintong; Giorgio, Todd D; Hong, Charles C; Baudenbacher, Franz J; Hatzopoulos, Antonis K; Sung, Hak-Joon

    2011-01-01

    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. PMID:22216144

  8. Synthesis and biological evaluation of a beauveriolide analogue library.

    PubMed

    Nagai, Kenichiro; Doi, Takayuki; Sekiguchi, Takafumi; Namatame, Ichiji; Sunazuka, Toshiaki; Tomoda, Hiroshi; Omura, Satoshi; Takahashi, Takashi

    2006-01-01

    Synthesis of beauveriolide III (1b), which is an inhibitor of lipid droplet accumulation in macrophages, was achieved by solid-phase assembly of linear depsipeptide using a 2-chlorotrityl linker followed by solution-phase cyclization. On the basis of this strategy, a combinatorial library of beauveriolide analogues was carried out by radio frequency-encoded combinatorial chemistry. After automated purification using preparative reversed-phase HPLC, the library was tested for inhibitory activity of CE synthesis in macrophages to determine structure-activity relationships of beauveriolides. Among them, we found that diphenyl derivative 7{9,1} is 10 times more potent than 1b. PMID:16398560

  9. Exploration of polymethacrylate structure-property correlations: Advances towards combinatorial and high-throughput methods for biomaterials discovery

    PubMed Central

    Holmes, Paul F.; Bohrer, Mike; Kohn, Joachim

    2008-01-01

    In this review, we discuss the synthesis, characterization, physical properties, and applications of polymethacrylates and describe physical and biological structure-property correlations relevant to many high performance applications. We also track the advancement of material-property space from the ‘traditional’ mode of materials design to the emerging, state-of-the-art combinatorial and in silico methods. Particularly, this article places emphasis on recent advances in the automated combinatorial synthesis and development of high-throughput characterization methods. As a future perspective, we believe that the realization of combinatorial, high-throughput, and computational methods will allow for the rapid exploration of a vast polymethacrylate library property space. PMID:19649142

  10. Combinatorial pathway engineering for optimized production of the anti-malarial FR900098.

    PubMed

    Freestone, Todd S; Zhao, Huimin

    2016-02-01

    As resistance to current anti-malarial therapeutics spreads, new compounds to treat malaria are increasingly needed. One promising compound is FR900098, a naturally occurring phosphonate. Due to limitations in both chemical synthesis and biosynthetic methods for FR900098 production, this potential therapeutic has yet to see widespread implementation. Here we applied a combinatorial pathway engineering strategy to improve the production of FR900098 in Escherichia coli by modulating each of the pathway's nine genes with four promoters of different strengths. Due to the large size of the library and the low screening throughput, it was necessary to develop a novel screening strategy that significantly reduced the sample size needed to find an optimal strain. This was done by using biased libraries that localize searching around top hits and home in on high-producing strains. By incorporating this strategy, a significantly improved strain was found after screening less than 3% of the entire library. When coupled with culturing optimization, a strain was found to produce 96 mg/L, a 16-fold improvement over the original strain. We believe the enriched library method developed here can be used on other large pathways that may be difficult to engineer by combinatorial methods due to low screening throughput. PMID:26245694

  11. Estimating meme fitness in adaptive memetic algorithms for combinatorial problems.

    PubMed

    Smith, J E

    2012-01-01

    Among the most promising and active research areas in heuristic optimisation is the field of adaptive memetic algorithms (AMAs). These gain much of their reported robustness by adapting the probability with which each of a set of local improvement operators is applied, according to an estimate of their current value to the search process. This paper addresses the issue of how the current value should be estimated. Assuming the estimate occurs over several applications of a meme, we consider whether the extreme or mean improvements should be used, and whether this aggregation should be global, or local to some part of the solution space. To investigate these issues, we use the well-established COMA framework that coevolves the specification of a population of memes (representing different local search algorithms) alongside a population of candidate solutions to the problem at hand. Two very different memetic algorithms are considered: the first using adaptive operator pursuit to adjust the probabilities of applying a fixed set of memes, and a second which applies genetic operators to dynamically adapt and create memes and their functional definitions. For the latter, especially on combinatorial problems, credit assignment mechanisms based on historical records, or on notions of landscape locality, will have limited application, and it is necessary to estimate the value of a meme via some form of sampling. The results on a set of binary encoded combinatorial problems show that both methods are very effective, and that for some problems it is necessary to use thousands of variables in order to tease apart the differences between different reward schemes. However, for both memetic algorithms, a significant pattern emerges that reward based on mean improvement is better than that based on extreme improvement. This contradicts recent findings from adapting the parameters of operators involved in global evolutionary search. The results also show that local reward schemes

  12. A New Approach for Proving or Generating Combinatorial Identities

    ERIC Educational Resources Information Center

    Gonzalez, Luis

    2010-01-01

    A new method for proving, in an immediate way, many combinatorial identities is presented. The method is based on a simple recursive combinatorial formula involving n + 1 arbitrary real parameters. Moreover, this formula enables one not only to prove, but also generate many different combinatorial identities (not being required to know them "a…

  13. Hypergraph-Based Combinatorial Optimization of Matrix-Vector Multiplication

    ERIC Educational Resources Information Center

    Wolf, Michael Maclean

    2009-01-01

    Combinatorial scientific computing plays an important enabling role in computational science, particularly in high performance scientific computing. In this thesis, we will describe our work on optimizing matrix-vector multiplication using combinatorial techniques. Our research has focused on two different problems in combinatorial scientific…

  14. Combinatorial Algorithms to Enable Computational Science and Engineering: The CSCAPES Institute

    SciTech Connect

    Pothen, Alex

    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 hyeprgraph 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.

  15. Combinatorial study on nano-particle mixture prepared by robot system

    NASA Astrophysics Data System (ADS)

    Yanase, Ikuo; Ohtaki, Takugo; Watanabe, Mamoru

    2002-04-01

    We have developed a combinatorial robot system for measuring, mixing and molding liquid samples with an automatic micropipette, which produces a group of sample libraries for ceramic powders on a reaction pallet. In this study, metal oxide nano-particle slurries and inorganic solutions were used as starting raw materials. Either of these starting materials was confirmed to become homogeneous mixtures with automatic mixing operation on the basis of a few experimental examples such as the synthesis of multi-component compounds. Homogeneous slurry mixtures were almost as reactive as gels obtained by sol-gel methods and also their slurries could be treated much more easily than sols. Nano-particle slurries were confirmed to be excellent starting raw materials for combinatorial powder synthesis with this robot system.

  16. Combinatorial fabrication of composite nanorods using oblique angle co-deposition

    NASA Astrophysics Data System (ADS)

    Larson, Steven; Huang, Weijie; Zhao, Yiping

    2016-09-01

    We demonstrate that oblique angle co-deposition can be used as a versatile combinatory nanofabrication technique to generate a library of nanomaterials. Using the Cu-Fe2O3 system as an example, by carefully characterizing the vapor plumes of the source materials, a composition map can be generated, which is used to design the locations of all the substrate holders. The resulting nanostructures at different locations show different thickness, morphology, crystallinity, composition, as well as inhomogeneity in microstructures, and material maps of all these structural parameters are established. By further oxidizing or reducing the composite nanostructures, their properties—such as band gap, photocatalytic performance, and magnetic properties—can be easily linked to their composition and other structural parameters. Optimal materials for photocatalytic and magnetic applications are efficiently identified. It is expected that oblique angle co-deposition and its variations could become the most powerful combinatory nanofabrication technique for nanomaterial survey.

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

    PubMed Central

    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

  18. Combinatorial Development of Fe-Co-Nb Thin Film Magnetic Nanocomposites.

    PubMed

    Alexandrakis, Vasileios; Wallisch, Wolfgang; Hamann, Sven; Varvaro, Gaspare; Fidler, Josef; Ludwig, Alfred

    2015-11-01

    A Fe-Co-Nb thin film materials library was deposited by combinatorial magnetron sputtering and investigated by high-throughput methods to identify new noncubic ferromagnetic phases, indicating that combinatorial experimentation is an efficient method to discover new ferromagnetic phases adequate for permanent magnet applications. Structural analysis indicated the formation of a new magnetic ternary compound (Fe,Co)3Nb with a hexagonal crystal structure (C36) embedded in an FeCo-based matrix. This nanocomposite exhibits characteristics of a two-phase ferromagnetic system, the so-called hard-soft nanocomposites, indicating that the new phase (Fe,Co)3Nb is ferromagnetic. Magnetic hysteresis loops at various angles revealed that the magnetization reversal process is governed by a domain wall pinning mechanism. PMID:26401900

  19. Speeding up directed evolution: Combining the advantages of solid-phase combinatorial gene synthesis with statistically guided reduction of screening effort.

    PubMed

    Hoebenreich, Sabrina; Zilly, Felipe E; Acevedo-Rocha, Carlos G; Zilly, Matías; Reetz, Manfred T

    2015-03-20

    Efficient and economic methods in directed evolution at the protein, metabolic, and genome level are needed for biocatalyst development and the success of synthetic biology. In contrast to random strategies, semirational approaches such as saturation mutagenesis explore the sequence space in a focused manner. Although several combinatorial libraries based on saturation mutagenesis have been reported using solid-phase gene synthesis, direct comparison with traditional PCR-based methods is currently lacking. In this work, we compare combinatorial protein libraries created in-house via PCR versus those generated by commercial solid-phase gene synthesis. Using descriptive statistics and probabilistic distributions on amino acid occurrence frequencies, the quality of the libraries was assessed and compared, revealing that the outsourced libraries are characterized by less bias and outliers than the PCR-based ones. Afterward, we screened all libraries following a traditional algorithm for almost complete library coverage and compared this approach with an emergent statistical concept suggesting screening a lower portion of the protein sequence space. Upon analyzing the biocatalytic landscapes and best hits of all combinatorial libraries, we show that the screening effort could have been reduced in all cases by more than 50%, while still finding at least one of the best mutants. PMID:24921161

  20. Running Clubs--A Combinatorial Investigation.

    ERIC Educational Resources Information Center

    Nissen, Phillip; Taylor, John

    1991-01-01

    Presented is a combinatorial problem based on the Hash House Harriers rule which states that the route of the run should not have previously been traversed by the club. Discovered is how many weeks the club can meet before the rule has to be broken. (KR)

  1. Quantum Resonance Approach to Combinatorial Optimization

    NASA Technical Reports Server (NTRS)

    Zak, Michail

    1997-01-01

    It is shown that quantum resonance can be used for combinatorial optimization. The advantage of the approach is in independence of the computing time upon the dimensionality of the problem. As an example, the solution to a constraint satisfaction problem of exponential complexity is demonstrated.

  2. A Model of Students' Combinatorial Thinking

    ERIC Educational Resources Information Center

    Lockwood, Elise

    2013-01-01

    Combinatorial topics have become increasingly prevalent in K-12 and undergraduate curricula, yet research on combinatorics education indicates that students face difficulties when solving counting problems. The research community has not yet addressed students' ways of thinking at a level that facilitates deeper understanding of how students…

  3. Students' Verification Strategies for Combinatorial Problems

    ERIC Educational Resources Information Center

    Mashiach Eizenberg, Michal; Zaslavsky, Orit

    2004-01-01

    We focus on a major difficulty in solving combinatorial problems, namely, on the verification of a solution. Our study aimed at identifying undergraduate students' tendencies to verify their solutions, and the verification strategies that they employ when solving these problems. In addition, an attempt was made to evaluate the level of efficiency…

  4. Multi-Point Combinatorial Optimization Method with Distance Based Interaction

    NASA Astrophysics Data System (ADS)

    Yasuda, Keiichiro; Jinnai, Hiroyuki; Ishigame, Atsushi

    This paper proposes a multi-point combinatorial optimization method based on Proximate Optimality Principle (POP), which method has several advantages for solving large-scale combinatorial optimization problems. The proposed algorithm uses not only the distance between search points but also the interaction among search points in order to utilize POP in several types of combinatorial optimization problems. The proposed algorithm is applied to several typical combinatorial optimization problems, a knapsack problem, a traveling salesman problem, and a flow shop scheduling problem, in order to verify the performance of the proposed algorithm. The simulation results indicate that the proposed method has higher optimality than the conventional combinatorial optimization methods.

  5. Dynamic chemistry of anion recognition

    SciTech Connect

    Custelcean, Radu

    2012-01-01

    In the past 40 years, anion recognition by synthetic receptors has grown into a rich and vibrant research topic, developing into a distinct branch of Supramolecular Chemistry. Traditional anion receptors comprise organic scaffolds functionalized with complementary binding groups that are assembled by multistep organic synthesis. Recently, a new approach to anion receptors has emerged, in which the host is dynamically self-assembled in the presence of the anionic guest, via reversible bond formation between functional building units. While coordination bonds were initially employed for the self-assembly of the anion hosts, more recent studies demonstrated that reversible covalent bonds can serve the same purpose. In both cases, due to their labile connections, the molecular constituents have the ability to assemble, dissociate, and recombine continuously, thereby creating a dynamic combinatorial library (DCL) of receptors. The anionic guests, through specific molecular recognition, may then amplify (express) the formation of a particular structure among all possible combinations (real or virtual) by shifting the equilibria involved towards the most optimal receptor. This approach is not limited to solution self-assembly, but is equally applicable to crystallization, where the fittest anion-binding crystal may be selected. Finally, the pros and cons of employing dynamic combinatorial chemistry (DCC) vs molecular design for developing anion receptors, and the implications of both approaches to selective anion separations, will be discussed.

  6. Combinatorial investigation of rare-earth free permanent magnets

    NASA Astrophysics Data System (ADS)

    Fackler, Sean Wu

    The combinatorial high throughput method allows one to rapidly study a large number of samples with systematically changing parameters. We apply this method to study Fe-Co-V alloys as alternatives to rare-earth permanent magnets. Rare-earth permanent magnets derive their unmatched magnetic properties from the hybridization of Fe and Co with the f-orbitals of rare-earth elements, which have strong spin-orbit coupling. It is predicted that Fe and Co may also have strong hybridization with 4d and 5d refractory transition metals with strong spin-orbit coupling. Refractory transition metals like V also have the desirable property of high temperature stability, which is important for permanent magnet applications in traction motors. In this work, we focus on the role of crystal structure, composition, and secondary phases in the origin of competitive permanent magnetic properties of a particular Fe-Co-V alloy. Fe38Co52V10, compositions are known as Vicalloys. Fe-CoV composition spreads were sputtered onto three-inch silicon wafers and patterned into discrete sample pads forming a combinatorial library. We employed highthroughput screening methods using synchrotron X-rays, wavelength dispersive spectroscopy, and magneto-optical Kerr effect (MOKE) to rapidly screen crystal structure, composition, and magnetic properties, respectively. We found that in-plane magnetic coercive fields of our Vicalloy thin films agree with known bulk values (300 G), but found a remarkable eight times increase of the out-of-plane coercive fields (˜2,500 G). To explain this, we measured the switching fields between in-plane and out-of-plane thin film directions which revealed that the Kondorsky model of 180° domain wall reversal was responsible for Vicalloy's enhanced out-of-plane coercive field and possibly its permanent magnetic properties. The Kondorsky model suggests that domain-wall pinning is the origin of Vicalloy's permanent magnetic properties, in contrast to strain, shape, or

  7. Library 2000.

    ERIC Educational Resources Information Center

    Drake, Miriam A.

    In fall 1984, the Georgia Institute of Technology administration and library staff began planning for Library 2000, a project aimed at creating a showcase library to demonstrate the application of the latest information technology in an academic and research environment. The purposes of Library 2000 include: increasing awareness of students,…

  8. Combinatorial approaches to gene recognition.

    PubMed

    Roytberg, M A; Astakhova, T V; Gelfand, M S

    1997-01-01

    Recognition of genes via exon assembly approaches leads naturally to the use of dynamic programming. We consider the general graph-theoretical formulation of the exon assembly problem and analyze in detail some specific variants: multicriterial optimization in the case of non-linear gene-scoring functions; context-dependent schemes for scoring exons and related procedures for exon filtering; and highly specific recognition of arbitrary gene segments, oligonucleotide probes and polymerase chain reaction (PCR) primers. PMID:9440930

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

    NASA Astrophysics Data System (ADS)

    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.

  10. Exploiting Quantum Resonance to Solve Combinatorial Problems

    NASA Technical Reports Server (NTRS)

    Zak, Michail; Fijany, Amir

    2006-01-01

    Quantum resonance would be exploited in a proposed quantum-computing approach to the solution of combinatorial optimization problems. In quantum computing in general, one takes advantage of the fact that an algorithm cannot be decoupled from the physical effects available to implement it. Prior approaches to quantum computing have involved exploitation of only a subset of known quantum physical effects, notably including parallelism and entanglement, but not including resonance. In the proposed approach, one would utilize the combinatorial properties of tensor-product decomposability of unitary evolution of many-particle quantum systems for physically simulating solutions to NP-complete problems (a class of problems that are intractable with respect to classical methods of computation). In this approach, reinforcement and selection of a desired solution would be executed by means of quantum resonance. Classes of NP-complete problems that are important in practice and could be solved by the proposed approach include planning, scheduling, search, and optimal design.

  11. Combinatorial reliability analysis of multiprocessor computers

    SciTech Connect

    Hwang, K.; Tian-Pong Chang

    1982-12-01

    The authors propose a combinatorial method to evaluate the reliability of multiprocessor computers. Multiprocessor structures are classified as crossbar switch, time-shared buses, and multiport memories. Closed-form reliability expressions are derived via combinatorial path enumeration on the probabilistic-graph representation of a multiprocessor system. The method can analyze the reliability performance of real systems like C.mmp, Tandem 16, and Univac 1100/80. User-oriented performance levels are defined for measuring the performability of degradable multiprocessor systems. For a regularly structured multiprocessor system, it is fast and easy to use this technique for evaluating system reliability with statistically independent component reliabilities. System availability can be also evaluated by this reliability study. 6 references.

  12. Neurotransmitters drive combinatorial multistate postsynaptic density networks.

    PubMed

    Coba, Marcelo P; Pocklington, Andrew J; Collins, Mark O; Kopanitsa, Maksym V; Uren, Rachel T; Swamy, Sajani; Croning, Mike D R; Choudhary, Jyoti S; Grant, Seth G N

    2009-01-01

    The mammalian postsynaptic density (PSD) comprises a complex collection of approximately 1100 proteins. Despite extensive knowledge of individual proteins, the overall organization of the PSD is poorly understood. Here, we define maps of molecular circuitry within the PSD based on phosphorylation of postsynaptic proteins. Activation of a single neurotransmitter receptor, the N-methyl-D-aspartate receptor (NMDAR), changed the phosphorylation status of 127 proteins. Stimulation of ionotropic and metabotropic glutamate receptors and dopamine receptors activated overlapping networks with distinct combinatorial phosphorylation signatures. Using peptide array technology, we identified specific phosphorylation motifs and switching mechanisms responsible for the integration of neurotransmitter receptor pathways and their coordination of multiple substrates in these networks. These combinatorial networks confer high information-processing capacity and functional diversity on synapses, and their elucidation may provide new insights into disease mechanisms and new opportunities for drug discovery. PMID:19401593

  13. A Synergistic Combinatorial and Chiroptical Study of Peptide Catalysts for Asymmetric Baeyer–Villiger Oxidation

    PubMed Central

    Giuliano, Michael W.; Lin, Chung-Yon; Romney, David K.

    2015-01-01

    We report an approach to the asymmetric Baeyer–Villiger oxidation utilizing bioinformatics-inspired combinatorial screening for catalyst discovery. Scaled-up validation of our on-bead efforts with a circular dichroism-based assay of alcohols derived from the products of solution-phase reactions established the absolute configuration of lactone products; this assay proved equivalent to HPLC in its ability to evaluate catalyst performance, but was far superior in its speed of analysis. Further solution-phase screening of a focused library suggested a mode of asymmetric induction that draws distinct parallels with the mechanism of Baeyer–Villiger monooxygenases. PMID:26543444

  14. Combinatorial Cis-regulation in Saccharomyces Species

    PubMed Central

    Spivak, Aaron T.; Stormo, Gary D.

    2016-01-01

    Transcriptional control of gene expression requires interactions between the cis-regulatory elements (CREs) controlling gene promoters. We developed a sensitive computational method to identify CRE combinations with conserved spacing that does not require genome alignments. When applied to seven sensu stricto and sensu lato Saccharomyces species, 80% of the predicted interactions displayed some evidence of combinatorial transcriptional behavior in several existing datasets including: (1) chromatin immunoprecipitation data for colocalization of transcription factors, (2) gene expression data for coexpression of predicted regulatory targets, and (3) gene ontology databases for common pathway membership of predicted regulatory targets. We tested several predicted CRE interactions with chromatin immunoprecipitation experiments in a wild-type strain and strains in which a predicted cofactor was deleted. Our experiments confirmed that transcription factor (TF) occupancy at the promoters of the CRE combination target genes depends on the predicted cofactor while occupancy of other promoters is independent of the predicted cofactor. Our method has the additional advantage of identifying regulatory differences between species. By analyzing the S. cerevisiae and S. bayanus genomes, we identified differences in combinatorial cis-regulation between the species and showed that the predicted changes in gene regulation explain several of the species-specific differences seen in gene expression datasets. In some instances, the same CRE combinations appear to regulate genes involved in distinct biological processes in the two different species. The results of this research demonstrate that (1) combinatorial cis-regulation can be inferred by multi-genome analysis and (2) combinatorial cis-regulation can explain differences in gene expression between species. PMID:26772747

  15. Combinatorial Cis-regulation in Saccharomyces Species.

    PubMed

    Spivak, Aaron T; Stormo, Gary D

    2016-01-01

    Transcriptional control of gene expression requires interactions between the cis-regulatory elements (CREs) controlling gene promoters. We developed a sensitive computational method to identify CRE combinations with conserved spacing that does not require genome alignments. When applied to seven sensu stricto and sensu lato Saccharomyces species, 80% of the predicted interactions displayed some evidence of combinatorial transcriptional behavior in several existing datasets including: (1) chromatin immunoprecipitation data for colocalization of transcription factors, (2) gene expression data for coexpression of predicted regulatory targets, and (3) gene ontology databases for common pathway membership of predicted regulatory targets. We tested several predicted CRE interactions with chromatin immunoprecipitation experiments in a wild-type strain and strains in which a predicted cofactor was deleted. Our experiments confirmed that transcription factor (TF) occupancy at the promoters of the CRE combination target genes depends on the predicted cofactor while occupancy of other promoters is independent of the predicted cofactor. Our method has the additional advantage of identifying regulatory differences between species. By analyzing the S. cerevisiae and S. bayanus genomes, we identified differences in combinatorial cis-regulation between the species and showed that the predicted changes in gene regulation explain several of the species-specific differences seen in gene expression datasets. In some instances, the same CRE combinations appear to regulate genes involved in distinct biological processes in the two different species. The results of this research demonstrate that (1) combinatorial cis-regulation can be inferred by multi-genome analysis and (2) combinatorial cis-regulation can explain differences in gene expression between species. PMID:26772747

  16. The Combinatorial Trace Method in Action

    ERIC Educational Resources Information Center

    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…

  17. Combinatorial and algorithm aspects of hyperbolic polynomials

    SciTech Connect

    Gurvits, Leonid I.

    2004-01-01

    Univariate polynomials with real roots appear quite often in modern combinatorics, especially in the context of integer polytopes. We discovered in this paper rather unexpected and very likely far-reaching connections between hyperbolic polynomials and many classical combinatorial and algorithmic problems. There are still several open problems. The most interesting is a hyperbolic generalization of the van der Waerden conjecture for permanents of doubly stochastic matrices.

  18. Adaptive Random Testing with Combinatorial Input Domain

    PubMed Central

    Lu, Yansheng

    2014-01-01

    Random testing (RT) is a fundamental testing technique to assess software reliability, by simply selecting test cases in a random manner from the whole input domain. As an enhancement of RT, adaptive random testing (ART) has better failure-detection capability and has been widely applied in different scenarios, such as numerical programs, some object-oriented programs, and mobile applications. However, not much work has been done on the effectiveness of ART for the programs with combinatorial input domain (i.e., the set of categorical data). To extend the ideas to the testing for combinatorial input domain, we have adopted different similarity measures that are widely used for categorical data in data mining and have proposed two similarity measures based on interaction coverage. Then, we propose a new version named ART-CID as an extension of ART in combinatorial input domain, which selects an element from categorical data as the next test case such that it has the lowest similarity against already generated test cases. Experimental results show that ART-CID generally performs better than RT, with respect to different evaluation metrics. PMID:24772036

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

    PubMed Central

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

    2014-01-01

    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. PMID:25049383

  20. Metallopeptidase inhibitors of tetanus toxin: A combinatorial approach.

    PubMed

    Martin, L; Cornille, F; Turcaud, S; Meudal, H; Roques, B P; Fournié-Zaluski, M C

    1999-02-11

    The bacterial protein tetanus toxin (TeNt), which belongs to the family of zinc endopeptidases, cleaves synaptobrevin, an essential synaptic protein component of the neurotransmitter exocytosis apparatus, at a single peptide bond (Gln76-Phe77). This protease activity is a particularly attractive target for designing potent and selective synthetic inhibitors as a possible drug therapy for tetanus. beta-Aminothiols mimicking Gln76 of synaptobrevin have been previously shown to inhibit the tetanus neurotoxin enzymatic activity in the 35-250 microM range. These compounds have now been modified to interact with S' subsites of the TeNt active site, with the aim of increasing their inhibitory potencies. Combinatorial libraries of pseudotripeptides, containing an ethylene sulfonamide or an m-sulfonamidophenyl moiety as the P1 side chain and natural amino acids in P1' and P2' positions, were synthesized. The best inhibitory activity was observed with Tyr and His as P1' and P2' components, respectively. This led to new inhibitors of TeNt with Ki values in the 3-4 microM range. These molecules are the most potent inhibitors of TeNt described so far. PMID:9986722

  1. Special Libraries

    ERIC Educational Resources Information Center

    Lavendel, Giuliana

    1977-01-01

    Discusses problems involved in maintaining special scientific or engineering libraries, including budget problems, remote storage locations, rental computer retrieval systems, protecting trade secrets, and establishing a magnetic tape library. (MLH)

  2. Combinatorial studies of silicon-based alloy negatives for lithium-ion batteries

    NASA Astrophysics Data System (ADS)

    Hatchard, Timothy D.

    Si-based materials are promising candidates to replace graphite as the negative electrode in Li-ion batteries. Si and Si-based materials are attractive because they can reversibly alloy with large amounts of Li. This leads to batteries with higher energy density when compared to cells made with graphite negative electrodes. A crucial problem remains to be overcome before Si-based materials can be used in commercial Li-ion cells. Graphite electrodes can withstand up to a thousand or more charge/discharge cycles without losing significant amounts of capacity. The Si-based materials, on the other hand, lose much of their capacity after only a few cycles. This makes them unacceptable for use in rechargeable batteries. Alloy electrodes that are amorphous tend to have better capacity retention than crystalline materials of similar composition. There are many elements that alloy with Li, so there is a large sample space of possible composite electrode materials that can be tested. A method is needed that can produce libraries with large composition ranges that also contain amorphous material. Amorphous films can be produced by sputter deposition that would not be amorphous if created by other means such as physical mixing or melt spinning. Sputter deposition also lends itself easily to combinatorial methods. This thesis describes the development of a combinatorial deposition system that can produce ternary films with linear and orthogonal composition variations and large amorphous ranges. Infrastructure to perform combinatorial electrochemical testing has also been developed. Studies of a-Si and a-Si-based alloys containing Al, Ag, Ge, Sn and Zn have been conducted. Results of combinatorial studies for binary and ternary systems are presented. In-situ XRD studies have been conducted for a-Si and some specific compositions of SiZn. These results are discussed as well as the phases formed during electrochemical cycling of these cells.

  3. Library screening by means of mass spectrometry (MS) binding assays-exemplarily demonstrated for a pseudostatic library addressing γ-aminobutyric acid (GABA) transporter 1 (GAT1).

    PubMed

    Sindelar, Miriam; Wanner, Klaus T

    2012-09-01

    In the present study, the application of mass spectrometry (MS) binding assays as a tool for library screening is reported. For library generation, dynamic combinatorial chemistry (DCC) was used. These libraries can be screened by means of MS binding assays when appropriate measures are taken to render the libraries pseudostatic. That way, the efficiency of MS binding assays to determine ligand binding in compound screening with the ease of library generation by DCC is combined. The feasibility of this approach is shown for γ-aminobutyric acid (GABA) transporter 1 (GAT1) as a target, representing the most important subtype of the GABA transporters. For the screening, hydrazone libraries were employed that were generated in the presence of the target by reacting various sets of aldehydes with a hydrazine derivative that is delineated from piperidine-3-carboxylic acid (nipecotic acid), a common fragment of known GAT1 inhibitors. To ensure that the library generated is pseudostatic, a large excess of the nipecotic acid derivative is employed. As the library is generated in a buffer system suitable for binding and the target is already present, the mixtures can be directly analyzed by MS binding assays-the process of library generation and screening thus becoming simple to perform. The binding affinities of the hits identified by deconvolution were confirmed in conventional competitive MS binding assays performed with single compounds obtained by separate synthesis. In this way, two nipecotic acid derivatives exhibiting a biaryl moiety, 1-{2-[2'-(1,1'-biphenyl-2-ylmethylidene)hydrazine]ethyl}piperidine-3-carboxylic acid and 1-(2-{2'-[1-(2-thiophenylphenyl)methylidene]hydrazine}ethyl)piperidine-3-carboxylic acid, were found to be potent GAT1 ligands exhibiting pK(i) values of 6.186 ± 0.028 and 6.229 ± 0.039, respectively. This method enables screening of libraries, whether generated by conventional chemistry or DCC, and is applicable to all kinds of targets including

  4. Library Skills.

    ERIC Educational Resources Information Center

    Paul, Karin; Kuhlthau, Carol C.; Branch, Jennifer L.; Solowan, Diane Galloway; Case, Roland; Abilock, Debbie; Eisenberg, Michael B.; Koechlin, Carol; Zwaan, Sandi; Hughes, Sandra; Low, Ann; Litch, Margaret; Lowry, Cindy; Irvine, Linda; Stimson, Margaret; Schlarb, Irene; Wilson, Janet; Warriner, Emily; Parsons, Les; Luongo-Orlando, Katherine; Hamilton, Donald

    2003-01-01

    Includes 19 articles that address issues related to library skills and Canadian school libraries. Topics include information literacy; inquiry learning; critical thinking and electronic research; collaborative inquiry; information skills and the Big 6 approach to problem solving; student use of online databases; library skills; Internet accuracy;…

  5. Synthesis of Chemiluminescent Esters: A Combinatorial Synthesis Experiment for Organic Chemistry Students

    ERIC Educational Resources Information Center

    Duarte, Robert; Nielson, Janne T.; Dragojlovic, Veljko

    2004-01-01

    A group of techniques aimed at synthesizing a large number of structurally diverse compounds is called combinatorial synthesis. Synthesis of chemiluminescence esters using parallel combinatorial synthesis and mix-and-split combinatorial synthesis is experimented.

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

    NASA Astrophysics Data System (ADS)

    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.

  7. A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds.

    PubMed

    Isidro-Llobet, Albert; Hadje Georgiou, Kathy; Galloway, Warren R J D; Giacomini, Elisa; Hansen, Mette R; Méndez-Abt, Gabriela; Tan, Yaw Sing; Carro, Laura; Sore, Hannah F; Spring, David R

    2015-04-21

    Macrocyclic peptidomimetics are associated with a broad range of biological activities. However, despite such potentially valuable properties, the macrocyclic peptidomimetic structural class is generally considered as being poorly explored within drug discovery. This has been attributed to the lack of general methods for producing collections of macrocyclic peptidomimetics with high levels of structural, and thus shape, diversity. In particular, there is a lack of scaffold diversity in current macrocyclic peptidomimetic libraries; indeed, the efficient construction of diverse molecular scaffolds presents a formidable general challenge to the synthetic chemist. Herein we describe a new, advanced strategy for the diversity-oriented synthesis (DOS) of macrocyclic peptidomimetics that enables the combinatorial variation of molecular scaffolds (core macrocyclic ring architectures). The generality and robustness of this DOS strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks. To the best of our knowledge this represents an unprecedented level of scaffold diversity in a synthetically derived library of macrocyclic peptidomimetics. Cheminformatic analysis indicated that the library compounds access regions of chemical space that are distinct from those addressed by top-selling brand-name drugs and macrocyclic natural products, illustrating the value of our DOS approach to sample regions of chemical space underexploited in current drug discovery efforts. An analysis of three-dimensional molecular shapes illustrated that the DOS library has a relatively high level of shape diversity. PMID:25778821

  8. Expanding the modular ester fermentative pathways for combinatorial biosynthesis of esters from volatile organic acids.

    PubMed

    Layton, Donovan S; Trinh, Cong T

    2016-08-01

    Volatile organic acids are byproducts of fermentative metabolism, for example, anaerobic digestion of lignocellulosic biomass or organic wastes, and are often times undesired inhibiting cell growth and reducing directed formation of the desired products. Here, we devised a general framework for upgrading these volatile organic acids to high-value esters that can be used as flavors, fragrances, solvents, and biofuels. This framework employs the acid-to-ester modules, consisting of an AAT (alcohol acyltransferase) plus ACT (acyl CoA transferase) submodule and an alcohol submodule, for co-fermentation of sugars and organic acids to acyl CoAs and alcohols to form a combinatorial library of esters. By assembling these modules with the engineered Escherichia coli modular chassis cell, we developed microbial manufacturing platforms to perform the following functions: (i) rapid in vivo screening of novel AATs for their catalytic activities; (ii) expanding combinatorial biosynthesis of unique fermentative esters; and (iii) upgrading volatile organic acids to esters using single or mixed cell cultures. To demonstrate this framework, we screened for a set of five unique and divergent AATs from multiple species, and were able to determine their novel activities as well as produce a library of 12 out of the 13 expected esters from co-fermentation of sugars and (C2-C6) volatile organic acids. We envision the developed framework to be valuable for in vivo characterization of a repertoire of not-well-characterized natural AATs, expanding the combinatorial biosynthesis of fermentative esters, and upgrading volatile organic acids to high-value esters. Biotechnol. Bioeng. 2016;113: 1764-1776. © 2016 Wiley Periodicals, Inc. PMID:26853081

  9. On schemes of combinatorial transcription logic

    NASA Astrophysics Data System (ADS)

    Buchler, Nicolas E.; Gerland, Ulrich; Hwa, Terence

    2003-04-01

    Cells receive a wide variety of cellular and environmental signals, which are often processed combinatorially to generate specific genetic responses. Here we explore theoretically the potentials and limitations of combinatorial signal integration at the level of cis-regulatory transcription control. Our analysis suggests that many complex transcription-control functions of the type encountered in higher eukaryotes are already implementable within the much simpler bacterial transcription system. Using a quantitative model of bacterial transcription and invoking only specific protein-DNA interaction and weak glue-like interaction between regulatory proteins, we show explicit schemes to implement regulatory logic functions of increasing complexity by appropriately selecting the strengths and arranging the relative positions of the relevant protein-binding DNA sequences in the cis-regulatory region. The architectures that emerge are naturally modular and evolvable. Our results suggest that the transcription regulatory apparatus is a "programmable" computing machine, belonging formally to the class of Boltzmann machines. Crucial to our results is the ability to regulate gene expression at a distance. In bacteria, this can be achieved for isolated genes via DNA looping controlled by the dimerization of DNA-bound proteins. However, if adopted extensively in the genome, long-distance interaction can cause unintentional intergenic cross talk, a detrimental side effect difficult to overcome by the known bacterial transcription-regulation systems. This may be a key factor limiting the genome-wide adoption of complex transcription control in bacteria. Implications of our findings for combinatorial transcription control in eukaryotes are discussed. Abbreviations: TF, transcription factor RNAP, RNA polymerase DNF, disjunctive normal form CNF, conjunctive normal form

  10. Apparatus for combinatorial screening of electrochemical materials

    DOEpatents

    A high throughput combinatorial screening method and apparatus for the evaluation of electrochemical materials using a single voltage source is disclosed wherein temperature changes arising from the application of an electrical load to a cell array are used to evaluate the relative electrochemical efficiency of the materials comprising the array. The apparatus may include an array of electrochemical cells that are connected to each other in parallel or in series, an electronic load for applying a voltage or current to the electrochemical cells , and a device , external to the cells, for monitoring the relative temperature of each cell when the load is applied.

    2009-12-15

    A high throughput combinatorial screening method and apparatus for the evaluation of electrochemical materials using a single voltage source (2) is disclosed wherein temperature changes arising from the application of an electrical load to a cell array (1) are used to evaluate the relative electrochemical efficiency of the materials comprising the array. The apparatus may include an array of electrochemical cells (1) that are connected to each other in parallel or in series, an electronic load (2) for applying a voltage or current to the electrochemical cells (1), and a device (3), external to the cells, for monitoring the relative temperature of each cell when the load is applied.

  11. Developing New Antibiotics with Combinatorial Biosynthesis

    NASA Astrophysics Data System (ADS)

    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.

  12. Method and apparatus for combinatorial chemistry

    DOEpatents

    Foote, Robert S.

    2007-02-20

    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.

  13. Method and apparatus for combinatorial chemistry

    DOEpatents

    Foote, Robert S.

    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.

  14. Solving combinatorial problems: the 15-puzzle.

    PubMed

    Pizlo, Zygmunt; Li, Zheng

    2005-09-01

    We present a series of experiments in which human subjects were tested with a well-known combinatorial problem called the 15-puzzle and in different-sized variants of this puzzle. Subjects can solve these puzzles reliably by systematically building a solution path, without performing much search and without using distances among the states of the problem. The computational complexity of the underlying mental mechanisms is very low. We formulated a computational model of the underlying cognitive processes on the basis of our results. This model applied a pyramid algorithm to individual stages of each problem. The model's performance proved to be quite similar to the subjects' performance. PMID:16496727

  15. Aerospace Applications of Integer and Combinatorial Optimization

    NASA Technical Reports Server (NTRS)

    Padula, S. L.; Kincaid, R. K.

    1995-01-01

    Research supported by NASA Langley Research Center includes many applications of aerospace design optimization and is conducted by teams of applied mathematicians and aerospace engineers. This paper investigates the benefits from this combined expertise in formulating and solving integer and combinatorial optimization problems. Applications range from the design of large space antennas to interior noise control. A typical problem, for example, seeks the optimal locations for vibration-damping devices on an orbiting platform and is expressed as a mixed/integer linear programming problem with more than 1500 design variables.

  16. Aerospace applications on integer and combinatorial optimization

    NASA Technical Reports Server (NTRS)

    Padula, S. L.; Kincaid, R. K.

    1995-01-01

    Research supported by NASA Langley Research Center includes many applications of aerospace design optimization and is conducted by teams of applied mathematicians and aerospace engineers. This paper investigates the benefits from this combined expertise in formulating and solving integer and combinatorial optimization problems. Applications range from the design of large space antennas to interior noise control. A typical problem. for example, seeks the optimal locations for vibration-damping devices on an orbiting platform and is expressed as a mixed/integer linear programming problem with more than 1500 design variables.

  17. Aerospace applications of integer and combinatorial optimization

    NASA Technical Reports Server (NTRS)

    Padula, S. L.; Kincaid, R. K.

    1995-01-01

    Research supported by NASA Langley Research Center includes many applications of aerospace design optimization and is conducted by teams of applied mathematicians and aerospace engineers. This paper investigates the benefits from this combined expertise in solving combinatorial optimization problems. Applications range from the design of large space antennas to interior noise control. A typical problem, for example, seeks the optimal locations for vibration-damping devices on a large space structure and is expressed as a mixed/integer linear programming problem with more than 1500 design variables.

  18. Method and apparatus for combinatorial chemistry

    SciTech Connect

    Foote, Robert S.

    2009-06-23

    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.

  19. Haplotype-resolved whole-genome sequencing by contiguity-preserving transposition and combinatorial indexing.

    PubMed

    Amini, Sasan; Pushkarev, Dmitry; Christiansen, Lena; Kostem, Emrah; Royce, Tom; Turk, Casey; Pignatelli, Natasha; Adey, Andrew; Kitzman, Jacob O; Vijayan, Kandaswamy; Ronaghi, Mostafa; Shendure, Jay; Gunderson, Kevin L; Steemers, Frank J

    2014-12-01

    Haplotype-resolved genome sequencing enables the accurate interpretation of medically relevant genetic variation, deep inferences regarding population history and non-invasive prediction of fetal genomes. We describe an approach for genome-wide haplotyping based on contiguity-preserving transposition (CPT-seq) and combinatorial indexing. Tn5 transposition is used to modify DNA with adaptor and index sequences while preserving contiguity. After DNA dilution and compartmentalization, the transposase is removed, resolving the DNA into individually indexed libraries. The libraries in each compartment, enriched for neighboring genomic elements, are further indexed via PCR. Combinatorial 96-plex indexing at both the transposition and PCR stage enables the construction of phased synthetic reads from each of the nearly 10,000 'virtual compartments'. We demonstrate the feasibility of this method by assembling >95% of the heterozygous variants in a human genome into long, accurate haplotype blocks (N50 = 1.4-2.3 Mb). The rapid, scalable and cost-effective workflow could enable haplotype resolution to become routine in human genome sequencing. PMID:25326703

  20. Haplotype-resolved whole genome sequencing by contiguity preserving transposition and combinatorial indexing

    PubMed Central

    Amini, Sasan; Pushkarev, Dmitry; Christiansen, Lena; Kostem, Emrah; Royce, Tom; Turk, Casey; Pignatelli, Natasha; Adey, Andrew; Kitzman, Jacob O.; Vijayan, Kandaswamy; Ronaghi, Mostafa; Shendure, Jay; Gunderson, Kevin L.; Steemers, Frank J.

    2015-01-01

    Haplotype-resolved genomes equencing enables accurate interpretation of medically relevant genetic variation, deep inferences regarding population history, and the non-invasive prediction of fetal genomes. We describe an approach for genome-wide haplotyping based on contiguity preserving transposition (CPT-Seq) and combinatorial indexing. Tn5 transposition is used to modify DNA with adapter and index sequences while preserving contiguity. After dilution and compartmentalization, the transposase is removed, resolving the DNA into individually indexed libraries. The libraries in each compartment, enriched for neighboring genomic elements, are further indexed via PCR. Combinatorial 96-plex indexing at both the transposition and PCR stage enables the construction of phased synthetic reads from each of the nearly 10,000 “virtual compartments”. We demonstrate feasibility of this method by assembling >95% of heterozygous variants in a human genome into long, accurate haplotype blocks (N50 = 1.4–2.3 Mb). The rapid, scalable, and cost-effective workflow could enable haplotype resolution to become routine in human genome sequencing. PMID:25326703

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

    PubMed Central

    Ito, Yoichiro; Yamanishi, Mamoru; Ikeuchi, Akinori; Imamura, Chie; Matsuyama, Takashi

    2015-01-01

    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. PMID:26692026

  2. Synthesis and biological evaluation of a focused library of beauveriolides.

    PubMed

    Nagai, Kenichiro; Doi, Takayuki; Ohshiro, Taichi; Sunazuka, Toshiaki; Tomoda, Hiroshi; Takahashi, Takashi; Omura, Satoshi

    2008-08-01

    Fungal beauveriolide III (1b), discovered as an inhibitor of lipid droplet accumulation in mouse macrophages and showing antiatherogenic activity in mouse model, consists of l-Phe, l-Ala, d-allo-Ile, and (3S, 4S)-3-hydroxy-4-methyloctanoic acid moieties. A combinatorial library of beauveriolide analogues focusing on l-Ala and d-allo-Ile of 1b was synthesized by combinatorial synthesis. Among them, d-Ala analogues consisting of A{2} improved their solubility, while those with 7{1,3,2},7{2,3,1}, and 7{2,3,2} were 20 times more potent than 1b. PMID:18620856

  3. Strategies and applications of combinatorial methods and high throughput screening to the discovery of non-noble metal catalyst

    NASA Astrophysics Data System (ADS)

    Bricker, Maureen L.; Sachtler, J. W. Adriaan; Gillespie, Ralph D.; McGonegal, Charles P.; Vega, Honorio; Bem, Dave S.; Holmgren, Jennifer S.

    2004-02-01

    The integrated End-to-End™ combinatorial process for catalyst preparation and screening, with emphasis on its capability to vary both process and compositional parameters will be demonstrated. Additionally, each step of the combinatorial screening process has been validated against results from traditional screening methods. The greatest challenge of all has been the adherence to the core concepts of the combinatorial approach. Catalyst libraries have been made and tested for naphthalene dehydrogenation chemistry. The preparation of these libraries has included the application of high throughput techniques for: metal impregnation; catalyst finishing; catalyst screening. The catalyst screening system has been used to find a non-noble metal catalyst system that can replace Pt in dehydrogenation applications in the petroleum industry. A proprietary catalytic composition was developed for the dehydrogenation of methylcyclohexane (MCH) to toluene starting with four non-noble metals of different proportions and four different supports (alumina, titania, zirconia and silica) prepared in different ways and applying a statistical design of experiments. These data demonstrate that all steps of catalyst preparation and screening are performed in a rapid, useful, high throughput manner. Data will be presented from the catalyst screening efforts will demonstrate that optimized metal composition is dependent on the support type.

  4. Cryptographic Combinatorial Clock-Proxy Auctions

    NASA Astrophysics Data System (ADS)

    Parkes, David C.; Rabin, Michael O.; Thorpe, Christopher

    We present a cryptographic protocol for conducting efficient, provably correct and secrecy-preserving combinatorial clock-proxy auctions. The “clock phase” functions as a trusted auction despite price discovery: bidders submit encrypted bids, and prove for themselves that they meet activity rules, and can compute total demand and thus verify price increases without revealing any information about individual demands. In the sealed-bid “proxy phase”, all bids are revealed the auctioneer via time-lapse cryptography and a branch-and-bound algorithm is used to solve the winner-determination problem. Homomorphic encryption is used to prove the correctness of the solution, and establishes the correctness of the solution to any interested party. Still an NP-hard optimization problem, the use of homomorphic encryption imposes additional computational time on winner-determination that is linear in the size of the branch-and-bound search tree, and thus roughly linear in the original (search-based) computational time. The result is a solution that avoids, in the usual case, the exponential complexity of previous cryptographically-secure combinatorial auctions.

  5. Combinatorial design of textured mechanical metamaterials.

    PubMed

    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. PMID:27466125

  6. A combinatorial morphospace for angiosperm pollen

    NASA Astrophysics Data System (ADS)

    Mander, Luke

    2016-04-01

    The morphology of angiosperm (flowering plant) pollen is extraordinarily diverse. This diversity results from variations in the morphology of discrete anatomical components. These components include the overall shape of a pollen grain, the stratification of the exine, the number and form of any apertures, the type of dispersal unit, and the nature of any surface ornamentation. Different angiosperm pollen morphotypes reflect different combinations of these discrete components. In this talk, I ask the following question: given the anatomical components of angiosperm pollen that are known to exist in the plant kingdom, how many unique biologically plausible combinations of these components are there? I explore this question from the perspective of enumerative combinatorics using an algorithm I have written in the Python programming language. This algorithm (1) calculates the number of combinations of these components; (2) enumerates those combinations; and (3) graphically displays those combinations. The result is a combinatorial morphospace that reflects an underlying notion that the process of morphogenesis in angiosperm pollen can be thought of as an n choose k counting problem. I compare the morphology of extant and fossil angiosperm pollen grains to this morphospace, and suggest that from a combinatorial point of view angiosperm pollen is not as diverse as it could be, which may be a result of developmental constraints.

  7. Combinatorial Multiobjective Optimization Using Genetic Algorithms

    NASA Technical Reports Server (NTRS)

    Crossley, William A.; Martin. Eric T.

    2002-01-01

    The research proposed in this document investigated multiobjective optimization approaches based upon the Genetic Algorithm (GA). Several versions of the GA have been adopted for multiobjective design, but, prior to this research, there had not been significant comparisons of the most popular strategies. The research effort first generalized the two-branch tournament genetic algorithm in to an N-branch genetic algorithm, then the N-branch GA was compared with a version of the popular Multi-Objective Genetic Algorithm (MOGA). Because the genetic algorithm is well suited to combinatorial (mixed discrete / continuous) optimization problems, the GA can be used in the conceptual phase of design to combine selection (discrete variable) and sizing (continuous variable) tasks. Using a multiobjective formulation for the design of a 50-passenger aircraft to meet the competing objectives of minimizing takeoff gross weight and minimizing trip time, the GA generated a range of tradeoff designs that illustrate which aircraft features change from a low-weight, slow trip-time aircraft design to a heavy-weight, short trip-time aircraft design. Given the objective formulation and analysis methods used, the results of this study identify where turboprop-powered aircraft and turbofan-powered aircraft become more desirable for the 50 seat passenger application. This aircraft design application also begins to suggest how a combinatorial multiobjective optimization technique could be used to assist in the design of morphing aircraft.

  8. Combinatorial design of textured mechanical metamaterials

    NASA Astrophysics Data System (ADS)

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

    2016-07-01

    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.

  9. Microbatteries for Combinatorial Studies of Conventional Lithium-Ion Batteries

    NASA Technical Reports Server (NTRS)

    West, William; Whitacre, Jay; Bugga, Ratnakumar

    2003-01-01

    Integrated arrays of microscopic solid-state batteries have been demonstrated in a continuing effort to develop microscopic sources of power and of voltage reference circuits to be incorporated into low-power integrated circuits. Perhaps even more importantly, arrays of microscopic batteries can be fabricated and tested in combinatorial experiments directed toward optimization and discovery of battery materials. The value of the combinatorial approach to optimization and discovery has been proven in the optoelectronic, pharmaceutical, and bioengineering industries. Depending on the specific application, the combinatorial approach can involve the investigation of hundreds or even thousands of different combinations; hence, it is time-consuming and expensive to attempt to implement the combinatorial approach by building and testing full-size, discrete cells and batteries. The conception of microbattery arrays makes it practical to bring the advantages of the combinatorial approach to the development of batteries.

  10. Systematic control of experimental inconsistency in combinatorial materials science.

    PubMed

    Sharma, Asish Kumar; Kulshreshtha, Chandramouli; Sohn, Keemin; Sohn, Kee-Sun

    2009-01-01

    We developed a method to systematically control experimental inconsistency, which is one of the most troublesome and difficult problems in high-throughput combinatorial experiments. The topic of experimental inconsistency is never addressed, even though all scientists in the field of combinatorial materials science face this very serious problem. Experimental inconsistency and material property were selected as dual objective functions that were simultaneously optimized. Specifically, in an attempt to search for promising phosphors with high reproducibility, photoluminescence (PL) intensity was maximized, and experimental inconsistency was minimized by employing a multiobjective evolutionary optimization-assisted combinatorial materials search (MOEO combinatorial material search) strategy. A tetravalent manganese-doped alkali earth germanium/titanium oxide system was used as a model system to be screened using MOEO combinatorial materials search. As a result of MOEO reiteration, we identified a halide-detached deep red phosphor with improved PL intensity and reliable reproducibility. PMID:19061418

  11. Libraries program

    USGS Publications Warehouse

    2011-01-01

    The U.S. Congress authorized a library for the U.S. Geological Survey (USGS) in 1879. The library was formally established in 1882 with the naming of the first librarian and began with a staff of three and a collection of 1,400 books. Today, the USGS Libraries Program is one of the world's largest Earth and natural science repositories and a resource of national significance used by researchers and the public worldwide.

  12. Solid-state combinatorial screening of (Sr,Ca,Ba, Mg)₂Si₅N₈:Eu(2+) phosphors.

    PubMed

    Lee, Bonghyun; Lee, Sangjun; Jeong, Hyung Gon; Sohn, Kee-Sun

    2011-03-14

    We employed a solid-state combinatorial chemistry technique to screen 4 ternary phosphor systems: (Sr,Ca,Ba)(2)Si(5)N(8):Eu(2+), (Sr,Ca,Mg)(2)Si(5)N(8):Eu(2+), (Sr,Mg,Ba)(2)Si(5)N(8):Eu(2+), and (Ca,Ba,Mg)(2)Si(5)N(8):Eu(2+). The current pure nitride-based system did not allow for the use of conventional liquid solution-based high-throughput experimentation, so that a specially designed solid-state high-throughput powder-dispensing synthesis technique was employed. As a result, four well-defined ternary combinatorial libraries were developed in terms of photoluminescent (PL) intensity and color chromaticity with no skipped compositions, which provided a quantitative relationship between PL properties and the composition of AE(2)Si(5)N(8):Eu(2+) (AE = alkaline earth elements) phosphors. PMID:21275428

  13. Combinatorial selection of molecular conformations and supramolecular synthons in quercetin cocrystal landscapes: a route to ternary solids

    PubMed Central

    Dubey, Ritesh; Desiraju, Gautam R.

    2015-01-01

    The crystallization of 28 binary and ternary cocrystals of quercetin with dibasic coformers is analyzed in terms of a combinatorial selection from a solution of preferred molecular conformations and supramolecular synthons. The crystal structures are characterized by distinctive O—H⋯N and O—H⋯O based synthons and are classified as nonporous, porous and helical. Variability in molecular conformation and synthon structure led to an increase in the energetic and structural space around the crystallization event. This space is the crystal structure landscape of the compound and is explored by fine-tuning the experimental conditions of crystallization. In the landscape context, we develop a strategy for the isolation of ternary cocrystals with the use of auxiliary template molecules to reduce the molecular and supramolecular ‘confusion’ that is inherent in a molecule like quercetin. The absence of concomitant polymorphism in this study highlights the selectivity in conformation and synthon choice from the virtual combinatorial library in solution. PMID:26175900

  14. Synthesis of a large library of macrocyclic peptides containing multiple and diverse N-alkylated residues.

    PubMed

    Morimoto, Jumpei; Kodadek, Thomas

    2015-10-01

    Large combinatorial libraries of macrocyclic peptides are a useful source of bioactive compounds. However, peptides are not generally cell permeable, so there is great interest in the development of methods to create large libraries of modified peptides. In particular, N-alkylation of peptides is known to improve their bioavailability significantly. Incorporation of some level of N-methylated amino acids into peptide libraries has been accomplished with ribosome display or related methods, but the modest efficiency and the inability to employ more diverse N-alkylated amino acids in this type of system argue for the development of synthetic libraries. Here we present optimized procedures for synthesizing macrocyclic peptides containing multiple N-alkylated units and show that this chemistry is efficient enough for the creation of high quality combinatorial libraries by split and pool solid-phase synthesis. PMID:26067000

  15. Library Intranets: Trends and Enhancements

    ERIC Educational Resources Information Center

    Thomas, Lisa Carlucci

    2010-01-01

    Libraries are widely known as institutions that access, organize, and preserve collections of information. Libraries are also dynamic administrative entities that generate and exchange internal business information. From small operations with limited staff and technology to large, multidepartmental institutions with full IT support, libraries…

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

    ERIC Educational Resources Information Center

    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,…

  17. Thermal Sensor Arrays for The Combinatorial Analysis of Thin Films

    NASA Astrophysics Data System (ADS)

    McCluskey, Patrick James

    2011-12-01

    Membrane-based thermal sensor arrays were developed for the high-throughput analysis of the thermophysical properties of thin films. The continuous growth of integrated circuits and microelectromechanical systems, as well as the development of functional materials and the optimization of materials properties, have produced the need for instruments capable of fast materials screening and analysis at reduced length scales. Two instruments were developed based on a similar architecture, one to measure thermal transport properties and the other to perform calorimetry measurements. Both have the capability to accelerate the pace of materials development and understanding using combinatorial measurement methods. The shared architecture of the instruments consists of a silicon-based micromachined array of thermal sensors. Each sensor consists of a SiN X membrane and a W heating element that also serves as a temperature gauge. The array design allows the simultaneous creation of a library of thin film samples by various deposition techniques while systematically varying a parameter of interest across the device. The membrane-based sensors have little thermal mass making them extremely sensitive to changes in thermal energy. The nano-thermal transport array has an array of sensors optimized for sensitivity to heat loss. The heat loss is determined from the temperature response of the sensor to an applied current. An analytical model is used with a linear regression analysis to fit the thermal properties of the samples to the temperature response. The assumptions of the analytical model are validated with a finite element model. Measured thermal properties include specific heat, thermal effusivity, thermal conductivity, and emissivity. The technique is demonstrated by measuring the thermal transport properties of sputter deposited Cu multilayers with a total film thickness from 15 to 470 nm. The experimental results compare well to a theory based on electronic thermal

  18. Privatizing Libraries

    ERIC Educational Resources Information Center

    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 legislation…

  19. Library Advocacy

    ERIC Educational Resources Information Center

    Plunkett, Kate

    2010-01-01

    This paper is about the issue of advocacy. Standing at the vanguard of literacy, library media specialists have a unique role. However, it is time for media specialists to advocate their services in a proactive way. If library media specialists cannot, both individually and collectively, put advocacy at the forefront, then students will suffer the…

  20. Macintoshed Libraries.

    ERIC Educational Resources Information Center

    Valauskas, Edward J., Ed.; John, Nancy R., Ed.

    Contributed by librarians from public, academic, school, and special libraries, the 17 essays in this collection describe ways in which the Apple Macintosh is used in their libraries: (1) "Workstations and the Apple Macintosh" (Edward J. Valauskas); (2) "The Macintosh Experience at Chesapeake College" (Liz Cooper); (3) "ANSEL Character Set for the…

  1. Library Lighting.

    ERIC Educational Resources Information Center

    Metcalf, Keyes D.

    Chapter I provides a background and explains pertinent library lighting problems such as quality, function, aesthetics, intensity, and costs. Emphasis is on the quality and function of lighting for library users. Chapter II deals with the comments and answers to questions by persons who have a special interest and competence in the field of…

  2. Library Research.

    ERIC Educational Resources Information Center

    Wright, Nancy Kirkpatrick

    This workbook, designed for a Library Research course at Yavapai College, provides 15 lessons in advanced library reference skills. Each lesson provides explanatory text and reinforcement exercises. After Lesson I introduces specialized dictionaries and encyclopedias (e.g., for foreign languages, medicine, music, economics, social sciences, and…

  3. Combinatorial and computational challenges for biocatalyst design

    NASA Astrophysics Data System (ADS)

    Arnold, Frances H.

    2001-01-01

    Nature provides a fantastic array of catalysts extremely well suited to supporting life, but usually not so well suited for technology. Whether biocatalysis will have a significant technological impact depends on our finding robust routes for tailoring nature's catalysts or redesigning them anew. Laboratory evolution methods are now used widely to fine-tune the selectivity and activity of enzymes. The current rapid development of these combinatorial methods promises solutions to more complex problems, including the creation of new biosynthetic pathways. Computational methods are also developing quickly. The marriage of these approaches will allow us to generate the efficient, effective catalysts needed by the pharmaceutical, food and chemicals industries and should open up new opportunities for producing energy and chemicals from renewable resources.

  4. Combinatorial Approach to Modeling Quantum Systems

    NASA Astrophysics Data System (ADS)

    Kornyak, Vladimir V.

    2016-02-01

    Using the fact that any linear representation of a group can be embedded into permutations, we propose a constructive description of quantum behavior that provides, in particular, a natural explanation of the appearance of complex numbers and unitarity in the formalism of the quantum mechanics. In our approach, the quantum behavior can be explained by the fundamental impossibility to trace the identity of the indistinguishable objects in their evolution. Any observation only provides information about the invariant relations between such objects. The trajectory of a quantum system is a sequence of unitary evolutions interspersed with observations—non-unitary projections. We suggest a scheme to construct combinatorial models of quantum evolution. The principle of selection of the most likely trajectories in such models via the large numbers approximation leads in the continuum limit to the principle of least action with the appropriate Lagrangians and deterministic evolution equations

  5. Fast combinatorial optimization using generalized deterministic annealing

    NASA Astrophysics Data System (ADS)

    Acton, Scott T.; Ghosh, Joydeep; Bovik, Alan C.

    1993-08-01

    Generalized Deterministic Annealing (GDA) is a useful new tool for computing fast multi-state combinatorial optimization of difficult non-convex problems. By estimating the stationary distribution of simulated annealing (SA), GDA yields equivalent solutions to practical SA algorithms while providing a significant speed improvement. Using the standard GDA, the computational time of SA may be reduced by an order of magnitude, and, with a new implementation improvement, Windowed GDA, the time improvements reach two orders of magnitude with a trivial compromise in solution quality. The fast optimization of GDA has enabled expeditious computation of complex nonlinear image enhancement paradigms, such as the Piecewise Constant (PICO) regression examples used in this paper. To validate our analytical results, we apply GDA to the PICO regression problem and compare the results to other optimization methods. Several full image examples are provided that show successful PICO image enhancement using GDA in the presence of both Laplacian and Gaussian additive noise.

  6. Combinatorial optimization methods for disassembly line balancing

    NASA Astrophysics Data System (ADS)

    McGovern, Seamus M.; Gupta, Surendra M.

    2004-12-01

    Disassembly takes place in remanufacturing, recycling, and disposal with a line being the best choice for automation. The disassembly line balancing problem seeks a sequence which: minimizes workstations, ensures similar idle times, and is feasible. Finding the optimal balance is computationally intensive due to factorial growth. Combinatorial optimization methods hold promise for providing solutions to the disassembly line balancing problem, which is proven to belong to the class of NP-complete problems. Ant colony optimization, genetic algorithm, and H-K metaheuristics are presented and compared along with a greedy/hill-climbing heuristic hybrid. A numerical study is performed to illustrate the implementation and compare performance. Conclusions drawn include the consistent generation of optimal or near-optimal solutions, the ability to preserve precedence, the speed of the techniques, and their practicality due to ease of implementation.

  7. Combinatorial Investigation of Crazes in Polymer Nanocomposites

    NASA Astrophysics Data System (ADS)

    Lee, Jong-Young; Crosby, Alfred

    2005-03-01

    Self-assembled block copolymer nanocomposite thin films aligned by external fields or surface energetics have potential applications as photonic crystals as well as magnetic storage media. However, the presence of surface terraces and embedded nanoparticles can initiate defects such as crazes which can alter the materials' intended functions. We combine the copper grid technique and combinatorial approaches to quantify craze growth in these systems. We present results on the effects of film thickness, surface terraces, and nanoparticles on crazing phenomena in polystyrene and model poly(styrene-b-2-vinyl pyridine) copolymers. These results guide the future design of advanced nanocomposite films while providing fundamental insight into the molecular interactions of polymers and inorganic nanoparticles under mechanical strain.

  8. The Evolving Educational Mission of the Library.

    ERIC Educational Resources Information Center

    Baker, Betsy, Ed.; Litzinger, Mary Ellen, Ed.

    At the 1989 annual meeting of the American Library Association (ALA), the Association of College and Research Libraries (ACRL) used a think tank as a dynamic mechanism for exploring future directions both in the discipline of library user education and for the Bibliographic Instruction (BI) Section of ACRL. Discussion centered on the following…

  9. Geometric differential evolution for combinatorial and programs spaces.

    PubMed

    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. PMID:23270388

  10. A Combinatorial Kin Discrimination System in Bacillus subtilis.

    PubMed

    Lyons, Nicholas A; Kraigher, Barbara; Stefanic, Polonca; Mandic-Mulec, Ines; Kolter, Roberto

    2016-03-21

    Multicellularity inherently involves a number of cooperative behaviors that are potentially susceptible to exploitation but can be protected by mechanisms such as kin discrimination. Discrimination of kin from non-kin has been observed in swarms of the bacterium Bacillus subtilis, but the underlying molecular mechanism has been unknown. We used genetic, transcriptomic, and bioinformatic analyses to uncover kin recognition factors in this organism. Our results identified many molecules involved in cell-surface modification and antimicrobial production and response. These genes varied significantly in expression level and mutation phenotype among B. subtilis strains, suggesting interstrain variation in the exact kin discrimination mechanism used. Genome analyses revealed a substantial diversity of antimicrobial genes present in unique combinations in different strains, with many likely acquired by horizontal gene transfer. The dynamic combinatorial effect derived from this plethora of kin discrimination genes creates a tight relatedness cutoff for cooperation that has likely led to rapid diversification within the species. Our data suggest that genes likely originally selected for competitive purposes also generate preferential interactions among kin, thus stabilizing multicellular lifestyles. PMID:26923784

  11. Combinatorial semantics strengthens angular-anterior temporal coupling.

    PubMed

    Molinaro, Nicola; Paz-Alonso, Pedro M; Duñabeitia, Jon Andoni; Carreiras, Manuel

    2015-04-01

    The human semantic combinatorial system allows us to create a wide number of new meanings from a finite number of existing representations. The present study investigates the neural dynamics underlying the semantic processing of different conceptual constructions based on predictions from previous neuroanatomical models of the semantic processing network. In two experiments, participants read sentences for comprehension containing noun-adjective pairs in three different conditions: prototypical (Redundant), nonsense (Anomalous) and low-typical but composable (Contrastive). In Experiment 1 we examined the processing costs associated to reading these sentences and found a processing dissociation between Anomalous and Contrastive word pairs, compared to prototypical (Redundant) stimuli. In Experiment 2, functional connectivity results showed strong co-activation across conditions between inferior frontal gyrus (IFG) and posterior middle temporal gyrus (MTG), as well as between these two regions and middle frontal gyrus (MFG), anterior temporal cortex (ATC) and fusiform gyrus (FG), consistent with previous neuroanatomical models. Importantly, processing of low-typical (but composable) meanings relative to prototypical and anomalous constructions was associated with a stronger positive coupling between ATC and angular gyrus (AG). Our results underscore the critical role of IFG-MTG co-activation during semantic processing and how other relevant nodes within the semantic processing network come into play to handle visual-orthographic information, to maintain multiple lexical-semantic representations in working memory and to combine existing representations while creatively constructing meaning. PMID:25682046

  12. Droplet pairing and coalescence control for generation of combinatorial signals

    NASA Astrophysics Data System (ADS)

    Um, Eujin; Rogers, Matthew; Stone, Howard

    2013-03-01

    A co-flowing aqueous phase with an immiscible oil phase in a microchannel generates uniformly spaced, monodisperse droplets, which retain their shape by not touching each other or by being stabilized with surfactants at the oil-water interface. However, droplet coalescence is required in many advanced applications, which can be achieved by a complex channel geometry or size differences in the droplets, and as well as by procedures to reduce the effect of a surfactant. These approaches, again, hinder the stability of droplets further downstream. We designed a microchannel which consistently inserts gas-bubble between droplets so that pairing and coalescence of droplets occurs even in the presence of surfactant, and yet prevents unwanted merging with other droplets. Aqueous droplets placed between the bubbles alter their relative speeds and spacing, and consequently we study the change in the number of droplet pairings in relation to the characteristics of the bubbles and the volume of aqueous droplets. By integrating this approach with droplets of different materials, we can program the output sequence of droplet compositions, and such complex combinatorial signals generated are aimed for concentration gradient generation and dynamic stimulation of biological cells with chemicals.

  13. On the existence of binary simplex codes. [using combinatorial construction

    NASA Technical Reports Server (NTRS)

    Taylor, H.

    1977-01-01

    Using a simple combinatorial construction, the existence of a binary simplex code with m codewords for all m is greater than or equal to 1 is proved. The problem of the shortest possible length is left open.

  14. Callpath Library

    SciTech Connect

    Gamblin, T.

    2013-11-09

    The "Callpath Library" is a software abstraction layer over a number of stack tracing utilities. It allows tool develoopers to conveniently represent and mNipulate call paths gathered fro U. Wisconsin's Stackwalker API and GNU Backtrace.

  15. Academic Libraries

    ERIC Educational Resources Information Center

    Library Journal, 1970

    1970-01-01

    Building data is given for the following academic libraries: (1) Rosary College, River Forest, Illinois; (2) Abilene Christian College, Abilene, Texas; (3) University of California, San Diego, La Jolla, California. (MF)

  16. Digital Libraries.

    ERIC Educational Resources Information Center

    Fox, Edward A.; Urs, Shalini R.

    2002-01-01

    Provides an overview of digital libraries research, practice, and literature. Highlights include new technologies; redefining roles; historical background; trends; creating digital content, including conversion; metadata; organizing digital resources; services; access; information retrieval; searching; natural language processing; visualization;…

  17. Combinatorial Dyson-Schwinger equations and inductive data types

    NASA Astrophysics Data System (ADS)

    Kock, Joachim

    2016-06-01

    The goal of this contribution is to explain the analogy between combinatorial Dyson-Schwinger equations and inductive data types to a readership of mathematical physicists. The connection relies on an interpretation of combinatorial Dyson-Schwinger equations as fixpoint equations for polynomial functors (established elsewhere by the author, and summarised here), combined with the now-classical fact that polynomial functors provide semantics for inductive types. The paper is expository, and comprises also a brief introduction to type theory.

  18. Array-based split-pool combinatorial screening of potential catalysts.

    PubMed

    Stanton, Matthew L; Holcombe, James A

    2007-01-01

    A new method for screening split-pool combinatorial libraries for catalytic activity is described. Site-selective detection of catalytic activity for solution-based reactions was made possible without cofunctionalizing beads or adding diffusion-limiting matrixes. This was done by spatially separating resin-bound catalysts on an adhesive array on a microscope slide and introducing the reacting liquid to the top of the slide. Convective mixing and evaporation was controlled using a cover slide and imaging both the formation of products within active beads and the diffusion of products out of the beads. Colored reaction products and pH-sensitive indicators were used to visually detect catalytically active beads in the presence of inactive ones. Quantitative analyses of the images support the assumption that color intensities can be used to assess the quality of hits from a combinatorial screen. The Knoevenagel condensation reaction catalysis as well as esterase screening using methyl red were used to validate the approach. Using the esterase data, it was shown that some information on activity could also be extracted from the colored plume surrounding individual beads although the precision is not as good as that from direct measurement of absorbance through the bead. It was also found that the distribution of products within a single bead can also be gleaned from the absorbance data for different-sized beads. PMID:17286445

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

    SciTech Connect

    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.

  20. Combinatorial preparation and characterization of thin-film multilayer electro-optical devices.

    PubMed

    Neuber, Christian; Bäte, Markus; Thelakkat, Mukundan; Schmidt, Hans-Werner; Hänsel, Helmut; Zettl, Heiko; Krausch, Georg

    2007-07-01

    In this article we present a setup for the combinatorial vapor deposition of thin-film multilayer devices as well as methods for the fast and efficient analytic screening of the libraries obtained. The preparation setup is based on a commercially available evaporation chamber equipped with various evaporation sources for both organic and metallic materials. The combinatorial approach is realized by the combination of a rotation stage for the substrate, a five-mask sampler, and an additional mask whose position can be deliberately varied along one axis during the evaporation process. The latter is used to evaporate linear as well as step gradients by continuous or stepwise movement of a shutter mask. The mask sampler allows to define the sectors of the library and to evaporate more complex structures, e.g., an electrode layout. Finally, the simultaneous evaporation of two or more materials enables us to produce layers of varying composition ratio in general and doped materials, in particular. For the control of the evaporation process we have developed an automation software, which is particularly helpful for complex library designs and which grants excellent repeatability of experiments. Efficient and fast characterization of the obtained libraries is realized by (i) a purely optical setup and (ii) an electro-optical setup. (i) The UV/vis reader FLASHScan 530 permits to map out the UV/vis absorbance or fluorescence of the whole library. The UV/vis absorbance is primarily used to determine layer thicknesses and to confirm thickness uniformity across larger regions. The fluorescence measurements are used to determine the composition of layers containing fluorescent dyes. (ii) For a detailed short- and long-term electro-optical analysis we have developed an automated measurement system, which allows the characterization of 8x8 optoelectronic devices and to study their degradation behavior. Both solar cells and organic light-emitting diodes can be tested. Finally, we

  1. Combinatorial matrix-assisted pulsed laser evaporation: Single-step synthesis of biopolymer compositional gradient thin film assemblies

    NASA Astrophysics Data System (ADS)

    Sima, F.; Axente, E.; Sima, L. E.; Tuyel, U.; Eroglu, M. S.; Serban, N.; Ristoscu, C.; Petrescu, S. M.; Toksoy Oner, E.; Mihailescu, I. N.

    2012-12-01

    We introduce a combinatorial approach for the fabrication of organic biopolymer thin films. Structures with compositional gradient are obtained by simultaneous laser vaporization of two distinct targets. Matrix-assisted pulsed laser evaporation deposition method was applied to obtain a compositional library of levan and oxidized levan in form of thin film. The gradient of film composition and structure was demonstrated by infrared spectroscopy while in vitro cell culture assays illustrated characteristic responses of cells to specific surface regions. The method can rapidly generate discrete areas of organic film compositions with improved properties than starting materials.

  2. Standards for British Libraries.

    ERIC Educational Resources Information Center

    Vaughan, Anthony

    1982-01-01

    Reviews developments in British library standards since 1971, highlighting types of standards, public libraries, academic libraries (university, polytechnic, college), school libraries, and special libraries (hospital and health sciences, prison, subject specializations). Thirty-nine references are cited. (EJS)

  3. DOLIB: Distributed Object Library

    SciTech Connect

    D`Azevedo, E.F.; Romine, C.H.

    1994-10-01

    This report describes the use and implementation of DOLIB (Distributed Object Library), a library of routines that emulates global or virtual shared memory on Intel multiprocessor systems. Access to a distributed global array is through explicit calls to gather and scatter. Advantages of using DOLIB include: dynamic allocation and freeing of huge (gigabyte) distributed arrays, both C and FORTRAN callable interfaces, and the ability to mix shared-memory and message-passing programming models for ease of use and optimal performance. DOLIB is independent of language and compiler extensions and requires no special operating system support. DOLIB also supports automatic caching of read-only data for high performance. The virtual shared memory support provided in DOLIB is well suited for implementing Lagrangian particle tracking techniques. We have also used DOLIB to create DONIO (Distributed Object Network I/O Library), which obtains over a 10-fold improvement in disk I/O performance on the Intel Paragon.

  4. Combinatorial effects of odorants on mouse behavior.

    PubMed

    Saraiva, Luis R; Kondoh, Kunio; Ye, Xiaolan; Yoon, Kyoung-Hye; Hernandez, Marcus; Buck, Linda B

    2016-06-01

    The mechanisms by which odors induce instinctive behaviors are largely unknown. Odor detection in the mouse nose is mediated by >1, 000 different odorant receptors (ORs) and trace amine-associated receptors (TAARs). Odor perceptions are encoded combinatorially by ORs and can be altered by slight changes in the combination of activated receptors. However, the stereotyped nature of instinctive odor responses suggests the involvement of specific receptors and genetically programmed neural circuits relatively immune to extraneous odor stimuli and receptor inputs. Here, we report that, contrary to expectation, innate odor-induced behaviors can be context-dependent. First, different ligands for a given TAAR can vary in behavioral effect. Second, when combined, some attractive and aversive odorants neutralize one another's behavioral effects. Both a TAAR ligand and a common odorant block aversion to a predator odor, indicating that this ability is not unique to TAARs and can extend to an aversive response of potential importance to survival. In vitro testing of single receptors with binary odorant mixtures indicates that behavioral blocking can occur without receptor antagonism in the nose. Moreover, genetic ablation of a single receptor prevents its cognate ligand from blocking predator odor aversion, indicating that the blocking requires sensory input from the receptor. Together, these findings indicate that innate odor-induced behaviors can depend on context, that signals from a single receptor can block innate odor aversion, and that instinctive behavioral responses to odors can be modulated by interactions in the brain among signals derived from different receptors. PMID:27208093

  5. Combinatorial effects of odorants on mouse behavior

    PubMed Central

    Saraiva, Luis R.; Kondoh, Kunio; Ye, Xiaolan; Yoon, Kyoung-hye; Hernandez, Marcus; Buck, Linda B.

    2016-01-01

    The mechanisms by which odors induce instinctive behaviors are largely unknown. Odor detection in the mouse nose is mediated by >1, 000 different odorant receptors (ORs) and trace amine-associated receptors (TAARs). Odor perceptions are encoded combinatorially by ORs and can be altered by slight changes in the combination of activated receptors. However, the stereotyped nature of instinctive odor responses suggests the involvement of specific receptors and genetically programmed neural circuits relatively immune to extraneous odor stimuli and receptor inputs. Here, we report that, contrary to expectation, innate odor-induced behaviors can be context-dependent. First, different ligands for a given TAAR can vary in behavioral effect. Second, when combined, some attractive and aversive odorants neutralize one another’s behavioral effects. Both a TAAR ligand and a common odorant block aversion to a predator odor, indicating that this ability is not unique to TAARs and can extend to an aversive response of potential importance to survival. In vitro testing of single receptors with binary odorant mixtures indicates that behavioral blocking can occur without receptor antagonism in the nose. Moreover, genetic ablation of a single receptor prevents its cognate ligand from blocking predator odor aversion, indicating that the blocking requires sensory input from the receptor. Together, these findings indicate that innate odor-induced behaviors can depend on context, that signals from a single receptor can block innate odor aversion, and that instinctive behavioral responses to odors can be modulated by interactions in the brain among signals derived from different receptors. PMID:27208093

  6. Combinatorial approaches for inverse metabolic engineering applications

    PubMed Central

    Skretas, Georgios; Kolisis, Fragiskos N.

    2013-01-01

    Traditional metabolic engineering analyzes biosynthetic and physiological pathways, identifies bottlenecks, and makes targeted genetic modifications with the ultimate goal of increasing the production of high-value products in living cells. Such efforts have led to the development of a variety of organisms with industrially relevant properties. However, there are a number of cellular phenotypes important for research and the industry for which the rational selection of cellular targets for modification is not easy or possible. In these cases, strain engineering can be alternatively carried out using “inverse metabolic engineering”, an approach that first generates genetic diversity by subjecting a population of cells to a particular mutagenic process, and then utilizes genetic screens or selections to identify the clones exhibiting the desired phenotype. Given the availability of an appropriate screen for a particular property, the success of inverse metabolic engineering efforts usually depends on the level and quality of genetic diversity which can be generated. Here, we review classic and recently developed combinatorial approaches for creating such genetic diversity and discuss the use of these methodologies in inverse metabolic engineering applications. PMID:24688681

  7. Fast combinatorial RNS processors for DSP applications

    SciTech Connect

    Di Claudio, E.D.; Piazza, F.; Orlandi, G.

    1995-05-01

    It is known that RNS VLSI processors can parallelize fixed-point addition and multiplication operations by the use of the Chinese Remainder Theorem (CRT). The required modular operations, however, must use specialized hardware whose design and implementation can create several problems. In this paper a modified residue arithmetic, called pseudo-RNS is introduced in order to alleviate some of the RNS problems when Digital Signal Processing (DSP) structures are implemented. Pseudo-RNS requires only the use of modified binary processors and exhibits a speed performance comparable with other RNS traditional approaches. Some applications of the pseudo-RNS to common DSP architectures, such as multipliers and filters, are also presented in this paper. They are compared in terms of the Area-Time Square product versus other RNS and weighted binary structures. It is proven that existing combinatorial or look-up table approaches for RNS are tailored to small designs or special applications, while the pseudo-RNS approach remains competitive also for complex systems. 32 refs.

  8. Scalable Combinatorial Tools for Health Disparities Research

    PubMed Central

    Langston, Michael A.; Levine, Robert S.; Kilbourne, Barbara J.; Rogers, Gary L.; Kershenbaum, Anne D.; Baktash, Suzanne H.; Coughlin, Steven S.; Saxton, Arnold M.; Agboto, Vincent K.; Hood, Darryl B.; Litchveld, Maureen Y.; Oyana, Tonny J.; Matthews-Juarez, Patricia; Juarez, Paul D.

    2014-01-01

    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. PMID:25310540

  9. Combinatorial molecular optimization of cement hydrates

    PubMed Central

    Abdolhosseini Qomi, M.J.; Krakowiak, K.J.; Bauchy, M.; Stewart, K.L.; Shahsavari, R.; Jagannathan, D.; Brommer, D.B.; Baronnet, A.; Buehler, M.J.; Yip, S.; Ulm, F.-J; Van Vliet, K.J.; Pellenq, R.J-.M.

    2014-01-01

    Despite its ubiquitous presence in the built environment, concrete’s molecular-level properties are only recently being explored using experimental and simulation studies. Increasing societal concerns about concrete’s environmental footprint have provided strong motivation to develop new concrete with greater specific stiffness or strength (for structures with less material). Herein, a combinatorial approach is described to optimize properties of cement hydrates. The method entails screening a computationally generated database of atomic structures of calcium-silicate-hydrate, the binding phase of concrete, against a set of three defect attributes: calcium-to-silicon ratio as compositional index and two correlation distances describing medium-range silicon-oxygen and calcium-oxygen environments. Although structural and mechanical properties correlate well with calcium-to-silicon ratio, the cross-correlation between all three defect attributes reveals an indentation modulus-to-hardness ratio extremum, analogous to identifying optimum network connectivity in glass rheology. We also comment on implications of the present findings for a novel route to optimize the nanoscale mechanical properties of cement hydrate. PMID:25248305

  10. Linear combinatorial approach to thin film research

    SciTech Connect

    Matias, Vladimir; Gibbons, Brady J.

    2007-07-15

    We describe high-throughput experimentation of film synthesis by use of a linear tape transport system (similar to a web-coating system). Metal tape is fed continuously in a reel-to-reel transport system inside the vacuum deposition chamber. Ion-beam assisted deposition (IBAD) texturing is used to enable the growth of epitaxial films on flexible, polycrystalline metal tapes which further enhances the capability of this research. The tape that is continuously fed can be used as a sample itself, via the use of IBAD-textured templates on the tape, or can be a carrier of other smaller substrates (even nonflexible ones). Characterization of samples is done by means of in situ monitoring as well as ex situ sequential analysis. We utilize in situ reflection high-energy electron diffraction for high-throughput analysis of samples. Epitaxial films are deposited on heated samples by evaporation and by pulsed laser deposition. Here, we explain the techniques and the methodologies developed for this type of combinatorial experimentation and show some examples of the material research completed.

  11. A rare-earth phosphor containing one-dimensional chains identified through combinatorial methods

    PubMed

    Danielson; Devenney; Giaquinta; Golden; Haushalter; McFarland; Poojary; Reaves; Weinberg; Wu

    1998-02-01

    An unusual luminescent inorganic oxide, Sr2CeO4, was identified by parallel screening techniques from within a combinatorial library of more than 25,000 members prepared by automated thin-film synthesis. A bulk sample of single-phase Sr2CeO4 was prepared, and its structure, determined from powder x-ray diffraction data, reveals one-dimensional chains of edge-sharing CeO6 octahedra, with two terminal oxygen atoms per cerium center, that are isolated from one another by Sr2+ cations. The emission maximum at 485 nanometers appears blue-white and has a quantum yield of 0.48 +/- 0.02. The excited-state lifetime, electron spin resonance, magnetic susceptibility, and structural data all suggest that luminescence originates from a ligand-to-metal Ce4+ charge transfer. PMID:9452377

  12. Combinatorial investigation of transition metals deposited on anatase TiO 2 surface

    NASA Astrophysics Data System (ADS)

    Ohsawa, T.; Matsumoto, Y.; Koinuma, H.

    2004-02-01

    By using a combinatorial laser molecular beam epitaxy (MBE)/ in situ low energy electron diffraction (LEED) and scanning tunneling microscope (STM) system, we have investigated a behavior of transition metals (TMs) deposited on the anatase TiO 2 (0 0 1)-(4 × 1) surface systematically. TiO 2 (0 0 1) thin films were fabricated on 0.05 mol% Nb doped SrTiO 3 (0 0 1) substrates and on each of those films TMs were deposited with gradual variation of its deposition amount. In situ analysis of the libraries with LEED and STM revealed the surface morphologies that were sensitive to TM element and on the process temperature. The results are discussed in terms of the oxide formation enthalpy Δ H kJ mol -1 of TMs.

  13. Expression profiling. Combinatorial labeling of single cells for gene expression cytometry.

    PubMed

    Fan, H Christina; Fu, Glenn K; Fodor, Stephen P A

    2015-02-01

    We present a technically simple approach for gene expression cytometry combining next-generation sequencing with stochastic barcoding of single cells. A combinatorial library of beads bearing cell- and molecular-barcoding capture probes is used to uniquely label transcripts and reconstruct the digital gene expression profile of thousands of individual cells in a single experiment without the need for robotics or automation. We applied the technology to dissect the human hematopoietic system and to characterize heterogeneous response to in vitro stimulation. High sensitivity is demonstrated by detection of low-abundance transcripts and rare cells. Under current implementation, the technique can analyze a few thousand cells simultaneously and can readily scale to 10,000s or 100,000s of cells. PMID:25657253

  14. Screening of Novel Li-Air Battery Catalyst Materials by a Thin Film Combinatorial Materials Approach.

    PubMed

    Hauck, John G; McGinn, Paul J

    2015-06-01

    A combinatorial synthesis and high-throughput screening process was developed for the investigation of potential oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) catalysts for use as Li-air battery cathode materials. Libraries of discrete ternary metal alloy compositions were deposited via thin-film sputtering. The samples were electrochemically tested in parallel using cyclic voltammetry in O2-saturated KOH electrolyte. Compositions were ranked by ORR and OER onset potentials with respect to an internal Pt reference. Results from the Pt-Mn-Co, Cr-Mn-Co, Pd-Mn-Co, and Pd-Mn-Ru systems are reported. Many alloy compositions showed marked improvement in catalytic activity compared to pure Pt. Among the systems considered, Pt12Mn44Co44, Pd43Co57 and Pd36Mn28Ru36 in particular exhibited lower overpotentials for oxygen reactions, which occur at the cathode in Li-air batteries. PMID:25965839

  15. Utilizing pulsed laser deposition lateral inhomogeneity as a tool in combinatorial material science.

    PubMed

    Keller, David A; Ginsburg, Adam; Barad, Hannah-Noa; Shimanovich, Klimentiy; Bouhadana, Yaniv; Rosh-Hodesh, Eli; Takeuchi, Ichiro; Aviv, Hagit; Tischler, Yaakov R; Anderson, Assaf Y; Zaban, Arie

    2015-04-13

    Pulsed laser deposition (PLD) is widely used in combinatorial material science, as it enables rapid fabrication of different composite materials. Nevertheless, this method was usually limited to small substrates, since PLD deposition on large substrate areas results in severe lateral inhomogeneity. A few technical solutions for this problem have been suggested, including the use of different designs of masks, which were meant to prevent inhomogeneity in the thickness, density, and oxidation state of a layer, while only the composition is allowed to be changed. In this study, a possible way to take advantage of the large scale deposition inhomogeneity is demonstrated, choosing an iron oxide PLD-deposited library with continuous compositional spread (CCS) as a model system. An Fe₂O₃-Nb₂O₅ library was fabricated using PLD, without any mask between the targets and the substrate. The library was measured using high-throughput scanners for electrical, structural, and optical properties. A decrease in electrical resistivity that is several orders of magnitude lower than pure α-Fe₂O₃ was achieved at ∼20% Nb-O (measured at 47 and 267 °C) but only at points that are distanced from the center of the PLD plasma plume. Using hierarchical clustering analysis, we show that the PLD inhomogeneity can be used as an additional degree of freedom, helping, in this case, to achieve iron oxide with much lower resistivity. PMID:25798538

  16. A combinatorial approach to determine functional group effects on lipidoid-mediated siRNA delivery

    PubMed Central

    Mahon, Kerry P.; Love, Kevin T.; Whitehead, Kathryn A.; Qin, June; Akinc, Akin; Leshchiner, Elizaveta; Leshchiner, Ignaty; Langer, Robert

    2010-01-01

    The application of RNA interference (RNAi), either in the clinic or laboratory, requires safe and effective delivery methods. Here we develop a combinatorial approach to synthesize a library of delivery vectors based on two lipid-like substrates with known siRNA delivery capabilities. Members of this library have a mixture of lipid-like tails and feature appendages containing hydroxyl, carbamate, ether or amine functional groups as well as variations in alkyl chain length and branching. Using a luciferase reporter system in HeLa cells, we study the relationship between lipid chemical modification and delivery performance in vitro. The impact of the functional group was shown to vary depending on the overall amine content and tail number of the delivery vector. Additionally, in vivo performance was evaluated using a Factor VII knockdown assay. Two library members, each containing ether groups, were found to knock down the target protein at levels comparable to the parent delivery vector. These results demonstrate that small chemical changes to the delivery vector impact knockdown efficiency and cell viability both in vitro and in vivo. The work described here identifies new materials for siRNA delivery, as well as provides new insight into the parameters for optimized chemical makeup of lipid-like siRNA delivery materials. PMID:20715849

  17. Combinatorial optimization of CO2 transport and fixation to improve succinate production by promoter engineering.

    PubMed

    Yu, Jun-Han; Zhu, Li-Wen; Xia, Shi-Tao; Li, Hong-Mei; Tang, Ya-Ling; Liang, Xin-Hua; Chen, Tao; Tang, Ya-Jie

    2016-07-01

    To balance the flux of an engineered metabolic pathway to achieve high yield of target product is a major challenge in metabolic engineering. In previous work, the collaborative regulation of CO2 transport and fixation was investigated with co-overexpressing exogenous genes regulating both CO2 transport (sbtA and bicA) and PEP carboxylation (phosphoenolpyruvate (PEP) carboxylase (ppc) and carboxykinase (pck)) under trc promoter in Escherichia coli for succinate biosynthesis. For balancing metabolic flux to maximize succinate titer, a combinatorial optimization strategy to fine-tuning CO2 transport and fixation process was implemented by promoter engineering in this study. Firstly, based on the energy matrix a synthetic promoter library containing 20 rationally designed promoters with strengths ranging from 0.8% to 100% compared with the widely used trc promoter was generated. Evaluations of rfp and cat reporter genes provided evidence that the synthetic promoters were stably and had certain applicability. Secondly, four designed promoters with different strengths were used for combinatorial assembly of single CO2 transport gene (sbtA or bicA) and single CO2 fixation gene (ppc or pck) expression. Three combinations, such as Tang1519 (P4 -bicA + pP19 -pck), Tang1522 (P4 -sbtA + P4 -ppc), Tang1523 (P4 -sbtA + P17 -ppc) with a more than 10% increase in succinate production were screened in bioreactor. Finally, based on the above results, co-expression of the four transport and fixation genes were further investigated. Co-expression of sbtA, bicA, and ppc with weak promoter P4 and pck with strong promoter P19 (AFP111/pT-P4 -bicA-P4 -sbtA + pACYC-P19 -pck-P4 -ppc) provided the best succinate production among all the combinations. The highest succinate production of 89.4 g/L was 37.5% higher than that obtained with empty vector control. This work significantly enhanced succinate production through combinatorial optimization of CO2 transport and fixation

  18. MDC-Analyzer-facilitated combinatorial strategy for improving the activity and stability of halohydrin dehalogenase from Agrobacterium radiobacter AD1.

    PubMed

    Wang, Xiong; Lin, Hao; Zheng, Yu; Feng, Juan; Yang, Zujun; Tang, Lixia

    2015-07-20

    Halohydrin dehalogenase from Agrobacterium radiobacter AD1 (HheC) displays a broad substrate range with high regio- and enantioselectivity of both ring-closure and ring-opening reactions, making the enzyme a useful catalyst for the production of optically pure epoxides and β-substituted alcohols. In this study, we report a novel method using an MDC-Analyzer-facilitated combinatorial strategy to improve the activity and stability of HheC by simultaneously randomizing multiple contiguous residues. Six contiguous active-site residues, which are the hotspots for improving the activity of HheC, were simultaneously selected and randomized using the MDC-Analyzer-facilitated combinatorial strategy, resulting in a high-quality mutagenesis library. After screening a total of 1152 clones, three positive mutants were obtained, which exhibited approximately 3.5-5.9-fold higher kcat values than the wild-type HheC toward 1,3-dichloro-2-propanol (1,3-DCP). However, the inactivation half-life of the best mutant (DG9) at 55 °C decreased 9-fold compared with that of the wild-type HheC. To improve the stability of mutant DG9, seven contiguous potential surface amino acids were revealed by using the B-FITTER tool. Two charged amino acids, Glu and Lys, which are more abundant in thermophilic proteins than in their mesophilic counterparts, were selected to substitute those seven amino acids and were combined together via an MDC-Analyzer-facilitated combinatorial strategy. Two mutants displaying 1.6- and 2.3-fold higher half-life τ1/2 (55 °C) values than their DG9 template were obtained after screening only 384 clones. The results indicated that an MDC-Analyzer-facilitated combinatorial strategy represents an efficient tool for the directed evolution of functional enzymes with multiple contiguous targeting sites. PMID:25896949

  19. Persistent heap Management library

    Energy Science and Technology Software Center (ESTSC)

    2012-01-17

    PERM is a C library for persistent heap management and is intended for use with a dynamic-memory allocator (e.g. malloc, free). The PERM memory allocator replaces the standard C dynamic memory allocation functions with compatible versions that provide persistent memory to application programs. Memory allocated with the PERM allocatory will persist between program invocations after a call to a checkpoint function. This function essentially saves the state of the heap and registered global variables tomore » a file which may reside in flash memory or other node local storage. A few other functions are also provided by the library to manage checkpoint files. Global variables in an application can be marked persistent and be included in a checkpoint by using a compiler attribute defined as PERM. The PERM checkpoint methof is not dependent on the programming model ans works with distributed memory or shared memory programs.« less

  20. Persistent heap Management library

    SciTech Connect

    2012-01-17

    PERM is a C library for persistent heap management and is intended for use with a dynamic-memory allocator (e.g. malloc, free). The PERM memory allocator replaces the standard C dynamic memory allocation functions with compatible versions that provide persistent memory to application programs. Memory allocated with the PERM allocatory will persist between program invocations after a call to a checkpoint function. This function essentially saves the state of the heap and registered global variables to a file which may reside in flash memory or other node local storage. A few other functions are also provided by the library to manage checkpoint files. Global variables in an application can be marked persistent and be included in a checkpoint by using a compiler attribute defined as PERM. The PERM checkpoint methof is not dependent on the programming model ans works with distributed memory or shared memory programs.

  1. America's Star Libraries

    ERIC Educational Resources Information Center

    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…

  2. Mapping the Materials Genome through Combinatorial Informatics

    NASA Astrophysics Data System (ADS)

    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''.

  3. Changing Libraries: Facilitating Self-Reflection and Action Research on Organizational Change in Academic Libraries

    ERIC Educational Resources Information Center

    Whitworth, Andrew; Torras I Calvo, Maria Carme; Moss, Bodil; Amlesom Kifle, Nazareth; Blåsternes, Terje

    2014-01-01

    Visualization and mapping techniques can build a dynamic picture of information practices, including action research, within libraries, raising awareness of how the information landscape at each library may both support and retard research into the library's information practices. These techniques have implications for researchers as they generate…

  4. Combinatorial Optimization by Amoeba-Based Neurocomputer with Chaotic Dynamics

    NASA Astrophysics Data System (ADS)

    Aono, Masashi; Hirata, Yoshito; Hara, Masahiko; Aihara, Kazuyuki

    We demonstrate a computing system based on an amoeba of a true slime mold Physarum capable of producing rich spatiotemporal oscillatory behavior. Our system operates as a neurocomputer because an optical feedback control in accordance with a recurrent neural network algorithm leads the amoeba's photosensitive branches to search for a stable configuration concurrently. We show our system's capability of solving the traveling salesman problem. Furthermore, we apply various types of nonlinear time series analysis to the amoeba's oscillatory behavior in the problem-solving process. The results suggest that an individual amoeba might be characterized as a set of coupled chaotic oscillators.

  5. Combinatorial effects on clumped isotopes and their significance in biogeochemistry

    NASA Astrophysics Data System (ADS)

    Yeung, Laurence Y.

    2016-01-01

    The arrangement of isotopes within a collection of molecules records their physical and chemical histories. Clumped-isotope analysis interrogates these arrangements, i.e., how often rare isotopes are bound together, which in many cases can be explained by equilibrium and/or kinetic isotope fractionation. However, purely combinatorial effects, rooted in the statistics of pairing atoms in a closed system, are also relevant, and not well understood. Here, I show that combinatorial isotope effects are most important when two identical atoms are neighbors on the same molecule (e.g., O2, N2, and D-D clumping in CH4). When the two halves of an atom pair are either assembled with different isotopic preferences or drawn from different reservoirs, combinatorial effects cause depletions in clumped-isotope abundance that are most likely between zero and -1‰, although they could potentially be -10‰ or larger for D-D pairs. These depletions are of similar magnitude, but of opposite sign, to low-temperature equilibrium clumped-isotope effects for many small molecules. Enzymatic isotope-pairing reactions, which can have site-specific isotopic fractionation factors and atom reservoirs, should express this class of combinatorial isotope effect, although it is not limited to biological reactions. Chemical-kinetic isotope effects, which are related to a bond-forming transition state, arise independently and express second-order combinatorial effects related to the abundance of the rare isotope. Heteronuclear moeties (e.g., Csbnd O and Csbnd H), are insensitive to direct combinatorial influences, but secondary combinatorial influences are evident. In general, both combinatorial and chemical-kinetic factors are important for calculating and interpreting clumped-isotope signatures of kinetically controlled reactions. I apply this analytical framework to isotope-pairing reactions relevant to geochemical oxygen, carbon, and nitrogen cycling that may be influenced by combinatorial

  6. IPRO: An Iterative Computational Protein Library Redesign and Optimization Procedure

    PubMed Central

    Saraf, Manish C.; Moore, Gregory L.; Goodey, Nina M.; Cao, Vania Y.; Benkovic, Stephen J.; Maranas, Costas D.

    2006-01-01

    A number of computational approaches have been developed to reengineer promising chimeric proteins one at a time through targeted point mutations. In this article, we introduce the computational procedure IPRO (iterative protein redesign and optimization procedure) for the redesign of an entire combinatorial protein library in one step using energy-based scoring functions. IPRO relies on identifying mutations in the parental sequences, which when propagated downstream in the combinatorial library, improve the average quality of the library (e.g., stability, binding affinity, specific activity, etc.). Residue and rotamer design choices are driven by a globally convergent mixed-integer linear programming formulation. Unlike many of the available computational approaches, the procedure allows for backbone movement as well as redocking of the associated ligands after a prespecified number of design iterations. IPRO can also be used, as a limiting case, for the redesign of a single or handful of individual sequences. The application of IPRO is highlighted through the redesign of a 16-member library of Escherichia coli/Bacillus subtilis dihydrofolate reductase hybrids, both individually and through upstream parental sequence redesign, for improving the average binding energy. Computational results demonstrate that it is indeed feasible to improve the overall library quality as exemplified by binding energy scores through targeted mutations in the parental sequences. PMID:16513775

  7. IPRO: an iterative computational protein library redesign and optimization procedure.

    PubMed

    Saraf, Manish C; Moore, Gregory L; Goodey, Nina M; Cao, Vania Y; Benkovic, Stephen J; Maranas, Costas D

    2006-06-01

    A number of computational approaches have been developed to reengineer promising chimeric proteins one at a time through targeted point mutations. In this article, we introduce the computational procedure IPRO (iterative protein redesign and optimization procedure) for the redesign of an entire combinatorial protein library in one step using energy-based scoring functions. IPRO relies on identifying mutations in the parental sequences, which when propagated downstream in the combinatorial library, improve the average quality of the library (e.g., stability, binding affinity, specific activity, etc.). Residue and rotamer design choices are driven by a globally convergent mixed-integer linear programming formulation. Unlike many of the available computational approaches, the procedure allows for backbone movement as well as redocking of the associated ligands after a prespecified number of design iterations. IPRO can also be used, as a limiting case, for the redesign of a single or handful of individual sequences. The application of IPRO is highlighted through the redesign of a 16-member library of Escherichia coli/Bacillus subtilis dihydrofolate reductase hybrids, both individually and through upstream parental sequence redesign, for improving the average binding energy. Computational results demonstrate that it is indeed feasible to improve the overall library quality as exemplified by binding energy scores through targeted mutations in the parental sequences. PMID:16513775

  8. Recent advances in combinatorial biosynthesis for drug discovery

    PubMed Central

    Sun, Huihua; Liu, Zihe; Zhao, Huimin; Ang, Ee Lui

    2015-01-01

    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 strategies will also be highlighted in this review. PMID:25709407

  9. Public Libraries

    ERIC Educational Resources Information Center

    Library Journal, 1972

    1972-01-01

    Building data is given for the following public libraries: New York, New York; Blue Island, Illinois; Corte Madera, California; Muskogee, Oklahoma: Charlotte, North Carolina; Washington, D.C.; Houston, Texas; Albermarle, North Carolina; Spokane, Washington; and Hemet, California. (Author/NH)

  10. Library Venturing.

    ERIC Educational Resources Information Center

    Wilson, H. Donald

    1986-01-01

    There is opportunity for service and profit to imaginative libraries organizing to provide new forms of knowledge. Librarians as entrepreneurs must learn venture management and finance. Available assistance includes growing entrepreneural understanding in large institutions; family and friends; private wealth-seeking investment; new business…

  11. Library Handbook.

    ERIC Educational Resources Information Center

    Cupp, Christian M., Ed.

    The purpose of this handbook is to help students, staff, and community patrons attain a reasonable degree of skill in using the Southeastern Community College Library effectively. The first section instructs the user on how to find information. A discussion of the card catalog and its use provides examples of catalog cards, reviews the…

  12. Library Environment.

    ERIC Educational Resources Information Center

    Computers in Libraries, 1993

    1993-01-01

    This special section includes two articles that review products and services for the automated library environment. Highlights include ergonomic products; products for visually, hearing-, and speech-impaired users; analog film recorders; computer filters; document imaging systems; electric filing systems; and printers. A list of vendors is…

  13. Variable epitope library carrying heavily mutated survivin-derived CTL epitope variants as a new class of efficient vaccine immunogen tested in a mouse model of breast cancer.

    PubMed

    NoeDominguez-Romero, Allan; Zamora-Alvarado, Rubén; Servín-Blanco, Rodolfo; Pérez-Hernández, Erendira G; Castrillon-Rivera, Laura E; Munguia, Maria Elena; Acero, Gonzalo; Govezensky, Tzipe; Gevorkian, Goar; Manoutcharian, Karen

    2014-01-01

    The antigenic variability of tumor cells leading to dynamic changes in cancer epitope landscape along with escape from immune surveillance by down-regulating tumor antigen expression/presentation and immune tolerance are major obstacles for the design of effective vaccines. We have developed a novel concept for immunogen construction based on introduction of massive mutations within the epitopes targeting antigenically variable pathogens and diseases. Previously, we showed that these immunogens carrying large combinatorial libraries of mutated epitope variants, termed as variable epitope libraries (VELs), induce potent, broad and long lasting CD8+IFN-γ+ T-cell response as well as HIV-neutralizing antibodies. In this proof-of-concept study, we tested immunogenic properties and anti-tumor effects of the VELs bearing survivin-derived CTL epitope (GWEPDDNPI) variants in an aggressive metastatic mouse 4T1 breast tumor model. The constructed VELs had complexities of 10,500 and 8,000 individual members, generated as combinatorial M13 phage display and synthetic peptide libraries, respectively, with structural composition GWXPXDXPI, where X is any of 20 natural amino acids. Statistically significant tumor growth inhibition was observed in BALB/c mice immunized with the VELs in both prophylactic and therapeutic settings. Vaccinated mice developed epitope-specific spleen cell and CD8+ IFN-γ+ T-cell responses that recognize more than 50% of the panel of 87 mutated epitope variants, as demonstrated in T-cell proliferation assays and FACS analysis. These data indicate the feasibility of the application of this new class of immunogens based on VEL concept as an alternative approach for the development of molecular vaccines against cancer. PMID:25483665

  14. Variable epitope library carrying heavily mutated survivin-derived CTL epitope variants as a new class of efficient vaccine immunogen tested in a mouse model of breast cancer

    PubMed Central

    NoeDominguez-Romero, Allan; Zamora-Alvarado, Rubén; Servín-Blanco, Rodolfo; Pérez-Hernández, Erendira G; Castrillon-Rivera, Laura E; Munguia, Maria Elena; Acero, Gonzalo; Govezensky, Tzipe; Gevorkian, Goar; Manoutcharian, Karen

    2014-01-01

    The antigenic variability of tumor cells leading to dynamic changes in cancer epitope landscape along with escape from immune surveillance by down-regulating tumor antigen expression/presentation and immune tolerance are major obstacles for the design of effective vaccines. We have developed a novel concept for immunogen construction based on introduction of massive mutations within the epitopes targeting antigenically variable pathogens and diseases. Previously, we showed that these immunogens carrying large combinatorial libraries of mutated epitope variants, termed as variable epitope libraries (VELs), induce potent, broad and long lasting CD8+IFN-γ+ T-cell response as well as HIV-neutralizing antibodies. In this proof-of-concept study, we tested immunogenic properties and anti-tumor effects of the VELs bearing survivin-derived CTL epitope (GWEPDDNPI) variants in an aggressive metastatic mouse 4T1 breast tumor model. The constructed VELs had complexities of 10,500 and 8,000 individual members, generated as combinatorial M13 phage display and synthetic peptide libraries, respectively, with structural composition GWXPXDXPI, where X is any of 20 natural amino acids. Statistically significant tumor growth inhibition was observed in BALB/c mice immunized with the VELs in both prophylactic and therapeutic settings. Vaccinated mice developed epitope-specific spleen cell and CD8+ IFN-γ+ T-cell responses that recognize more than 50% of the panel of 87 mutated epitope variants, as demonstrated in T-cell proliferation assays and FACS analysis. These data indicate the feasibility of the application of this new class of immunogens based on VEL concept as an alternative approach for the development of molecular vaccines against cancer. PMID:25483665

  15. Sponge derived bromotyrosines: structural diversity through natural combinatorial chemistry.

    PubMed

    Niemann, Hendrik; Marmann, Andreas; Lin, Wenhan; Proksch, Peter

    2015-01-01

    Sponge derived bromotyrosines are a multifaceted class of marine bioactive compounds that are important for the chemical defense of sponges but also for drug discovery programs as well as for technical applications in the field of antifouling constituents. These compounds, which are mainly accumulated by Verongid sponges, exhibit a diverse range of bioactivities including antibiotic, cytotoxic and antifouling effects. In spite of the simple biogenetic building blocks, which consist only of brominated tyrosine and tyramine units, an impressive diversity of different compounds is obtained through different linkages between these precursors and through structural modifications of the side chains and/or aromatic rings resembling strategies that are known from combinatorial chemistry. As examples for bioactive, structurally divergent bromotyrosines psammaplin A, Aplysina alkaloids featuring aerothionin, aeroplysinin-1 and the dienone, and the bastadins, including the synthetically derived hemibastadin congeners, have been selected for this review. Whereas all of these natural products are believed to be involved in the chemical defense of sponges, some of them may also be of particular relevance to drug discovery due to their interaction with specific molecular targets in eukaryotic cells. These targets involve important enzymes and receptors, such as histone deacetylases (HDAC) and DNA methyltransferases (DNMT), which are inhibited by psammaplin A, as well as ryanodine receptors that are targeted by bastadine type compounds. The hemibastadins such as the synthetically derived dibromohemibastadin are of particular interest due to their antifouling activity. For the latter, a phenoloxidase which catalyzes the bioglue formation needed for firm attachment of fouling organisms to a given substrate was identified as a molecular target. The Aplysina alkaloids finally provide a vivid example for dynamic wound induced bioconversions of natural products that generate highly

  16. Cellular phosphatases facilitate combinatorial processing of receptor-activated signals

    PubMed Central

    Kumar, Dhiraj; Dua, Raina; Srikanth, Ravichandran; Jayaswal, Shilpi; Siddiqui, Zaved; Rao, Kanury VS

    2008-01-01

    Background Although reciprocal regulation of protein phosphorylation represents a key aspect of signal transduction, a larger perspective on how these various interactions integrate to contribute towards signal processing is presently unclear. For example, a key unanswered question is that of how phosphatase-mediated regulation of phosphorylation at the individual nodes of the signaling network translates into modulation of the net signal output and, thereby, the cellular phenotypic response. Results To address the above question we, in the present study, examined the dynamics of signaling from the B cell antigen receptor (BCR) under conditions where individual cellular phosphatases were selectively depleted by siRNA. Results from such experiments revealed a highly enmeshed structure for the signaling network where each signaling node was linked to multiple phosphatases on the one hand, and each phosphatase to several nodes on the other. This resulted in a configuration where individual signaling intermediates could be influenced by a spectrum of regulatory phosphatases, but with the composition of the spectrum differing from one intermediate to another. Consequently, each node differentially experienced perturbations in phosphatase activity, yielding a unique fingerprint of nodal signals characteristic to that perturbation. This heterogeneity in nodal experiences, to a given perturbation, led to combinatorial manipulation of the corresponding signaling axes for the downstream transcription factors. Conclusion Our cumulative results reveal that it is the tight integration of phosphatases into the signaling network that provides the plasticity by which perturbation-specific information can be transmitted in the form of a multivariate output to the downstream transcription factor network. This output in turn specifies a context-defined response, when translated into the resulting gene expression profile. PMID:18798986

  17. Automated mass spectrometric sequence determination of cyclic peptide library members.

    PubMed

    Redman, James E; Wilcoxen, Keith M; Ghadiri, M Reza

    2003-01-01

    Cyclic peptides have come under scrutiny as potential antimicrobial therapeutic agents. Combinatorial split-and-pool synthesis of cyclic peptides can afford single compound per well libraries for antimicrobial screening, new lead identification, and construction of quantitative structure-activity relationships (QSAR). Here, we report a new sequencing protocol for rapid identification of the members of a cyclic peptide library based on automated computer analysis of mass spectra, obviating the need for library encoding/decoding strategies. Furthermore, the software readily integrates with common spreadsheet and database packages to facilitate data visualization and archiving. The utility of the new MS-sequencing approach is demonstrated using sonic spray ionization ion trap MS and MS/MS spectrometry on a single compound per bead cyclic peptide library and validated with individually synthesized pure cyclic D,L-alpha-peptides. PMID:12523832

  18. A methodology for linking 2D overland flow models with the sewer network model SWMM 5.1 based on dynamic link libraries.

    PubMed

    Leandro, Jorge; Martins, Ricardo

    2016-01-01

    Pluvial flooding in urban areas is characterized by a gradually varying inundation process caused by surcharge of the sewer manholes. Therefore urban flood models need to simulate the interaction between the sewer network and the overland flow in order to accurately predict the flood inundation extents. In this work we present a methodology for linking 2D overland flow models with the storm sewer model SWMM 5. SWMM 5 is a well-known free open-source code originally developed in 1971. The latest major release saw its structure re-written in C ++ allowing it to be compiled as a command line executable or through a series of calls made to function inside a dynamic link library (DLL). The methodology developed herein is written inside the same DLL in C + +, and is able to simulate the bi-directional interaction between both models during simulation. Validation is done in a real case study with an existing urban flood coupled model. The novelty herein is that the new methodology can be added to SWMM without the need for editing SWMM's original code. Furthermore, it is directly applicable to other coupled overland flow models aiming to use SWMM 5 as the sewer network model. PMID:27332848

  19. View Discovery in OLAP Databases through Statistical Combinatorial Optimization

    SciTech Connect

    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.

  20. Pb-free electronics: from nanotechnology to combinatorial materials science

    NASA Astrophysics Data System (ADS)

    Diaz Gonzalez, Alfredo J.

    , alloys that are prone to tin whiskers growth. These libraries are samples containing a range of sub-samples with varying compositions within it than can be processed simultaneously. Using sputtering, a physical vapor deposition technique, a gradient composed of Ag-Cu was deposited over a Sn-plated Cu substrate. After reflow, the growth mechanism of the whiskers was accelerated using the IEC60068-82-2 standard. SEM and EDS analysis was used to charac-terize the growth of the tin whiskers at different elemental compositions. The gradients found across the samples are in accordance with the theoretical geometrical spacing. Tin whiskers were found on control samples, whereas almost all elemental compositions showed mitigation or elimination of the whiskers. This combinatorial material science methodology proved to be an efficient and fast screening method for the plating materials selection process in Pb-free electronics.

  1. High-throughput screening of solid-state catalyst libraries

    NASA Astrophysics Data System (ADS)

    Senkan, Selim M.

    1998-07-01

    Combinatorial synthesis methods allow the rapid preparation and processing of large libraries of solid-state materials. The use of these methods, together with the appropriate screening techniques, has recently led to the discovery of materials with promising superconducting, magnetoresistive, luminescent and dielectric properties. Solid-state catalysts, which play an increasingly important role in the chemical and oil industries, represent another class of material amenable to combinatorial synthesis. Yet typically, catalyst discovery still involves inefficient trial-and-error processes, because catalytic activity is inherently difficult to screen. In contrast to superconductivity, magnetoresistivity and dielectric properties, which can be tested by contact probes, or luminescence, which can be observed directly, the assessment of catalytic activity requires the unambiguous detection of a specific product molecule above a small catalyst site on a large library. Screening by in situ infrared thermography and microprobe sampling mass spectrometry, have been suggested, but the first method, while probing activity, provides no information on reaction products, whereas the second is difficult to implement because it requires the transport of minute gas samples from each library site to the detection system. Here I describe the use of laser-induced resonance-enhanced multiphoton ionization for sensitive, selective and high-throughput screening of a library of solid-state catalysts that activate the dehydrogenation of cyclohexane to benzene. I show that benzene, the product molecule, can be selectively photoionized in the vicinity of the catalytic sites, and that the detection of the resultant photoions by an array of microelectrodes provides information on the activity of individual sites. Adaptation of this technique for the screening of other catalytic reactions and larger libraries with smaller site size seems feasible, thus opening up the possibility of exploiting

  2. Library Automation and Library Education.

    ERIC Educational Resources Information Center

    Drabenstott, Jon, Ed.

    1987-01-01

    Several consultants address the issue of competencies required of professional librarians for the effective management of the automation process. Highlights include formal and professional ongoing education and the need for technical training and problem solving skills to enable librarians to evaluate and develop library systems effectively.…

  3. Mitigation of Control Channel Jamming via Combinatorial Key Distribution

    NASA Astrophysics Data System (ADS)

    Falahati, Abolfazl; Azarafrooz, Mahdi

    The problem of countering control channel jamming against internal adversaries in wireless ad hoc networks is addressed. Using combinatorial key distribution, a new method to secure the control channel access is introduced. This method, utilizes the established keys in the key establishment phase to hide the location of control channels without the need for a secure BS. This is in obtained by combination of a collision free one-way function and a combinatorial key establishment method. The proposed scheme can be considered as a special case of the ALOHA random access schemes which uses the common established keys as its seeds to generate the pattern of transmission.

  4. Some functional metrics in algebraic and combinatorial coding

    NASA Astrophysics Data System (ADS)

    Choen, G.

    1980-06-01

    Three approaches to coding problems can be systematically distinguished: probabilistic (essentially existential), algebraic, and combinatorial. This last approach searches for optimal configurations and relegates to the second order, the problems of complexity related to decoding. Enumeration, graphs, designs, and the extreme theory of groups are used. The optimization of a functional metric was used with the combinatorial approach in order to define the space considered and the distance. The codes then become particular groups of the metric space, which is defined by parameters such as length, number of words, and capacity for correction. Some of these parameters are imposed.

  5. 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.

    PubMed

    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. PMID:22133077

  6. Fast Combinatorial Algorithm for the Solution of Linearly Constrained Least Squares Problems

    DOEpatents

    Van Benthem, Mark H.; Keenan, Michael R.

    2008-11-11

    A fast combinatorial algorithm can significantly reduce the computational burden when solving general equality and inequality constrained least squares problems with large numbers of observation vectors. The combinatorial algorithm provides a mathematically rigorous solution and operates at great speed by reorganizing the calculations to take advantage of the combinatorial nature of the problems to be solved. The combinatorial algorithm exploits the structure that exists in large-scale problems in order to minimize the number of arithmetic operations required to obtain a solution.

  7. Symposium on Presidential Libraries.

    ERIC Educational Resources Information Center

    Relyea, Harold C.; And Others

    1994-01-01

    Includes five articles that discuss presidential libraries. Highlights include an overview of the development of the federal presidential library system; the Ronald Reagan library; the Richard Nixon library archives; access at the Gerald Ford library; and computerizing the Jimmy Carter library. (LRW)

  8. Turkish Libraries: Historical Context.

    ERIC Educational Resources Information Center

    Cakin, Irfan

    1984-01-01

    Summary of the development of libraries in Turkey highlights the existence of libraries in the ninth century, the Shamssaddin Altunaba Medrese library in Konya, libraries established during the Ottoman era, reports to reform libraries (1869-70, 1909), and reports and library developments attributed to the Republican Era beginning in 1923. (EJS)

  9. Library Research and Statistics.

    ERIC Educational Resources Information Center

    Lynch, Mary Jo; St. Lifer, Evan; Halstead, Kent; Fox, Bette-Lee; Miller, Marilyn L.; Shontz, Marilyn L.

    2001-01-01

    These nine articles discuss research and statistics on libraries and librarianship, including libraries in the United States, Canada, and Mexico; acquisition expenditures in public, academic, special, and government libraries; price indexes; state rankings of public library data; library buildings; expenditures in school library media centers; and…

  10. Theory of site-specific interactions of the combinatorial transcription factors with DNA

    NASA Astrophysics Data System (ADS)

    Murugan, R.

    2010-05-01

    We derive a functional relationship between the mean first passage time associated with the concurrent binding of multiple transcription factors (TFs) at their respective combinatorial cis-regulatory module sites (CRMs) and the number n of TFs involved in the regulation of the initiation of transcription of a gene of interest. Our results suggest that the overall search time τs that is required by the n TFs to locate their CRMs which are all located on the same DNA chain scales with n as τs~nα where α ~ (2/5). When the jump size k that is associated with the dynamics of all the n TFs along DNA is higher than that of the critical jump size kc that scales with the size of DNA N as kc ~ N2/3, we observe a similar power law scaling relationship and also the exponent α. When k < kc, α shows a strong dependence on both n and k. Apparently there is a critical number of combinatorial TFs nc ~ 20 that is required to efficiently regulate the initiation of transcription of a given gene below which (2/5) < α < 1 and beyond which α > 1. These results seem to be independent of the initial distances between the TFs and their corresponding CRMs and also suggest that the maximum number of TFs involved in a given combinatorial regulation of the initiation of transcription of a gene of interest seems to be restricted by the degree of condensation of the genomic DNA. The optimum number mopt of roadblock protein molecules per genome at which the search time associated with these n TFs to locate their binding sites is a minimum seems to scale as mopt~Lnα/2 where L is the sliding length of TFs whose maximum value seems to be such that L <= 104 bps for the E. coli bacterial genome.

  11. Assessing the combinatorial potential of the RiPP cyanobactin tru pathway.

    PubMed

    Ruffner, Duane E; Schmidt, Eric W; Heemstra, John R

    2015-04-17

    Ribosomally produced natural products, the RiPPs, exhibit features that are potentially useful in the creation of large chemical libraries using simple mutagenesis. RiPPs are encoded on ribosomal precursor peptides, but they are extensively posttranslationally modified, endowing them with properties that are useful in drug discovery and biotechnology. In order to determine which mutations are acceptable, strategies are required to determine sequence selectivity independently of the context of flanking amino acids. Here, we examined the absolute sequence selectivity of the trunkamide cyanobactin pathway, tru. A series of random double and quadruple simultaneous mutants were synthesized and produced in Escherichia coli. Out of a total of 763 mutated amino acids examined in 325 unique sequences, 323 amino acids were successfully incorporated in 159 sequences, leading to >300 new compounds. Rules for tru sequence selectivity were determined, which will be useful for the design and synthesis of combinatorial biosynthetic libraries. The results are also interpreted in comparison to the known natural products of tru and pat cyanobactin pathways. PMID:25140729

  12. Assessing the Combinatorial Potential of the RiPP Cyanobactin tru Pathway

    PubMed Central

    2015-01-01

    Ribosomally produced natural products, the RiPPs, exhibit features that are potentially useful in the creation of large chemical libraries using simple mutagenesis. RiPPs are encoded on ribosomal precursor peptides, but they are extensively posttranslationally modified, endowing them with properties that are useful in drug discovery and biotechnology. In order to determine which mutations are acceptable, strategies are required to determine sequence selectivity independently of the context of flanking amino acids. Here, we examined the absolute sequence selectivity of the trunkamide cyanobactin pathway, tru. A series of random double and quadruple simultaneous mutants were synthesized and produced in Escherichia coli. Out of a total of 763 mutated amino acids examined in 325 unique sequences, 323 amino acids were successfully incorporated in 159 sequences, leading to >300 new compounds. Rules for tru sequence selectivity were determined, which will be useful for the design and synthesis of combinatorial biosynthetic libraries. The results are also interpreted in comparison to the known natural products of tru and pat cyanobactin pathways. PMID:25140729

  13. Combinatorial targeting and discovery of ligand-receptors in organelles of mammalian cells

    PubMed Central

    Rangel, Roberto; Guzman-Rojas, Liliana; le Roux, Lucia G.; Staquicini, Fernanda I.; Hosoya, Hitomi; Barbu, E. Magda; Ozawa, Michael G.; Nie, Jing; Jr, Kenneth Dunner; Langley, Robert R.; Sage, E. Helene; Koivunen, Erkki; Gelovani, Juri G.; Lobb, Roy R.; Sidman, Richard L.; Pasqualini, Renata; Arap, Wadih

    2012-01-01

    Phage display screening allows the study of functional protein–protein interactions at the cell surface, but investigating intracellular organelles remains a challenge. Here we introduce internalizing-phage libraries to identify clones that enter mammalian cells through a receptor-independent mechanism and target-specific organelles as a tool to select ligand peptides and identify their intracellular receptors. We demonstrate that penetratin, an antennapedia-derived peptide, can be displayed on the phage envelope and mediate receptor-independent uptake of internalizing phage into cells. We also show that an internalizing-phage construct displaying an established mitochondria-specific localization signal targets mitochondria, and that an internalizing-phage random peptide library selects for peptide motifs that localize to different intracellular compartments. As a proof-of-concept, we demonstrate that one such peptide, if chemically fused to penetratin, is internalized receptor-independently, localizes to mitochondria, and promotes cell death. This combinatorial platform technology has potential applications in cell biology and drug development. PMID:22510693

  14. ePathOptimize: A Combinatorial Approach for Transcriptional Balancing of Metabolic Pathways

    PubMed Central

    Jones, J. Andrew; Vernacchio, Victoria R.; Lachance, Daniel M.; Lebovich, Matthew; Fu, Li; Shirke, Abhijit N.; Schultz, Victor L.; Cress, Brady; Linhardt, Robert J.; Koffas, Mattheos A. G.

    2015-01-01

    The ability to fine tune gene expression has created the field of metabolic pathway optimization and balancing where a variety of factors affecting flux balance are carefully modulated to improve product titers, yields, and productivity. Using a library of isopropyl β-D-1-thiogalactopyranoside (IPTG)-inducible mutant T7 promoters of varied strength a combinatorial method was developed for transcriptional balancing of the violacein pathway. Violacein biosynthesis involves a complex five-gene pathway that is an excellent model for exploratory metabolic engineering efforts into pathway regulation and control due to many colorful intermediates and side products allowing for easy analysis and strain comparison. Upon screening approximately 4% of the total initial library, several high-titer mutants were discovered that resulted in up to a 63-fold improvement over the control strain. With further fermentation optimization, titers were improved to 1829 ± 46 mg/L; a 2.6-fold improvement in titer and a 30-fold improvement in productivity from previous literature reports. PMID:26062452

  15. Development of a Membrane-Bound Random DNA Sequence Combinatorial Array Recognition Surface (CARS)

    PubMed Central

    Bruno, John G.

    2010-01-01

    A partially overlapping population of random sequence 60mer DNA molecules consisting of many concatamers of varied lengths was spatially separated in one and two dimensions by electrophoresis in polyacrylamide and transferred to nitrocellulose membranes. The spatially separated library serves as a potential sensor interface on which many different molecular recognition events or target analyte-binding patterns may emerge, thereby theoretically representing a “universal sensor” surface. The separated DNA library has been referred to as a DNA combinatorial array recognition surface or “CARS.” After UV baking and various fluorescence staining or fluorescent probe interactions, the one-dimensional (1-D) and 2-D membrane-bound CARS were digitally photographed and subjected to image analysis with National Institutes of Health Image-Java software. Image analysis demonstrated relatively consistent and more similar spatial fluorescence patterns within CARS analyte treatment groups but noteworthy pattern differences before and after analyte addition and between different analyte treatments. Taken together, these data suggest a potential role for CARS as a novel, inexpensive, self-assembling universal molecular recognition surface that could be coupled to sophisticated Bayesian or other pattern recognition algorithms to classify analytes or make specific identifications, much like the senses of smell or taste. PMID:20357981

  16. Combinatorial effect of maytansinol and radiation in Drosophila and human cancer cells

    PubMed Central

    Edwards, Anthony; Gladstone, Mara; Yoon, Petros; Raben, David; Frederick, Barbara; Su, Tin Tin

    2011-01-01

    SUMMARY Combination therapy, in which two or more agents are applied, is more effective than single therapies for combating cancer. For this reason, combinations of chemotherapy with radiation are being explored in clinical trials, albeit with an empirical approach. We developed a screen to identify, from the onset, molecules that act in vivo in conjunction with radiation, using Drosophila as a model. Screens through two small molecule libraries from the NCI Developmental Therapeutics Program yielded microtubule poisons; this class of agents is known to enhance the effect of radiation in mammalian cancer models. Here we report an analysis of one microtubule depolymerizing agent, maytansinol isobutyrate (NSC292222; maytansinol), in Drosophila and in human cancer cells. We find that the effect of maytansinol is p53 dependent in Drosophila cells and human cancer cells, that maytansinol enhances the effect of radiation in both systems, and that the combinatorial effect of drug and radiation is additive. We also uncover a differential sensitivity to maytansinol between Drosophila cells and Drosophila larvae, which illustrates the value of studying cell behavior in the context of a whole organism. On the basis of these results, we propose that Drosophila might be a useful model for unbiased screens through new molecule libraries to find cancer drugs for combination therapy. PMID:21504911

  17. Combinatorial investigation of ferromagnetic shape memory alloys

    NASA Astrophysics Data System (ADS)

    Takeuchi, Ichiro; Famodu, Olugbenga; Aronova, Maria; Jaworski, Allan; Craciunescu, Corneliu; Wuttig, Manfred; Wellstood, Fred

    2002-03-01

    We have established a comprehensive methodology for rapidly exploring and mapping novel materials phases of ferromagnetic shape memory alloys. A UHV multi-gun magnetron co-sputtering system designed for fabricating composition spreads is used to map out different regions of a variety of ternary phase diagrams on 3 inch Si wafers. A scanning SQUID microscope is used to identify composition regions displaying strong ferromagnetism at room temperature on the spread samples, and magnetization mapping is obtained. In order to quickly characterize the martensitic transition temperatures, composition spreads are directly fabricated on micromachined cantilever libraries. All wafers are deposited at 400 450 C. A novel optical detection method is used to rapidly identify cantilevers undergoing martensitic transitions by visual inspection as a function of temperature. A scanning x-ray microdiffractometer is also used to detect regions displaying structural phase transitions. We have mapped out the ternary phase diagram of the Ni-Mn-Ga system.

  18. CPL: Common Pipeline Library

    NASA Astrophysics Data System (ADS)

    ESO CPL Development Team

    2014-02-01

    The Common Pipeline Library (CPL) is a set of ISO-C libraries that provide a comprehensive, efficient and robust software toolkit to create automated astronomical data reduction pipelines. Though initially developed as a standardized way to build VLT instrument pipelines, the CPL may be more generally applied to any similar application. The code also provides a variety of general purpose image- and signal-processing functions, making it an excellent framework for the creation of more generic data handling packages. The CPL handles low-level data types (images, tables, matrices, strings, property lists, etc.) and medium-level data access methods (a simple data abstraction layer for FITS files). It also provides table organization and manipulation, keyword/value handling and management, and support for dynamic loading of recipe modules using programs such as EsoRex (ascl:1504.003).

  19. Strengthening State Library Administrative Agency (Territorial Library).

    ERIC Educational Resources Information Center

    Nieves M. Flores Memorial Library, Agana, Guam.

    This document describes the Basic State Plan Amendments for the Library Services and Construction Act in Guam and the regulations promulgated thereunder. The major projects described under the plan are: Strengthening State Library Administrative Agency; Staff Development; Library Collections, Extention Services, Institutional Libraries; and…

  20. Library Instruction Assessment in Academic Libraries

    ERIC Educational Resources Information Center

    Tancheva, Kornelia; Andrews, Camille; Steinhart, Gail

    2007-01-01

    Determining the best methods of assessment for a library instruction program in a large research university can be a challenging task. Albert R. Mann Library at Cornell University Library has pilot-tested three methods of formative and summative assessment for its library instruction program--attitudinal, outcomes-based, and gap-measure--and…

  1. Combinatorial epigenetic patterns as quantitative predictors of chromatin biology

    PubMed Central

    2014-01-01

    Background Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) is the most widely used method for characterizing the epigenetic states of chromatin on a genomic scale. With the recent availability of large genome-wide data sets, often comprising several epigenetic marks, novel approaches are required to explore functionally relevant interactions between histone modifications. Computational discovery of "chromatin states" defined by such combinatorial interactions enabled descriptive annotations of genomes, but more quantitative approaches are needed to progress towards predictive models. Results We propose non-negative matrix factorization (NMF) as a new unsupervised method to discover combinatorial patterns of epigenetic marks that frequently co-occur in subsets of genomic regions. We show that this small set of combinatorial "codes" can be effectively displayed and interpreted. NMF codes enable dimensionality reduction and have desirable statistical properties for regression and classification tasks. We demonstrate the utility of codes in the quantitative prediction of Pol2-binding and the discrimination between Pol2-bound promoters and enhancers. Finally, we show that specific codes can be linked to molecular pathways and targets of pluripotency genes during differentiation. Conclusions We have introduced and evaluated a new computational approach to represent combinatorial patterns of epigenetic marks as quantitative variables suitable for predictive modeling and supervised machine learning. To foster widespread adoption of this method we make it available as an open-source software-package – epicode at https://github.com/mcieslik-mctp/epicode. PMID:24472558

  2. Identities for Generalized Fibonacci Numbers: A Combinatorial Approach

    ERIC Educational Resources Information Center

    Plaza, A.; Falcon, S.

    2008-01-01

    This note shows a combinatorial approach to some identities for generalized Fibonacci numbers. While it is a straightforward task to prove these identities with induction, and also by arithmetical manipulations such as rearrangements, the approach used here is quite simple to follow and eventually reduces the proof to a counting problem. (Contains…

  3. Design of a Microfluidic Chip for Magnetic-Activated Sorting of One-Bead-One-Compound Libraries.

    PubMed

    Cho, Choi-Fong; Lee, Kyungheon; Speranza, Maria-Carmela; Bononi, Fernanda C; Viapiano, Mariano S; Luyt, Leonard G; Weissleder, Ralph; Chiocca, E Antonio; Lee, Hakho; Lawler, Sean E

    2016-06-13

    Molecular targeting using ligands specific to disease markers has shown great promise for early detection and directed therapy. Bead-based combinatorial libraries have served as powerful tools for the discovery of novel targeting agents. Screening platforms employing magnetic capture have been used to achieve rapid and efficient identification of high-affinity ligands from one-bead-one-compound (OBOC) libraries. Traditional manual methodologies to isolate magnetized "hit" beads are tedious and lack accuracy, and existing instruments to expedite bead sorting tend to be costly and complex. Here, we describe the design and construction of a simple and inexpensive microfluidic magnetic sorting device using standard photolithography and soft lithography approaches to facilitate high-throughput isolation of magnetized positive hit beads from combinatorial libraries. We have demonstrated that the device is able to sort magnetized beads with superior accuracy compared to conventional manual sorting approaches. This chip offers a very convenient yet inexpensive alternative for screening OBOC libraries. PMID:27124678

  4. Therapeutic enzyme deimmunization by combinatorial T-cell epitope removal using neutral drift

    PubMed Central

    Cantor, Jason R.; Yoo, Tae Hyeon; Dixit, Aakanksha; Iverson, Brent L.; Forsthuber, Thomas G.; Georgiou, George

    2011-01-01

    A number of heterologous enzymes have been investigated for cancer treatment and other therapeutic applications; however, immunogenicity issues have limited their clinical utility. Here, a new approach has been created for heterologous enzyme deimmunization whereby combinatorial saturation mutagenesis is coupled with a screening strategy that capitalizes on the evolutionary biology concept of neutral drift, and combined with iterative computational prediction of T-cell epitopes to achieve extensive reengineering of a protein sequence for reduced MHC-II binding propensity without affecting catalytic and pharmacological properties. Escherichia coli L-asparaginase II (EcAII), the only nonhuman enzyme approved for repeated administration, is critical in treatment of childhood acute lymphoblastic leukemia (ALL), but elicits adverse antibody responses in a significant fraction of patients. The neutral drift screening of combinatorial saturation mutagenesis libraries at a total of 12 positions was used to isolate an EcAII variant containing eight amino acid substitutions within computationally predicted T-cell epitopes—of which four were nonconservative—while still exhibiting kcat/KM = 106 M-1 s-1 for L-Asn hydrolysis. Further, immunization of HLA-transgenic mice expressing the ALL-associated DRB1*0401 allele with the engineered variant resulted in significantly reduced T-cell responses and a 10-fold reduction in anti-EcAII IgG titers relative to the existing therapeutic. This significant reduction in the immunogenicity of EcAII may be clinically relevant for ALL treatment and illustrates the potential of employing neutral drift screens to achieve large jumps in sequence space as may be required for the deimmunization of heterologous proteins. PMID:21209329

  5. Defining RNA motif–aminoglycoside interactions via two-dimensional combinatorial screening and structure–activity relationships through sequencing

    PubMed Central

    Velagapudi, Sai Pradeep; Disney, Matthew D.

    2013-01-01

    RNA is an extremely important target for the development of chemical probes of function or small molecule therapeutics. Aminoglycosides are the most well studied class of small molecules to target RNA. However, the RNA motifs outside of the bacterial rRNA A-site that are likely to be bound by these compounds in biological systems is largely unknown. If such information were known, it could allow for aminoglycosides to be exploited to target other RNAs and, in addition, could provide invaluable insights into potential bystander targets of these clinically used drugs. We utilized two-dimensional combinatorial screening (2DCS), a library-versus-library screening approach, to select the motifs displayed in a 3 × 3 nucleotide internal loop library and in a 6-nucleotide hairpin library that bind with high affinity and selectivity to six aminoglycoside derivatives. The selected RNA motifs were then analyzed using structure–activity relationships through sequencing (StARTS), a statistical approach that defines the privileged RNA motif space that binds a small molecule. StARTS allowed for the facile annotation of the selected RNA motif–aminoglycoside interactions in terms of affinity and selectivity. The interactions selected by 2DCS generally have nanomolar affinities, which is higher affinity than the binding of aminoglycosides to a mimic of their therapeutic target, the bacterial rRNA A-site. PMID:23719281

  6. Defining RNA motif-aminoglycoside interactions via two-dimensional combinatorial screening and structure-activity relationships through sequencing.

    PubMed

    Velagapudi, Sai Pradeep; Disney, Matthew D

    2013-10-15

    RNA is an extremely important target for the development of chemical probes of function or small molecule therapeutics. Aminoglycosides are the most well studied class of small molecules to target RNA. However, the RNA motifs outside of the bacterial rRNA A-site that are likely to be bound by these compounds in biological systems is largely unknown. If such information were known, it could allow for aminoglycosides to be exploited to target other RNAs and, in addition, could provide invaluable insights into potential bystander targets of these clinically used drugs. We utilized two-dimensional combinatorial screening (2DCS), a library-versus-library screening approach, to select the motifs displayed in a 3×3 nucleotide internal loop library and in a 6-nucleotide hairpin library that bind with high affinity and selectivity to six aminoglycoside derivatives. The selected RNA motifs were then analyzed using structure-activity relationships through sequencing (StARTS), a statistical approach that defines the privileged RNA motif space that binds a small molecule. StARTS allowed for the facile annotation of the selected RNA motif-aminoglycoside interactions in terms of affinity and selectivity. The interactions selected by 2DCS generally have nanomolar affinities, which is higher affinity than the binding of aminoglycosides to a mimic of their therapeutic target, the bacterial rRNA A-site. PMID:23719281

  7. Cell Libraries

    NASA Technical Reports Server (NTRS)

    1994-01-01

    A NASA contract led to the development of faster and more energy efficient semiconductor materials for digital integrated circuits. Gallium arsenide (GaAs) conducts electrons 4-6 times faster than silicon and uses less power at frequencies above 100-150 megahertz. However, the material is expensive, brittle, fragile and has lacked computer automated engineering tools to solve this problem. Systems & Processes Engineering Corporation (SPEC) developed a series of GaAs cell libraries for cell layout, design rule checking, logic synthesis, placement and routing, simulation and chip assembly. The system is marketed by Compare Design Automation.

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

    PubMed

    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. PMID:27053324

  9. Combinatorial screening of osteoblast response to 3D calcium phosphate/poly(ε-caprolactone) scaffolds using gradients and arrays

    PubMed Central

    Chatterjee, Kaushik; Sun, Limin; Chow, Laurence C.; Young, Marian F.; Simon, Carl G.

    2012-01-01

    There is a need for combinatorial and high-throughput methods for screening cell–biomaterial interactions to maximize tissue generation in scaffolds. Current methods employ a flat two-dimensional (2D) format even though three-dimensional (3D) scaffolds are more representative of the tissue environment in vivo and cells are responsive to topographical differences of 2D substrates and 3D scaffolds. Thus, combinatorial libraries of 3D porous scaffolds were developed and used to screen the effect of nano-amorphous calcium phosphate (nACP) particles on osteoblast response. Increasing nACP content in poly (ε-caprolactone) (PCL) scaffolds promoted osteoblast adhesion and proliferation. The nACP-containing scaffolds released calcium and phosphate ions which are known to activate osteoblast function. Scaffold libraries were fabricated in two formats, gradients and arrays, and the magnitude of the effect of nACP on osteoblast proliferation was greater for arrays than gradients. The enhanced response in arrays can be explained by differences in cell culture designs, diffusional effects and differences in the ratio of “scaffold mass to culture medium”. These results introduce a gradient library approach for screening large pore 3D scaffolds and demonstrate that inclusion of the nACP particles enhances osteoblast proliferation in 3D scaffolds. Further, comparison of gradients and arrays suggests that gradients were more sensitive for detecting effects of scaffold composition on cell adhesion (short time points, 1 day) whereas arrays were more sensitive at detecting effects on cell proliferation (longer time points, 14 day). PMID:21074846

  10. FASTAptamer: A Bioinformatic Toolkit for High-throughput Sequence Analysis of Combinatorial Selections

    PubMed Central

    Alam, Khalid K; Chang, Jonathan L; Burke, Donald H

    2015-01-01

    High-throughput sequence (HTS) analysis of combinatorial selection populations accelerates lead discovery and optimization and offers dynamic insight into selection processes. An underlying principle is that selection enriches high-fitness sequences as a fraction of the population, whereas low-fitness sequences are depleted. HTS analysis readily provides the requisite numerical information by tracking the evolutionary trajectory of individual sequences in response to selection pressures. Unlike genomic data, for which a number of software solutions exist, user-friendly tools are not readily available for the combinatorial selections field, leading many users to create custom software. FASTAptamer was designed to address the sequence-level analysis needs of the field. The open source FASTAptamer toolkit counts, normalizes and ranks read counts in a FASTQ file, compares populations for sequence distribution, generates clusters of sequence families, calculates fold-enrichment of sequences throughout the course of a selection and searches for degenerate sequence motifs. While originally designed for aptamer selections, FASTAptamer can be applied to any selection strategy that can utilize next-generation DNA sequencing, such as ribozyme or deoxyribozyme selections, in vivo mutagenesis and various surface display technologies (peptide, antibody fragment, mRNA, etc.). FASTAptamer software, sample data and a user's guide are available for download at http://burkelab.missouri.edu/fastaptamer.html. PMID:25734917

  11. Combinatorial Investigations of High Temperature CuNb Oxide Phases for Photoelectrochemical Water Splitting.

    PubMed

    Skorupska, Katarzyna; Maggard, Paul A; Eichberger, Rainer; Schwarzburg, Klaus; Shahbazi, Paria; Zoellner, Brandon; Parkinson, Bruce A

    2015-12-14

    High-throughput combinatorial methods have been useful in identifying new oxide semiconductors with the potential to be applied to solar water splitting. Most of these techniques have been limited to producing and screening oxide phases formed at temperatures below approximately 550 °C. We report the development of a combinatorial approach to discover and optimize high temperature phases for photoelectrochemical water splitting. As a demonstration material, we chose to produce thin films of high temperature CuNb oxide phases by inkjet printing on two different substrates: fluorine-doped tin oxide and crystalline Si, which required different sample pyrolysis procedures. The selection of pyrolysis parameters, such as temperature/time programs, and the use of oxidizing, nonreactive or reducing atmospheres determines the composition of the thin film materials and their photoelectrochemical performance. XPS, XRD, and SEM analyses were used to determine the composition and oxidation states within the copper niobium oxide phases and to then guide the production of target Cu(1+)Nb(5+)-oxide phases. The charge carrier dynamics of the thin films produced by the inkjet printing are compared with pure CuNbO3 microcrystalline material obtained from inorganic bulk synthesis. PMID:26505910

  12. Development of combinatorial chemistry methods for coatings: high-throughput weathering evaluation and scale-up of combinatorial leads.

    PubMed

    Potyrailo, Radislav A; Ezbiansky, Karin; Chisholm, Bret J; Morris, William G; Cawse, James N; Hassib, Lamyaa; Medford, George; Reitz, Hariklia

    2005-01-01

    Combinatorial screening of materials formulations followed by the scale-up of combinatorial leads has been applied for the development of high-performance coating materials for automotive applications. We replaced labor-intensive coating formulation, testing, and measurement with a "combinatorial factory" that includes robotic formulation of coatings, their deposition as 48 coatings on a 9x12-cm plastic substrate, accelerated performance testing, and automated spectroscopic and image analysis of resulting performance. This high-throughput (HT) performance testing and measurement of the resulting properties provided a powerful set of tools for the 10-fold accelerated discovery of these coating materials. Performance of coatings is evaluated with respect to their weathering, because this parameter is one of the primary considerations in end-use automotive applications. Our HT screening strategy provides previously unavailable capabilities of (1) high speed and reproducibility of testing by using robotic automation and (2) improved quantification by using optical spectroscopic analysis of discoloration of coating-substrate structure and automatic imaging of the integrity loss of coatings. Upon testing, the coatings undergo changes that are impossible to quantitatively predict using existing knowledge. Using our HT methodology, we have developed several cost-competitive coatings leads that match the performance of more costly coatings. These HT screening results for the best coating compositions have been validated on the traditional scales of coating formulation and weathering testing. These validation results have confirmed the improved weathering performance of combinatorially developed coatings over conventional coatings on the traditional scale. PMID:15762746

  13. Drawing Blueprints for "Pulsing Content" Libraries

    ERIC Educational Resources Information Center

    Chudnov, Daniel

    2007-01-01

    This column presents a continuation of an article published in last month's issue of "Libraries in Computers," in which the author began to consider what it might mean to build dynamic, instantaneous libraries based solely on the materials held on the computers of people in the same space. The goal of this column is to think about what libraries…

  14. Selection of a potential diagnostic biomarker for HIV infection from a random library of non-biological synthetic peptoid oligomers.

    PubMed

    Gearhart, Tricia L; Montelaro, Ronald C; Schurdak, Mark E; Pilcher, Chris D; Rinaldo, Charles R; Kodadek, Thomas; Park, Yongseok; Islam, Kazi; Yurko, Raymond; Marques, Ernesto T A; Burke, Donald S

    2016-08-01

    Non-biological synthetic oligomers can serve as ligands for antibodies. We hypothesized that a random combinatorial library of synthetic poly-N-substituted glycine oligomers, or peptoids, could represent a random "shape library" in antigen space, and that some of these peptoids would be recognized by the antigen-binding pocket of disease-specific antibodies. We synthesized and screened a one bead one compound combinatorial library of peptoids, in which each bead displayed an 8-mer peptoid with ten possible different amines at each position (10(8) theoretical variants). By screening one million peptoid/beads we found 112 (approximately 1 in 10,000) that preferentially bound immunoglobulins from human sera known to be positive for anti-HIV antibodies. Reactive peptoids were then re-synthesized and rigorously evaluated in plate-based ELISAs. Four peptoids showed very good, and one showed excellent, properties for establishing a sero-diagnosis of HIV. These results demonstrate the feasibility of constructing sero-diagnostic assays for infectious diseases from libraries of random molecular shapes. In this study we sought a proof-of-principle that we could identify a potential diagnostic antibody ligand biomarker for an infectious disease in a random combinatorial library of 100 million peptoids. We believe that this is the first evidence that it is possible to develop sero-diagnostic assays - for any infectious disease - based on screening random libraries of non-biological molecular shapes. PMID:27182050

  15. A High Throughput Combinatorial Library Technique for Identifying Formalin-Sensitive Epitopes

    PubMed Central

    Vani, Kodela; Bogen, Steven A.; Sompuram, Seshi R.

    2007-01-01

    We present a technique for identifying the amino acids responsible for a loss of immunoreactivity in response to treating an antigen with a chemical modifier. This is of particular interest for the chemical formaldehyde, the cross-linking agent in formalin. Formalin is a commonly used fixative to preserve the cellular architecture of cells and tissues and to prevent degradation from proteases and nucleases. Formalin is also routinely used in the preparation of vaccines, to inactivate both toxins and microbes. Formalin fixation attenuates infectivity and pathogenicity by cross-linking while often preserving antigenicity. However, some epitopes are irreversibly modified by formalin while others are not. An understanding of how formalin affects epitope immunoreactivity may be useful in vaccine development or in the development of diagnostic antibody reagents for formalin-fixed tissues. In this report, we describe a method for systematically identifying formalin-sensitive and formalin-insensitive epitopes in a high throughput fashion, for any particular antibody. The data from this effort underscore the importance of certain amino acids, notably lysine, in affecting antibody immunoreactivity after formalin fixation. The method can be generally applicable in exploring the sensitivity of protein epitopes to an agent or condition of interest. PMID:17056057

  16. Immunodiagnosis of Canine Visceral Leishmaniasis Using Mimotope Peptides Selected from Phage Displayed Combinatorial Libraries

    PubMed Central

    Toledo-Machado, Christina Monerat; Machado de Avila, Ricardo Andrez; NGuyen, Christophe; Granier, Claude; Bueno, Lilian Lacerda; Carneiro, Claudia Martins; Menezes-Souza, Daniel; Carneiro, Rubens Antonio; Chávez-Olórtegui, Carlos; Fujiwara, Ricardo Toshio

    2015-01-01

    ELISA and RIFI are currently used for serodiagnosis of canine visceral leishmaniasis (CVL). The accuracy of these tests is controversial in endemic areas where canine infections by Trypanosoma cruzi may occur. We evaluated the usefulness of synthetic peptides that were selected through phage display technique in the serodiagnosis of CVL. Peptides were chosen based on their ability to bind to IgGs purified from infected dogs pooled sera. We selected three phage clones that reacted only with those IgGs. Peptides were synthesized, polymerized with glutaraldehyde, and used as antigens in ELISA assays. Each individual peptide or a mix of them was reactive with infected dogs serum. The assay was highly sensitive and specific when compared to soluble Leishmania antigen that showed cross-reactivity with anti-T. cruzi IgGs. Our results demonstrate that phage display technique is useful for selection of peptides that may represent valuable synthetic antigens for an improved serodiagnosis of CVL. PMID:25710003

  17. Library Services. Miscellaneous Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    Papers on library journal cooperation, interlibrary lending, library services to minorities, and school library media centers, which were presented at the 1983 International Federation of Library Associations (IFLA) conference, include: (1) "The Co-operation between Editors of Library Journals in Socialist Countries," in which Wolfgang Korluss…

  18. Marketing the Virtual Library

    ERIC Educational Resources Information Center

    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…

  19. Library Research and Statistics.

    ERIC Educational Resources Information Center

    Lynch, Mary Jo; Brier, David J.; Lebbin, Vickery K.; Halstead, Kent; Fox, Bette-Lee; Kremen, Maya L.; Miller, Marilyn L.; Shontz, Marilyn L.

    1998-01-01

    Provides nine articles: research on libraries and librarianship, 1997; changing faces of library education (ALA-accredited graduate program title changes); number of libraries in the U.S., Canada, and Mexico; highlights of NCES surveys; library acquisition expenditures; price indexes for public and academic libraries; state rankings of selected…

  20. Library Handbook for Faculty.

    ERIC Educational Resources Information Center

    Martinez, Angelina, Ed.

    Discussions of library resources, services and related activities as well as library materials selection and acquisition are provided for faculty to facilitate and enhance their use of the library. Included in the library resources section are books, periodicals, microforms, and special collections and archives. Instruction in library use,…

  1. Library Directions in 1988.

    ERIC Educational Resources Information Center

    DeCandido, GraceAnne A.

    1989-01-01

    Reviews major library issues and events of 1988, including: (1) the Federal Bureau of Investigation's Library Awareness Program; (2) cooperation with USSR libraries; (3) library finance; (4) preservation; and (5) special programing. News about a number of prominent library professionals is included in a sidebar. (MES)

  2. Public Library in Thailand.

    ERIC Educational Resources Information Center

    Lerdsuriyakul, Kulthorn

    This paper on public libraries in Thailand begins with a section that provides background on public libraries in the past, lists the functions of the public library, and describes three size classifications of public libraries. The second section outlines the tasks of the current public library in three areas: informal education; nonformal…

  3. Homecoming for Library Symbol.

    ERIC Educational Resources Information Center

    Egan, Bessie

    1987-01-01

    Discusses the significance and development of the library symbol and the history of its acceptance by the American Library Association (ALA) and the Canadian Library Association (CLA). Suggestions are made for its use. (CLB)

  4. From linking of metal-oxide building blocks in a dynamic library to giant clusters with unique properties and towards adaptive chemistry.

    PubMed

    Müller, Achim; Gouzerh, Pierre

    2012-11-21

    Following Nature's lessons, today chemists can cross the boundary of the small molecule world to construct multifunctional and highly complex molecular nano-objects up to protein size and even cell-like nanosystems showing responsive sensing. Impressive examples emerge from studies of the solutions of some oxoanions of the early transition metals especially under reducing conditions which enable the controlled linking of metal-oxide building blocks. The latter are available from constitutional dynamic libraries, thus providing the option to generate multifunctional unique nanoscale molecular systems with exquisite architectures, which even opens the way towards adaptive and evolutive (Darwinian) chemistry. The present review presents the first comprehensive report of current knowledge (including synthesis aspects not discussed before) regarding the related giant metal-oxide clusters mainly of the type {Mo(57)M'(6)} (M' = Fe(III), V(IV)) (torus structure), {M(72)M'(30)} (M = Mo, M' = V(IV), Cr(III), Fe(III), Mo(V)), {M(72)Mo(60)} (M = Mo, W) (Keplerates), {Mo(154)}, {Mo(176)}, {Mo(248)} ("big wheels"), and {Mo(368)} ("blue lemon") - all having the important transferable pentagonal {(M)M(5)} groups in common. These discoveries expanded the frontiers of inorganic chemistry to the mesoscopic world, while there is probably no collection of discrete inorganic compounds which offers such a versatile chemistry and the option to study new phenomena of interdisciplinary interest. The variety of different properties of the sphere- and wheel-type metal-oxide-based clusters can directly be related to their unique architectures: The spherical Keplerate-type capsules having 20 crown-ether-type pores and tunable internal functionalities allow the investigation of confined matter as well as that of sphere-surface-supramolecular and encapsulation chemistry - including related new aspects of the biologically important hydrophobic effects - but also of nanoscale ion transport and

  5. Single-molecule decoding of combinatorially modified nucleosomes.

    PubMed

    Shema, Efrat; Jones, Daniel; Shoresh, Noam; Donohue, Laura; Ram, Oren; Bernstein, Bradley E

    2016-05-01

    Different combinations of histone modifications have been proposed to signal distinct gene regulatory functions, but this area is poorly addressed by existing technologies. We applied high-throughput single-molecule imaging to decode combinatorial modifications on millions of individual nucleosomes from pluripotent stem cells and lineage-committed cells. We identified definitively bivalent nucleosomes with concomitant repressive and activating marks, as well as other combinatorial modification states whose prevalence varies with developmental potency. We showed that genetic and chemical perturbations of chromatin enzymes preferentially affect nucleosomes harboring specific modification states. Last, we combined this proteomic platform with single-molecule DNA sequencing technology to simultaneously determine the modification states and genomic positions of individual nucleosomes. This single-molecule technology has the potential to address fundamental questions in chromatin biology and epigenetic regulation. PMID:27151869

  6. Characterization of Combinatorial Polymer Blend Composition Gradients by FTIR Microspectroscopy

    PubMed Central

    Eidelman, Naomi; Simon, Carl G.

    2004-01-01

    A new FTIR technique was developed for characterizing thin polymer films used in combinatorial materials science. Fourier transform infrared microspectroscopy mapping technique was used to determine the composition of polymer blend gradients. Composition gradients were made from poly(L-lactic acid) (PLLA) and poly(D,L-lactic acid) (PDLLA) in the form of thin films (6 cm × 2 cm) deposited on IR reflective substrates. Three composition gradient films were prepared and characterized. The results demonstrate the reproducibility and feasibility of a new, high-throughput approach for preparing and characterizing polymer composition gradients. The combination of composition gradient film technology and automated nondestructive FTIR microspectroscopy makes it possible to rapidly and quantitatively characterize polymer composition gradients for use in combinatorial materials science. PMID:27366606

  7. Combinatorial geometry domain decomposition strategies for Monte Carlo simulations

    SciTech Connect

    Li, G.; Zhang, B.; Deng, L.; Mo, Z.; Liu, Z.; Shangguan, D.; Ma, Y.; Li, S.; Hu, Z.

    2013-07-01

    Analysis and modeling of nuclear reactors can lead to memory overload for a single core processor when it comes to refined modeling. A method to solve this problem is called 'domain decomposition'. In the current work, domain decomposition algorithms for a combinatorial geometry Monte Carlo transport code are developed on the JCOGIN (J Combinatorial Geometry Monte Carlo transport INfrastructure). Tree-based decomposition and asynchronous communication of particle information between domains are described in the paper. Combination of domain decomposition and domain replication (particle parallelism) is demonstrated and compared with that of MERCURY code. A full-core reactor model is simulated to verify the domain decomposition algorithms using the Monte Carlo particle transport code JMCT (J Monte Carlo Transport Code), which has being developed on the JCOGIN infrastructure. Besides, influences of the domain decomposition algorithms to tally variances are discussed. (authors)

  8. Elements of informatics for combinatorial solid-state materials science

    NASA Astrophysics Data System (ADS)

    Meguro, S.; Ohnishi, T.; Lippmaa, M.; Koinuma, H.

    2005-01-01

    The main purpose of using combinatorial techniques for materials science studies is to achieve higher experimental throughput than what is possible when samples are synthesized and characterized one at a time. The instrumentation needed for performing high-throughput synthesis and characterization has seen rapid development in recent years. The software tools needed to connect all parts of the materials development process are still largely lacking. In this paper we discuss the requirements of a combinatorial informatics system for materials science experiments. Specifically, we focus on solid-state thin film synthesis. We also describe an implementation of such a system that is based on widely-available open-source software. The system offers features such as remote access via a Web browser, an electronic notebook-style Web interface, automatic upload of new measurement or processing results and rapid preview of experimental data.

  9. An atlas of combinatorial transcriptional regulation in mouse and man

    PubMed Central

    2010-01-01

    SUMMARY 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. PMID:20211142

  10. A verification library for multibody simulation software

    NASA Technical Reports Server (NTRS)

    Kim, Sung-Soo; Haug, Edward J.; Frisch, Harold P.

    1989-01-01

    A multibody dynamics verification library, that maintains and manages test and validation data is proposed, based on RRC Robot arm and CASE backhoe validation and a comparitive study of DADS, DISCOS, and CONTOPS that are existing public domain and commercial multibody dynamic simulation programs. Using simple representative problems, simulation results from each program are cross checked, and the validation results are presented. Functionalities of the verification library are defined, in order to automate validation procedure.

  11. Authorizing multiple chemical passwords by a combinatorial molecular keypad lock.

    PubMed

    Rout, Bhimsen; Milko, Petr; Iron, Mark A; Motiei, Leila; Margulies, David

    2013-10-16

    A combinatorial fluorescent molecular sensor operates as a highly efficient molecular security system. The ability of a pattern-generating molecule to process diverse sets of chemical inputs, discriminate among their concentrations, and form multivalent and kinetically stable complexes is demonstrated as a powerful tool for processing a wide range of chemical "passwords" of different lengths. This system thus indicates the potential for obtaining unbreakable combination locks at the molecular scale. PMID:24088016

  12. Thermal analysis of combinatorial solid geometry models using SINDA

    NASA Technical Reports Server (NTRS)

    Gerencser, Diane; Radke, George; Introne, Rob; Klosterman, John; Miklosovic, Dave

    1993-01-01

    Algorithms have been developed using Monte Carlo techniques to determine the thermal network parameters necessary to perform a finite difference analysis on Combinatorial Solid Geometry (CSG) models. Orbital and laser fluxes as well as internal heat generation are modeled to facilitate satellite modeling. The results of the thermal calculations are used to model the infrared (IR) images of targets and assess target vulnerability. Sample analyses and validation are presented which demonstrate code products.

  13. Combinatorial aspects of representations of U(n)

    SciTech Connect

    Louck, J.D.

    1996-12-31

    The boson operator theory of the representations of the unitary group, its Wigner-Clebsch-Gordan, and Racah coefficients is reformulated in terms of the ring of polynomials in any number of indeterminates with the goal of bringing the theory, as nearly as possible, under the purview of combinatorial oriented concepts. Four of the basic relations in unitary group theory are interpreted from this viewpoint.

  14. ORGBUG -- A windows-based combinatorial geometry debugger

    SciTech Connect

    Burns, T.J.

    1993-06-01

    ORGBUG is the second half of a two part graphical display and debugging system for combinatorial geometry. The first part of the system consists of a ``view`` generator, CGVIEW. ORGBUG itself is a Microsoft Windows-based application designed to run on a 386 personal computer and to display the ``view`` produced by CGVIEW as an aid to debugging. ORGBUG also includes specific tools to facilitate the identification of geometric features which are inconsistent or in error.

  15. ORGBUG -- A windows-based combinatorial geometry debugger

    SciTech Connect

    Burns, T.J.

    1993-06-01

    ORGBUG is the second half of a two part graphical display and debugging system for combinatorial geometry. The first part of the system consists of a view'' generator, CGVIEW. ORGBUG itself is a Microsoft Windows-based application designed to run on a 386 personal computer and to display the view'' produced by CGVIEW as an aid to debugging. ORGBUG also includes specific tools to facilitate the identification of geometric features which are inconsistent or in error.

  16. The Library of Virginia's Digital Library Project.

    ERIC Educational Resources Information Center

    Roderick, Elizabeth; Taylor, Jean Marie; Byrd, Sam; Courson, Glenn

    1997-01-01

    Describes The Library of Virginia's Digital Library Project that has made many of its state library collections available via the Internet and World Wide Web. Highlights include digitization decisions; the HTML Web gateway; the online catalog; microfilm digitization; users and use statistics; and future projects. (LRW)

  17. A combinatorial perspective of the protein inference problem.

    PubMed

    Yang, Chao; He, Zengyou; Yu, Weichuan

    2013-01-01

    In a shotgun proteomics experiment, proteins are the most biologically meaningful output. The success of proteomics studies depends on the ability to accurately and efficiently identify proteins. Many methods have been proposed to facilitate the identification of proteins from peptide identification results. However, the relationship between protein identification and peptide identification has not been thoroughly explained before. In this paper, we devote ourselves to a combinatorial perspective of the protein inference problem. We employ combinatorial mathematics to calculate the conditional protein probabilities (protein probability means the probability that a protein is correctly identified) under three assumptions, which lead to a lower bound, an upper bound, and an empirical estimation of protein probabilities, respectively. The combinatorial perspective enables us to obtain an analytical expression for protein inference. Our method achieves comparable results with ProteinProphet in a more efficient manner in experiments on two data sets of standard protein mixtures and two data sets of real samples. Based on our model, we study the impact of unique peptides and degenerate peptides (degenerate peptides are peptides shared by at least two proteins) on protein probabilities. Meanwhile, we also study the relationship between our model and ProteinProphet. We name our program ProteinInfer. Its Java source code, our supplementary document and experimental results are available at: >http://bioinformatics.ust.hk/proteininfer. PMID:24407311

  18. View discovery in OLAP databases through statistical combinatorial optimization

    SciTech Connect

    Hengartner, Nick W; Burke, John; Critchlow, Terence; Joslyn, Cliff; Hogan, Emilie

    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.

  19. Controlling Combinatorial Complexity in Software and Malware Behavior Computation

    SciTech Connect

    Pleszkoch, Mark G; Linger, Richard C

    2015-01-01

    Virtually all software is out of intellectual control in that no one knows its full behavior. Software Behavior Computation (SBC) is a new technology for understanding everything software does. SBC applies the mathematics of denotational semantics implemented by function composition in Functional Trace Tables (FTTs) to compute the behavior of programs, expressed as disjoint cases of conditional concurrent assignments. In some circumstances, combinatorial explosions in the number of cases can occur when calculating the behavior of sequences of multiple branching structures. This paper describes computational methods that avoid combinatorial explosions. The predicates that control branching structures such as ifthenelses can be organized into three categories: 1) Independent, resulting in no behavior case explosion, 2) Coordinated, resulting in two behavior cases, or 3) Goaloriented, with potential exponential growth in the number of cases. Traditional FTT-based behavior computation can be augmented by two additional computational methods, namely, Single-Value Function Abstractions (SVFAs) and, introduced in this paper, Relational Trace Tables (RTTs). These methods can be applied to the three predicate categories to avoid combinatorial growth in behavior cases while maintaining mathematical correctness.

  20. Combinatorial search for oxygen reduction reaction electrocatalysts: A review

    NASA Astrophysics Data System (ADS)

    Jeon, Min Ku; Lee, Chang Hwa; Park, Geun Il; Kang, Kweon Ho

    2012-10-01

    Oxygen reduction reaction (ORR) is one of the most interesting research issues in the academia and industries due to its importance in polymer electrolyte membrane fuel cells. Development of new ORR catalysts with low cost and high activity is under intensive research, but it is a time-consuming process because of wide range of alloys to be explored. Combinatorial synthesis and high-throughput screening techniques were suggested as new experimental approaches to accelerate the ORR electrocatalyst research. The combinatorial method is focused on the synthesis of concentrated arrays and quick evaluation of the arrays via various screening techniques. In this report, the combinatorial approaches for the ORR catalyst research were reviewed based on the screening methods. Four screening techniques of optical screening, scanning electrochemical microscopy, multielectrode half cell, and multielectrode full cell were introduced as the representative ones. Other approaches were also briefly introduced. Merits and limitations of each method were discussed and representative research results of each method were shown in detail.

  1. Quantum Adiabatic Optimization and Combinatorial Landscapes

    NASA Technical Reports Server (NTRS)

    Smelyanskiy, V. N.; Knysh, S.; Morris, R. D.

    2003-01-01

    In this paper we analyze the performance of the Quantum Adiabatic Evolution (QAE) algorithm on a variant of Satisfiability problem for an ensemble of random graphs parametrized by the ratio of clauses to variables, gamma = M / N. We introduce a set of macroscopic parameters (landscapes) and put forward an ansatz of universality for random bit flips. We then formulate the problem of finding the smallest eigenvalue and the excitation gap as a statistical mechanics problem. We use the so-called annealing approximation with a refinement that a finite set of macroscopic variables (verses only energy) is used, and are able to show the existence of a dynamic threshold gamma = gammad, beyond which QAE should take an exponentially long time to find a solution. We compare the results for extended and simplified sets of landscapes and provide numerical evidence in support of our universality ansatz.

  2. Combinatorial Regulation in Yeast Transcription Networks

    NASA Astrophysics Data System (ADS)

    Li, Hao

    2006-03-01

    Yeast has evolved a complex network to regulate its transcriptional program in response to changes in environment. It is quite common that in response to an external stimulus, several transcription factors will be activated and they work in combinations to control different subsets of genes in the genome. We are interested in how the promoters of genes are designed to integrate signals from multiple transcription factors and what are the functional and evolutionary constraints. To answer how, we have developed a number of computational algorithms to systematically map the binding sites and target genes of transcription factors using sequence and gene expression data. To analyze the functional constraints, we have employed mechanistic models to study the dynamic behavior of genes regulated by multiple factors. We have also developed methods to trace the evolution of transcriptional networks via comparative analysis of multiple species.

  3. Alabama Public Library Service Library Directory and 1996 Statistical Report.

    ERIC Educational Resources Information Center

    Alabama Public Library Service, Montgomery.

    This publication presents library contact information and statistics for Alabama public libraries for fiscal year 1996 (October 1, 1995-September 30, 1996). The library directory is arranged by type of library: public libraries, single-county public library systems, multi-county public library systems, and multitype library systems. Entries…

  4. Web 2.0 Strategy in Libraries and Information Services

    ERIC Educational Resources Information Center

    Byrne, Alex

    2008-01-01

    Web 2.0 challenges libraries to change from their predominantly centralised service models with integrated library management systems at the hub. Implementation of Web 2.0 technologies and the accompanying attitudinal shifts will demand reconceptualisation of the nature of library and information service around a dynamic, ever changing, networked,…

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

    PubMed Central

    2016-01-01

    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 1013 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. PMID:27053324

  6. Biomathematical Description of Synthetic Peptide Libraries

    PubMed Central

    Trepel, Martin

    2015-01-01

    Libraries of randomised peptides displayed on phages or viral particles are essential tools in a wide spectrum of applications. However, there is only limited understanding of a library's fundamental dynamics and the influences of encoding schemes and sizes on their quality. Numeric properties of libraries, such as the expected number of different peptides and the library's coverage, have long been in use as measures of a library's quality. Here, we present a graphical framework of these measures together with a library's relative efficiency to help to describe libraries in enough detail for researchers to plan new experiments in a more informed manner. In particular, these values allow us to answer-in a probabilistic fashion-the question of whether a specific library does indeed contain one of the "best" possible peptides. The framework is implemented in a web-interface based on two packages, discreteRV and peptider, to the statistical software environment R. We further provide a user-friendly web-interface called PeLiCa (Peptide Library Calculator, http://www.pelica.org), allowing scientists to plan and analyse their peptide libraries. PMID:26042419

  7. Biomathematical description of synthetic peptide libraries.

    PubMed

    Sieber, Timo; Hare, Eric; Hofmann, Heike; Trepel, Martin

    2015-01-01

    Libraries of randomised peptides displayed on phages or viral particles are essential tools in a wide spectrum of applications. However, there is only limited understanding of a library's fundamental dynamics and the influences of encoding schemes and sizes on their quality. Numeric properties of libraries, such as the expected number of different peptides and the library's coverage, have long been in use as measures of a library's quality. Here, we present a graphical framework of these measures together with a library's relative efficiency to help to describe libraries in enough detail for researchers to plan new experiments in a more informed manner. In particular, these values allow us to answer-in a probabilistic fashion-the question of whether a specific library does indeed contain one of the "best" possible peptides. The framework is implemented in a web-interface based on two packages, discreteRV and peptider, to the statistical software environment R. We further provide a user-friendly web-interface called PeLiCa (Peptide Library Calculator, http://www.pelica.org), allowing scientists to plan and analyse their peptide libraries. PMID:26042419

  8. Acquisition of a Potent and Selective TC-PTP Inhibitor via a Stepwise Fluorophoretagged Combinatorial Synthesis and Screening Strategy

    PubMed Central

    Zhang, Sheng; Chen, Lan; Luo, Yong; Gunawan, Andrea; Lawrence, David S.; Zhang, Zhong-Yin

    2009-01-01

    Protein tyrosine phosphatases (PTPs) regulate a broad range of cellular processes including proliferation, differentiation, migration, apoptosis, and the immune responses. Dysfunction of PTP activity is associated with cancers, metabolic syndromes, and autoimmune disorders. Consequently, small molecule PTP inhibitors should not only serve as powerful tools to delineate the physiological roles of these enzymes in vivo, but also as lead compounds for therapeutic development. We describe a novel stepwise fluorophore-tagged combinatorial library synthesis and competitive fluorescence polarization screening approach that transforms a weak and general PTP inhibitor into an extremely potent and selective TC-PTP inhibitor with highly efficacious cellular activity. The result serves as a proof-of-concept in PTP inhibitor development, as it demonstrates the feasibility of acquiring potent, yet highly selective, cell permeable PTP inhibitory agents. Given the general nature of the approach, this strategy should be applicable to other PTP targets. PMID:19737019

  9. Vector Design Tour de Force: Integrating Combinatorial and Rational Approaches to Derive Novel Adeno-associated Virus Variants

    PubMed Central

    Marsic, Damien; Govindasamy, Lakshmanan; Currlin, Seth; Markusic, David M; Tseng, Yu-Shan; Herzog, Roland W; Agbandje-McKenna, Mavis; Zolotukhin, Sergei

    2014-01-01

    Methodologies to improve existing adeno-associated virus (AAV) vectors for gene therapy include either rational approaches or directed evolution to derive capsid variants characterized by superior transduction efficiencies in targeted tissues. Here, we integrated both approaches in one unified design strategy of “virtual family shuffling” to derive a combinatorial capsid library whereby only variable regions on the surface of the capsid are modified. Individual sublibraries were first assembled in order to preselect compatible amino acid residues within restricted surface-exposed regions to minimize the generation of dead-end variants. Subsequently, the successful families were interbred to derive a combined library of ~8 × 105 complexity. Next-generation sequencing of the packaged viral DNA revealed capsid surface areas susceptible to directed evolution, thus providing guidance for future designs. We demonstrated the utility of the library by deriving an AAV2-based vector characterized by a 20-fold higher transduction efficiency in murine liver, now equivalent to that of AAV8. PMID:25048217

  10. Vector design Tour de Force: integrating combinatorial and rational approaches to derive novel adeno-associated virus variants.

    PubMed

    Marsic, Damien; Govindasamy, Lakshmanan; Currlin, Seth; Markusic, David M; Tseng, Yu-Shan; Herzog, Roland W; Agbandje-McKenna, Mavis; Zolotukhin, Sergei

    2014-11-01

    Methodologies to improve existing adeno-associated virus (AAV) vectors for gene therapy include either rational approaches or directed evolution to derive capsid variants characterized by superior transduction efficiencies in targeted tissues. Here, we integrated both approaches in one unified design strategy of "virtual family shuffling" to derive a combinatorial capsid library whereby only variable regions on the surface of the capsid are modified. Individual sublibraries were first assembled in order to preselect compatible amino acid residues within restricted surface-exposed regions to minimize the generation of dead-end variants. Subsequently, the successful families were interbred to derive a combined library of ~8 × 10(5) complexity. Next-generation sequencing of the packaged viral DNA revealed capsid surface areas susceptible to directed evolution, thus providing guidance for future designs. We demonstrated the utility of the library by deriving an AAV2-based vector characterized by a 20-fold higher transduction efficiency in murine liver, now equivalent to that of AAV8. PMID:25048217

  11. Two-dimensional combinatorial screening and the RNA Privileged Space Predictor program efficiently identify aminoglycoside–RNA hairpin loop interactions

    PubMed Central

    Paul, Dustin J.; Seedhouse, Steven J.; Disney, Matthew D.

    2009-01-01

    Herein, we report the identification of RNA hairpin loops that bind derivatives of kanamycin A, tobramycin, neamine, and neomycin B via two-dimensional combinatorial screening, a method that screens chemical and RNA spaces simultaneously. An arrayed aminoglycoside library was probed for binding to a 6-nucleotide RNA hairpin loop library (4096 members). Members of the loop library that bound each aminoglycoside were excised from the array, amplified and sequenced. Sequences were analyzed with our newly developed RNA Privileged Space Predictor (RNA-PSP) program, which analyzes selected sequences to identify statistically significant trends. RNA-PSP identified the following unique trends: 5′UNNNC3′ loops for the kanamycin A derivative (where N is any nucleotide); 5′UNNC3′ loops for the tobramycin derivative; 5′UNC3′ loops for the neamine derivative; and 5′UNNG3′ loops for the neomycin B derivative. The affinities and selectivities of a subset of the ligand–hairpin loop interactions were determined. The selected interactions have Kd values ranging from 10 nM to 605 nM. Selectivities ranged from 0.4 to >200-fold. Interestingly, the results from RNA-PSP are able to qualitatively predict specificity based on overlap between the RNA sequences selected for the ligands. These studies expand the information available on small molecule–RNA motif interactions, which could be useful to design ligands targeting RNA. PMID:19726586

  12. Preparation of 24 ternary thin film materials libraries on a single substrate in one experiment for irreversible high-throughput studies.

    PubMed

    Buenconsejo, Pio John S; Siegel, Alexander; Savan, Alan; Thienhaus, Sigurd; Ludwig, Alfred

    2012-01-01

    For different areas of combinatorial materials science, it is desirable to have multiple materials libraries: especially for irreversible high-throughput studies, like, for example, corrosion resistance testing in different media or annealing of complete materials libraries at different temperatures. Therefore a new combinatorial sputter-deposition process was developed which yields 24 materials libraries in one experiment on a single substrate. It is discussed with the example of 24 Ti-Ni-Ag materials libraries. They are divided based on the composition coverage and orientation of composition gradient into two sets of 12 nearly identical materials libraries. Each materials library covers at least 30-40% of the complete ternary composition range. An acid etch test in buffered-HF solution was performed, illustrating the feasibility of our approach for destructive materials characterization. The results revealed that within the composition range of Ni < 30 at.%, the films were severely etched. The composition range which shows reversible martensitic transformations was confirmed to be outside this region. The high output of the present method makes it attractive for combinatorial studies requiring multiple materials libraries. PMID:22126321

  13. Parallel combinatorial chemical synthesis using single-layer poly(dimethylsiloxane) microfluidic devices

    PubMed Central

    Dexter, Joseph P.; Parker, William

    2009-01-01

    Improving methods for high-throughput combinatorial chemistry has emerged as a major area of research because of the importance of rapidly synthesizing large numbers of chemical compounds for drug discovery and other applications. In this investigation, a novel microfluidic chip for performing parallel combinatorial chemical synthesis was developed. Unlike past microfluidic systems designed for parallel combinatorial chemistry, the chip is a single-layer device made of poly(dimethylsiloxane) that is extremely easy and inexpensive to fabricate. Using the chip, a 2×2 combinatorial series of amide-formation reactions was performed. The results of this combinatorial synthesis indicate that the new device is an effective platform for running parallel organic syntheses at significantly higher throughput than with past methodologies. Additionally, a design algorithm for scaling up the 2×2 combinatorial synthesis chip to address more complex cases was developed. PMID:20216962

  14. Evolution on folding landscapes in combinatorial structures

    SciTech Connect

    Fraser, S.M.; Reidys, C.M.

    1997-11-01

    In this paper the authors investigate the evolution of molecular structures by random point mutations. They will consider two types of molecular structures: (a) (RNA) secondary structures, and (b) random structures. In both cases structure consists of: (1) a contact graph, and (2) a family of relations imposed on its adjacent vertices. The vertex set of the contact graph is simply the set of all indices of a sequence, and its edges are the bonds. The corresponding relations associated with the edges are viewed as secondary base pairing rules and tertiary interaction rules respectively. Mapping of sequences into secondary and random structures are modeled and analyzed. Here, the set of all sequences that map into a particular structure is modeled as a random graph in the sequence space, the so called neutral network and they study how neutral networks are embedded in sequence space. A basic replication of deletion experiment reveals how effective secondary and random structures can be searched by random point mutations and to what extent the structure effects the dynamics of this optimization process. In particular the authors can report a nonlinear relation between the fraction of tertiary interactions in random structures, and the times taken for a population of sequences to find a high fitness target random structure.

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

    PubMed Central

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

    2016-01-01

    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. PMID:26481354

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

    PubMed

    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. PMID:26481354

  17. Combinatorial optimization of La, Ce-co-doped pyrosilicate phosphors as potential scintillator materials.

    PubMed

    Wei, Qinhua; Wan, Jieqiong; Liu, Guanghui; Zhou, Zhenzhen; Yang, Hua; Wang, Jiacheng; Liu, Qian

    2015-04-13

    A combinatorial method was employed to rapidly screen the effects of La, Ce-co-doping on the luminescent properties of Gd2Si2O7 pyrosilicate using an 8 × 8 library. The candidate formulations (Gd1-x-yLax)2Si2O7:Ce2y were evaluated by luminescence pictures under ultraviolet excitation. The optimal composition was found to be (Gd0.89La0.1)2Si2O7:Ce0.02 after scaled-up preparation and detailed characterization of powder samples, which shows an excellent light output under both ultraviolet and X-ray excitation (about 5.43 times of commercial YAG:Ce powders). The XRD results indicate that the phase structure sequence is tetragonal-orthorhombic-triclinic for different calcination temperatures and doping ions. The (Gd0.89La0.1)2Si2O7:Ce0.02 powder sample also demonstrated excellent temperature stability of luminescence up to 200 °C and a short decay time of several tens of nanoseconds, suggesting that this may represent a new kind of scintillation material, such as single crystals, ceramics, glass, or phosphors. PMID:25679047

  18. A combinatorial approach towards the design of nanofibrous scaffolds for chondrogenesis

    NASA Astrophysics Data System (ADS)

    Ahmed, Maqsood; Ramos, Tiago André Da Silva; Damanik, Febriyani; Quang Le, Bach; Wieringa, Paul; Bennink, Martin; van Blitterswijk, Clemens; de Boer, Jan; Moroni, Lorenzo

    2015-10-01

    The extracellular matrix (ECM) is a three-dimensional (3D) structure composed of proteinaceous fibres that provide physical and biological cues to direct cell behaviour. Here, we build a library of hybrid collagen-polymer fibrous scaffolds with nanoscale dimensions and screen them for their ability to grow chondrocytes for cartilage repair. Poly(lactic acid) and poly (lactic-co-glycolic acid) at two different monomer ratios (85:15 and 50:50) were incrementally blended with collagen. Physical properties (wettability and stiffness) of the scaffolds were characterized and related to biological performance (proliferation, ECM production, and gene expression) and structure-function relationships were developed. We found that soft scaffolds with an intermediate wettability composed of the highly biodegradable PLGA50:50 and collagen, in two ratios (40:60 and 60:40), were optimal for chondrogenic differentiation of ATDC5 cells as determined by increased ECM production and enhanced cartilage specific gene expression. Long-term cultures indicated a stable phenotype with minimal de-differentiation or hypertrophy. The combinatorial methodology applied herein is a promising approach for the design and development of scaffolds for regenerative medicine.

  19. A combinatorial approach towards the design of nanofibrous scaffolds for chondrogenesis.

    PubMed

    Ahmed, Maqsood; Ramos, Tiago André da Silva; Damanik, Febriyani; Quang Le, Bach; Wieringa, Paul; Bennink, Martin; van Blitterswijk, Clemens; de Boer, Jan; Moroni, Lorenzo

    2015-01-01

    The extracellular matrix (ECM) is a three-dimensional (3D) structure composed of proteinaceous fibres that provide physical and biological cues to direct cell behaviour. Here, we build a library of hybrid collagen-polymer fibrous scaffolds with nanoscale dimensions and screen them for their ability to grow chondrocytes for cartilage repair. Poly(lactic acid) and poly (lactic-co-glycolic acid) at two different monomer ratios (85:15 and 50:50) were incrementally blended with collagen. Physical properties (wettability and stiffness) of the scaffolds were characterized and related to biological performance (proliferation, ECM production, and gene expression) and structure-function relationships were developed. We found that soft scaffolds with an intermediate wettability composed of the highly biodegradable PLGA50:50 and collagen, in two ratios (40:60 and 60:40), were optimal for chondrogenic differentiation of ATDC5 cells as determined by increased ECM production and enhanced cartilage specific gene expression. Long-term cultures indicated a stable phenotype with minimal de-differentiation or hypertrophy. The combinatorial methodology applied herein is a promising approach for the design and development of scaffolds for regenerative medicine. PMID:26445026

  20. Sugar amino acid based scaffolds--novel peptidomimetics and their potential in combinatorial synthesis.

    PubMed

    Chakraborty, Tushar K; Jayaprakash, Sarva; Ghosh, Subhash

    2002-08-01

    To meet the growing demands for the development of new molecular entities for discovering new drugs and materials, organic chemists have started looking for new concepts to supplement traditional approaches. In one such approach, the expertise gained over the years in the area of organic synthesis and the rational drug-design concepts are combined together to create "nature-like" and yet unnatural organic molecules that are expected to provide leads in discovering new molecules. Emulating the basic principles followed by nature to build its vast repertoire of biomolecules, organic chemists are developing many novel multifunctional building blocks. Sugar amino acids constitute an important class of such polyfunctional scaffolds where the carboxyl, amino and hydroxyl groups provide an excellent opportunity for organic chemists to create structural diversities akin to nature's molecular arsenal. Recent advances in the area of combinatorial chemistry give unprecedented technological support for rapid compilations of sugar amino acid-based libraries exploiting the diversities of carbohydrate molecules and well-developed solid-phase peptide synthesis methods. This review chronicles the development of sugar amino acids as a novel class of peptidomimetic building blocks and their applications in generating desired secondary structures in peptides as well as in creating mimics of natural biopolymers. PMID:12180903

  1. A combinatorial approach towards the design of nanofibrous scaffolds for chondrogenesis

    PubMed Central

    Ahmed, Maqsood; Ramos, Tiago André da Silva; Damanik, Febriyani; Quang Le, Bach; Wieringa, Paul; Bennink, Martin; van Blitterswijk, Clemens; de Boer, Jan; Moroni, Lorenzo

    2015-01-01

    The extracellular matrix (ECM) is a three-dimensional (3D) structure composed of proteinaceous fibres that provide physical and biological cues to direct cell behaviour. Here, we build a library of hybrid collagen-polymer fibrous scaffolds with nanoscale dimensions and screen them for their ability to grow chondrocytes for cartilage repair. Poly(lactic acid) and poly (lactic-co-glycolic acid) at two different monomer ratios (85:15 and 50:50) were incrementally blended with collagen. Physical properties (wettability and stiffness) of the scaffolds were characterized and related to biological performance (proliferation, ECM production, and gene expression) and structure-function relationships were developed. We found that soft scaffolds with an intermediate wettability composed of the highly biodegradable PLGA50:50 and collagen, in two ratios (40:60 and 60:40), were optimal for chondrogenic differentiation of ATDC5 cells as determined by increased ECM production and enhanced cartilage specific gene expression. Long-term cultures indicated a stable phenotype with minimal de-differentiation or hypertrophy. The combinatorial methodology applied herein is a promising approach for the design and development of scaffolds for regenerative medicine. PMID:26445026

  2. Wafer-scale growth of VO2 thin films using a combinatorial approach

    PubMed Central

    Zhang, Hai-Tian; Zhang, Lei; Mukherjee, Debangshu; Zheng, Yuan-Xia; Haislmaier, Ryan C.; Alem, Nasim; Engel-Herbert, Roman

    2015-01-01

    Transition metal oxides offer functional properties beyond conventional semiconductors. Bridging the gap between the fundamental research frontier in oxide electronics and their realization in commercial devices demands a wafer-scale growth approach for high-quality transition metal oxide thin films. Such a method requires excellent control over the transition metal valence state to avoid performance deterioration, which has been proved challenging. Here we present a scalable growth approach that enables a precise valence state control. By creating an oxygen activity gradient across the wafer, a continuous valence state library is established to directly identify the optimal growth condition. Single-crystalline VO2 thin films have been grown on wafer scale, exhibiting more than four orders of magnitude change in resistivity across the metal-to-insulator transition. It is demonstrated that ‘electronic grade' transition metal oxide films can be realized on a large scale using a combinatorial growth approach, which can be extended to other multivalent oxide systems. PMID:26450653

  3. Libraries, Ebooks, and Competition

    ERIC Educational Resources Information Center

    Hellman, Eric

    2010-01-01

    People keep writing articles about how valuable libraries are, even with ebooks and the Internet. What people are overlooking is that the reason libraries are having such fits dealing with a changing environment is not that libraries are unrecognized as fountains of value, it's that libraries are so valuable that they attract voracious new…

  4. The Library Building Tomorrow.

    ERIC Educational Resources Information Center

    Waters, Richard L.

    1987-01-01

    Examination of the library of tomorrow speculates about the impact of changes in the functions of government, technology, demographics, lifestyle, and values on the role of the library. A facility for the contemporary public library is described that can both accommodate traditional services and respond to changes in the library's role. (17…

  5. School Libraries in Hawaii.

    ERIC Educational Resources Information Center

    Bard, Therese Bissen

    This paper outlines the history, functions, administration, and current focus of school library services in Hawaii, which is the only state in the United States with a library staffed by a trained librarian in every public school. Its first school library was established in 1882. Elementary school libraries developed concurrently with secondary…

  6. California: Library Information Technologies.

    ERIC Educational Resources Information Center

    Will, Barbara, Ed.

    1996-01-01

    Describes six information technology projects in California libraries, including Internet access in public libraries; digital library developments at the University of California, Berkeley; the World Wide Web home page for the state library; Pacific Bell's role in statewide connectivity; state government initiatives; and services of the state…

  7. Economics of Academic Libraries.

    ERIC Educational Resources Information Center

    Baumol, William J.; Marcus, Matityahu

    An analysis is conducted of economic issues pertinent to library planning in higher education in the face of rising costs and diminishing financial support. The individual chapters deal with: 1) growth rates in large university libraries; 2) library costs in colleges and universities; 3) cost trends and long-range plans; 4) library data; and 5) a…

  8. Alaska Library Directory, 1996.

    ERIC Educational Resources Information Center

    Jennings, Mary, Ed.

    This directory of Alaska's Libraries lists: members of the Alaska Library Association (AkLA) Executive Council and Committee Chairs; State Board of Education members; members of the Governor's Advisory Council on Libraries; school, academic and public libraries and their addresses, phone and fax numbers, and contact persons; personal,…

  9. Growing Competition for Libraries.

    ERIC Educational Resources Information Center

    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…

  10. The New Library Professional

    ERIC Educational Resources Information Center

    Wilder, Stanley

    2007-01-01

    This article discusses what the growing generation gap among library employees mean for academic research libraries and for the profession. Viewed collectively, the members of the under-35 cohort are a harbinger of a new kind of academic library professional, one whose traits bear directly on the ability of libraries to thrive amid the continuing…

  11. AMERICA 2000 Library Partnership.

    ERIC Educational Resources Information Center

    Office of Educational Research and Improvement (ED), Washington, DC.

    The United States Department of Education, the National Endowment for the Humanities, the Library of Congress, the National Commission on Libraries and Information Science, and the National Institute for Literacy have formed the AMERICA 2000 Library Partnership to support libraries in their work toward the six National Education Goals announced by…

  12. Conservation of Library Materials.

    ERIC Educational Resources Information Center

    Illinois Libraries, 1985

    1985-01-01

    Twelve articles cover books as artifacts; workstations for conservation of library materials; care of scrapbooks, albums, and photographs; map preservation; library environment; flood recovery; disaster prevention and preparedness; incorporating preservation into library organization; and bibliography of Chester Public Library (Illinois) First…

  13. The Bush Memorial Library.

    ERIC Educational Resources Information Center

    Hamline University Bulletin, 1971

    1971-01-01

    The Bush Memorial Library was formally dedicated on October 9, 1971. As part of Hamline University in St. Paul, Minnesota, the Bush Memorial Library has a reading room, audio booths, and audio-visual classroom as well as an audio control room. The Bush Memorial Library is a member of the Cooperating Libraries in Consortium which is a cooperative…

  14. Analytical reduction of combinatorial complexity arising from multiple protein modification sites.

    PubMed

    Birtwistle, Marc R

    2015-02-01

    Combinatorial complexity is a major obstacle to ordinary differential equation (ODE) modelling of biochemical networks. For example, a protein with 10 sites that can each be unphosphorylated, phosphorylated or bound to adaptor protein requires 3(10) ODEs. This problem is often dealt with by making ad hoc assumptions which have unclear validity and disallow modelling of site-specific dynamics. Such site-specific dynamics, however, are important in many biological systems. We show here that for a common biological situation where adaptors bind modified sites, binding is slow relative to modification/demodification, and binding to one modified site hinders binding to other sites, for a protein with n modification sites and m adaptor proteins the number of ODEs needed to simulate the site-specific dynamics of biologically relevant, lumped bound adaptor states is independent of the number of modification sites and equal to m + 1, giving a significant reduction in system size. These considerations can be relaxed considerably while retaining reasonably accurate descriptions of the true system dynamics. We apply the theory to model, using only 11 ODEs, the dynamics of ligand-induced phosphorylation of nine tyrosines on epidermal growth factor receptor (EGFR) and primary recruitment of six signalling proteins (Grb2, PI3K, PLCγ1, SHP2, RasA1 and Shc1). The model quantitatively accounts for experimentally determined site-specific phosphorylation and dephosphorylation rates, differential affinities of binding proteins for the phosphorylated sites and binding protein expression levels. Analysis suggests that local concentration of site-specific phosphatases such as SHP2 in membrane subdomains by a factor of approximately 10(7) is critical for effective site-specific regulation. We further show how our framework can be extended with minimal effort to consider binding cooperativity between Grb2 and c-Cbl, which is important for receptor trafficking. Our theory has potentially

  15. Time-dependent combinatory effects of active mechanical loading and passive topographical cues on cell orientation.

    PubMed

    Wang, Qian; Huang, Hanyang; Wei, Kang; Zhao, Yi

    2016-10-01

    Mechanical stretching and topographical cues are both effective mechanical stimulations for regulating cell morphology, orientation, and behaviors. The competition of these two mechanical stimulations remains largely underexplored. Previous studies have suggested that a small cyclic mechanical strain is not able to reorient cells that have been pre-aligned by relatively large linear microstructures, but can reorient those pre-aligned by small linear micro/nanostructures if the characteristic dimension of these structures is below a certain threshold. Likewise, for micro/nanostructures with a given characteristic dimension, the strain must exceed a certain magnitude to overrule the topographic cues. There are however no in-depth investigations of such "thresholds" due to the lack of close examination of dynamic cell orientation during and shortly after the mechanical loading. In this study, the time-dependent combinatory effects of active and passive mechanical stimulations on cell orientation are investigated by developing a micromechanical stimulator. The results show that the cells pre-aligned by linear micro/nanostructures can be altered by cyclic in-plane strain, regardless of the structure size. During the loading, the micro/nanostructures can resist the reorientation effects by cyclic in-plane strain while the resistive capability (measured by the mean orientation angle change and the reorientation speed) increases with the increasing characteristic dimension. The micro/nanostructures also can recover the cell orientation after the cessation of cyclic in-plane strain, while the recovering capability increases with the characteristic dimension. The previously observed thresholds are largely dependent on the observation time points. In order to accurately evaluate the combinatory effects of the two mechanical stimulations, observations during the active loading with a short time interval or endpoint observations shortly after the loading are preferred. This

  16. Constructing high complexity synthetic libraries of long ORFs using in vitro selection

    NASA Technical Reports Server (NTRS)

    Cho, G.; Keefe, A. D.; Liu, R.; Wilson, D. S.; Szostak, J. W.

    2000-01-01

    We present a method that can significantly increase the complexity of protein libraries used for in vitro or in vivo protein selection experiments. Protein libraries are often encoded by chemically synthesized DNA, in which part of the open reading frame is randomized. There are, however, major obstacles associated with the chemical synthesis of long open reading frames, especially those containing random segments. Insertions and deletions that occur during chemical synthesis cause frameshifts, and stop codons in the random region will cause premature termination. These problems can together greatly reduce the number of full-length synthetic genes in the library. We describe a strategy in which smaller segments of the synthetic open reading frame are selected in vitro using mRNA display for the absence of frameshifts and stop codons. These smaller segments are then ligated together to form combinatorial libraries of long uninterrupted open reading frames. This process can increase the number of full-length open reading frames in libraries by up to two orders of magnitude, resulting in protein libraries with complexities of greater than 10(13). We have used this methodology to generate three types of displayed protein library: a completely random sequence library, a library of concatemerized oligopeptide cassettes with a propensity for forming amphipathic alpha-helical or beta-strand structures, and a library based on one of the most common enzymatic scaffolds, the alpha/beta (TIM) barrel. Copyright 2000 Academic Press.

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

    ERIC Educational Resources Information Center

    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…

  18. Identifying combinatorial regulation of transcription factors and binding motifs

    PubMed Central

    Kato, Mamoru; Hata, Naoya; Banerjee, Nilanjana; Futcher, Bruce; Zhang, Michael Q

    2004-01-01

    Background Combinatorial interaction of transcription factors (TFs) is important for gene regulation. Although various genomic datasets are relevant to this issue, each dataset provides relatively weak evidence on its own. Developing methods that can integrate different sequence, expression and localization data have become important. Results Here we use a novel method that integrates chromatin immunoprecipitation (ChIP) data with microarray expression data and with combinatorial TF-motif analysis. We systematically identify combinations of transcription factors and of motifs. The various combinations of TFs involved multiple binding mechanisms. We reconstruct a new combinatorial regulatory map of the yeast cell cycle in which cell-cycle regulation can be drawn as a chain of extended TF modules. We find that the pairwise combination of a TF for an early cell-cycle phase and a TF for a later phase is often used to control gene expression at intermediate times. Thus the number of distinct times of gene expression is greater than the number of transcription factors. We also see that some TF modules control branch points (cell-cycle entry and exit), and in the presence of appropriate signals they can allow progress along alternative pathways. Conclusions Combining different data sources can increase statistical power as demonstrated by detecting TF interactions and composite TF-binding motifs. The original picture of a chain of simple cell-cycle regulators can be extended to a chain of composite regulatory modules: different modules may share a common TF component in the same pathway or a TF component cross-talking to other pathways. PMID:15287978

  19. Star clusters evolution simulation on basement of linguo- combinatorial approach

    NASA Astrophysics Data System (ADS)

    Ignatyev, Mikhail B.

    2015-08-01

    Each of the clusters of star systems can be described using linguo- combinatorial approach through a formula that determines the number of arbitrary factors in the structure of equivalent equations as the number of combinations of n by m + 1, where n - number of stars in the cluster, m - number of constraints imposed on the stars cluster(M.Ignatyev “The linguo- combinatorial simulation in modern physics”\\\\ J. of Modern Physics,USA, 2012, Vol.1, No 1, p.7-11). Such clusters can be multiple, they can be combined into larger clusters or clusters can decay based on the effect of the collective. For example, if we have two clusters are characterized by the number of arbitrary coefficients S1 and S2, wherem1 + 1 m2 + 1S1 = C S2 = Cn1 n2then by imposing general restrictions mcol we will havem1 + m2 + mcol +1Scol = Cn1 + n2At the same time, depending on the specific parameters can be Scol > S1 + S2, when the union in collective increases the adaptive capabilities, and can be Scol < S1 + S2, where adaptive capacity of less than the sum of the collective adaptation a possibly initial clusters. In the first case, we can observe the effect of the formation of new large clusters, in the second case - the collapse of large clusters into smaller ones. The report deals with the simulation of the evolution of star clusters on the basement of linguo- combinatorial approach.

  20. Combinatorial Gene Regulatory Functions Underlie Ultraconserved Elements in Drosophila

    PubMed Central

    Warnefors, Maria; Hartmann, Britta; Thomsen, Stefan; Alonso, Claudio R.

    2016-01-01

    Ultraconserved elements (UCEs) are discrete genomic elements conserved across large evolutionary distances. Although UCEs have been linked to multiple facets of mammalian gene regulation their extreme evolutionary conservation remains largely unexplained. Here, we apply a computational approach to investigate this question in Drosophila, exploring the molecular functions of more than 1,500 UCEs shared across the genomes of 12 Drosophila species. Our data indicate that Drosophila UCEs are hubs for gene regulatory functions and suggest that UCE sequence invariance originates from their combinatorial roles in gene control. We also note that the gene regulatory roles of intronic and intergenic UCEs (iUCEs) are distinct from those found in exonic UCEs (eUCEs). In iUCEs, transcription factor (TF) and epigenetic factor binding data strongly support iUCE roles in transcriptional and epigenetic regulation. In contrast, analyses of eUCEs indicate that they are two orders of magnitude more likely than the expected to simultaneously include protein-coding sequence, TF-binding sites, splice sites, and RNA editing sites but have reduced roles in transcriptional or epigenetic regulation. Furthermore, we use a Drosophila cell culture system and transgenic Drosophila embryos to validate the notion of UCE combinatorial regulatory roles using an eUCE within the Hox gene Ultrabithorax and show that its protein-coding region also contains alternative splicing regulatory information. Taken together our experiments indicate that UCEs emerge as a result of combinatorial gene regulatory roles and highlight common features in mammalian and insect UCEs implying that similar processes might underlie ultraconservation in diverse animal taxa. PMID:27247329

  1. Combinatorial Gene Regulatory Functions Underlie Ultraconserved Elements in Drosophila.

    PubMed

    Warnefors, Maria; Hartmann, Britta; Thomsen, Stefan; Alonso, Claudio R

    2016-09-01

    Ultraconserved elements (UCEs) are discrete genomic elements conserved across large evolutionary distances. Although UCEs have been linked to multiple facets of mammalian gene regulation their extreme evolutionary conservation remains largely unexplained. Here, we apply a computational approach to investigate this question in Drosophila, exploring the molecular functions of more than 1,500 UCEs shared across the genomes of 12 Drosophila species. Our data indicate that Drosophila UCEs are hubs for gene regulatory functions and suggest that UCE sequence invariance originates from their combinatorial roles in gene control. We also note that the gene regulatory roles of intronic and intergenic UCEs (iUCEs) are distinct from those found in exonic UCEs (eUCEs). In iUCEs, transcription factor (TF) and epigenetic factor binding data strongly support iUCE roles in transcriptional and epigenetic regulation. In contrast, analyses of eUCEs indicate that they are two orders of magnitude more likely than the expected to simultaneously include protein-coding sequence, TF-binding sites, splice sites, and RNA editing sites but have reduced roles in transcriptional or epigenetic regulation. Furthermore, we use a Drosophila cell culture system and transgenic Drosophila embryos to validate the notion of UCE combinatorial regulatory roles using an eUCE within the Hox gene Ultrabithorax and show that its protein-coding region also contains alternative splicing regulatory information. Taken together our experiments indicate that UCEs emerge as a result of combinatorial gene regulatory roles and highlight common features in mammalian and insect UCEs implying that similar processes might underlie ultraconservation in diverse animal taxa. PMID:27247329

  2. Discovery of methanol electro-oxidation catalysts by combinatorial analysis

    SciTech Connect

    Mallouk, T.E.; Reddington, E.; Pu, C.

    1996-12-31

    Hydrogen fuel cells are likely to become a major energy source in the next century, but they are not ideal for all applications. A safe alternative fuel with a high energy density will be necessary for transportation and mobile applications. Direct methanol-air fuel cells (DMFCs) are an attractive alternative to hydrogen fuel cells because of the high energy density and low cost of methanol as a fuel. However, in order for DMFCs to become commercially viable, better electrocatalysts for the anode reaction need to be developed. This paper describes a combinatorial technique for generating an array of electrodes with varying metal compositions.

  3. A macromolecular prodrug strategy for combinatorial drug delivery.

    PubMed

    Li, Nan-Nan; Lin, Jiantao; Gao, Di; Zhang, Li-Ming

    2014-03-01

    A novel macromolecular prodrug strategy was developed for the combinatorial delivery of two poorly water-soluble drugs, dexamethasone and doxorubicin. In this work, dexamethasone was firstly conjugated onto a water-soluble modified polysaccharide by an acid-labile hydrazone linkage. The resultant macromolecular prodrug had an amphiphilic character and could self-assemble into spherical polymeric micelles in aqueous system. With these micelles, doxorubicin was then encapsulated into their hydrophobic cores. For the conjugated dexamethasone and encapsulated doxorubicin, they could exhibit independent and acid-sensitive release characteristics. For the doxorubicin-loaded prodrug micelles, they were easily be internalized by living cells and showed obvious antitumor activity. PMID:24407691

  4. Strategies for the discovery of new catalysts with combinatorial chemistry

    NASA Astrophysics Data System (ADS)

    Kirsten, Guido; Maier, Wilhelm F.

    2004-02-01

    The combination of random selection and evolutionary strategies with the high-throughput approaches of combinatorial chemistry is demonstrated for the discovery of new heterogeneous catalysts. An approach entirely based on software control was used and a high degree of automation could be achieved. As model reaction we chose CO-oxidation and used heats of reactions monitored by emissivity corrected IR-thermography as figure of merit. New catalysts compositions have been discovered. The catalytic activity of selected compositions was confirmed by conventional catalyst preparation and testing with a conventional fixed bed reactor. Multi-element materials appear to dominate the catalyst evolution.

  5. A matrix product state method for solving combinatorial optimization problems

    NASA Astrophysics Data System (ADS)

    Pelton, S. S.; Chamon, C.; Mucciolo, E. R.

    2015-03-01

    We present a method based on a matrix product state representation to solve combinatorial optimization problems. All constraints are met by mapping Boolean gates into projection operators and applying operators sequentially. The method provides exact solutions with high success probability, even in the case of frustrated systems. The computational cost of the method is controlled by the maximum relative entropy of the system. Results of numerical simulations for several types of problems will be shown and discussed. NSF Grants CCF-1116590 and CCF-1117241.

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

    PubMed

    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. PMID:25023617

  7. A solid-phase combinatorial approach for indoloquinolizidine-peptides with high affinity at D(1) and D(2) dopamine receptors.

    PubMed

    Molero, Anabel; Vendrell, Marc; Bonaventura, Jordi; Zachmann, Julian; López, Laura; Pardo, Leonardo; Lluis, Carme; Cortés, Antoni; Albericio, Fernando; Casadó, Vicent; Royo, Miriam

    2015-06-01

    Ligands acting at multiple dopamine receptors hold potential as therapeutic agents for a number of neurodegenerative disorders. Specifically, compounds able to bind at D1R and D2R with high affinity could restore the effects of dopamine depletion and enhance motor activation on degenerated nigrostriatal dopaminergic systems. We have directed our research towards the synthesis and characterisation of heterocycle-peptide hybrids based on the indolo[2,3-a]quinolizidine core. This privileged structure is a water-soluble and synthetically accessible scaffold with affinity for diverse GPCRs. Herein we have prepared a solid-phase combinatorial library of 80 indoloquinolizidine-peptides to identify compounds with enhanced binding affinity at D2R, a receptor that is crucial to re-establish activity on dopamine-depleted degenerated GABAergic neurons. We applied computational tools and high-throughput screening assays to identify 9a{1,3,3} as a ligand for dopamine receptors with nanomolar affinity and agonist activity at D2R. Our results validate the application of indoloquinolizidine-peptide combinatorial libraries to fine-tune the pharmacological profiles of multiple ligands at D1 and D2 dopamine receptors. PMID:25969169

  8. Molecular Library Synthesis Using Complex Substrates: Expanding the Framework of Triterpenoids

    PubMed Central

    Ignatenko, Vasily A.; Han, Yong; Tochtrop, Gregory P.

    2013-01-01

    The remodelling of a natural product core framework by means of diversity-oriented synthesis (DOS) is a valuable approach to access diverse/biologically relevant chemical space and to overcome the limitations of combinatorial-type compounds. Here we provide proof of principle and a thorough conformational analysis for a general strategy whereby the inherent complexity of a starting material is used to define the regio- and stereochemical outcomes of reactions in chemical library construction. This is in contrast to the traditional DOS logic employing reaction development and catalysis to drive library diversity PMID:23245400

  9. To Think without Thinking: The Implications of Combinatory Play and the Creative Process for Neuroaesthetics

    ERIC Educational Resources Information Center

    Stevens, Victoria

    2014-01-01

    The author considers combinatory play as an intersection between creativity, play, and neuroaesthetics. She discusses combinatory play as vital to the creative process in art and science, particularly with regard to the incubation of new ideas. She reviews findings from current neurobiological research and outlines the way that the brain activates…

  10. A barcode-free combinatorial screening platform for matrix metalloproteinase screening.

    PubMed

    Rane, Tushar D; Zec, Helena C; Wang, Tza-Huei

    2015-02-01

    Application of droplet microfluidics to combinatorial screening applications remains elusive because of the need for composition-identifying unique barcodes. Here we propose a barcode-free continuous flow droplet microfluidic platform to suit the requirements of combinatorial screening applications. We demonstrate robust and repeatable functioning of this platform with matrix metalloproteinase activity screening as a sample application. PMID:25543856

  11. A Barcode-Free Combinatorial Screening Platform for Matrix Metalloproteinase Screening

    PubMed Central

    2015-01-01

    Application of droplet microfluidics to combinatorial screening applications remains elusive because of the need for composition-identifying unique barcodes. Here we propose a barcode-free continuous flow droplet microfluidic platform to suit the requirements of combinatorial screening applications. We demonstrate robust and repeatable functioning of this platform with matrix metalloproteinase activity screening as a sample application. PMID:25543856

  12. Combinatorial influence of environmental parameters on transcription factor activity

    PubMed Central

    Knijnenburg, T.A.; Wessels, L.F.A.; Reinders, M.J.T.

    2008-01-01

    Motivation: Cells receive a wide variety of environmental signals, which are often processed combinatorially to generate specific genetic responses. Changes in transcript levels, as observed across different environmental conditions, can, to a large extent, be attributed to changes in the activity of transcription factors (TFs). However, in unraveling these transcription regulation networks, the actual environmental signals are often not incorporated into the model, simply because they have not been measured. The unquantified heterogeneity of the environmental parameters across microarray experiments frustrates regulatory network inference. Results: We propose an inference algorithm that models the influence of environmental parameters on gene expression. The approach is based on a yeast microarray compendium of chemostat steady-state experiments. Chemostat cultivation enables the accurate control and measurement of many of the key cultivation parameters, such as nutrient concentrations, growth rate and temperature. The observed transcript levels are explained by inferring the activity of TFs in response to combinations of cultivation parameters. The interplay between activated enhancers and repressors that bind a gene promoter determine the possible up- or downregulation of the gene. The model is translated into a linear integer optimization problem. The resulting regulatory network identifies the combinatorial effects of environmental parameters on TF activity and gene expression. Availability: The Matlab code is available from the authors upon request. Contact: t.a.knijnenburg@tudelft.nl Supplementary information: Supplementary data are available at Bioinformatics online. PMID:18586711

  13. Combinatorial function of ETS transcription factors in the developing vasculature

    PubMed Central

    Pham, Van N.; Lawson, Nathan D.; Mugford, Joshua W.; Dye, Louis; Castranova, Daniel; Lo, Brigid; Weinstein, Brant M.

    2007-01-01

    Members of the ETS family of transcription factors are among the first genes expressed in the developing vasculature, but loss-of-function experiments for individual ETS factors in mice have not uncovered important early functional roles for these genes. However, multiple ETS factors are expressed in spatially and temporally overlapping patterns in the developing vasculature, suggesting possible functional overlap. We have taken a comprehensive approach to exploring the function of these factors during vascular development by employing the genetic and experimental tools available in the zebrafish to analyze four ETS family members expressed together in the zebrafish vasculature; fli1, fli1b, ets1, and etsrp. We isolated and characterized an ENU-induced mutant with defects in trunk angiogenesis and positionally cloned the defective gene from this mutant, etsrp. Using the etsrp morpholinos targeting each of the four genes, we show that the four ETS factors function combinatorially during vascular and hematopoietic development. Reduction of etsrp or any of the other genes alone results in either partial or no defects in endothelial differentiation, while combined reduction in the function of all four genes causes dramatic loss of endothelial cells. Our results demonstrate that combinatorial ETS factor function is essential for early endothelial specification and differentiation. PMID:17125762

  14. Combinatorial approach to cancer immunotherapy: strength in numbers.

    PubMed

    Vilgelm, Anna E; Johnson, Douglas B; Richmond, Ann

    2016-08-01

    Immune-checkpoint blockade therapy with antibodies targeting CTLA-4 and PD-1 has revolutionized melanoma treatment by eliciting responses that can be remarkably durable and is now advancing to other malignancies. However, not all patients respond to immune-checkpoint inhibitors. Extensive preclinical evidence suggests that combining immune-checkpoint inhibitors with other anti-cancer treatments can greatly improve the therapeutic benefit. The first clinical success of the combinatorial approach to cancer immunotherapy was demonstrated using a dual-checkpoint blockade with CTLA-4 and PD-1 inhibitors, which resulted in accelerated FDA approval of this therapeutic regimen. In this review, we discuss the combinations of current and emerging immunotherapeutic agents in clinical and preclinical development and summarize the insights into potential mechanisms of synergistic anti-tumor activity gained from animal studies. These promising combinatorial partners for the immune-checkpoint blockade include therapeutics targeting additional inhibitory receptors of T cells, such as TIM-3, LAG-3, TIGIT, and BTLA, and agonists of T cell costimulatory receptors 4-1BB, OX40, and GITR, as well as agents that promote cancer cell recognition by the immune system, such as tumor vaccines, IDO inhibitors, and agonists of the CD40 receptor of APCs. We also review the therapeutic potential of regimens combining the immune-checkpoint blockade with therapeutic interventions that have been shown to enhance immunogenicity of cancer cells, including oncolytic viruses, RT, epigenetic therapy, and senescence-inducing therapy. PMID:27256570

  15. A combinatorial approach to diffeomorphism invariant quantum gauge theories

    SciTech Connect

    Zapata, J.A.

    1997-11-01

    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 {ital 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} {ital 1997 American Institute of Physics.}

  16. Novel Heterotypic Rox Sites for Combinatorial Dre Recombination Strategies

    PubMed Central

    Chuang, Katherine; Nguyen, Eileen; Sergeev, Yuri; Badea, Tudor C.

    2015-01-01

    Site-specific recombinases (SSRs) such as Cre are widely used in gene targeting and genetic approaches for cell labeling and manipulation. They mediate DNA strand exchange between two DNA molecules at dedicated recognition sites. Precise understanding of the Cre recombination mechanism, including the role of individual base pairs in its loxP target site, guided the generation of mutant lox sites that specifically recombine with themselves but not with the wild type loxP. This has led to the development of a variety of combinatorial Cre-dependent genetic strategies, such as multicolor reporters, irreversible inversions, or recombination-mediated cassette exchange. Dre, a Cre-related phage integrase that recognizes roxP sites, does not cross-react with the Cre-loxP system, but has similar recombination efficiency. We have previously described intersectional genetic strategies combining Dre and Cre. We now report a mutagenesis screen aimed at identifying roxP base pairs critical for self-recognition. We describe several rox variant sites that are incompatible with roxP, but are able to efficiently recombine with themselves in either purified systems or bacterial and eukaryotic tissue culture systems. These newly identified rox sites are not recognized by Cre, thus enabling potential combinatorial strategies involving Cre, Dre, and target loci including multiple loxP and roxP variants. PMID:26715092

  17. A combinatorial approach to the design of vaccines.

    PubMed

    Martínez, Luis; Milanič, Martin; Legarreta, Leire; Medvedev, Paul; Malaina, Iker; de la Fuente, Ildefonso M

    2015-05-01

    We present two new problems of combinatorial optimization and discuss their applications to the computational design of vaccines. In the shortest λ-superstring problem, given a family S1,...,S(k) of strings over a finite alphabet, a set Τ of "target" strings over that alphabet, and an integer λ, the task is to find a string of minimum length containing, for each i, at least λ target strings as substrings of S(i). In the shortest λ-cover superstring problem, given a collection X1,...,X(n) of finite sets of strings over a finite alphabet and an integer λ, the task is to find a string of minimum length containing, for each i, at least λ elements of X(i) as substrings. The two problems are polynomially equivalent, and the shortest λ-cover superstring problem is a common generalization of two well known combinatorial optimization problems, the shortest common superstring problem and the set cover problem. We present two approaches to obtain exact or approximate solutions to the shortest λ-superstring and λ-cover superstring problems: one based on integer programming, and a hill-climbing algorithm. An application is given to the computational design of vaccines and the algorithms are applied to experimental data taken from patients infected by H5N1 and HIV-1. PMID:24859149

  18. Combinatorial metabolic engineering of Saccharomyces cerevisiae for terminal alkene production.

    PubMed

    Chen, Binbin; Lee, Dong-Yup; Chang, Matthew Wook

    2015-09-01

    Biological production of terminal alkenes has garnered a significant interest due to their industrial applications such as lubricants, detergents and fuels. Here, we engineered the yeast Saccharomyces cerevisiae to produce terminal alkenes via a one-step fatty acid decarboxylation pathway and improved the alkene production using combinatorial engineering strategies. In brief, we first characterized eight fatty acid decarboxylases to enable and enhance alkene production. We then increased the production titer 7-fold by improving the availability of the precursor fatty acids. We additionally increased the titer about 5-fold through genetic cofactor engineering and gene expression tuning in rich medium. Lastly, we further improved the titer 1.8-fold to 3.7 mg/L by optimizing the culturing conditions in bioreactors. This study represents the first report of terminal alkene biosynthesis in S. cerevisiae, and the abovementioned combinatorial engineering approaches collectively increased the titer 67.4-fold. We envision that these approaches could provide insights into devising engineering strategies to improve the production of fatty acid-derived biochemicals in S. cerevisiae. PMID:26164646

  19. Single-Parameter Combinatorial Auctions with Partially Public Valuations

    NASA Astrophysics Data System (ADS)

    Goel, Gagan; Karande, Chinmay; Wang, Lei

    We consider the problem of designing truthful auctions, when the bidders' valuations have a public and a private component. In particular, we consider combinatorial auctions where the valuation of an agent i for a set S of items can be expressed as v i f(S), where v i is a private single parameter of the agent, and the function f is publicly known. Our motivation behind studying this problem is two-fold: (a) Such valuation functions arise naturally in the case of ad-slots in broadcast media such as Television and Radio. For an ad shown in a set S of ad-slots, f(S) is, say, the number of unique viewers reached by the ad, and v i is the valuation per-unique-viewer. (b) From a theoretical point of view, this factorization of the valuation function simplifies the bidding language, and renders the combinatorial auction more amenable to better approximation factors. We present a general technique, based on maximal-in-range mechanisms, that converts any α-approximation non-truthful algorithm (α ≤ 1) for this problem into Ω(α/log{n}) and Ω(α)-approximate truthful mechanisms which run in polynomial time and quasi-polynomial time, respectively.

  20. Combinatorial evolution of regression nodes in feedforward neural networks.

    PubMed

    Schmitz, Gregor P.J.; Aldrich, Chris

    1999-01-01

    A number of techniques exist with which neural network architectures such as multilayer perceptrons and radial basis function networks can be trained. These include backpropagation, k-means clustering and evolutionary algorithms. The latter method is particularly useful as it is able to avoid local optima in the search space and can optimise parameters for which no gradient information exists. Unfortunately, only moderately sized networks can be trained by this method, owing to the fact that evolutionary optimisation is very computationally intensive. In this paper a novel algorithm (CERN) is therefore proposed which uses a special form of combinatorial search to optimise groups of neural nodes. Oriented, ellipsoidal basis nodes optimised with CERN achieved significantly better accuracy with fewer nodes than spherical basis nodes optimised by k-means clustering. Multilayer perceptrons optimised by CERN were found to be as accurate as those trained by advanced gradient descent techniques. CERN was also found to be significantly more efficient than a conventional evolutionary algorithm that does not use a combinatorial search. PMID:12662726

  1. Art Libraries Section. Special Libraries Division. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    Papers on art libraries and information services for the arts, which were presented at the 1983 International Federation of Library Associations (IFLA) conference, include: (1) "'I See All': Information Technology and the Universal Availability of Images" by Philip Pacey (United Kingdom); (2) "Online Databases in the Fine Arts" by Michael Rinehart…

  2. Fragment based G-QSAR and molecular dynamics based mechanistic simulations into hydroxamic-based HDAC inhibitors against spinocerebellar ataxia.

    PubMed

    Sinha, Siddharth; Tyagi, Chetna; Goyal, Sukriti; Jamal, Salma; Somvanshi, Pallavi; Grover, Abhinav

    2016-10-01

    Expansion of polyglutamine (CAG) triplets within the coding gene ataxin 2 results in transcriptional repression, forming the molecular basis of the neurodegenerative disorder named spinocerebellar ataxia type-2 (SCA2). HDAC inhibitors (HDACi) have been elements of great interest in polyglutamine disorders such as Huntington's and Ataxia's. In this study, we have selected hydroxamic acid derivatives as HDACi and performed fragment-based G-QSAR, molecular docking studies and molecular dynamics simulations for elucidating the dynamic mode of action of HDACi with His-Asp catalytic dyad of HDAC4. The model was statistically validated to establish its predictive robustness. The model was statistically significant with r(2) value of .6297, cross-validated co-relation coefficient q(2) value of .5905 and pred_r(2) (predicted square co-relation coefficient) value of .85. An F-test value of 56.11 confirms absolute robustness of the model. Two combinatorial libraries comprising of 3180 compounds were created with hydroxamate moiety as the template and their pIC50 activities were predicted based on the G-QSAR model. The combinatorial library created was screened on the basis of predicted activity (pIC50), with two resultant top scoring compounds, HIC and DHC. The interaction of the compounds with His-Asp dyad in terms of H-bond interactions with His802, Asp840, Pro942, and Gly975 residues of HDAC4 was evaluated by docking and 20 ns long molecular dynamics simulations. This study provides valuable leads for structural substitutions required for hydroxamate moiety to exhibit enhanced inhibitory activity against HDAC4. The reported compounds demonstrated good binding and thus can be considered as potent therapeutic leads against ataxia. PMID:26510381

  3. High-throughput screening of thin-film semiconductor material libraries II: characterization of Fe-W-O libraries.

    PubMed

    Meyer, Robert; Sliozberg, Kirill; Khare, Chinmay; Schuhmann, Wolfgang; Ludwig, Alfred

    2015-04-13

    Metal oxides are promising materials for solar water splitting. To identify suitable materials within the ternary system FeWO, thin-film material libraries with combined thickness and compositional gradients were synthesized by combinatorial reactive magnetron sputtering. These libraries (>1000 different samples) were investigated by means of structural and functional high-throughput characterization techniques to establish correlations between composition, crystallinity, morphology, thickness, and photocurrent density in the compositional range between (Fe6 W94 )Ox and (Fe61 W39 )Ox . In addition to the well-known phase WO3 , the binary phase W5 O14 and the ternary phase Fe2 O6 W show enhanced photoelectrochemical activity. The highest photocurrent density of 65 μA cm(-2) was achieved for the composition (Fe15 W85 )Ox , which contains the W5 O14 phase and has a thickness of 1060 nm. PMID:25727483

  4. The Libraries of Rio.

    ERIC Educational Resources Information Center

    Foster, Barbara

    1988-01-01

    Describes aspects of several libraries in Rio de Janeiro. Topics covered include library policies, budgets, periodicals and books in the collections, classification schemes used, and literary areas of interest to patrons. (6 references) (CLB)

  5. Facility Focus: Libraries.

    ERIC Educational Resources Information Center

    College Planning & Management, 2003

    2003-01-01

    Describes the designs of the Ferris State University Library for Information, Technology and Education (FLITE), and the Meyer Library and Information Technology Center at Southwest Missouri State University. Includes photographs. (EV)

  6. Selecting Library Furniture & Equipment.

    ERIC Educational Resources Information Center

    Media & Methods, 1997

    1997-01-01

    Offers suggestions for selecting school library furniture and equipment. Describes various models of computer workstations; reading tables and chairs; and shelving. Sidebar lists names and addresses of library furniture manufactures and distributors. (AEF)

  7. Medical Library Association

    MedlinePlus

    ... 11th, 2016 Patricia Flatley Brennan, registered nurse, informatician, industrial engineer, and renowned researcher is appointed as Director of the National Library of Medicine Tweets Copyright © 2016 Medical Library Association. ...

  8. Israeli Special Libraries

    ERIC Educational Resources Information Center

    Foster, Barbara

    1974-01-01

    Israel is sprinkled with a noteworthy representation of special libraries which run the gamut from modest kibbutz efforts to highly technical scientific and humanities libraries. A few examples are discussed here. (Author/CH)

  9. Computer-assisted combinatorial design of bicyclic thymidine analogs as inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase.

    PubMed

    Frecer, Vladimir; Seneci, Pierfausto; Miertus, Stanislav

    2011-01-01

    Thymidine monophosphate kinase (TMPK(mt)) is an essential enzyme for nucleotide metabolism in Mycobacterium tuberculosis, and thus an attractive target for novel antituberculosis agents. In this work, we have explored the chemical space around the 2',3'-bicyclic thymidine nucleus by designing and in silico screening of a virtual focused library selected via structure based methods to identify more potent analogs endowed with favorable ADME-related properties. In all the library members we have exchanged the ribose ring of the template with a cyclopentane moiety that is less prone to enzymatic degradation. In addition, we have replaced the six-membered 2',3'-ring by a number of five-membered and six-membered heterocyclic rings containing alternative proton donor and acceptor groups, to exploit the interaction with the carboxylate groups of Asp9 and Asp163 as well as with several cationic residues present in the vicinity of the TMPK(mt) binding site. The three-dimensional structure of the TMPK(mt) complexed with 5-hydroxymethyl-dUMP, an analog of dTMP, was employed to develop a QSAR model, to parameterize a scoring function specific for the TMPK(mt) target and to select analogues which display the highest predicted binding to the target. As a result, we identified a small highly focused combinatorial subset of bicyclic thymidine analogues as virtual hits that are predicted to inhibit the mycobacterial TMPK in the submicromolar concentration range and to display favorable ADME-related properties. PMID:21082329

  10. Finding the Right Candidate for the Right Position: A Fast NMR-Assisted Combinatorial Method for Optimizing Nucleic Acids Binders.

    PubMed

    Jiménez-Moreno, Ester; Montalvillo-Jiménez, Laura; Santana, Andrés G; Gómez, Ana M; Jiménez-Osés, Gonzalo; Corzana, Francisco; Bastida, Agatha; Jiménez-Barbero, Jesús; Cañada, Francisco Javier; Gómez-Pinto, Irene; González, Carlos; Asensio, Juan Luis

    2016-05-25

    Development of strong and selective binders from promiscuous lead compounds represents one of the most expensive and time-consuming tasks in drug discovery. We herein present a novel fragment-based combinatorial strategy for the optimization of multivalent polyamine scaffolds as DNA/RNA ligands. Our protocol provides a quick access to a large variety of regioisomer libraries that can be tested for selective recognition by combining microdialysis assays with simple isotope labeling and NMR experiments. To illustrate our approach, 20 small libraries comprising 100 novel kanamycin-B derivatives have been prepared and evaluated for selective binding to the ribosomal decoding A-Site sequence. Contrary to the common view of NMR as a low-throughput technique, we demonstrate that our NMR methodology represents a valuable alternative for the detection and quantification of complex mixtures, even integrated by highly similar or structurally related derivatives, a common situation in the context of a lead optimization process. Furthermore, this study provides valuable clues about the structural requirements for selective A-site recognition. PMID:27123740

  11. Electrochemical synthesis and reactivity screening of a ternary composition gradient for combinatorial discovery of fuel cell catalysts

    NASA Astrophysics Data System (ADS)

    Jayaraman, S.; Hillier, A. C.

    2005-01-01

    This paper describes a method for synthesis of multi-component gradient libraries for combinatorial catalyst discovery. A 'gel-transfer' synthesis method is demonstrated that involves localized diffusion of aqueous precursor metal salts into a hydrated gel to establish spatially varying concentration fields. Electrodeposition is then used to transfer the gradient in metal precursors to a surface. To illustrate the utility of this method, a platinum-ruthenium-rhodium (PtxRuyRhz) catalyst gradient was constructed, and its reactivity towards several fuel cell reactions evaluated. An optical screening technique based upon the pH-sensitive fluorescence of quinine was used to visualize the spatial onset of reactivity on the ternary catalyst gradient. The evolution of protons from several reactions of interest for low temperature fuel cells was visualized by quinine fluorescence. The oxidation of hydrogen, carbon monoxide, methanol and ethanol were tested on the catalyst library. Catalyst regions that exhibited fluorescence (and hence the onset of activity) at lowest potentials were identified for each of the above reactions.

  12. Bookmarking Your Library's Teens.

    ERIC Educational Resources Information Center

    Williams, Mary Pasek

    1999-01-01

    Describes one public library's project of photographing teenagers reading around the library and making the photos into bookmarks with the library logo and a "read" message. Discusses the background, arrangements, photo session, assembly, distribution and publicity, and funding and community response. (AEF)

  13. The End of Libraries.

    ERIC Educational Resources Information Center

    Thompson, James

    1983-01-01

    Suggests that if librarians and libraries are to continue to fulfill their true tasks, they need to adapt to changes resulting from new technology and overcome the professional paralysis that has made most major libraries largely unusable. Problems of size, arrangement, and catalogs are identified as contributors to unusable library. (EJS)

  14. Library Studies I Workbook.

    ERIC Educational Resources Information Center

    Frost, William J.

    Developed for use in the Library Studies I component of the Library Studies Program at Bloomsburg University (Pennsylvania), this self-paced workbook is intended to acquaint students with the Harvey A. Andruss Library and help them develop information-seeking skills. The workbook is designed to be used in conjunction with an exercise book, and…

  15. Art for Libraries' Sake.

    ERIC Educational Resources Information Center

    Lugo, Mark-Elliot

    1999-01-01

    Illustrates the benefits of an aggressive library program of regularly scheduled and professionally curated art exhibitions and related events. Describes the Visual Arts Program at the Pacific Beach branch library (San Diego). A sidebar by Debra Wilcox Johnson discusses libraries' development of cultural programming for adults. (AEF)

  16. California Library Laws, 2009

    ERIC Educational Resources Information Center

    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.…

  17. California Library Laws, 2008

    ERIC Educational Resources Information Center

    Smith, Paul G., Ed.

    2008-01-01

    "California Library Laws 2008" 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…

  18. A Library That Swings

    ERIC Educational Resources Information Center

    Spragens, Thomas A.

    1971-01-01

    The Grace Doherty Library (Centre College, Danville, Kentucky) is a library that "swings," being so designed that a substantial part of its space is used alternately for classroom purposes during the day and for library reading-study space in the peak evening hours. (Author)

  19. School Libraries in Fiji.

    ERIC Educational Resources Information Center

    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. Marketing Academic Libraries

    ERIC Educational Resources Information Center

    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…