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Sample records for design rational snake

  1. Identification of new snake venom metalloproteinase inhibitors using compound screening and rational Peptide design.

    PubMed

    Villalta-Romero, Fabián; Gortat, Anna; Herrera, Andrés E; Arguedas, Rebeca; Quesada, Javier; de Melo, Robson Lopes; Calvete, Juan J; Montero, Mavis; Murillo, Renato; Rucavado, Alexandra; Gutiérrez, José María; Pérez-Payá, Enrique

    2012-07-12

    The majority of snakebite envenomations in Central America are caused by the viperid species Bothrops asper, whose venom contains a high proportion of zinc-dependent metalloproteinases that play a relevant role in the pathogenesis of hemorrhage characteristic of these envenomations. Broad metalloproteinase inhibitors, such as the peptidomimetic hydroxamate Batimastat, have been shown to inhibit snake venom metalloproteinases (SVMP). However, the difficulty in having open public access to Batimastat and similar molecules highlights the need to design new inhibitors of SVMPs that could be applied in the treatment of snakebite envenomations. We have chosen the SVMP BaP1 as a model to search for new inhibitors using different strategies, that is, screening of the Prestwick Chemical Library and rational peptide design. Results from these approaches provide clues on the structural requirements for efficient BaP1 inhibition and pave the way for the design of new inhibitors of SVMP. PMID:24900507

  2. Identification of New Snake Venom Metalloproteinase Inhibitors Using Compound Screening and Rational Peptide Design

    PubMed Central

    2012-01-01

    The majority of snakebite envenomations in Central America are caused by the viperid species Bothrops asper, whose venom contains a high proportion of zinc-dependent metalloproteinases that play a relevant role in the pathogenesis of hemorrhage characteristic of these envenomations. Broad metalloproteinase inhibitors, such as the peptidomimetic hydroxamate Batimastat, have been shown to inhibit snake venom metalloproteinases (SVMP). However, the difficulty in having open public access to Batimastat and similar molecules highlights the need to design new inhibitors of SVMPs that could be applied in the treatment of snakebite envenomations. We have chosen the SVMP BaP1 as a model to search for new inhibitors using different strategies, that is, screening of the Prestwick Chemical Library and rational peptide design. Results from these approaches provide clues on the structural requirements for efficient BaP1 inhibition and pave the way for the design of new inhibitors of SVMP. PMID:24900507

  3. Snakes! Snakes! Snakes!

    ERIC Educational Resources Information Center

    Nature Naturally, 1983

    1983-01-01

    Designed for students in grades 4-6, the teaching unit presents illustrations and facts about snakes. Topics include common snakes found in the United States, how snakes eat, how snakes shed their skin, poisonous snakes, the Eastern Indigo snake, and the anatomy of a snake. A student page includes a crossword puzzle and surprising snake facts. A…

  4. Rational design of helical architectures

    PubMed Central

    Chakrabarti, Dwaipayan; Fejer, Szilard N.; Wales, David J.

    2009-01-01

    Nature has mastered the art of creating complex structures through self-assembly of simpler building blocks. Adapting such a bottom-up view provides a potential route to the fabrication of novel materials. However, this approach suffers from the lack of a sufficiently detailed understanding of the noncovalent forces that hold the self-assembled structures together. Here we demonstrate that nature can indeed guide us, as we explore routes to helicity with achiral building blocks driven by the interplay between two competing length scales for the interactions, as in DNA. By characterizing global minima for clusters, we illustrate several realizations of helical architecture, the simplest one involving ellipsoids of revolution as building blocks. In particular, we show that axially symmetric soft discoids can self-assemble into helical columnar arrangements. Understanding the molecular origin of such spatial organisation has important implications for the rational design of materials with useful optoelectronic applications.

  5. Rational Design of Improved Pharmabiotics

    PubMed Central

    Sleator, Roy D.; Hill, Colin

    2009-01-01

    Herein we review the most recent advances in probiotic research and applications with particular emphasis on the novel concept of patho-biotechnology: the application of pathogen-derived (ex vivo and in vivo) stress survival strategies for the design of more technologically robust and effective probiotic cultures with improved biotechnological and clinical applications. PMID:19753318

  6. Rational design of improved pharmabiotics.

    PubMed

    Sleator, Roy D; Hill, Colin

    2009-01-01

    Herein we review the most recent advances in probiotic research and applications with particular emphasis on the novel concept of patho-biotechnology: the application of pathogen-derived (ex vivo and in vivo) stress survival strategies for the design of more technologically robust and effective probiotic cultures with improved biotechnological and clinical applications. PMID:19753318

  7. Rational design of nanomaterials for water treatment

    NASA Astrophysics Data System (ADS)

    Li, Renyuan; Zhang, Lianbin; Wang, Peng

    2015-10-01

    The ever-increasing human demand for safe and clean water is gradually pushing conventional water treatment technologies to their limits. It is now a popular perception that the solutions to the existing and future water challenges will hinge upon further developments in nanomaterial sciences. The concept of rational design emphasizes on `design-for-purpose' and it necessitates a scientifically clear problem definition to initiate the nanomaterial design. The field of rational design of nanomaterials for water treatment has experienced a significant growth in the past decade and is poised to make its contribution in creating advanced next-generation water treatment technologies in the years to come. Within the water treatment context, this review offers a comprehensive and in-depth overview of the latest progress in rational design, synthesis and applications of nanomaterials in adsorption, chemical oxidation and reduction reactions, membrane-based separation, oil-water separation, and synergistic multifunctional all-in-one nanomaterials/nanodevices. Special attention is paid to the chemical concepts related to nanomaterial design throughout the review.

  8. Rational design of nanomaterials for water treatment.

    PubMed

    Li, Renyuan; Zhang, Lianbin; Wang, Peng

    2015-11-01

    The ever-increasing human demand for safe and clean water is gradually pushing conventional water treatment technologies to their limits. It is now a popular perception that the solutions to the existing and future water challenges will hinge upon further developments in nanomaterial sciences. The concept of rational design emphasizes on 'design-for-purpose' and it necessitates a scientifically clear problem definition to initiate the nanomaterial design. The field of rational design of nanomaterials for water treatment has experienced a significant growth in the past decade and is poised to make its contribution in creating advanced next-generation water treatment technologies in the years to come. Within the water treatment context, this review offers a comprehensive and in-depth overview of the latest progress in rational design, synthesis and applications of nanomaterials in adsorption, chemical oxidation and reduction reactions, membrane-based separation, oil-water separation, and synergistic multifunctional all-in-one nanomaterials/nanodevices. Special attention is paid to the chemical concepts related to nanomaterial design throughout the review. PMID:26437738

  9. Strategies in the rational drug design.

    PubMed

    Mavromoustakos, T; Durdagi, S; Koukoulitsa, C; Simcic, M; Papadopoulos, M G; Hodoscek, M; Grdadolnik, S Golic

    2011-01-01

    Rational design is applied in the discovery of novel lead drugs. Its rapid development is mainly attributed to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few decades. The promising feature that characterizes the application of rational drug design is that it uses for developing potential leads in drug discovery all known theoretical and experimental knowledge of the system under study. The utilization of the knowledge of the molecular basis of the system ultimately aims to reduce human power cost, time saving and laboratory expenses in the drug discovery. In this review paper various strategies applied for systems which include: (i) absence of knowledge of the receptor active site; (ii) the knowledge of a homology model of a receptor, (iii) the knowledge of the experimentally determined (i.e. X-ray crystallography, NMR spectroscopy) coordinates of the active site of the protein in absence and (iv) the presence of the ligand will be analyzed. PMID:21568895

  10. Rational design of class I MHC ligands

    NASA Astrophysics Data System (ADS)

    Rognan, D.; Scapozza, L.; Folkers, G.; Daser, Angelika

    1995-04-01

    From the knowledge of the three-dimensional structure of a class I MHC protein, several non natural peptides were designed in order to either optimize the interactions of one secondary anchor amino acid with its HLA binding pocket or to substitute the non interacting part with spacer residues. All peptides were synthesized and tested for binding to the class I MHC protein in an in vitro reconstitution assay. As predicted, the non natural peptides present an enhanced binding to the HLA-B27 molecule with respect to their natural parent peptides. This study constitutes the first step towards the rational design of non peptidic MHC ligands that should be very promising tools for the selective immunotherapy of autoimmune diseases.

  11. Rational Experimental Design for Electrical Resistivity Imaging

    NASA Astrophysics Data System (ADS)

    Mitchell, V.; Pidlisecky, A.; Knight, R.

    2008-12-01

    Over the past several decades advances in the acquisition and processing of electrical resistivity data, through multi-channel acquisition systems and new inversion algorithms, have greatly increased the value of these data to near-surface environmental and hydrological problems. There has, however, been relatively little advancement in the design of actual surveys. Data acquisition still typically involves using a small number of traditional arrays (e.g. Wenner, Schlumberger) despite a demonstrated improvement in data quality from the use of non-standard arrays. While optimized experimental design has been widely studied in applied mathematics and the physical and biological sciences, it is rarely implemented for non-linear problems, such as electrical resistivity imaging (ERI). We focus specifically on using ERI in the field for monitoring changes in the subsurface electrical resistivity structure. For this application we seek an experimental design method that can be used in the field to modify the data acquisition scheme (spatial and temporal sampling) based on prior knowledge of the site and/or knowledge gained during the imaging experiment. Some recent studies have investigated optimized design of electrical resistivity surveys by linearizing the problem or with computationally-intensive search algorithms. We propose a method for rational experimental design based on the concept of informed imaging, the use of prior information regarding subsurface properties and processes to develop problem-specific data acquisition and inversion schemes. Specifically, we use realistic subsurface resistivity models to aid in choosing source configurations that maximize the information content of our data. Our approach is based on first assessing the current density within a region of interest, in order to provide sufficient energy to the region of interest to overcome a noise threshold, and then evaluating the direction of current vectors, in order to maximize the

  12. Rationally designed nanovehicles to overcome cancer chemoresistance.

    PubMed

    Livney, Yoav D; Assaraf, Yehuda G

    2013-11-01

    Drug resistance is a primary hindrance towards curative cancer chemotherapy. Nanotechnology holds great promise in establishing efficacious and innovative strategies to overcome chemoresistance, and markedly facilitate complementary treatments and cancer diagnostics. Various nanomedical devices are being introduced and evaluated, demonstrating encouraging results. While stealth liposomes serve as a benchmark, astonishing progress is witnessed in polymeric nanovehicles, sometimes combined with low molecular weight surfactants, some of which inhibit drug resistance in addition to solubilizing drugs. Cutting edge multifunctional or quadrugnostic nanoparticles currently developed offer simultaneous targeted delivery of chemotherapeutics and chemosensitizers or drug-resistance gene silencing cargo, along with diagnostic imaging agents, like metallic NPs. Viral and cellular components offer exciting new routes for cancer targeting and treatment. Targeting intracellular compartments is another challenging frontier spawning pioneering approaches and results. To further enhance rational design of nanomedicine for overcoming drug resistance, we review the latest thoughts and accomplishments in recent literature. PMID:23954781

  13. Rational Design of Biobetters with Enhanced Stability.

    PubMed

    Courtois, Fabienne; Schneider, Curtiss P; Agrawal, Neeraj J; Trout, Bernhardt L

    2015-08-01

    Biotherapeutics are the fastest growing class of pharmaceutical with a rapidly evolving market facing the rise of biosimilar and biobetter products. In contrast to a biosimilar, which is derived from the same gene sequence as the innovator product, a biobetter has enhanced properties, such as enhanced efficacy or reduced immunogenicity. Little work has been carried out so far to increase the intrinsic stability of biotherapeutics via sequence changes, even though, aggregation, the primary degradation pathway of proteins, leads to issues ranging from manufacturing failure to immunological response and to loss of therapeutic activity. Using our spatial aggregation propensity tool as a first step to a rational design approach to identify aggregation-prone regions, biobetters of rituximab have been produced with enhanced stability by introducing site-specific mutations. Significant stabilization against aggregation was achieved for rituximab with no decrease in its binding affinity to the antigen. PMID:26096711

  14. Towards the Rational Design of Nanoparticle Catalysts

    NASA Astrophysics Data System (ADS)

    Dash, Priyabrat

    This research is focused on development of routes towards the rational design of nanoparticle catalysts. Primarily, it is focused on two main projects; (1) the use of imidazolium-based ionic liquids (ILs) as greener media for the design of quasi-homogeneous nanoparticle catalysts and (2) the rational design of heterogeneous-supported nanoparticle catalysts from structured nanoparticle precursors. Each project has different studies associated with the main objective of the design of nanoparticle catalysts. In the first project, imidazolium-based ionic liquids have been used for the synthesis of nanoparticle catalysts. In particular, studies on recyclability, reuse, mode-of-stability, and long-term stability of these ionic-liquid supported nanoparticle catalysts have been done; all of which are important factors in determining the overall "greenness" of such synthetic routes. Three papers have been published/submitted for this project. In the first publication, highly stable polymer-stabilized Au, Pd and bimetallic Au-Pd nanoparticle catalysts have been synthesized in imidazolium-based 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM]PF6) ionic liquid (Journal of Molecular Catalysis A: Chemical, 2008, 286, 114). The resulting nanoparticles were found to be effective and selective quasi-homogeneous catalysts towards a wide-range of hydrogenation reactions and the catalyst solution was reused for further catalytic reactions with minimal loss in activity. The synthesis of very pure and clean ILs has allowed a platform to study the effects of impurities in the imidazolium ILs on nanoparticle stability. In a later study, a new mode of stabilization was postulated where the presence of low amounts of 1-methylimidazole has substantial effects on the resulting stability of Au and Pd-Au nanoparticles in these ILs (Chemical Communications, 2009, 812). In further continuation of this study, a comparative study involving four stabilization protocols for nanoparticle

  15. Rationally designed substrates for SERS biosensing

    NASA Astrophysics Data System (ADS)

    Yan, Bo

    The large electromagnetic field enhancement provided by nanostructured noble metal surfaces forms the foundation for a series of enabling optical analytical techniques, such as surface enhanced Raman spectroscopy (SERS), surface enhanced IR absorption spectroscopy (SEIRA), surface enhanced fluorescent microscopy (SEF), to name only a few. Critical sensing applications have, however, other substrate requirements than mere peak signal enhancement. The substrate needs to be reliable, provide reproducible signal enhancements, and be amenable to a combination with microfluidic chips or other integrated sensor platforms. These needs motivate the development of engineerable SERS substrate "chips" with defined near- and far-field responses. In this dissertation, two types of rationally designed SERS substrates - nanoparticle cluster arrays (NCAs) and SERS stamp - will be introduced and characterized. NCAs were fabricated through a newly developed template guided self-assembly fabrication approach, in which chemically synthesized nanoparticles are integrated into predefined patterns using a hybrid top-down/bottom-up approach. Since this method relies on chemically defined building blocks, it can overcome the resolution limit of conventional lithographical methods and facilitates higher structural complexity. NCAs sustain near-field interactions within individual clusters as well as between entire neighboring clusters and create a multi-scale cascaded E-field enhancement throughout the entire array. SERS stamps were generated using an oblique angle metal deposition on a lithographically defined piston. When mounted on a nanopositioning stage, the SERS stamps were enabled to contact biological surfaces with pristine nanostructured metal surfaces for a label-free spectroscopic characterization. The developed engineered substrates were applied and tested in critical sensing applications, including the ultra-trace detection of explosive vapors, the rapid discrimination of

  16. Rationality.

    PubMed

    Sosis, Clifford; Bishop, Michael A

    2014-01-01

    A theory of rationality is a theory that evaluates instances of reasoning as rational, irrational, or (ir)rational to some degree. Theories can be categorized as rule-based or consequentialist. Rule-based theories say that rational reasoning accords with certain rules (e.g., of logic or probability). Consequentialist theories say that rational reasoning tends to produce good consequences. For instance, the reliabilist takes rationality to be reasoning that tends to produce mostly true beliefs. The pragmatist takes it to be reasoning that tends to produce mostly useful beliefs. This article reviews some of the features and the challenges of rule-based, reliabilist, and pragmatist theories of rationality. WIREs Cogn Sci 2014, 5:27-37. doi: 10.1002/wcs.1263 CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. PMID:26304295

  17. Rationally designing the mechanical properties of protein hydrogels

    NASA Astrophysics Data System (ADS)

    Cao, Yi

    Naturally occurring biomaterials possess diverse mechanical properties, which are critical to their unique biological functions. However, it remains challenging to rationally control the mechanical properties of synthetic biomaterials. Here we provide a bottom-up approach to rationally design the mechanical properties of protein-based hydrogels. We first use atomic fore microscope (AFM) based single-molecule force spectroscopy to characterize the mechanical stability of individual protein building blocks. We then rationally design the mechanical properties of hydrogels by selecting different combination of protein building blocks of known mechanical properties. As a proof-of-principle, we demonstrate the engineering of hydrogels of distinct extensibility and toughness. This simple combinatorial approach allows direct translation of the mechanical properties of proteins from the single molecule level to the macroscopic level and represents an important step towards rationally designing the mechanical properties of biomaterials.

  18. Rational drug design paradigms: the odyssey for designing better drugs.

    PubMed

    Kellici, Tahsin; Ntountaniotis, Dimitrios; Vrontaki, Eleni; Liapakis, George; Moutevelis-Minakakis, Panagiota; Kokotos, George; Hadjikakou, Sotiris; Tzakos, Andreas G; Afantitis, Antreas; Melagraki, Georgia; Bryant, Sharon; Langer, Thierry; Di Marzo, Vincenzo; Mavromoustakos, Thomas

    2015-01-01

    Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design. This approach reduces the consumables and human personnel involved in the initial steps of the drug design. In this review real examples from our research activity aiming to discover new leads will be given for various dire warnings diseases. There is no recipe to follow for discovering new leads. The strategy to be followed depends on the knowledge of the studied system and the experience of the researchers. The described examples constitute successful and unsuccessful efforts and reflect the reality which medicinal chemists have to face in drug design and development. The drug stability is also discussed in both organic molecules and metallotherapeutics. This is an important issue in drug discovery as drug metabolism in the body can lead to various toxic and undesired molecules. PMID:25747445

  19. Rational Design of Immunostimulatory siRNAs

    PubMed Central

    Gantier, Michael P; Tong, Stephen; Behlke, Mark A; Irving, Aaron T; Lappas, Martha; Nilsson, Ulrika W; Latz, Eicke; McMillan, Nigel AJ; Williams, Bryan RG

    2010-01-01

    Short-interfering RNAs (siRNAs) have engendered much enthusiasm for their ability to silence the expression of specific genes. However, it is now well established that siRNAs, depending on their sequence, can be variably sensed by the innate immune system through recruitment of toll-like receptors 7 and 8 (TLR7/8). Here, we aimed to identify sequence-based modifications allowing for the design of bifunctional siRNAs with both proinflammatory and specific silencing activities, and with potentially increased therapeutic benefits. We found that the introduction of a micro-RNA (miRNA)-like nonpairing uridine-bulge in the passenger strand robustly increased immunostimulatory activity on human immune cells. This sequence modification had no effect on the silencing efficiency of the siRNA. Increased immunostimulation with the uridine-bulge design was specific to human cells, and conserved silencing efficiency required a Dicer-substrate scaffold. The increased cytokine production with the uridine-bulge design resulted in enhanced protection against Semliki Forest virus (SFV) infection, in viral assays. Thus, we characterize a design scaffold applicable to any given siRNA sequence, that results in increased innate immune activation without affecting gene silencing. Our data suggest that this sequence modification coupled with structural modification differentially recruits human TLR8 over TLR7, and could have potential application in antiviral therapies. PMID:20125126

  20. Computational approaches for rational design of proteins with novel functionalities

    PubMed Central

    Tiwari, Manish Kumar; Singh, Ranjitha; Singh, Raushan Kumar; Kim, In-Won; Lee, Jung-Kul

    2012-01-01

    Proteins are the most multifaceted macromolecules in living systems and have various important functions, including structural, catalytic, sensory, and regulatory functions. Rational design of enzymes is a great challenge to our understanding of protein structure and physical chemistry and has numerous potential applications. Protein design algorithms have been applied to design or engineer proteins that fold, fold faster, catalyze, catalyze faster, signal, and adopt preferred conformational states. The field of de novo protein design, although only a few decades old, is beginning to produce exciting results. Developments in this field are already having a significant impact on biotechnology and chemical biology. The application of powerful computational methods for functional protein designing has recently succeeded at engineering target activities. Here, we review recently reported de novo functional proteins that were developed using various protein design approaches, including rational design, computational optimization, and selection from combinatorial libraries, highlighting recent advances and successes. PMID:24688643

  1. Rational Design of Metal Ion Sequestering Agents

    SciTech Connect

    Raymond, Kenneth N.

    2000-09-30

    The discriminate bonding of metal ions is a challenge to the synthetic chemist and a phenomenon of considerable practical importance.1 An important feature of many technical applications is the specific or preferential binding of a single metal ion in the presence of many metals. Examples range from large-volume uses (e.g. ferric EDTA as a plant food, calcium complexing agents as water softeners or anticaking formulations) to very high technology applications (technetium complexation in radiopharmaceuticals, synthetic metalloenzymes). We are interested in efficient and discriminate binding of actinides for waste stream remediation. Actinides represent a major and long-lived contaminant in nuclear waste. While the separation of actinides from other radioactive components of waste, such as Sr and Cs, is relatively well established, the separation of actinides from each other and in complex solutions (e.g. those found in tank wastes) is not as well resolved. The challenge of designing metal-specific (actinide) ligands is facilitated by examples from nature. Bacteria synthesize Fe(III)-specific ligands, called siderophores, to sequester Fe(III) from the environment and return it to the cell. The similarities between Fe(III) and Pu(IV) (their charge-to-size ratios and acidity), make the siderophores prototypical for designing actinide-specific ligands. The chelating groups present in siderophores are usually hydroxamic acids and catecholamides. We have developed derivatives of these natural products which have improved properties. The catechol derivatives are the 2,3-dihydroxyterephthalamides (TAMs), and 3,4-dihydroxysulfonamides (SFAMs), and the hydroxamic acid derivatives are three isomers of hydroxypyridinones, 1,2- HOPO, 3,2-HOPO, and 3,4-HOPO. All of these ligands are attached to molecular backbones by amides and a very important feature of HOPO and CAM ligands is a strong hydrogen bonds formed between the amide proton and the adjacent phenolic oxygen in the metal

  2. Refolding of proteins from inclusion bodies: rational design and recipes.

    PubMed

    Basu, Anindya; Li, Xiang; Leong, Susanna Su Jan

    2011-10-01

    The need to develop protein biomanufacturing platforms that can deliver proteins quickly and cost-effectively is ever more pressing. The rapid rate at which genomes can now be sequenced demands efficient protein production platforms for gene function identification. There is a continued need for the biotech industry to deliver new and more effective protein-based drugs to address new diseases. Bacterial production platforms have the advantage of high expression yields, but insoluble expression of many proteins necessitates the development of diverse and optimised refolding-based processes. Strategies employed to eliminate insoluble expression are reviewed, where it is concluded that inclusion bodies are difficult to eliminate for various reasons. Rational design of refolding systems and recipes are therefore needed to expedite production of recombinant proteins. This review article discusses efforts towards rational design of refolding systems and recipes, which can be guided by the development of refolding screening platforms that yield both qualitative and quantitative information on the progression of a given refolding process. The new opportunities presented by light scattering technologies for developing rational protein refolding buffer systems which in turn can be used to develop new process designs armed with better monitoring and controlling functionalities are discussed. The coupling of dynamic and static light scattering methodologies for incorporation into future bioprocess designs to ensure delivery of high-quality refolded proteins at faster rates is also discussed. PMID:21822901

  3. Rational design of inorganic dielectric materials with expected permittivity.

    PubMed

    Xie, Congwei; Oganov, Artem R; Dong, Dong; Liu, Ning; Li, Duan; Debela, Tekalign Terfa

    2015-01-01

    Techniques for rapid design of dielectric materials with appropriate permittivity for many important technological applications are urgently needed. It is found that functional structure blocks (FSBs) are helpful in rational design of inorganic dielectrics with expected permittivity. To achieve this, coordination polyhedra are parameterized as FSBs and a simple empirical model to evaluate permittivity based on these FSB parameters is proposed. Using this model, a wide range of examples including ferroelectric, high/low permittivity materials are discussed, resulting in several candidate materials for experimental follow-up. PMID:26617342

  4. Rational design of inorganic dielectric materials with expected permittivity

    PubMed Central

    Xie, Congwei; Oganov, Artem R.; Dong, Dong; Liu, Ning; Li, Duan; Debela, Tekalign Terfa

    2015-01-01

    Techniques for rapid design of dielectric materials with appropriate permittivity for many important technological applications are urgently needed. It is found that functional structure blocks (FSBs) are helpful in rational design of inorganic dielectrics with expected permittivity. To achieve this, coordination polyhedra are parameterized as FSBs and a simple empirical model to evaluate permittivity based on these FSB parameters is proposed. Using this model, a wide range of examples including ferroelectric, high/low permittivity materials are discussed, resulting in several candidate materials for experimental follow-up. PMID:26617342

  5. Evolving protocells to prototissues: rational design of a missing link.

    PubMed

    Mantri, Shiksha; Sapra, K Tanuj

    2013-10-01

    Realization of a functional artificial cell, the so-called protocell, is a major challenge posed by synthetic biology. A subsequent goal is to use the protocellular units for the bottom-up assembly of prototissues. There is, however, a looming chasm in our knowledge between protocells and prototissues. In the present paper, we give a brief overview of the work on protocells to date, followed by a discussion on the rational design of key structural elements specific to linking two protocellular bilayers. We propose that designing synthetic parts capable of simultaneous insertion into two bilayers may be crucial in the hierarchical assembly of protocells into a functional prototissue. PMID:24059502

  6. Rational design and synthesis of semi-conducting polymers.

    SciTech Connect

    Wong, Bryan Matthew; Reeder, Craig; Cordaro, Joseph Gabriel

    2010-12-01

    A rational approach was used to design polymeric materials for thin-film electronics applications, whereby theoretical modeling was used to determine synthetic targets. Time-dependent density functional theory calculations were used as a tool to predict the electrical properties of conjugated polymer systems. From these results, polymers with desirable energy levels and band-gaps were designed and synthesized. Measurements of optoelectronic properties were performed on the synthesized polymers and the results were compared to those of the theoretical model. From this work, the efficacy of the model was evaluated and new target polymers were identified.

  7. Rational design of inorganic dielectric materials with expected permittivity

    NASA Astrophysics Data System (ADS)

    Xie, Congwei; Oganov, Artem R.; Dong, Dong; Liu, Ning; Li, Duan; Debela, Tekalign Terfa

    2015-11-01

    Techniques for rapid design of dielectric materials with appropriate permittivity for many important technological applications are urgently needed. It is found that functional structure blocks (FSBs) are helpful in rational design of inorganic dielectrics with expected permittivity. To achieve this, coordination polyhedra are parameterized as FSBs and a simple empirical model to evaluate permittivity based on these FSB parameters is proposed. Using this model, a wide range of examples including ferroelectric, high/low permittivity materials are discussed, resulting in several candidate materials for experimental follow-up.

  8. Concepts and software for a rational design of polynucleotide probes.

    PubMed

    Moraru, Cristina; Moraru, Gabriel; Fuchs, Bernhard M; Amann, Rudolf

    2011-02-01

    Fluorescence in situ hybridization (FISH) of genes and mRNA is most often based on polynucleotide probes. However, so far there was no published framework for the rational design of polynucleotide probes. The well-established concepts for oligonucleotide probe design cannot be transferred to polynucleotides. Due to the high allele diversity of genes, a single probe is not sufficient to detect all alleles of a gene. Therefore, the main objective of this study was to develop a concept and software (PolyPro) for rational design of polynucleotide probe mixes to target particular genes. PolyPro consists of three modules: a GenBank Taxonomy Extractor (GTE), a Polynucleotide Probe Designer (PPD) and a Hybridization Parameters Calculator (HPC). The new concept proposes the construction of defined polynucleotide mixes to target the habitat specific sequence diversity of a particular gene. The concept and the software are intended as a first step towards a more frequent application of polynucleotides for in situ identification of mRNA and genes in environmental microbiology. PMID:23761233

  9. Using Fitness Landscapes for Rational Hepatitis C Immunogen Design

    NASA Astrophysics Data System (ADS)

    Hart, Gregory; Ferguson, Andrew

    2015-03-01

    Hepatitis C virus afflicts 170 million people worldwide, 2-3% of the global population. Prophylactic vaccination offers the most realistic and cost effective hope of controlling this epidemic, particularly in the developing world where expensive drug therapies are unavailable. Despite 20 years of research, the high mutability of the virus, and lack of knowledge of what constitutes effective immune responses, have impeded development of an effective vaccine. Coupling data mining of sequence databases with the Potts model, we have developed a computational approach to systematically identify viral vulnerabilities and perform rational design of vaccine immunogens. We applied our approach to the nonstructural proteins NS3, NSA, NSA, and NSB which are crucial for viral replication.The predictions of our model are in good accord with experimental measurements and clinical observations, and we have used our model to design immunogen candidates to elicit T-cell responses against vulnerable regions of theseviral proteins.

  10. Beyond directed evolution - semi-rational protein engineering and design

    PubMed Central

    Lutz, Stefan

    2010-01-01

    Over the last two decades, directed evolution has transformed the field of protein engineering. The advances in understanding protein structure and function, in no insignificant part a result of directed evolution studies, are increasingly empowering scientists and engineers to device more effective methods for manipulating and tailoring biocatalysts. Abandoning large combinatorial libraries, the focus has shifted to small, functionally-rich libraries and rational design. A critical component to the success of these emerging engineering strategies are computational tools for the evaluation of protein sequence datasets and the analysis of conformational variations of amino acids in proteins. Highlighting the opportunities and limitations of such approaches, this review focuses on recent engineering and design examples that require screening or selection of small libraries. PMID:20869867

  11. Principles underlying rational design of live attenuated influenza vaccines

    PubMed Central

    Jang, Yo Han

    2012-01-01

    Despite recent innovative advances in molecular virology and the developments of vaccines, influenza virus remains a serious burden for human health. Vaccination has been considered a primary countermeasure for prevention of influenza infection. Live attenuated influenza vaccines (LAIVs) are particularly attracting attention as an effective strategy due to several advantages over inactivated vaccines. Cold-adaptation, as a classical means for attenuating viral virulence, has been successfully used for generating safe and effective donor strains of LAIVs against seasonal epidemics and occasional pandemics. Recently, the advent of reverse genetics technique expedited a variety of rational strategies to broaden the pool of LAIVs. Considering the breadth of antigenic diversity of influenza virus, the pool of LAIVs is likely to equip us with better options for controlling influenza pandemics. With a brief reflection on classical attenuating strategies used at the initial stage of development of LAIVs, especially on the principles underlying the development of cold-adapted LAIVs, we further discuss and outline other attenuation strategies especially with respect to the rationales for attenuation, and their practicality for mass production. Finally, we propose important considerations for a rational vaccine design, which will provide us with practical guidelines for improving the safety and effectiveness of LAIVs. PMID:23596576

  12. Rational clinical trial design for antibody mediated renal allograft injury

    PubMed Central

    Sandal, Shaifali; Zand, Martin S.

    2015-01-01

    Antibody mediated renal allograft rejection is a significant cause of acute and chronic graft loss. Recent work has revealed that AMR is a complex processes, involving B and plasma cells, donor-specific antibodies, complement, vascular endothelial cells, NK cells, Fc receptors, cytokines and chemokines. These insights have led to the development of numerous new therapies, and adaptation of others originally developed for treatment of hemetologic malignancies, autoimmune and complement mediated conditions. Here we review emerging insights into the pathophysiology of AMR as well as current and emerging therapies for both acute and chronic AMR. Finally, we discuss rational clinical trial design in light of antibody and B cell immunobiology, as well as appropriate efficacy metrics to identify robust protocols and therapeutic agents. PMID:25553476

  13. New generation adjuvants--from empiricism to rational design.

    PubMed

    O'Hagan, Derek T; Fox, Christopher B

    2015-06-01

    Adjuvants are an essential component of modern vaccine development. Despite many decades of development, only a few types of adjuvants are currently included in vaccines approved for human use. In order to better understand the reasons that development of some adjuvants succeeded while many others failed, we discuss some of the common attributes of successful first generation adjuvants. Next, we evaluate current trends in the development of second generation adjuvants, including the potential advantages of rationally designed synthetic immune potentiators appropriately formulated. Finally, we discuss desirable attributes of next generation adjuvants. Throughout, we emphasize that the importance of formulation and analytical characterization in all aspects of vaccine adjuvant development is often underappreciated. We highlight the formulation factors that must be evaluated in order to optimize interactions between vaccine antigens, immune potentiators, and particulate formulations, and the resulting effects on safety, biological activity, manufacturability, and stability. PMID:26022561

  14. Rational design of functional and tunable oscillating enzymatic networks.

    PubMed

    Semenov, Sergey N; Wong, Albert S Y; van der Made, R Martijn; Postma, Sjoerd G J; Groen, Joost; van Roekel, Hendrik W H; de Greef, Tom F A; Huck, Wilhelm T S

    2015-02-01

    Life is sustained by complex systems operating far from equilibrium and consisting of a multitude of enzymatic reaction networks. The operating principles of biology's regulatory networks are known, but the in vitro assembly of out-of-equilibrium enzymatic reaction networks has proved challenging, limiting the development of synthetic systems showing autonomous behaviour. Here, we present a strategy for the rational design of programmable functional reaction networks that exhibit dynamic behaviour. We demonstrate that a network built around autoactivation and delayed negative feedback of the enzyme trypsin is capable of producing sustained oscillating concentrations of active trypsin for over 65 h. Other functions, such as amplification, analog-to-digital conversion and periodic control over equilibrium systems, are obtained by linking multiple network modules in microfluidic flow reactors. The methodology developed here provides a general framework to construct dissipative, tunable and robust (bio)chemical reaction networks. PMID:25615670

  15. Toward rational design of electrical stimulation strategies for epilepsy control.

    PubMed

    Sunderam, Sridhar; Gluckman, Bruce; Reato, Davide; Bikson, Marom

    2010-01-01

    Electrical stimulation is emerging as a viable alternative for patients with epilepsy whose seizures are not alleviated by drugs or surgery. Its attractions are temporal and spatial specificity of action, flexibility of waveform parameters and timing, and the perception that its effects are reversible unlike resective surgery. However, despite significant advances in our understanding of mechanisms of neural electrical stimulation, clinical electrotherapy for seizures relies heavily on empirical tuning of parameters and protocols. We highlight concurrent treatment goals with potentially conflicting design constraints that must be resolved when formulating rational strategies for epilepsy electrotherapy, namely, seizure reduction versus cognitive impairment, stimulation efficacy versus tissue safety, and mechanistic insight versus clinical pragmatism. First, treatment markers, objectives, and metrics relevant to electrical stimulation for epilepsy are discussed from a clinical perspective. Then the experimental perspective is presented, with the biophysical mechanisms and modalities of open-loop electrical stimulation, and the potential benefits of closed-loop control for epilepsy. PMID:19926525

  16. Toward rational design of electrical stimulation strategies for epilepsy control

    PubMed Central

    Sunderam, Sridhar; Gluckman, Bruce; Reato, Davide; Bikson, Marom

    2009-01-01

    Electrical stimulation is emerging as a viable alternative for epilepsy patients whose seizures are not alleviated by drugs or surgery. Its attractions are temporal and spatial specificity of action, flexibility of waveform parameters and timing, and the perception that its effects are reversible unlike resective surgery. However, despite significant advances in our understanding of mechanisms of neural electrical stimulation, clinical electrotherapy for seizures relies heavily on empirical tuning of parameters and protocols. We highlight concurrent treatment goals with potentially conflicting design constraints that must be resolved when formulating rational strategies for epilepsy electrotherapy: namely seizure reduction versus cognitive impairment, stimulation efficacy versus tissue safety, and mechanistic insight versus clinical pragmatism. First, treatment markers, objectives, and metrics relevant to electrical stimulation for epilepsy are discussed from a clinical perspective. Then the experimental perspective is presented, with the biophysical mechanisms and modalities of open-loop electrical stimulation, and the potential benefits of closed-loop control for epilepsy. PMID:19926525

  17. Rational design of functional and tunable oscillating enzymatic networks

    NASA Astrophysics Data System (ADS)

    Semenov, Sergey N.; Wong, Albert S. Y.; van der Made, R. Martijn; Postma, Sjoerd G. J.; Groen, Joost; van Roekel, Hendrik W. H.; de Greef, Tom F. A.; Huck, Wilhelm T. S.

    2015-02-01

    Life is sustained by complex systems operating far from equilibrium and consisting of a multitude of enzymatic reaction networks. The operating principles of biology's regulatory networks are known, but the in vitro assembly of out-of-equilibrium enzymatic reaction networks has proved challenging, limiting the development of synthetic systems showing autonomous behaviour. Here, we present a strategy for the rational design of programmable functional reaction networks that exhibit dynamic behaviour. We demonstrate that a network built around autoactivation and delayed negative feedback of the enzyme trypsin is capable of producing sustained oscillating concentrations of active trypsin for over 65 h. Other functions, such as amplification, analog-to-digital conversion and periodic control over equilibrium systems, are obtained by linking multiple network modules in microfluidic flow reactors. The methodology developed here provides a general framework to construct dissipative, tunable and robust (bio)chemical reaction networks.

  18. Rational design of high affinity tachykinin NK1 receptor antagonists.

    PubMed

    Boyle, S; Guard, S; Higginbottom, M; Horwell, D C; Howson, W; McKnight, A T; Martin, K; Pritchard, M C; O'Toole, J; Raphy, J

    1994-05-01

    The rational design of a non-peptide tachykinin NK1 receptor antagonist, [(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)P h (28, PD 154075) is described. Compound 28 has a Ki = 9 and 0.35 nM for the NK1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [125I] Bolton-Hunter-SP as the radioligand). It is a potent antagonist in vitro where it antagonises the contractions mediated by SPOMe in the guinea-pig ileum (KB = 0.3 nM). Compound 28 is active in vivo in the guinea-pig plasma extravasation model, where it is able to block the SPOMe-induced protein plasma extravasation (monitored by Evans Blue) in the bladder with an ID50 of 0.02 mg kg-1 iv. PMID:7922147

  19. Rational clinical trial design for antibody mediated renal allograft injury.

    PubMed

    Sandal, Shaifali; Zand, Martin S

    2015-01-01

    Antibody mediated renal allograft rejection is a significant cause of acute and chronic graft loss. Recent work has revealed that AMR is a complex processes, involving B and plasma cells, donor-specific antibodies, complement, vascular endothelial cells, NK cells, Fc receptors, cytokines and chemokines. These insights have led to the development of numerous new therapies, and adaptation of others originally developed for treatment of hemetologic malignancies, autoimmune and complement mediated conditions. Here we review emerging insights into the pathophysiology of AMR as well as current and emerging therapies for both acute and chronic AMR. Finally, we discuss rational clinical trial design in light of antibody and B cell immunobiology, as well as appropriate efficacy metrics to identify robust protocols and therapeutic agents. PMID:25553476

  20. A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Jameson, Bradford A.; McDonnell, James M.; Marini, Joseph C.; Korngold, Robert

    1994-04-01

    EXPERIMENTAL allergic encephalomyelitis (EAE) is an acute inflammatory autoimmune disease of the central nervous system that can be elicited in rodents and is the major animal model for the study of multiple sclerosis (MS)1,2. The pathogenesis of both EAE and MS directly involves the CD4+ helper T-cell subset3-5. Anti-CD4 monoclonal antibodies inhibit the development of EAE in rodents6-9, and are currently being used in human clinical trials for MS. We report here that similar therapeutic effects can be achieved in mice using a small (rationally designed) synthetic analogue of the CD4 protein surface. It greatly inhibits both clinical incidence and severity of EAE with a single injection, but does so without depletion of the CD4+ subset and without the inherent immunogenicity of an antibody. Furthermore, this analogue is capable of exerting its effects on disease even after the onset of symptoms.

  1. Rational design of the exchange-spring permanent magnet.

    PubMed

    Jiang, J S; Bader, S D

    2014-02-12

    The development of the optimal exchange-spring permanent magnet balances exchange hardening, magnetization enhancement, and the feasibility of scalable fabrication. These requirements can be met with a rational design of the microstructural characteristics. The magnetization processes in several model exchange-spring structures with different geometries have been analyzed with both micromagnetic simulations and nucleation theory. The multilayer geometry and the soft-cylinders-in-hard-matrix geometry have the highest achievable figure of merit (BH)max, while the soft-spheres-in-hard-matrix geometry has the lowest upper limit for (BH)max. The cylindrical geometry permits the soft phase to be larger and does not require strict size control. Exchange-spring permanent magnets based on the cylindrical geometry may be amenable to scaled-up fabrication. PMID:24469386

  2. Rational Co-Design of Polymer Dielectrics for Energy Storage.

    PubMed

    Mannodi-Kanakkithodi, Arun; Treich, Gregory M; Huan, Tran Doan; Ma, Rui; Tefferi, Mattewos; Cao, Yang; Sotzing, Gregory A; Ramprasad, Rampi

    2016-08-01

    Although traditional materials discovery has historically benefited from intuition-driven experimental approaches and serendipity, computational strategies have risen in prominence and proven to be a powerful complement to experiments in the modern materials research environment. It is illustrated here how one may harness a rational co-design approach-involving synergies between high-throughput computational screening and experimental synthesis and testing-with the example of polymer dielectrics design for electrostatic energy storage applications. Recent co-design efforts that can potentially enable going beyond present-day "standard" polymer dielectrics (such as biaxially oriented polypropylene) are highlighted. These efforts have led to the identification of several new organic polymer dielectrics within known generic polymer subclasses (e.g., polyurea, polythiourea, polyimide), and the recognition of the untapped potential inherent in entirely new and unanticipated chemical subspaces offered by organometallic polymers. The challenges that remain and the need for additional methodological developments necessary to further strengthen the co-design concept are then presented. PMID:27167752

  3. Potential of fragment recombination for rational design of proteins.

    PubMed

    Eisenbeis, Simone; Proffitt, William; Coles, Murray; Truffault, Vincent; Shanmugaratnam, Sooruban; Meiler, Jens; Höcker, Birte

    2012-03-01

    It is hypothesized that protein domains evolved from smaller intrinsically stable subunits via combinatorial assembly. Illegitimate recombination of fragments that encode protein subunits could have quickly led to diversification of protein folds and their functionality. This evolutionary concept presents an attractive strategy to protein engineering, e.g., to create new scaffolds for enzyme design. We previously combined structurally similar parts from two ancient protein folds, the (βα)(8)-barrel and the flavodoxin-like fold. The resulting "hopeful monster" differed significantly from the intended (βα)(8)-barrel fold by an extra β-strand in the core. In this study, we ask what modifications are necessary to form the intended structure and what potential this approach has for the rational design of functional proteins. Guided by computational design, we optimized the interface between the fragments with five targeted mutations yielding a stable, monomeric protein whose predicted structure was verified experimentally. We further tested binding of a phosphorylated compound and detected that some affinity was already present due to an intact phosphate-binding site provided by one fragment. The affinity could be improved quickly to the level of natural proteins by introducing two additional mutations. The study illustrates the potential of recombining protein fragments with unique properties to design new and functional proteins, offering both a possible pathway of protein evolution and a protocol to rapidly engineer proteins for new applications. PMID:22329686

  4. Rational use of water in trickle irrigation design.

    NASA Astrophysics Data System (ADS)

    Saad, J. C. C.; da Silva Junior, H. M.

    2012-04-01

    In trickle irrigation systems, the design is based on the pre-established emission uniformity (EU) which is the combined result of the equipment characteristics and its hydraulic configuration. However, this desired value of the EU may not be confirmed by the final project (in field conditions) and neither by the yield uniformity. However, the most important is to assure yield uniformity with rational use of water. The hypotheses of this research were: a) the EU of a trickle irrigation system at field conditions is equal to the emission uniformity pre-established in the design; b) EU has always the lowest value when compared with other indicators of uniformity; c) the discharge variation coefficient is not equal to production variation coefficient in the operational unit; d) the productivity variation coefficient is more dependent on water depth applied than the EU. This study aimed to evaluate the relationships among EU used in the irrigation system design, water depth applied and the final yield uniformity. The uniformity indicators evaluated were: EU, distribution uniformity (UD) and the index proposed by Barragan & Wu (2005). They were compared estimating the performance of a trickle irrigation system applied in a citrus orchard with dimensions of 400m x 600m. The design of the irrigation system was optimized by a Linear Programming model. The tree rows were leveled in the larger direction and the spacing adopted in the orchard was 7m x 4m. The manifold line was always operating on a slope condition. The sensitivity analysis involved different slopes, 0, 3, 6, 9 and 12%, and different values of emission uniformity, 60, 70, 75, 80, 85, 90 and 94%. The citrus yield uniformity was evaluated by the variation coefficient. The emission uniformity (EU) after design differed from the EU pre-established, more sharply in the initial values lower than 90%. Comparing the uniformity indexes, the EU always generated lower values when compared with the UD and with the index

  5. Rational Design of MMP Degradable Peptide-Based Supramolecular Filaments

    PubMed Central

    2015-01-01

    One-dimensional nanostructures formed by self-assembly of small molecule peptides have been extensively explored for use as biomaterials in various biomedical contexts. However, unlike individual peptides that can be designed to be specifically degradable by enzymes/proteases of interest, their self-assembled nanostructures, particularly those rich in β-sheets, are generally resistant to enzymatic degradation because the specific cleavage sites are often embedded inside the nanostructures. We report here on the rational design of β-sheet rich supramolecular filaments that can specifically dissociate into less stable micellar assemblies and monomers upon treatment with matrix metalloproteases-2 (MMP-2). Through linkage of an oligoproline segment to an amyloid-derived peptide sequence, we first synthesized an amphiphilic peptide that can undergo a rapid morphological transition in response to pH variations. We then used MMP-2 specific peptide substrates as multivalent cross-linkers to covalently fix the amyloid-like filaments in the self-assembled state at pH 4.5. Our results show that the cross-linked filaments are stable at pH 7.5 but gradually break down into much shorter filaments upon cleavage of the peptidic cross-linkers by MMP-2. We believe that the reported work presents a new design platform for the creation of amyloid-like supramolecular filaments responsive to enzymatic degradation. PMID:24611531

  6. Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy

    NASA Astrophysics Data System (ADS)

    Paraskar, Abhimanyu; Soni, Shivani; Roy, Bhaskar; Papa, Anne-Laure; Sengupta, Shiladitya

    2012-02-01

    Nanoscale drug delivery vehicles have been extensively studied as carriers for cancer chemotherapeutics. However, the formulation of platinum chemotherapeutics in nanoparticles has been a challenge arising from their physicochemical properties. There are only a few reports describing oxaliplatin nanoparticles. In this study, we derivatized the monomeric units of a polyisobutylene maleic acid copolymer with glucosamine, which chelates trans-1,2-diaminocyclohexane (DACH) platinum (II) through a novel monocarboxylato and O → Pt coordination linkage. At a specific polymer to platinum ratio, the complex self-assembled into a nanoparticle, where the polymeric units act as the leaving group, releasing DACH-platinum in a sustained pH-dependent manner. Sizing was done using dynamic light scatter and electron microscopy. The nanoparticles were evaluated for efficacy in vitro and in vivo. Biodistribution was quantified using inductively coupled plasma atomic absorption spectroscopy (ICP-AAS). The PIMA-GA-DACH-platinum nanoparticle was found to be more active than free oxaliplatin in vitro. In vivo, the nanoparticles resulted in greater tumor inhibition than oxaliplatin (equivalent to 5 mg kg-1 platinum dose) with minimal nephrotoxicity or body weight loss. ICP-AAS revealed significant preferential tumor accumulation of platinum with reduced biodistribution to the kidney or liver following PIMA-GA-DACH-platinum nanoparticle administration as compared with free oxaliplatin. These results indicate that the rational engineering of a novel polymeric nanoparticle inspired by the bioactivation of oxaliplatin results in increased antitumor potency with reduced systemic toxicity compared with the parent cytotoxic. Rational design can emerge as an exciting strategy in the synthesis of nanomedicines for cancer chemotherapy.

  7. Snake bites

    MedlinePlus

    ... bites by any of the following: Cobra Copperhead Coral snake Cottonmouth (water moccasin) Rattlesnake Various snakes found ... Swelling Thirst Tiredness Tissue damage Weakness Weak pulse Coral snake bites may be painless at first. Major ...

  8. Rationally designed molecular beacons for bioanalytical and biomedical applications.

    PubMed

    Zheng, Jing; Yang, Ronghua; Shi, Muling; Wu, Cuichen; Fang, Xiaohong; Li, Yinhui; Li, Jishan; Tan, Weihong

    2015-05-21

    Nucleic acids hold promise as biomolecules for future applications in biomedicine and biotechnology. Their well-defined structures and compositions afford unique chemical properties and biological functions. Moreover, the specificity of hydrogen-bonded Watson-Crick interactions allows the construction of nucleic acid sequences with multiple functions. In particular, the development of nucleic acid probes as essential molecular engineering tools will make a significant contribution to advancements in biosensing, bioimaging and therapy. The molecular beacon (MB), first conceptualized by Tyagi and Kramer in 1996, is an excellent example of a double-stranded nucleic acid (dsDNA) probe. Although inactive in the absence of a target, dsDNA probes can report the presence of a specific target through hybridization or a specific recognition-triggered change in conformation. MB probes are typically fluorescently labeled oligonucleotides that range from 25 to 35 nucleotides (nt) in length, and their structure can be divided into three components: stem, loop and reporter. The intrinsic merit of MBs depends on predictable design, reproducibility of synthesis, simplicity of modification, and built-in signal transduction. Using resonance energy transfer (RET) for signal transduction, MBs are further endowed with increased sensitivity, rapid response and universality, making them ideal for chemical sensing, environmental monitoring and biological imaging, in contrast to other nucleic acid probes. Furthermore, integrating MBs with targeting ligands or molecular drugs can substantially support their in vivo applications in theranositics. In this review, we survey advances in bioanalytical and biomedical applications of rationally designed MBs, as they have evolved through the collaborative efforts of many researchers. We first discuss improvements to the three components of MBs: stem, loop and reporter. The current applications of MBs in biosensing, bioimaging and therapy will then

  9. Rational material design for ultrafast rechargeable lithium-ion batteries.

    PubMed

    Tang, Yuxin; Zhang, Yanyan; Li, Wenlong; Ma, Bing; Chen, Xiaodong

    2015-10-01

    Rechargeable lithium-ion batteries (LIBs) are important electrochemical energy storage devices for consumer electronics and emerging electrical/hybrid vehicles. However, one of the formidable challenges is to develop ultrafast charging LIBs with the rate capability at least one order of magnitude (>10 C) higher than that of the currently commercialized LIBs. This tutorial review presents the state-of-the-art developments in ultrafast charging LIBs by the rational design of materials. First of all, fundamental electrochemistry and related ionic/electronic conduction theories identify that the rate capability of LIBs is kinetically limited by the sluggish solid-state diffusion process in electrode materials. Then, several aspects of the intrinsic materials, materials engineering and processing, and electrode materials architecture design towards maximizing both ionic and electronic conductivity in the electrode with a short diffusion length are deliberated. Finally, the future trends and perspectives for the ultrafast rechargeable LIBs are discussed. Continuous rapid progress in this area is essential and urgent to endow LIBs with ultrafast charging capability to meet huge demands in the near future. PMID:25857819

  10. Rational Co-Design of Polymer Dielectrics for Energy Storage

    NASA Astrophysics Data System (ADS)

    Mannodi-Kanakkithodi, Arun; Tran, Huan; Pilania, Ghanshyam; Lookman, Turab; Ramprasad, Rampi

    While intuition-driven experiments and serendipity have guided traditional materials discovery, computational strategies have become increasingly important and a powerful complement to experiments in modern day materials research. With the example of polymer dielectrics for electrostatic energy storage applications, we demonstrate how a rational co-design approach--involving synergies between high-throughput computational screening and experimental synthesis and testing--can be harnessed for quick and efficient discovery. We highlight recent co-design efforts that can potentially lead to replacement of present-day ``standard'' polymer dielectrics (such as biaxially oriented polypropylene) not only by new organic polymer candidates within known generic polymer subclasses (e.g., polyurea, polythiourea, polyimide), but also by organometallic polymers, a hitherto untapped but promising chemical subspace. We also discuss the utilization of vast computational data (generated in the aforementioned process) towards the development of statistical learning models for relevant properties of dielectric polymers, which can further accelerate the guidance to experiments and thus the successful discovery of new materials.

  11. Protocol for rational design of covalently interacting inhibitors.

    PubMed

    Schmidt, Thomas C; Welker, Armin; Rieger, Max; Sahu, Prabhat K; Sotriffer, Christoph A; Schirmeister, Tanja; Engels, Bernd

    2014-10-20

    The inhibition potencies of covalent inhibitors mainly result from the formation of a covalent bond to the enzyme during the inhibition mechanism. This class of inhibitors has essentially been ignored in previous target-directed drug discovery projects because of concerns about possible side effects. However, their advantages, such as higher binding energies and longer drug-target residence times moved them into the focus of recent investigations. While the rational design of non-covalent inhibitors became standard the corresponding design of covalent inhibitors is still in its early stages. Potent covalent inhibitors can be retrieved from large compound libraries by covalent docking approaches but protocols are missing that can reliably predict the influence of variations in the substitution pattern on the affinity and/or reactivity of a given covalent inhibitor. Hence, the wanted property profile can only be obtained from trial-and-error proceedings. This paper presents an appropriate protocol which is able to predict improved covalent inhibitors. It uses hybrid approaches, which mix quantum mechanical (QM) and molecular mechanical (MM) methods to predict variations in the reactivity of the inhibitor. They are also used to compute the required information about the non-covalent enzyme-inhibitor complex. Docking tools are employed to improve the inhibitor with respect to the non-covalent interactions formed in the binding site. PMID:25251382

  12. Structure-Based, Rational Design of T Cell Receptors

    PubMed Central

    Zoete, V.; Irving, M.; Ferber, M.; Cuendet, M. A.; Michielin, O.

    2013-01-01

    Adoptive cell transfer using engineered T cells is emerging as a promising treatment for metastatic melanoma. Such an approach allows one to introduce T cell receptor (TCR) modifications that, while maintaining the specificity for the targeted antigen, can enhance the binding and kinetic parameters for the interaction with peptides (p) bound to major histocompatibility complexes (MHC). Using the well-characterized 2C TCR/SIYR/H-2K(b) structure as a model system, we demonstrated that a binding free energy decomposition based on the MM-GBSA approach provides a detailed and reliable description of the TCR/pMHC interactions at the structural and thermodynamic levels. Starting from this result, we developed a new structure-based approach, to rationally design new TCR sequences, and applied it to the BC1 TCR targeting the HLA-A2 restricted NY-ESO-1157–165 cancer-testis epitope. Fifty-four percent of the designed sequence replacements exhibited improved pMHC binding as compared to the native TCR, with up to 150-fold increase in affinity, while preserving specificity. Genetically engineered CD8+ T cells expressing these modified TCRs showed an improved functional activity compared to those expressing BC1 TCR. We measured maximum levels of activities for TCRs within the upper limit of natural affinity, KD = ∼1 − 5 μM. Beyond the affinity threshold at KD < 1 μM we observed an attenuation in cellular function, in line with the “half-life” model of T cell activation. Our computer-aided protein-engineering approach requires the 3D-structure of the TCR-pMHC complex of interest, which can be obtained from X-ray crystallography. We have also developed a homology modeling-based approach, TCRep 3D, to obtain accurate structural models of any TCR-pMHC complexes when experimental data is not available. Since the accuracy of the models depends on the prediction of the TCR orientation over pMHC, we have complemented the approach with a simplified rigid method

  13. Rational design and synthesis of excavated trioctahedral Au nanocrystals

    NASA Astrophysics Data System (ADS)

    Chen, Qiaoli; Jia, Yanyan; Shen, Wei; Xie, Shuifen; Yang, Yanan; Cao, Zhenming; Xie, Zhaoxiong; Zheng, Lansun

    2015-06-01

    Excavated polyhedral nanostructures, possessing the features of high surface area and well-defined surface structure with a specific crystal facet and avoidance of aggregation, could be one of the best choices for the purpose of reducing consumption and improving performance of noble metals in many application fields. However, the formation of the excavated structures is thermodynamically unfavourable and its rational synthesis is far beyond our knowledge. In this work, taking overgrowth of Pd onto trioctahedral Au nanocrystals as a model, we present a deep insight study for synthesizing an excavated structure relying on the protection role of surfactants under suitable crystal growth kinetics. Based on the abovementioned understanding, we designed a simple and effective strategy to synthesize Au nanocrystals with excavated trioctahedral structure in one step. Due to the novel feature of the excavated structure and exposed high energy {110} facets, excavated trioctahedral Au NCs exhibited optical extinction at the near-infrared region and showed high catalytic activity towards the reduction of p-nitrophenol. Moreover, the synthetic strategy can be extended to the synthesis of excavated Au-Pd alloys.Excavated polyhedral nanostructures, possessing the features of high surface area and well-defined surface structure with a specific crystal facet and avoidance of aggregation, could be one of the best choices for the purpose of reducing consumption and improving performance of noble metals in many application fields. However, the formation of the excavated structures is thermodynamically unfavourable and its rational synthesis is far beyond our knowledge. In this work, taking overgrowth of Pd onto trioctahedral Au nanocrystals as a model, we present a deep insight study for synthesizing an excavated structure relying on the protection role of surfactants under suitable crystal growth kinetics. Based on the abovementioned understanding, we designed a simple and effective

  14. In silico ADME/T modelling for rational drug design.

    PubMed

    Wang, Yulan; Xing, Jing; Xu, Yuan; Zhou, Nannan; Peng, Jianlong; Xiong, Zhaoping; Liu, Xian; Luo, Xiaomin; Luo, Cheng; Chen, Kaixian; Zheng, Mingyue; Jiang, Hualiang

    2015-11-01

    In recent decades, in silico absorption, distribution, metabolism, excretion (ADME), and toxicity (T) modelling as a tool for rational drug design has received considerable attention from pharmaceutical scientists, and various ADME/T-related prediction models have been reported. The high-throughput and low-cost nature of these models permits a more streamlined drug development process in which the identification of hits or their structural optimization can be guided based on a parallel investigation of bioavailability and safety, along with activity. However, the effectiveness of these tools is highly dependent on their capacity to cope with needs at different stages, e.g. their use in candidate selection has been limited due to their lack of the required predictability. For some events or endpoints involving more complex mechanisms, the current in silico approaches still need further improvement. In this review, we will briefly introduce the development of in silico models for some physicochemical parameters, ADME properties and toxicity evaluation, with an emphasis on the modelling approaches thereof, their application in drug discovery, and the potential merits or deficiencies of these models. Finally, the outlook for future ADME/T modelling based on big data analysis and systems sciences will be discussed. PMID:26328949

  15. Patterning symmetry in the rational design of colloidal crystals.

    PubMed

    Romano, Flavio; Sciortino, Francesco

    2012-01-01

    Colloidal particles have the right size to form ordered structures with periodicities comparable to the wavelength of visible light. The tantalizing colours of precious opals and the colour of some species of birds are examples of polycrystalline colloidal structures found in nature. Driven by the demands of several emergent technologies, efforts have been made to develop efficient, self-assembly-based methodologies for generating colloidal single crystals with well-defined morphologies. Somewhat unfortunately, these efforts are often frustrated by the formation of structures lacking long-range order. Here we show that the rational design of patch shape and symmetry can drive patchy colloids to crystallize in a single, selected morphology by structurally eliminating undesired polymorphs. We provide a proof of this concept through the numerical investigation of triblock Janus colloids. One particular choice of patch symmetry yields, via spontaneous crystallization, a pure tetrastack lattice, a structure with attractive photonic properties, whereas another one results in a colloidal clathrate-like structure, in both cases without any interfering polymorphs. PMID:22828635

  16. Rationally designed polyimides for high-energy density capacitor applications.

    PubMed

    Ma, Rui; Baldwin, Aaron F; Wang, Chenchen; Offenbach, Ido; Cakmak, Mukerrem; Ramprasad, Rampi; Sotzing, Gregory A

    2014-07-01

    Development of new dielectric materials is of great importance for a wide range of applications for modern electronics and electrical power systems. The state-of-the-art polymer dielectric is a biaxially oriented polypropylene (BOPP) film having a maximal energy density of 5 J/cm(3) and a high breakdown field of 700 MV/m, but with a limited dielectric constant (∼2.2) and a reduced breakdown strength above 85 °C. Great effort has been put into exploring other materials to fulfill the demand of continuous miniaturization and improved functionality. In this work, a series of polyimides were investigated as potential polymer materials for this application. Polyimide with high dielectric constants of up to 7.8 that exhibits low dissipation factors (<1%) and high energy density around 15 J/cm(3), which is 3 times that of BOPP, was prepared. Our syntheses were guided by high-throughput density functional theory calculations for rational design in terms of a high dielectric constant and band gap. Correlations of experimental and theoretical results through judicious variations of polyimide structures allowed for a clear demonstration of the relationship between chemical functionalities and dielectric properties. PMID:24911181

  17. Rational design of enhanced photoresistance in a photoswitchable fluorescent protein

    NASA Astrophysics Data System (ADS)

    Duan, Chenxi; Byrdin, Martin; El Khatib, Mariam; Henry, Xavier; Adam, Virgile; Bourgeois, Dominique

    2015-03-01

    Fluorescent proteins are particularly susceptible to photobleaching, the permanent loss of fluorescence emission resulting from photodestruction of the chromophore. In the case of Reversibly Switchable Fluorescent Proteins (RSFPs), which can be switched back and forth between a non-fluorescent and a fluorescent state, the achievable number of switching cycles is limited by photobleaching, a process known as photofatigue. Photofatigue has become a crucial limitation in a number of advanced applications based on repeated photoswitching of RSFPs, notably in the field of super-resolution fluorescence microscopy. Here, based on our previous structural investigation of photobleaching mechanisms in IrisFP, an RSFP also capable of green-to-red photoconversion, we present the rational design of a single-mutant IrisFP-M159A that displays considerably enhanced photostability. The results suggest that, under moderate illumination intensities, photobleaching of IrisFP-like Anthozoan fluorescent proteins such as EosFP, Dendra or Dronpa derivatives is mainly driven by an oxygen-dependent mechanism resulting in the irreversible sulfoxidation of methionine 159. The photofatigue decay profiles of IrisFP and its photoresistant mutant IrisFP-M159A were investigated in different experimental conditions, in vitro and in cellulo. Although the performance of the mutant was found to be always superior, the results showed switching behaviors strongly dependent on the nanoenvironment. Thus, in general, assessment of photostability and switching properties of RSFPs should be carried out in real experimental conditions.

  18. A thermostable exo-β-fructosidase immobilised through rational design.

    PubMed

    Martínez, Duniesky; Cutiño-Avila, Bessy; Pérez, Enrique Rosendo; Menéndez, Carmen; Hernández, Lázaro; Del Monte-Martínez, Alberto

    2014-02-15

    Thermotoga maritima exo-β-fructosidase (BfrA) secreted by a recombinant Pichia pastoris strain was optimally immobilised on Glyoxyl-Sepharose CL 4B using the Rational Design of Immobilised Derivatives (RDID) strategy. Covalent attachment of the N-glycosylated BfrA onto the activated support at pH 10 allowed total recovery of the loaded enzyme and its activity. The immobilisation process caused no variation in the catalytic properties of the enzyme and allowed further enhancement of the thermal stability. Complete inversion of cane sugar (2.04 M) in a batch stirred tank reactor at 60 °C was achieved with a productivity of 22.2 g of substrate hydrolysed/gram of biocatalyst/hour. Half-life of the immobilised enzyme of 5 days at 60 °C was determined in a continuously operated fixed-bed column reactor. Our results promote the applicability of the BfrA-immobilised biocatalyst for the complete hydrolysis of concentrated sucrose solutions under industrial conditions, especially at a high reaction temperature. PMID:24128552

  19. Systems vaccinology: Enabling rational vaccine design with systems biological approaches.

    PubMed

    Hagan, Thomas; Nakaya, Helder I; Subramaniam, Shankar; Pulendran, Bali

    2015-09-29

    Vaccines have drastically reduced the mortality and morbidity of many diseases. However, vaccines have historically been developed empirically, and recent development of vaccines against current pandemics such as HIV and malaria has been met with difficulty. The advent of high-throughput technologies, coupled with systems biological methods of data analysis, has enabled researchers to interrogate the entire complement of a variety of molecular components within cells, and characterize the myriad interactions among them in order to model and understand the behavior of the system as a whole. In the context of vaccinology, these tools permit exploration of the molecular mechanisms by which vaccines induce protective immune responses. Here we review the recent advances, challenges, and potential of systems biological approaches in vaccinology. If the challenges facing this developing field can be overcome, systems vaccinology promises to empower the identification of early predictive signatures of vaccine response, as well as novel and robust correlates of protection from infection. Such discoveries, along with the improved understanding of immune responses to vaccination they impart, will play an instrumental role in development of the next generation of rationally designed vaccines. PMID:25858860

  20. Rationally designed, heterologous S. cerevisiae transcripts expose novel expression determinants

    PubMed Central

    Ben-Yehezkel, Tuval; Atar, Shimshi; Zur, Hadas; Diament, Alon; Goz, Eli; Marx, Tzipy; Cohen, Rafael; Dana, Alexandra; Feldman, Anna; Shapiro, Ehud; Tuller, Tamir

    2015-01-01

    Deducing generic causal relations between RNA transcript features and protein expression profiles from endogenous gene expression data remains a major unsolved problem in biology. The analysis of gene expression from heterologous genes contributes significantly to solving this problem, but has been heavily biased toward the study of the effect of 5′ transcript regions and to prokaryotes. Here, we employ a synthetic biology driven approach that systematically differentiates the effect of different regions of the transcript on gene expression up to 240 nucleotides into the ORF. This enabled us to discover new causal effects between features in previously unexplored regions of transcripts, and gene expression in natural regimes. We rationally designed, constructed, and analyzed 383 gene variants of the viral HRSVgp04 gene ORF, with multiple synonymous mutations at key positions along the transcript in the eukaryote S. cerevisiae. Our results show that a few silent mutations at the 5′UTR can have a dramatic effect of up to 15 fold change on protein levels, and that even synonymous mutations in positions more than 120 nucleotides downstream from the ORF 5′end can modulate protein levels up to 160%–300%. We demonstrate that the correlation between protein levels and folding energy increases with the significance of the level of selection of the latter in endogenous genes, reinforcing the notion that selection for folding strength in different parts of the ORF is related to translation regulation. Our measured protein abundance correlates notably(correlation up to r = 0.62 (p=0.0013)) with mean relative codon decoding times, based on ribosomal densities (Ribo-Seq) in endogenous genes, supporting the conjecture that translation elongation and adaptation to the tRNA pool can modify protein levels in a causal/direct manner. This report provides an improved understanding of transcript evolution, design principles of gene expression regulation, and suggests simple

  1. Rationally designed, heterologous S. cerevisiae transcripts expose novel expression determinants.

    PubMed

    Ben-Yehezkel, Tuval; Atar, Shimshi; Zur, Hadas; Diament, Alon; Goz, Eli; Marx, Tzipy; Cohen, Rafael; Dana, Alexandra; Feldman, Anna; Shapiro, Ehud; Tuller, Tamir

    2015-01-01

    Deducing generic causal relations between RNA transcript features and protein expression profiles from endogenous gene expression data remains a major unsolved problem in biology. The analysis of gene expression from heterologous genes contributes significantly to solving this problem, but has been heavily biased toward the study of the effect of 5' transcript regions and to prokaryotes. Here, we employ a synthetic biology driven approach that systematically differentiates the effect of different regions of the transcript on gene expression up to 240 nucleotides into the ORF. This enabled us to discover new causal effects between features in previously unexplored regions of transcripts, and gene expression in natural regimes. We rationally designed, constructed, and analyzed 383 gene variants of the viral HRSVgp04 gene ORF, with multiple synonymous mutations at key positions along the transcript in the eukaryote S. cerevisiae. Our results show that a few silent mutations at the 5'UTR can have a dramatic effect of up to 15 fold change on protein levels, and that even synonymous mutations in positions more than 120 nucleotides downstream from the ORF 5'end can modulate protein levels up to 160%-300%. We demonstrate that the correlation between protein levels and folding energy increases with the significance of the level of selection of the latter in endogenous genes, reinforcing the notion that selection for folding strength in different parts of the ORF is related to translation regulation. Our measured protein abundance correlates notably(correlation up to r = 0.62 (p=0.0013)) with mean relative codon decoding times, based on ribosomal densities (Ribo-Seq) in endogenous genes, supporting the conjecture that translation elongation and adaptation to the tRNA pool can modify protein levels in a causal/direct manner. This report provides an improved understanding of transcript evolution, design principles of gene expression regulation, and suggests simple rules for

  2. Interfacial Templating of Inorganic Nanostructures Using Rationally Designed Peptide Molecules

    NASA Astrophysics Data System (ADS)

    Leon Gibbons, Lorraine

    In nature, biological molecules form interfaces that assemble patterns of chemical functionality with exceptional precision. The role of dynamics during the assembly of biological molecules appears to be important for mineralization processes. The work presented in this dissertation applies model sheet-forming peptides at interfaces to explore the dynamics of assembly in order to template mineral growth. The peptide molecules are rationally designed to have amphiphilic properties and a propensity for sheet-like secondary structure. These designed peptides are deposited at the air/water interface to explore the dynamics of their self-assembly and investigate their 2D order. To characterize the phase behavior, techniques such as Langmuir Blodgett and Brewster Angle Microscopy are used. In addition, we verify the hypothesized sheet-forming propensity using both Circular Dichroism and Attenuated Total Reflection Fourier Transform Infrared Spectroscopy, while the characterization of the inorganic phase is done using Transmission Electron Microscopy, Electron Diffraction, and Atomic Force Microscopy. Thermodynamic analysis of structure formation with increasing pressure allows us to understand the nature of self-assembly with iterative changes in the peptide sequence. Additionally, we look at the dynamics of the self-assembled state, where the organic phase switches between short- and long-range order as a function of surface pressure. We use this model system to explore the influence of electrostatic interactions on self-assembly, and additionally, the influence of short- and long-range order on the nucleation and growth of inorganic material. This is in contrast to a system that starts with a well-ordered preformed template that defines the epitaxial growth of the mineral phase. Two versions of our model peptides are constructed by substituting histidine for glutamic acid in order to nucleate Au nanocrystals in both the short and long range ordered organic matrix, to

  3. Harvesting bioenergy with rationally designed complex functional materials

    NASA Astrophysics Data System (ADS)

    Kuang, Liangju

    A key challenge in renewable energy is to capture, convert and store solar power with earth-abundant materials and environmentally benign technologies. The goal of this thesis is to develop rationally designed complex functional materials for bio-renewable energy applications. On one hand, photoconversion membrane proteins (MPs) are nature's nanoengineering feats for renewable energy management. Harnessing their functions in synthetic systems could help understand, predict, and ultimately control matter and energy at the nanoscale. This is particularly enticing in the post-genome era as recombinant or cell-free expression of many MPs with high yields becomes possible. However, the labile nature of lipid bilayers renders them unsuitable for use in a broad range of engineered systems. A knowledge gap exists about how to design robust synthetic nanomembranes as lipid-bilayer-mimics to support MP functions and how to direct hierarchical MP reconstitution into those membranes to form 2-D or 3-D ordered proteomembrane arrays. Our studies on proteorhodopsin (PR) and bacterial reaction center (BRC), the two light-harvesting MPs, reveal that a charge-interaction-directed reconstitution (CIDR) mechanism induces spontaneous reconstitution of detergent-solubilized MPs into various amphiphilic block copolymer membranes, many of which have far superior stability than lipid bilayers. Our preliminary data also suggest MPs are not enslaved by the biological membranes they derive from; rather, the chemically nonspecific material properties of MP-supporting membranes may act as allosteric regulators. Versatile chemical designs are possible to modulate the conformational energetics of MPs, hence their transport performance in synthetic systems. On the other hand, microalgae are widely regarded as a sustainable feedstock for biofuel production. Microalgae-derived biofuels have not been commercialized yet because current technologies for microalgae dewatering add a huge cost to the

  4. Rational design of single-molecule magnets: a supramolecular approach.

    PubMed

    Glaser, Thorsten

    2011-01-01

    Since the discovery that Mn(12)OAc acts as a single-molecule magnet (SMM), an increasing number of transition metal complexes have been demonstrated to behave as SMMs. The signature of a SMM is a slow relaxation of the magnetization at low temperatures accompanied by a magnetic hysteresis. The origin of SMM behaviour is the existence of an appreciable thermal barrier U for spin-reversal called magnetic anisotropy barrier which is related to the combination of a large total spin ground state (S(t)) and an easy-axis magnetic anisotropy. The extensive research on Mn(12)OAc and other SMMs has established more prerequisites for a rational development of new SMMs besides the high-spin ground state and the magnetic anisotropy: the symmetry should be at least C(3) to minimize the quantum tunneling of the magnetization through the anisotropy barrier but lower than cubic to avoid the cancellation of the local anisotropies upon projection onto the spin ground state. Based on these prerequisites, we have designed the ligand triplesalen which combines the phloroglucinol bridging unit for high spin ground states by the spin-polarization mechanism with a salen-like ligand environment for single-site magnetic anisotropies by a strong tetragonal ligand field. The C(3) symmetric, trinuclear complexes of the triplesalen ligand (talen(t-Bu(2)))(6-) exhibit a strong ligand folding resulting in an overall bowl-shaped molecular structure. This ligand folding preorganizes the axial coordination sites of the metal salen subunits for the complementary binding of three facial nitrogen atoms of a hexacyanometallate unit. This leads to a high driving force for the formation of heptanuclear complexes [M(t)(6)M(c)](n+) by the assembly of three molecular building blocks. Attractive van der Waals interactions of the tert-butyl phenyl units of two triplesalen trinuclear building blocks increase the driving force. In this respect, we have been able to synthesize the isostructural series [Mn(III)(6

  5. Rational design of metal-organic frameworks with anticipated porosities and functionalities

    SciTech Connect

    Zhang, MW; Bosch, M; Gentle, T; Zhou, HC

    2014-01-01

    Metal-organic frameworks have emerged as a new category of porous materials that have intriguing structures and diverse applications. Even though the early discovery of new MOFs appears to be serendipitous, much effort has been made to reveal their structure-property relationships for the purpose of rationally designing novel frameworks with expected properties. Until now, much progress has been made to rationalize the design and synthesis of MOFs. This highlight review will outline the recent advances on this topic from both our and other groups and provide a systematic overview of different methods for the rational design of MOFs with desired porosities and functionalities. In this review, we will categorize the recent efforts for rational MOF design into two different approaches: a structural approach and a functional approach.

  6. Laccase engineering: from rational design to directed evolution.

    PubMed

    Mate, Diana M; Alcalde, Miguel

    2015-01-01

    Laccases are multicopper oxidoreductases considered by many in the biotechonology field as the ultimate "green catalysts". This is mainly due to their broad substrate specificity and relative autonomy (they use molecular oxygen from air as an electron acceptor and they only produce water as by-product), making them suitable for a wide array of applications: biofuel production, bioremediation, organic synthesis, pulp biobleaching, textiles, the beverage and food industries, biosensor and biofuel cell development. Since the beginning of the 21st century, specific features of bacterial and fungal laccases have been exhaustively adapted in order to reach the industrial demands for high catalytic activity and stability in conjunction with reduced production cost. Among the goals established for laccase engineering, heterologous functional expression, improved activity and thermostability, tolerance to non-natural media (organic solvents, ionic liquids, physiological fluids) and resistance to different types of inhibitors are all challenges that have been met, while obtaining a more comprehensive understanding of laccase structure-function relationships. In this review we examine the most significant advances in this exciting research area in which rational, semi-rational and directed evolution approaches have been employed to ultimately convert laccases into high value-added biocatalysts. PMID:25545886

  7. Sidewinding snakes on sand

    NASA Astrophysics Data System (ADS)

    Marvi, Hamidreza; Dimenichi, Dante; Chrystal, Robert; Mendelson, Joseph; Goldman, Daniel; Hu, David; Georgia Tech and Zoo Atlanta Collaboration

    2012-11-01

    Desert snakes such as the rattlesnake Crotalus cerastes propel themselves over sand using sidewinding, a mode of locomotion relying upon helical traveling waves. While sidewinding on hard ground has been described, the mechanics of movement on more natural substrates such as granular media remain poorly understood. In this experimental study, we use 3-D high speed video to characterize the motion of a sidewinder rattlesnake as it moves on a granular bed. We study the movement both on natural desert sand and in an air-fluidized bed trackway which we use to challenge the animal on different compactions of granular media. Particular attention is paid to rationalizing the snake's thrust on this media using friction and normal forces on the piles of sand created by the snake's body. The authors thank the NSF (PHY-0848894), Georgia Tech, and the Elizabeth Smithgall Watts endowment for support. We would also like to thank Zoo Atlanta staff for their generous help with this project.

  8. A rational design change methodology based on experimental and analytical modal analysis

    SciTech Connect

    Weinacht, D.J.; Bennett, J.G.

    1993-08-01

    A design methodology that integrates analytical modeling and experimental characterization is presented. This methodology represents a powerful tool for making rational design decisions and changes. An example of its implementation in the design, analysis, and testing of a precisions machine tool support structure is given.

  9. Rational design of small molecules as vaccine adjuvants.

    PubMed

    Wu, Tom Y-H; Singh, Manmohan; Miller, Andrew T; De Gregorio, Ennio; Doro, Francesco; D'Oro, Ugo; Skibinski, David A G; Mbow, M Lamine; Bufali, Simone; Herman, Ann E; Cortez, Alex; Li, Yongkai; Nayak, Bishnu P; Tritto, Elaine; Filippi, Christophe M; Otten, Gillis R; Brito, Luis A; Monaci, Elisabetta; Li, Chun; Aprea, Susanna; Valentini, Sara; Calabrό, Samuele; Laera, Donatello; Brunelli, Brunella; Caproni, Elena; Malyala, Padma; Panchal, Rekha G; Warren, Travis K; Bavari, Sina; O'Hagan, Derek T; Cooke, Michael P; Valiante, Nicholas M

    2014-11-19

    Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants. PMID:25411473

  10. Rational design of a zinc phthalocyanine binding protein.

    PubMed

    Mutter, Andrew C; Norman, Jessica A; Tiedemann, Michael T; Singh, Sunaina; Sha, Sha; Morsi, Sara; Ahmed, Ismail; Stillman, Martin J; Koder, Ronald L

    2014-02-01

    Phthalocyanines have long been used as primary donor molecules in synthetic light-powered devices due to their superior properties when compared to natural light activated molecules such as chlorophylls. Their use in biological contexts, however, has been severely restricted due to their high degree of self-association, and its attendant photoquenching, in aqueous environments. To this end we report the rational redesign of a de novo four helix bundle di-heme binding protein into a heme and Zinc(II) phthalocyanine (ZnPc) dyad in which the ZnPc is electronically and photonically isolated. The redesign required transformation of the homodimeric protein into a single chain four helix bundle and the addition of a negatively charge sulfonate ion to the ZnPc macrocycle. To explore the role of topology on ZnPc binding two constructs were made and the resulting differences in affinity can be explained by steric interference of the newly added connecting loop. Singular binding of ZnPc was verified by absorption, fluorescence, and magnetic circular dichroism spectroscopy. The engineering guidelines determined here, which enable the simple insertion of a monomeric ZnPc binding site into an artificial helical bundle, are a robust starting point for the creation of functional photoactive nanodevices. PMID:23827257

  11. Rational Design of Molecular Ferroelectric Materials and Nanostructures

    SciTech Connect

    Ducharme, Stephen

    2012-09-25

    The purpose of this project was to gain insight into the properties of molecular ferroelectrics through the detailed study of oligomer analogs of polyvinylidene fluoride (PVDF). By focusing on interactions at both the molecular level and the nanoscale level, we expect to gain improved understanding about the fundamental mechanism of ferroelectricity and its key properties. The research consisted of three complementary components: 1) Rational synthesis of VDF oligomers by Prof. Takacs' group; 2) Detailed structural and electrical studies of thin by Prof. Ducharme's Group; and 3) First-principles computational studies by DOE Lab Partner Dr. Serge Nakhman-son at Argonne National Laboratory. The main results of the work was a detailed understanding of the relationships between the molecular interactions and macroscopic phenomenology of fer-roelectricity VDF oligomers. This is valuable information supporting the development of im-proved electromechanical materials for, e.g., sonar, ultrasonic imaging, artificial muscles, and compliant actuators. Other potential applications include nonvolatile ferroelectric memories, heat-sensing imaging arrays, photovoltaic devices, and functional biomimetic materials. The pro-ject contributed to the training and professional development of undergraduate students and graduate students, post-doctoral assistants, and a high-school teacher. Project personnel took part in several outreach and education activities each year.

  12. Rational Design of a Zinc Phthalocyanine Binding Protein

    PubMed Central

    Mutter, Andrew C.; Norman, Jessica A.; Tiedemann, Michael T.; Singh, Sunaina; Sha, Sha; Morsi, Sara; Ahmed, Ismail; Stillman, Martin J.; Koder, Ronald L.

    2014-01-01

    Phthalocyanines have long been used as primary donor molecules in synthetic light-powered devices due to their superior properties when compared to natural light activated molecules such as chlorophylls. Their use in biological contexts, however, has been severely restricted due to their high degree of self-association, and its attendant photoquenching, in aqueous environments. To this end we report the rational redesign of a de novo four helix bundle di-heme binding protein into a heme and Zinc(II) phthalocyanine (ZnPc) dyad in which the ZnPc is electronically and photonically isolated. The redesign required transformation of the homodimeric protein into a single chain four helix bundle and the addition of a negatively charge sulfonate ion to the ZnPc macrocycle. To explore the role of topology on ZnPc binding two constructs were made and the resulting differences in affinity can be explained by steric interference of the newly added connecting loop. Singular binding of ZnPc was verified by absorption, fluorescence, and magnetic circular dichroism spectroscopy. The engineering guidelines determined here, which enable the simple insertion of a monomeric ZnPc binding site into an artificial helical bundle, are a robust starting point for the creation of functional photoactive nanodevices. PMID:23827257

  13. Integrating research and development: the emergence of rational drug design in the pharmaceutical industry.

    PubMed

    Adam, Matthias

    2005-09-01

    Rational drug design is a method for developing new pharmaceuticals that typically involves the elucidation of fundamental physiological mechanisms. It thus combines the quest for a scientific understanding of natural phenomena with the design of useful technology and hence integrates epistemic and practical aims of research and development. Case studies of the rational design of the cardiovascular drugs propranolol, captopril and losartan provide insights into characteristics and conditions of this integration. Rational drug design became possible in the 1950s when theoretical knowledge of drug-target interaction and experimental drug testing could interlock in cycles of mutual advancement. The integration does not, however, diminish the importance of basic research for pharmaceutical development. Rather, it can be shown that still in the 1990s, linear processes of innovation and the close combination of practical and epistemic work were interdependent. PMID:16137601

  14. Design of Catalytic Peptides and Proteins Through Rational and Combinatorial Approaches.

    PubMed

    Maeda, Yoshiaki; Makhlynets, Olga V; Matsui, Hiroshi; Korendovych, Ivan V

    2016-07-11

    This review focuses on recent progress in noncomputational methods to introduce catalytic function into proteins, peptides, and peptide assemblies. We discuss various approaches to creating catalytic activity and classification of noncomputational methods into rational and combinatorial classes. The section on rational design covers recent progress in the development of short peptides and oligomeric peptide assemblies for various natural and unnatural reactions. The section on combinatorial design describes recent advances in the discovery of catalytic peptides. We present the future prospects of these and other new approaches in a broader context, including implications for functional material design. PMID:27022702

  15. Rational design of orthogonal libraries of protein coding genes.

    PubMed

    Ryan, Daniel; Papamichail, Dimitris

    2013-05-17

    Array-based oligonucleotide synthesis technologies provide access to thousands of custom-designed sequence variants at low cost. Large-scale synthesis and high-throughput assays have become valuable experimental tools to study in detail the interplay between sequence and function. We have developed a methodology and corresponding algorithms for the design of diverse protein coding gene libraries, to exploit the potential of multiplex synthesis and help elucidate the effects of codon utilization and other factors in gene expression. Using our algorithm, we have computationally designed gene libraries with hundreds to thousands of orthogonal codon usage variants, uniformly exploring the design space of codon utilization, while demanding only a small fraction of the synthesis cost that would be required if these variants were synthesized independently. PMID:23654273

  16. Rational design of mirror-like peptides with alanine regulation.

    PubMed

    Li, Weizhong; Tan, Tingting; Xu, Wei; Xu, Lin; Dong, Na; Ma, Deying; Shan, Anshan

    2016-02-01

    To generate effective antimicrobial peptides (AMPs) with good antimicrobial activities and cell selectivity, many synthetic strategies have been implemented to facilitate the development of AMPs. However, these synthetic strategies represent only a small proportion of the methods used for the development of AMPs and are not optimal with the requirements needed for the design of AMPs. In this investigation, we designed a mirror-like structure with a lower charge and a higher number of hydrophobic amino acids. The amino acid sequence of the designed mirror-like peptides was XXYXXXYXXXYXX [X represents L (Leu) and/or A (Ala); Y represents K (Lys)]. These mirror-like peptides displayed antimicrobial activity against both Gram-positive and Gram-negative bacteria. Hemolysis activity and cytotoxicity, detected by using human red blood cells (hRBCs) and human embryonic kidney cells (HEK293), respectively, demonstrated that the frequency of Ala residues in this structure had a regulatory effect on the high hydrophobic region. In particular, KL4A6 showed a greater antimicrobial potency than the other three mirror-like peptides, folded into an α-helical structure, and displayed the highest therapeutic index, suggesting its good cell selectivity. Observations from fluorescence spectroscopy, flow cytometry, and electron microscopy experiments indicated that KL4A6 exhibited good membrane penetration potential by inducing membrane blebbing, disruption and lysis. Therefore, generating mirror-like peptides is a promising strategy for designing effective AMPs with regions of high hydrophobicity. PMID:26385363

  17. Rational design of an organometallic glutathione transferase inhibitor

    SciTech Connect

    Ang, W.H.; Parker, L.J.; De Luca, A.; Juillerat-Jeanneret, L.; Morton, C.J.; LoBello, M.; Parker, M.W.; Dyson, P.J.

    2010-08-17

    A hybrid organic-inorganic (organometallic) inhibitor was designed to target glutathione transferases. The metal center is used to direct protein binding, while the organic moiety acts as the active-site inhibitor. The mechanism of inhibition was studied using a range of biophysical and biochemical methods.

  18. Rational Design of Pathogen-Mimicking Amphiphilic Materials as Nanoadjuvants

    NASA Astrophysics Data System (ADS)

    Ulery, Bret D.; Petersen, Latrisha K.; Phanse, Yashdeep; Kong, Chang Sun; Broderick, Scott R.; Kumar, Devender; Ramer-Tait, Amanda E.; Carrillo-Conde, Brenda; Rajan, Krishna; Wannemuehler, Michael J.; Bellaire, Bryan H.; Metzger, Dennis W.; Narasimhan, Balaji

    2011-12-01

    An opportunity exists today for cross-cutting research utilizing advances in materials science, immunology, microbial pathogenesis, and computational analysis to effectively design the next generation of adjuvants and vaccines. This study integrates these advances into a bottom-up approach for the molecular design of nanoadjuvants capable of mimicking the immune response induced by a natural infection but without the toxic side effects. Biodegradable amphiphilic polyanhydrides possess the unique ability to mimic pathogens and pathogen associated molecular patterns with respect to persisting within and activating immune cells, respectively. The molecular properties responsible for the pathogen-mimicking abilities of these materials have been identified. The value of using polyanhydride nanovaccines was demonstrated by the induction of long-lived protection against a lethal challenge of Yersinia pestis following a single administration ten months earlier. This approach has the tantalizing potential to catalyze the development of next generation vaccines against diseases caused by emerging and re-emerging pathogens.

  19. Rational Design of Proteasome Inhibitors as Antimalarial Drugs.

    PubMed

    Le Chapelain, Camille; Groll, Michael

    2016-05-23

    One life, two strategies: Crucial structural differences between the human and the Plasmodium falciparum proteasomes were recently identified. A combination of cryo-EM and functional characterization enabled the design of a selective antimalarial proteasome inhibitor that shows low toxicity in the host. When used with artemisinin, this ligand offers a new approach for the efficient treatment of malaria at all stages of the parasite lifecycle. PMID:27079849

  20. On the rational design of compressible flow ejectors

    NASA Technical Reports Server (NTRS)

    Ortwerth, P. J.

    1979-01-01

    A fluid mechanics review of chemical laser ejectors is presented. The characteristics of ejectors with single and multiple driver nozzles are discussed. Methods to compute an optimized performance map in which secondary Mach number and performance are computed versus mass ratio, to compute the flow distortion at each optimized condition, and to determine the thrust area for the design point to match diffuser impedence are examined.

  1. Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

    PubMed Central

    Onuoha, Shimobi C.; Ferrari, Mathieu; Sblattero, Daniele

    2015-01-01

    Objective Biologic drugs, such as the anti–tumor necrosis factor (anti‐TNF) antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Yet, concerns remain over their lack of efficacy in a sizable proportion of patients and their potential for systemic side effects such as infection. Improved biologic prodrugs specifically targeted to the site of inflammation have the potential to alleviate current concerns surrounding biologic anticytokine therapies. The purpose of this study was to design, construct, and evaluate in vitro and ex vivo the targeting and antiinflammatory capacity of activatable bispecific antibodies. Methods Activatable dual variable domain (aDVD) antibodies were designed and constructed to target intercellular adhesion molecule 1 (ICAM‐1), which is up‐regulated at sites of inflammation, and anti‐TNF antibodies (adalimumab and infliximab). These bispecific molecules included an external arm that targets ICAM‐1 and an internal arm that comprises the therapeutic domain of an anti‐TNF antibody. Both arms were linked to matrix metalloproteinase (MMP)–cleavable linkers. The constructs were tested for their ability to bind and neutralize both in vitro and ex vivo targets. Results Intact aDVD constructs demonstrated significantly reduced binding and anti‐TNF activity in the prodrug formulation as compared to the parent antibodies. Human synovial fluid and physiologic concentrations of MMP enzyme were capable of cleaving the external domain of the antibody, revealing a fully active molecule. Activated antibodies retained the same binding and anti‐TNF inhibitory capacities as the parent molecules. Conclusion The design of a biologic prodrug with enhanced specificity for sites of inflammation (synovium) and reduced specificity for off‐target TNF is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of

  2. Rational Design of Calpain Inhibitors Based on Calpastatin Peptidomimetics.

    PubMed

    Low, Kristin E; Ler, Spencer; Chen, Kevin J; Campbell, Robert L; Hickey, Jennifer L; Tan, Joanne; Scully, Conor C G; Davies, Peter L; Yudin, Andrei K; Zaretsky, Serge

    2016-06-01

    Our previously reported structures of calpain bound to its endogenous inhibitor calpastatin have motivated the use of aziridine aldehyde-mediated peptide macrocyclization toward the design of cyclic peptides and peptidomimetics as calpain inhibitors. Inspired by nature's hint that a β-turn loop within calpastatin forms a broad interaction around calpain's active site cysteine, we have constructed and tested a library of 45 peptidic compounds based on this loop sequence. Four molecules have shown reproducibly low micromolar inhibition of calpain-2. Further systematic sequence changes led to the development of probes that displayed increased potency and specificity of inhibition against calpain over other cysteine proteases. Calculated Ki values were in the low micromolar range, rivaling other peptidomimetic calpain inhibitors and presenting an improved selectivity profile against other therapeutically relevant proteases. Competitive and mixed inhibition against calpain-2 was observed, and an allosteric inhibition site on the enzyme was identified for a noncompetitive inhibitor. PMID:27148623

  3. Rational design of potent human transthyretin amyloid disease inhibitors.

    PubMed

    Klabunde, T; Petrassi, H M; Oza, V B; Raman, P; Kelly, J W; Sacchettini, J C

    2000-04-01

    The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein-drug complexes have been determined to allow detailed analyses of the protein-drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases. PMID:10742177

  4. Synthesis of a Potent Vinblastine: Rationally Designed Added Benign Complexity.

    PubMed

    Allemann, Oliver; Brutsch, Manuela; Lukesh, John C; Brody, Daniel M; Boger, Dale L

    2016-07-13

    Many natural products, including vinblastine, have not been easily subjected to simplifications in their structures by synthetic means or modifications by late-stage semisynthetic derivatization in ways that enhance their biological potency. Herein, we detail a synthetic vinblastine that incorporates added benign complexity (ABC), which improves activity 10-fold, and is now accessible as a result of advances in the total synthesis of the natural product. The compound incorporates designed added molecular complexity but no new functional groups and maintains all existing structural and conformational features of the natural product. It constitutes a member of an analogue class presently inaccessible by semisynthetic derivatization of the natural product, by its late-stage functionalization, or by biosynthetic means. Rather, it was accessed by synthetic means, using an appropriately modified powerful penultimate single-step vindoline-catharanthine coupling strategy that proceeds with a higher diastereoselectivity than found for the natural product itself. PMID:27356080

  5. Rational design of a split-Cas9 enzyme complex

    DOE PAGESBeta

    Wright, Addison V.; Sternberg, Samuel H.; Taylor, David W.; Staahl, Brett T.; Bardales, Jorge A.; Kornfeld, Jack E.; Doudna, Jennifer A.

    2015-02-23

    Cas9, an RNA-guided DNA endonuclease found in clustered regularly interspaced short palindromic repeats (CRISPR) bacterial immune systems, is a versatile tool for genome editing, transcriptional regulation, and cellular imaging applications. Structures of Streptococcus pyogenes Cas9 alone or bound to single-guide RNA (sgRNA) and target DNA revealed a bilobed protein architecture that undergoes major conformational changes upon guide RNA and DNA binding. To investigate the molecular determinants and relevance of the interlobe rearrangement for target recognition and cleavage, we designed a split-Cas9 enzyme in which the nuclease lobe and α-helical lobe are expressed as separate polypeptides. The lobes do not interactmore » on their own, the sgRNA recruits them into a ternary complex that recapitulates the activity of full-length Cas9 and catalyzes site-specific DNA cleavage. The use of a modified sgRNA abrogates split-Cas9 activity by preventing dimerization, allowing for the development of an inducible dimerization system. We propose that split-Cas9 can act as a highly regulatable platform for genome-engineering applications.« less

  6. Rationally Designed Peptidomimetic Modulators of Aβ Toxicity in Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Rajasekhar, K.; Suresh, S. N.; Manjithaya, Ravi; Govindaraju, T.

    2015-01-01

    Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21st century. The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the β-amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process may act as therapeutic agents for the treatment of the disease. Use of recognition unit based peptidomimetics as inhibitors are a promising approach, as they exhibit greater protease stability compared to natural peptides. Here, we present peptidomimetic inhibitors of Aβ aggregation designed based on the KLVFF (P1) sequence that is known to bind Aβ aggregates. We improved inhibition efficiency of P1 by introducing multiple hydrogen bond donor-acceptor moieties (thymine/barbiturate) at the N-terminal (P2 and P3), and blood serum stability by modifying the backbone by incorporating sarcosine (N-methylglycine) units at alternate positions (P4 and P5). The peptidomimetics showed moderate to good activity in both inhibition and dissolution of Aβ aggregates as depicted by thioflavin assay, circular dichroism (CD) measurements and microscopy (TEM). The activity of P4 and P5 were studied in a yeast cell model showing Aβ toxicity. P4 and P5 could rescue yeast cells from Aβ toxicity and Aβ aggregates were cleared by the process of autophagy.

  7. Resistance identification and rational process design in Capacitive Deionization.

    PubMed

    Dykstra, J E; Zhao, R; Biesheuvel, P M; van der Wal, A

    2016-01-01

    Capacitive Deionization (CDI) is an electrochemical method for water desalination employing porous carbon electrodes. To enhance the performance of CDI, identification of electronic and ionic resistances in the CDI cell is important. In this work, we outline a method to identify these resistances. We illustrate our method by calculating the resistances in a CDI cell with membranes (MCDI) and by using this knowledge to improve the cell design. To identify the resistances, we derive a full-scale MCDI model. This model is validated against experimental data and used to calculate the ionic resistances across the MCDI cell. We present a novel way to measure the electronic resistances in a CDI cell, as well as the spacer channel thickness and porosity after assembly of the MCDI cell. We identify that for inflow salt concentrations of 20 mM the resistance is mainly located in the spacer channel and the external electrical circuit, not in the electrodes. Based on these findings, we show that the carbon electrode thickness can be increased without significantly increasing the energy consumption per mol salt removed, which has the advantage that the desalination time can be lengthened significantly. PMID:26512814

  8. Rational design of the car hearth of a tunnel furnace

    SciTech Connect

    Kryzhanovskii, K.S.; Chernyi, V.I.; Dunaevskii, O.M.; Mokhort, V.N.; Sedoi, N.I.

    1985-09-01

    In tunnel furnaces the heat losses into the environment amount to 15-20% of the burnt-fuel heat. The heat is essentially lost through the car (carrier) hearth into the corridor of the furnace bottom. A light-weight car has been designed that is thermally insulated using a high-alumina kaolin fiber of the VGR-130 mark. The car-hearth weight was reduced by 1.5 times by using a light-weight fireclay and incorporating an air space within the hearth. Using the method of finite differences, the authors determined the dynamics of temperature field variation along the height of the car-hearth before and after its reconstruction as applied to the firing parameters of the products in the tunnel furnace. The results of the determinations are presented. An additional thermal insulation of the car hearth using a 15-20 mm thick high-alumina kaolin fiber also makes it possible to reduce the heat losses in the furnace-bottom corridor by 30-40%, and thereby, to decrease the maximum temperature in the corridor from 90 to 60 degrees C, which significantly improves energy efficiency.

  9. Rational medium design for Bordetella pertussis: basic metabolism.

    PubMed

    Thalen, M; van den IJssel, J; Jiskoot, W; Zomer, B; Roholl, P; de Gooijer, C; Beuvery, C; Tramper, J

    1999-10-01

    In current Bordetella pertussis media ammonium accumulates because of an imbalance in the nitrogen:carbon ratio of the substrates used, which is one of the factors limiting cell density in fed-batch cultures. The aim of this study was to map B. pertussis catabolic and anabolic capabilities, in order to design a medium that avoids ammonium accumulation, while substrates are metabolised completely. Besides the known dysfunctional glycolysis, B. pertussis also possessed a partially dysfunctional citric-acid cycle. Although ammonium accumulation was avoided by adding various carbon sources to medium with glutamate, nuclear magnetic resonance (NMR) showed excretion of acetate, acetoacetate and beta-hydroxy-butyrate, thereby reducing the biomass yield. Acetoacetate and beta-hydroxy-butyrate were also formed in Verwey, B2 and modified Stainer-Scholte medium. Electron microscopy in combination with NMR showed that cells early on in these cultures contained poly-hydroxy-butyrate (PHB) globules, which disappeared later during the culture, coinciding with the appearance of beta-hydroxy-butyrate and/or acetoacetate. No globules nor metabolite excretion was detected when lactate in combination with glutamate were used as substrates. Thus, metabolite excretion and ammonium accumulation were avoided, while the yield of 8.8 g C-mol-1 compared favourably with literature values, averaging 6.5 g C-mol-1. Optimisation of this medium for pertussis toxin production will be reported in a separate article. PMID:10553654

  10. Rationally Designed Peptidomimetic Modulators of Aβ Toxicity in Alzheimer's Disease

    PubMed Central

    Rajasekhar, K.; Suresh, S. N.; Manjithaya, Ravi; Govindaraju, T.

    2015-01-01

    Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21st century. The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the β-amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process may act as therapeutic agents for the treatment of the disease. Use of recognition unit based peptidomimetics as inhibitors are a promising approach, as they exhibit greater protease stability compared to natural peptides. Here, we present peptidomimetic inhibitors of Aβ aggregation designed based on the KLVFF (P1) sequence that is known to bind Aβ aggregates. We improved inhibition efficiency of P1 by introducing multiple hydrogen bond donor-acceptor moieties (thymine/barbiturate) at the N-terminal (P2 and P3), and blood serum stability by modifying the backbone by incorporating sarcosine (N-methylglycine) units at alternate positions (P4 and P5). The peptidomimetics showed moderate to good activity in both inhibition and dissolution of Aβ aggregates as depicted by thioflavin assay, circular dichroism (CD) measurements and microscopy (TEM). The activity of P4 and P5 were studied in a yeast cell model showing Aβ toxicity. P4 and P5 could rescue yeast cells from Aβ toxicity and Aβ aggregates were cleared by the process of autophagy. PMID:25633824

  11. Rational design of bleachable nonchemically amplified DUV photoactive compounds

    NASA Astrophysics Data System (ADS)

    Rathsack, Benjamen M.; Tattersall, Peter I.; Tabery, Cyrus E.; Lou, Kathleen; Stachowiak, Timothy B.; Medeiros, David R.; Albelo, Jeff A.; Pirogovsky, Peter Y.; McKean, Dennis R.; Willson, C. Grant

    2001-08-01

    Photoactive compounds have been designed, synthesized and characterized for deep ultraviolet non-chemically amplified resist applications. These resist materials may have potential use in next generation 257nm mask fabrication. Mask fabrication requires stringent linewidth specifications over long post-coat and post-exposure bake delays. Lithography simulation and imaging experiments have been done to determine the lithographic performance of resists formulated with these new photoactive compounds. Previously studied chromophores, 7 substituted 3-diazo 4- hydroxycoumarin and N-substituted 3-diazo-2, 4-piperidione, both have the transparency, bleaching and exposure rate kinetics in the DUV that are analogous to those exhibited by the diazonaphthoquinone chromophore at 365nm. The sulfonate linkages attached to these photoactive compounds provide dissolution rate inhibition of novolak that is very similar to the diazonaphthoquinone-sulfonates. The trifunctional diazopiperidione that incorporates three sulfonate linkages provides more efficient inhibition per chromophore than the corresponding bisfunctional photoactive compound. The diazocoumarin based novolak resist demonstrates image reversal (negative tone) with the use of a post-exposure bake. The post-exposure bake causes the exposed photoactive compound to decarboxylate, which dramatically reduces its solubility in aqueous base. The trifunctional diazopiperidione provides the best overall imaging results due to almost complete bleaching and high contrast.

  12. Rational design of a split-Cas9 enzyme complex

    PubMed Central

    Wright, Addison V.; Sternberg, Samuel H.; Taylor, David W.; Staahl, Brett T.; Bardales, Jorge A.; Kornfeld, Jack E.; Doudna, Jennifer A.

    2015-01-01

    Cas9, an RNA-guided DNA endonuclease found in clustered regularly interspaced short palindromic repeats (CRISPR) bacterial immune systems, is a versatile tool for genome editing, transcriptional regulation, and cellular imaging applications. Structures of Streptococcus pyogenes Cas9 alone or bound to single-guide RNA (sgRNA) and target DNA revealed a bilobed protein architecture that undergoes major conformational changes upon guide RNA and DNA binding. To investigate the molecular determinants and relevance of the interlobe rearrangement for target recognition and cleavage, we designed a split-Cas9 enzyme in which the nuclease lobe and α-helical lobe are expressed as separate polypeptides. Although the lobes do not interact on their own, the sgRNA recruits them into a ternary complex that recapitulates the activity of full-length Cas9 and catalyzes site-specific DNA cleavage. The use of a modified sgRNA abrogates split-Cas9 activity by preventing dimerization, allowing for the development of an inducible dimerization system. We propose that split-Cas9 can act as a highly regulatable platform for genome-engineering applications. PMID:25713377

  13. Rational design of a split-Cas9 enzyme complex

    SciTech Connect

    Wright, Addison V.; Sternberg, Samuel H.; Taylor, David W.; Staahl, Brett T.; Bardales, Jorge A.; Kornfeld, Jack E.; Doudna, Jennifer A.

    2015-02-23

    Cas9, an RNA-guided DNA endonuclease found in clustered regularly interspaced short palindromic repeats (CRISPR) bacterial immune systems, is a versatile tool for genome editing, transcriptional regulation, and cellular imaging applications. Structures of Streptococcus pyogenes Cas9 alone or bound to single-guide RNA (sgRNA) and target DNA revealed a bilobed protein architecture that undergoes major conformational changes upon guide RNA and DNA binding. To investigate the molecular determinants and relevance of the interlobe rearrangement for target recognition and cleavage, we designed a split-Cas9 enzyme in which the nuclease lobe and α-helical lobe are expressed as separate polypeptides. The lobes do not interact on their own, the sgRNA recruits them into a ternary complex that recapitulates the activity of full-length Cas9 and catalyzes site-specific DNA cleavage. The use of a modified sgRNA abrogates split-Cas9 activity by preventing dimerization, allowing for the development of an inducible dimerization system. We propose that split-Cas9 can act as a highly regulatable platform for genome-engineering applications.

  14. Rational method for design of wick drain systems

    NASA Astrophysics Data System (ADS)

    Landau, Richard E.

    the time to complete 90% of primary consolidation in the field. Procedures are described to determine the field induced pore pressure profile needed to apply the empirical relationship in design.

  15. Rational Design of Plasmonic Nanoparticles for Enhanced Cavitation and Cell Perforation.

    PubMed

    Lachaine, Rémi; Boutopoulos, Christos; Lajoie, Pierre-Yves; Boulais, Étienne; Meunier, Michel

    2016-05-11

    Metallic nanoparticles are routinely used as nanoscale antenna capable of absorbing and converting photon energy with subwavelength resolution. Many applications, notably in nanomedicine and nanobiotechnology, benefit from the enhanced optical properties of these materials, which can be exploited to image, damage, or destroy targeted cells and subcellular structures with unprecedented precision. Modern inorganic chemistry enables the synthesis of a large library of nanoparticles with an increasing variety of shapes, composition, and optical characteristic. However, identifying and tailoring nanoparticles morphology to specific applications remains challenging and limits the development of efficient nanoplasmonic technologies. In this work, we report a strategy for the rational design of gold plasmonic nanoshells (AuNS) for the efficient ultrafast laser-based nanoscale bubble generation and cell membrane perforation, which constitute one of the most crucial challenges toward the development of effective gene therapy treatments. We design an in silico rational design framework that we use to tune AuNS morphology to simultaneously optimize for the reduction of the cavitation threshold while preserving the particle structural integrity. Our optimization procedure yields optimal AuNS that are slightly detuned compared to their plasmonic resonance conditions with an optical breakdown threshold 30% lower than randomly selected AuNS and 13% lower compared to similarly optimized gold nanoparticles (AuNP). This design strategy is validated using time-resolved bubble spectroscopy, shadowgraphy imaging and electron microscopy that confirm the particle structural integrity and a reduction of 51% of the cavitation threshold relative to optimal AuNP. Rationally designed AuNS are finally used to perforate cancer cells with an efficiency of 61%, using 33% less energy compared to AuNP, which demonstrate that our rational design framework is readily transferable to a cell environment

  16. Rational design of metal oxide nanocomposite anodes for advanced lithium ion batteries

    NASA Astrophysics Data System (ADS)

    Li, Yong; Yu, Shenglan; Yuan, Tianzhi; Yan, Mi; Jiang, Yinzhu

    2015-05-01

    Metal-oxide anodes represent a significant future direction for advanced lithium ion batteries. However, their practical applications are still seriously hampered by electrode disintegration and capacity fading during cycling. Here, we report a rational design of 3D-staggered metal-oxide nanocomposite electrode directly fabricated by pulsed spray evaporation chemical vapor deposition, where various oxide nanocomponents are in a staggered distribution uniformly along three dimensions and across the whole electrode. Such a special design of nanoarchitecture combines the advantages of nanoscale materials in volume change and Li+/electron conduction as well as uniformly staggered and compact structure in atom migration during lithiation/delithiation, which exhibits high specific capacity, good cycling stability and excellent rate capability. The rational design of metal-oxide nanocomposite electrode opens up new possibilities for high performance lithium ion batteries.

  17. Rational design and optimization of fed-batch and continuous fermentations.

    PubMed

    Zhang, Wenhui; Inan, Mehmet; Meagher, Michael M

    2007-01-01

    This chapter provides rational approaches to design and optimize fed-batch and continuous fermentations of both Mut+ and Muts (methanol utilization plus and slow) Pichia pastoris strains. The methods are described in detail for glycerol batch, glycerol fed-batch, transition, and methanol fed-batch/mixed feed/ continuous stirred tank reactor (CSTR) phases of the process based on glycerol and methanol consumption models. Cell density, broth volume, substrate feed rate, and the length of each phase are rationally designed to conduct runs with selected parameters for optimizing a process. The optimization is anchored by the impact of a specific growth rate/dilution time (for CSTRs) on productivity. Equations for simulation of a process with optimal parameters are derived for an optimal process design. This protocol can be used as a practical manual for process development of a P. pastoris recombinant fermentation, and also as a reference for fermentation of other microorganisms. PMID:17951634

  18. 50 CFR Table 3 to Part 226 - Hydrologic Units Containing Critical Habitat for Snake River Sockeye Salmon and Snake River...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Habitat for Snake River Sockeye Salmon and Snake River Spring/Summer and Fall Chinook Salmon 3 Table 3 to... ADMINISTRATION, DEPARTMENT OF COMMERCE MARINE MAMMALS DESIGNATED CRITICAL HABITAT Pt. 226, Table 3 Table 3 to Part 226—Hydrologic Units Containing Critical Habitat for Snake River Sockeye Salmon and Snake...

  19. 50 CFR Table 3 to Part 226 - Hydrologic Units Containing Critical Habitat for Snake River Sockeye Salmon and Snake River...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Habitat for Snake River Sockeye Salmon and Snake River Spring/Summer and Fall Chinook Salmon 3 Table 3 to... ADMINISTRATION, DEPARTMENT OF COMMERCE MARINE MAMMALS DESIGNATED CRITICAL HABITAT Pt. 226, Table 3 Table 3 to Part 226—Hydrologic Units Containing Critical Habitat for Snake River Sockeye Salmon and Snake...

  20. 50 CFR Table 3 to Part 226 - Hydrologic Units Containing Critical Habitat for Snake River Sockeye Salmon and Snake River...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Habitat for Snake River Sockeye Salmon and Snake River Spring/Summer and Fall Chinook Salmon 3 Table 3 to... ADMINISTRATION, DEPARTMENT OF COMMERCE MARINE MAMMALS DESIGNATED CRITICAL HABITAT Pt. 226, Table 3 Table 3 to Part 226—Hydrologic Units Containing Critical Habitat for Snake River Sockeye Salmon and Snake...

  1. Controlling the Spin Texture of Topological Insulators by Rational Design of Organic Molecules.

    PubMed

    Jakobs, Sebastian; Narayan, Awadhesh; Stadtmüller, Benjamin; Droghetti, Andrea; Rungger, Ivan; Hor, Yew S; Klyatskaya, Svetlana; Jungkenn, Dominik; Stöckl, Johannes; Laux, Martin; Monti, Oliver L A; Aeschlimann, Martin; Cava, Robert J; Ruben, Mario; Mathias, Stefan; Sanvito, Stefano; Cinchetti, Mirko

    2015-09-01

    We present a rational design approach to customize the spin texture of surface states of a topological insulator. This approach relies on the extreme multifunctionality of organic molecules that are used to functionalize the surface of the prototypical topological insulator (TI) Bi2Se3. For the rational design we use theoretical calculations to guide the choice and chemical synthesis of appropriate molecules that customize the spin texture of Bi2Se3. The theoretical predictions are then verified in angular-resolved photoemission experiments. We show that, by tuning the strength of molecule-TI interaction, the surface of the TI can be passivated, the Dirac point can energetically be shifted at will, and Rashba-split quantum-well interface states can be created. These tailored interface properties-passivation, spin-texture tuning, and creation of hybrid interface states-lay a solid foundation for interface-assisted molecular spintronics in spin-textured materials. PMID:26262825

  2. Rational design of new electrolyte materials for electrochemical double layer capacitors

    NASA Astrophysics Data System (ADS)

    Schütter, Christoph; Husch, Tamara; Viswanathan, Venkatasubramanian; Passerini, Stefano; Balducci, Andrea; Korth, Martin

    2016-09-01

    The development of new electrolytes is a centerpiece of many strategies to improve electrochemical double layer capacitor (EDLC) devices. We present here a computational screening-based rational design approach to find new electrolyte materials. As an example application, the known chemical space of almost 70 million compounds is investigated in search of electrochemically more stable solvents. Cyano esters are identified as especially promising new compound class. Theoretical predictions are validated with subsequent experimental studies on a selected case. These studies show that based on theoretical predictions only, a previously untested, but very well performing compound class was identified. We thus find that our rational design strategy is indeed able to successfully identify completely new materials with substantially improved properties.

  3. Rationally designed multifunctional plasmonic nanostructures for surface-enhanced Raman spectroscopy: a review

    NASA Astrophysics Data System (ADS)

    Xie, Wei; Schlücker, Sebastian

    2014-11-01

    Rationally designed multifunctional plasmonic nanostructures efficiently integrate two or more functionalities into a single entity, for example, with both plasmonic and catalytic activity. This review article is focused on their synthesis and use in surface-enhanced Raman scattering (SERS) as a molecular spectroscopic technique with high sensitivity, fingerprint specificity, and surface selectivity. After a short tutorial on the fundamentals of Raman scattering and SERS in particular, applications ranging from chemistry (heterogeneous catalysis) to biology and medicine (diagnostics/imaging, therapy) are summarized.

  4. Rational design and synthesis of a porous, task-specific polycarbazole for efficient CO2 capture.

    PubMed

    Jin, Tian; Xiong, Yan; Zhu, Xiang; Tian, Ziqi; Tao, Duan-Jian; Hu, Jun; Jiang, De-en; Wang, Hualin; Liu, Honglai; Dai, Sheng

    2016-03-25

    We present a rational design and synthesis of a novel porous pyridine-functionalized polycarbazole for efficient CO2 capture based on the density functional theory calculations. The task-specific polymer, generated through a one-step FeCl3-catalyzed oxidative coupling reaction, exhibits a superior CO2 uptake at 1.0 bar and 273 K (5.57 mmol g(-1)). PMID:26864392

  5. Selected Approaches for Rational Drug Design and High Throughput Screening to Identify Anti-Cancer Molecules

    PubMed Central

    Hedvat, Michael; Emdad, Luni; Das, Swadesh K.; Kim, Keetae; Dasgupta, Santanu; Thomas, Shibu; Hu, Bin; Zhu, Shan; Dash, Rupesh; Quinn, Bridget A.; Oyesanya, Regina A.; Kegelman, Timothy P.; Sokhi, Upneet K.; Sarkar, Siddik; Erdogan, Eda; Menezes, Mitchell E.; Bhoopathi, Praveen; Wang, Xiang-Yang; Pomper, Martin G.; Wei, Jun; Wu, Bainan; Stebbins, John L.; Diaz, Paul W.; Reed, John C.; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B.

    2013-01-01

    Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specific-promoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity. The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy. PMID:22931411

  6. Rational peptide design for functional materials via molecular self-assembly

    NASA Astrophysics Data System (ADS)

    Rajagopal, Karthikan

    Supra-molecular self-assembly of rationally designed peptides is a promising approach to construct functional materials. This thesis specifically focuses on hydrogels, an important class of materials with potential for applications in tissue engineering, drug delivery and micro-fluidic systems. The objective is to design short peptides that would specifically adopt a stimulus dependent conformation that is strongly amenable to self-assembly resulting in material formation. With this concept the rational design of a 20 amino acid peptide (MAX1) that folds into an amphiphilic beta-hairpin structure and then self-assembles to form a rigid hydrogel under alkaline conditions is presented. The molecular level conformation of MAX1 was characterized using circular dichroism and FTIR spectroscopies. The mesoscale structure of the hydrogel assessed using confocal and transmission electron micron microscopies and neutron scattering techniques shows that peptide self-assembly results in the formation of fibrils that are homogeneously 3 nm in diameter. The mechanical properties of the hydrogel probed using oscillatory rheology shows that MAX1 forms a stiff hydrogel. Since the self-assembly process is coupled to the intra-molecularly folded state of the peptide, stimulus responsiveness can be specifically engineered into the sequence by rational design. This was demonstrated in the design of peptides that form hydrogels in response to a specific stimulus such as temperature, pH or ionic strength. The significance of peptide design in the context of self-assembly and its relationship to the nanostructure was studied by designing a series of peptides derived from MAX1. Evolving from these studies is an understanding of the relationship between molecular level peptide structure and the nanoscale supra-molecular morphology. Based on this, it has been shown that alternate morphologies distinct from those observed with the gel forming peptides, such as non-twisting laminates or tube

  7. Rational design of carbon nitride photocatalysts by identification of cyanamide defects as catalytically relevant sites

    NASA Astrophysics Data System (ADS)

    Lau, Vincent Wing-Hei; Moudrakovski, Igor; Botari, Tiago; Weinberger, Simon; Mesch, Maria B.; Duppel, Viola; Senker, Jürgen; Blum, Volker; Lotsch, Bettina V.

    2016-07-01

    The heptazine-based polymer melon (also known as graphitic carbon nitride, g-C3N4) is a promising photocatalyst for hydrogen evolution. Nonetheless, attempts to improve its inherently low activity are rarely based on rational approaches because of a lack of fundamental understanding of its mechanistic operation. Here we employ molecular heptazine-based model catalysts to identify the cyanamide moiety as a photocatalytically relevant `defect'. We exploit this knowledge for the rational design of a carbon nitride polymer populated with cyanamide groups, yielding a material with 12 and 16 times the hydrogen evolution rate and apparent quantum efficiency (400 nm), respectively, compared with the unmodified melon. Computational modelling and material characterization suggest that this moiety improves coordination (and, in turn, charge transfer kinetics) to the platinum co-catalyst and enhances the separation of the photogenerated charge carriers. The demonstrated knowledge transfer for rational catalyst design presented here provides the conceptual framework for engineering high-performance heptazine-based photocatalysts.

  8. Rational design of carbon nitride photocatalysts by identification of cyanamide defects as catalytically relevant sites

    PubMed Central

    Lau, Vincent Wing-hei; Moudrakovski, Igor; Botari, Tiago; Weinberger, Simon; Mesch, Maria B.; Duppel, Viola; Senker, Jürgen; Blum, Volker; Lotsch, Bettina V.

    2016-01-01

    The heptazine-based polymer melon (also known as graphitic carbon nitride, g-C3N4) is a promising photocatalyst for hydrogen evolution. Nonetheless, attempts to improve its inherently low activity are rarely based on rational approaches because of a lack of fundamental understanding of its mechanistic operation. Here we employ molecular heptazine-based model catalysts to identify the cyanamide moiety as a photocatalytically relevant ‘defect'. We exploit this knowledge for the rational design of a carbon nitride polymer populated with cyanamide groups, yielding a material with 12 and 16 times the hydrogen evolution rate and apparent quantum efficiency (400 nm), respectively, compared with the unmodified melon. Computational modelling and material characterization suggest that this moiety improves coordination (and, in turn, charge transfer kinetics) to the platinum co-catalyst and enhances the separation of the photogenerated charge carriers. The demonstrated knowledge transfer for rational catalyst design presented here provides the conceptual framework for engineering high-performance heptazine-based photocatalysts. PMID:27387536

  9. Rational design of carbon nitride photocatalysts by identification of cyanamide defects as catalytically relevant sites.

    PubMed

    Lau, Vincent Wing-Hei; Moudrakovski, Igor; Botari, Tiago; Weinberger, Simon; Mesch, Maria B; Duppel, Viola; Senker, Jürgen; Blum, Volker; Lotsch, Bettina V

    2016-01-01

    The heptazine-based polymer melon (also known as graphitic carbon nitride, g-C3N4) is a promising photocatalyst for hydrogen evolution. Nonetheless, attempts to improve its inherently low activity are rarely based on rational approaches because of a lack of fundamental understanding of its mechanistic operation. Here we employ molecular heptazine-based model catalysts to identify the cyanamide moiety as a photocatalytically relevant 'defect'. We exploit this knowledge for the rational design of a carbon nitride polymer populated with cyanamide groups, yielding a material with 12 and 16 times the hydrogen evolution rate and apparent quantum efficiency (400 nm), respectively, compared with the unmodified melon. Computational modelling and material characterization suggest that this moiety improves coordination (and, in turn, charge transfer kinetics) to the platinum co-catalyst and enhances the separation of the photogenerated charge carriers. The demonstrated knowledge transfer for rational catalyst design presented here provides the conceptual framework for engineering high-performance heptazine-based photocatalysts. PMID:27387536

  10. Inventing and improving ribozyme function: rational design versus iterative selection methods

    NASA Technical Reports Server (NTRS)

    Breaker, R. R.; Joyce, G. F.

    1994-01-01

    Two major strategies for generating novel biological catalysts exist. One relies on our knowledge of biopolymer structure and function to aid in the 'rational design' of new enzymes. The other, often called 'irrational design', aims to generate new catalysts, in the absence of detailed physicochemical knowledge, by using selection methods to search a library of molecules for functional variants. Both strategies have been applied, with considerable success, to the remodeling of existing ribozymes and the development of ribozymes with novel catalytic function. The two strategies are by no means mutually exclusive, and are best applied in a complementary fashion to obtain ribozymes with the desired catalytic properties.

  11. Impact of Binding Site Comparisons on Medicinal Chemistry and Rational Molecular Design.

    PubMed

    Ehrt, Christiane; Brinkjost, Tobias; Koch, Oliver

    2016-05-12

    Modern rational drug design not only deals with the search for ligands binding to interesting and promising validated targets but also aims to identify the function and ligands of yet uncharacterized proteins having impact on different diseases. Additionally, it contributes to the design of inhibitors with distinct selectivity patterns and the prediction of possible off-target effects. The identification of similarities between binding sites of various proteins is a useful approach to cope with those challenges. The main scope of this perspective is to describe applications of different protein binding site comparison approaches to outline their applicability and impact on molecular design. The article deals with various substantial application domains and provides some outstanding examples to show how various binding site comparison methods can be applied to promote in silico drug design workflows. In addition, we will also briefly introduce the fundamental principles of different protein binding site comparison methods. PMID:27046190

  12. Rational design and application of a redox-active, photoresponsive, discrete metallogelator.

    PubMed

    Afrasiabi, Rouzbeh; Kraatz, Heinz-Bernhard

    2015-05-18

    A photoresponsive discrete metallogelator was rationally designed by incorporating a photochromic azobenzene subunit in the structure of a redox-active ferrocene-peptide conjugate. The target molecule was purposefully equipped with a dipeptide unit capable of self-assembly in response to sonication. The designed molecule was shown to undergo supramolecular self-assembly and achieve organogelation in response to ultrasound, light, heat, and redox signals. The sol-gel phase transition of the designed gelator was found to be sensitive to a plethora of input stimuli, allowing the application of the sol-gel transition behavior in basic logic gate operations. A gel-based NOT logic gate operation was realized when the redox-active property of the organogel was examined by using different oxidizing agents. The smart response of the gelator was further exploited in designing XOR operations under oxidizing or non-oxidizing conditions. PMID:25827318

  13. Rationally designed multifunctional plasmonic nanostructures for surface-enhanced Raman spectroscopy: a review.

    PubMed

    Xie, Wei; Schlücker, Sebastian

    2014-11-01

    Rationally designed multifunctional plasmonic nanostructures efficiently integrate two or more functionalities into a single entity, for example, with both plasmonic and catalytic activity. This review article is focused on their synthesis and use in surface-enhanced Raman scattering (SERS) as a molecular spectroscopic technique with high sensitivity, fingerprint specificity, and surface selectivity. After a short tutorial on the fundamentals of Raman scattering and SERS in particular, applications ranging from chemistry (heterogeneous catalysis) to biology and medicine (diagnostics/imaging, therapy) are summarized. PMID:25373417

  14. Rationally designed micropores within a metal-organic framework for selective sorption of gas molecules.

    PubMed

    Chen, Banglin; Ma, Shengqian; Zapata, Fatima; Fronczek, Frank R; Lobkovsky, Emil B; Zhou, Hong-Cai

    2007-02-19

    A microporous metal-organic framework, MOF, Cu(FMA)(4,4'-Bpe)0.5 (3a, FMA = fumarate; 4,4'-Bpe = 4,4'-Bpe = trans-bis(4-pyridyl)ethylene) was rationally designed from a primitive cubic net whose pores are tuned by double framework interpenetration. With pore cavities of about 3.6 A, which are interconnected by pore windows of 2.0 x 3.2 A, 3a shows highly selective sorption behaviors of gas molecules. PMID:17291116

  15. Novel ligands rationally designed for characterizing I2-imidazoline binding sites nature and functions.

    PubMed

    Gentili, Francesco; Cardinaletti, Claudia; Vesprini, Cristian; Ghelfi, Francesca; Farande, Aniket; Giannella, Mario; Piergentili, Alessandro; Quaglia, Wilma; Mattioli, Laura; Perfumi, Marina; Hudson, Alan; Pigini, Maria

    2008-08-28

    The study of two series of 2-aryl-ethylen-imidazolines 3-7 and 8-12 inspired by I2-IBS ligands phenyzoline (1) and diphenyzoline (2), respectively, confirmed the interesting "positive" or "negative" morphine analgesia modulation displayed by their corresponding leads and demonstrated that these effects might be correlated with morphine tolerance and dependence, respectively. By comparative examination of rationally designed compounds, some analogies between binding site cavity of I2-IBS proteins and alpha 2C-adrenoreceptor emerged. PMID:18661965

  16. Crystals of Human Serum Albumin for Use in Genetic Engineering and Rational Drug Design

    NASA Technical Reports Server (NTRS)

    Carter, Daniel C. (Inventor)

    1994-01-01

    This invention pertains to crystals of serum albumin and processes for growing them. The purpose of the invention is to provide crystals of serum albumin which can be studied to determine binding sites for drugs. Form 2 crystals grow in the monoclinic space P2(sub 1), and possesses the following unit cell constraints: a = 58.9 +/- 7, b = 88.3 +/- 7, c = 60.7 +/- 7, Beta = 101.0 +/- 2 degrees. One advantage of the invention is that it will allow rational drug design

  17. Rational design of nanofiber scaffolds for orthopedic tissue repair and regeneration

    PubMed Central

    Ma, Bing; Xie, Jingwei; Jiang, Jiang; Shuler, Franklin D; Bartlett, David E

    2013-01-01

    This article reviews recent significant advances in the design of nanofiber scaffolds for orthopedic tissue repair and regeneration. It begins with a brief introduction on the limitations of current approaches for orthopedic tissue repair and regeneration. It then illustrates that rationally designed scaffolds made up of electrospun nanofibers could be a promising solution to overcome the problems that current approaches encounter. The article also discusses the intriguing properties of electrospun nanofibers, including control of composition, structures, orders, alignments and mechanical properties, use as carriers for topical drug and/or gene sustained delivery, and serving as substrates for the regulation of cell behaviors, which could benefit musculoskeletal tissue repair and regeneration. It further highlights a few of the many recent applications of electrospun nanofiber scaffolds in repairing and regenerating various orthopedic tissues. Finally, the article concludes with perspectives on the challenges and future directions for better design, fabrication and utilization of nanofiber scaffolds for orthopedic tissue engineering. PMID:23987110

  18. Rational design of the column of a heavy multipurpose machining center

    NASA Astrophysics Data System (ADS)

    Atapin, V. V.; Kurlaev, N. V.

    2016-04-01

    The main purpose in the design of supporting constructions of heavy multipurpose machining center is the reduction of mass at the given precision and productivity of machining. Accomplish these ends the technology of rational design of supporting constructions is offered. This technology is based on the decomposition method and the finite elements method in the combination with optimization methods. The technology has four stages: 1) calculation of external forces and loads, 2) as a result the boundary conditions (force, kinematics) for individual supporting constructions are formed, 3) a problem about final optimal distribution of a material by the individual supporting constructions with the real cross-section is solved; 4) dynamic analysis. By the example of design of the column of a heavy multipurpose machining center the main stages of rational design of the individual supporting constructions are shown. At a design stage of the carrying system consisting of load-bearing structures with simplified geometry, optimum overall dimensions of the column are identified. For the admitted system of preferences, it is necessary to accept the fact that the carrying system with the column with the sizes of cross section of 1.8 m (along х axis) and 2.6 m (along y axis) is the best. The analysis of the work of the column under the torsion condition with the use of method of mechanics shows that the column with square cross sections = 2.46·2.46 m which rigidity on torsion is 26 % higher in comparison with a production version is the best. The results of calculation show that a production-release design of the column with longitudinal and transverse edges of rigidity is 24 % heavier than the column with the edges located on a diagonally at equal rigidity.

  19. Rational design of metal nitride redox materials for solar-driven ammonia synthesis.

    PubMed

    Michalsky, Ronald; Pfromm, Peter H; Steinfeld, Aldo

    2015-06-01

    Fixed nitrogen is an essential chemical building block for plant and animal protein, which makes ammonia (NH3) a central component of synthetic fertilizer for the global production of food and biofuels. A global project on artificial photosynthesis may foster the development of production technologies for renewable NH3 fertilizer, hydrogen carrier and combustion fuel. This article presents an alternative path for the production of NH3 from nitrogen, water and solar energy. The process is based on a thermochemical redox cycle driven by concentrated solar process heat at 700-1200°C that yields NH3 via the oxidation of a metal nitride with water. The metal nitride is recycled via solar-driven reduction of the oxidized redox material with nitrogen at atmospheric pressure. We employ electronic structure theory for the rational high-throughput design of novel metal nitride redox materials and to show how transition-metal doping controls the formation and consumption of nitrogen vacancies in metal nitrides. We confirm experimentally that iron doping of manganese nitride increases the concentration of nitrogen vacancies compared with no doping. The experiments are rationalized through the average energy of the dopant d-states, a descriptor for the theory-based design of advanced metal nitride redox materials to produce sustainable solar thermochemical ammonia. PMID:26052421

  20. Rational design and application of responsive α-helical peptide hydrogels

    PubMed Central

    Banwell, Eleanor F.; Abelardo, Edgardo S.; Adams, Dave J.; Birchall, Martin A.; Corrigan, Adam; Donald, Athene M.; Kirkland, Mark; Serpell, Louise C.; Butler, Michael F.; Woolfson, Derek N.

    2009-01-01

    Biocompatible hydrogels have a wide variety of potential applications in biotechnology and medicine, such as the controlled delivery and release of cells, cosmetics and drugs; and as supports for cell growth and tissue engineering1. Rational peptide design and engineering are emerging as promising new routes to such functional biomaterials2-4. Here we present the first examples of rationally designed and fully characterized self-assembling hydrogels based on standard linear peptides with purely α-helical structures, which we call hydrogelating self-assembling fibres (hSAFs). These form spanning networks of α-helical fibrils that interact to give self-supporting physical hydrogels of >99% water content. The peptide sequences can be engineered to alter the underlying mechanism of gelation and, consequently, the hydrogel properties. Interestingly, for example, those with hydrogen-bonded networks melt upon heating, whereas those formed via hydrophobic interactions strengthen when warmed. The hSAFs are dual-peptide systems that only gel on mixing, which gives tight control over assembly5. These properties raise possibilities for using the hSAFs as substrates in cell culture. We have tested this in comparison with the widely used Matrigel substrate, and demonstrate that, like Matrigel, hSAFs support both growth and differentiation of rat adrenal pheochromocytoma cells for sustained periods in culture. PMID:19543314

  1. The Use of Drug Discovery Tools in Rational Organometallic Catalyst Design

    SciTech Connect

    Sumpter, Bobby G; Drummond, Michael L

    2007-01-01

    A computational procedure is detailed where techniques common in the drug discovery process - 2D- and 3D-Quantitative Structure-Activity Relationships (QSAR) - are applied to rationalize the catalytic activity of a synthetically flexible, Ti-N=P ethylene polymerization catalyst system. Once models relating molecular properties to catalyst activity are built with the two QSAR approaches, two database mining approaches are used to select a small number of ligands from a larger database that are likely to produce catalysts with high activity when grafted onto the Ti-N=P framework.. The software employed throughout this work is freely available, easy to use, and was applied in a "black box" approach, to highlight areas where the drug discovery tools, designed to address organic molecules, have difficulty in addressing issues arising from the presence of a metal atom. In general, 3D-QSAR offers an efficient way to screen new potential ligands and separate those likely to lead to poor catalysts from those that are likely to contribute to highly active catalysts. The results for 2D-QSAR appear to be quantitatively unreliable, likely due to the presence of a metal atom; nonetheless, there is evidence that qualitative predictions from different models may be reliable. Pitfalls in the database mining techniques are identified, none of which are insurmountable. The lessons learned about the potential uses and drawbacks of the techniques described herein are readily applicable to other catalyst frameworks, thereby enabling a rational approach to catalyst improvement and design.

  2. Rational design and application of responsive α-helical peptide hydrogels

    NASA Astrophysics Data System (ADS)

    Banwell, Eleanor F.; Abelardo, Edgardo S.; Adams, Dave J.; Birchall, Martin A.; Corrigan, Adam; Donald, Athene M.; Kirkland, Mark; Serpell, Louise C.; Butler, Michael F.; Woolfson, Derek N.

    2009-07-01

    Biocompatible hydrogels have a wide variety of potential applications in biotechnology and medicine, such as the controlled delivery and release of cells, cosmetics and drugs, and as supports for cell growth and tissue engineering. Rational peptide design and engineering are emerging as promising new routes to such functional biomaterials. Here, we present the first examples of rationally designed and fully characterized self-assembling hydrogels based on standard linear peptides with purely α-helical structures, which we call hydrogelating self-assembling fibres (hSAFs). These form spanning networks of α-helical fibrils that interact to give self-supporting physical hydrogels of >99% water content. The peptide sequences can be engineered to alter the underlying mechanism of gelation and, consequently, the hydrogel properties. Interestingly, for example, those with hydrogen-bonded networks of fibrils melt on heating, whereas those formed through hydrophobic fibril-fibril interactions strengthen when warmed. The hSAFs are dual-peptide systems that gel only on mixing, which gives tight control over assembly. These properties raise possibilities for using the hSAFs as substrates in cell culture. We have tested this in comparison with the widely used Matrigel substrate, and demonstrate that, like Matrigel, hSAFs support both growth and differentiation of rat adrenal pheochromocytoma cells for sustained periods in culture.

  3. Rational Design of Chiral Nanostructures from Self-Assembly of a Ferrocene-Modified Dipeptide.

    PubMed

    Wang, Yuefei; Qi, Wei; Huang, Renliang; Yang, Xuejiao; Wang, Mengfan; Su, Rongxin; He, Zhimin

    2015-06-24

    We report a new paradigm for the rational design of chiral nanostructures that is based on the hierarchical self-assembly of a ferrocene (Fc)-modified dipeptide, ferrocene-L-Phe-L-Phe-OH (Fc-FF). Compared to other chiral self-assembling systems, Fc-FF is unique because of its smaller size, biocompatibility, multiple functions (a redox center), and environmental responsiveness. X-ray and spectroscopic analyses showed that the incorporation of counterions during the hierarchical self-assembly of Fc-FF changed the conformations of the secondary structures from flat β sheets into twisted β sheets. This approach enables chiral self-assembly and the formation of well-defined chiral nanostructures composed of helical twisted β sheets. We identified two elementary forms for the helical twist of the β sheets, which allowed us to create a rich variety of rigid chiral nanostructures over a wide range of scales. Furthermore, through subtle modulations in the counterions, temperature, and solvent, we are able to precisely control the helical pitch, diameter, and handedness of the self-assembled chiral nanostructures. This unprecedented level of control not only offers insights into how rationally designed chiral nanostructures can be formed from simple molecular building blocks but also is of significant practical value for the use in chiroptics, templates, chiral sensing, and separations. PMID:26018930

  4. Rational design of metal nitride redox materials for solar-driven ammonia synthesis

    PubMed Central

    Michalsky, Ronald; Pfromm, Peter H.; Steinfeld, Aldo

    2015-01-01

    Fixed nitrogen is an essential chemical building block for plant and animal protein, which makes ammonia (NH3) a central component of synthetic fertilizer for the global production of food and biofuels. A global project on artificial photosynthesis may foster the development of production technologies for renewable NH3 fertilizer, hydrogen carrier and combustion fuel. This article presents an alternative path for the production of NH3 from nitrogen, water and solar energy. The process is based on a thermochemical redox cycle driven by concentrated solar process heat at 700–1200°C that yields NH3 via the oxidation of a metal nitride with water. The metal nitride is recycled via solar-driven reduction of the oxidized redox material with nitrogen at atmospheric pressure. We employ electronic structure theory for the rational high-throughput design of novel metal nitride redox materials and to show how transition-metal doping controls the formation and consumption of nitrogen vacancies in metal nitrides. We confirm experimentally that iron doping of manganese nitride increases the concentration of nitrogen vacancies compared with no doping. The experiments are rationalized through the average energy of the dopant d-states, a descriptor for the theory-based design of advanced metal nitride redox materials to produce sustainable solar thermochemical ammonia. PMID:26052421

  5. 20% PARTIAL SIBERIAN SNAKE IN THE AGS.

    SciTech Connect

    Huang, H; Bai, M; Brown, K A; Glenn, W; Luccio, A U; Mackay, W W; Montag, C; Ptitsyn, V; Roser, T; Tsoupas, N; Zeno, K; Ranjbar, V; Spinka, H; Underwood, D

    2002-11-06

    An 11.4% partial Siberian snake was used to successfully accelerate polarized proton through a strong intrinsic depolarizing spin resonance in the AGS. No noticeable depolarization was observed. This opens up the possibility of using a 20% to 30% partial Siberian snake in the AGS to overcome all weak and strong depolarizing spin resonances. Some design and operation issues of the new partial Siberian snake are discussed.

  6. Rational design of crystalline supermicroporous covalent organic frameworks with triangular topologies

    PubMed Central

    Dalapati, Sasanka; Addicoat, Matthew; Jin, Shangbin; Sakurai, Tsuneaki; Gao, Jia; Xu, Hong; Irle, Stephan; Seki, Shu; Jiang, Donglin

    2015-01-01

    Covalent organic frameworks (COFs) are an emerging class of highly ordered porous polymers with many potential applications. They are currently designed and synthesized through hexagonal and tetragonal topologies, limiting the access to and exploration of new structures and properties. Here, we report that a triangular topology can be developed for the rational design and synthesis of a new class of COFs. The triangular topology features small pore sizes down to 12 Å, which is among the smallest pores for COFs reported to date, and high π-column densities of up to 0.25 nm−2, which exceeds those of supramolecular columnar π-arrays and other COF materials. These crystalline COFs facilitate π-cloud delocalization and are highly conductive, with a hole mobility that is among the highest reported for COFs and polygraphitic ensembles. PMID:26178865

  7. Rational Design of Polynuclear Organometallic Assemblies from a Simple Heteromultifunctional Ligand.

    PubMed

    Zhang, Long; Lin, Yue-Jian; Li, Zhen-Hua; Jin, Guo-Xin

    2015-10-28

    In modern coordination chemistry, supramolecular coordination complexes take advantage of ligand design to control the shapes and sizes of such architectures. Here we describe how to utilize starting building blocks and a multifunctional ligand to rationally design and synthesize different types of discrete assemblies. Using a hydroxamate ligand featuring two pair of chelating sites together with half-sandwich iridium and rhodium fragments, we were able to construct a series multinuclear organometallic macrocycles and cages through stepwise coordination-driven self-assembly. Experimental observations, supported by computational work, show that selective coordination modes were ascribed to the significant electronic density differences of the two chelating sites, (O,O') and (N,N'). The results underline the advantages of the discrimination between soft and hard binding sites, and suggest that hydroxamic acids can be used as a versatile class of facile multifunctional scaffold for the construction of novel two-dimensional and three-dimensional architectures. PMID:26440304

  8. Rational Design and Adaptive Management of Combination Therapies for Hepatitis C Virus Infection

    PubMed Central

    Ke, Ruian; Loverdo, Claude; Qi, Hangfei; Sun, Ren; Lloyd-Smith, James O.

    2015-01-01

    Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensate when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design. PMID:26125950

  9. Rational design of crystalline supermicroporous covalent organic frameworks with triangular topologies

    NASA Astrophysics Data System (ADS)

    Dalapati, Sasanka; Addicoat, Matthew; Jin, Shangbin; Sakurai, Tsuneaki; Gao, Jia; Xu, Hong; Irle, Stephan; Seki, Shu; Jiang, Donglin

    2015-07-01

    Covalent organic frameworks (COFs) are an emerging class of highly ordered porous polymers with many potential applications. They are currently designed and synthesized through hexagonal and tetragonal topologies, limiting the access to and exploration of new structures and properties. Here, we report that a triangular topology can be developed for the rational design and synthesis of a new class of COFs. The triangular topology features small pore sizes down to 12 Å, which is among the smallest pores for COFs reported to date, and high π-column densities of up to 0.25 nm-2, which exceeds those of supramolecular columnar π-arrays and other COF materials. These crystalline COFs facilitate π-cloud delocalization and are highly conductive, with a hole mobility that is among the highest reported for COFs and polygraphitic ensembles.

  10. Enhancing thermoelectric performance of Bi2Te3-based nanostructures through rational structure design.

    PubMed

    Hong, Min; Chen, Zhi-Gang; Yang, Lei; Zou, Jin

    2016-04-28

    Nanostructuring has been successfully employed to enhance the thermoelectric performance of Bi2Te3 due to its obtained low thermal conductivity. In order to further reduce the thermal conductivity, we designed a hierarchical nanostructure assembled with well-aligned Bi2Te3 nanoplates using Te nanotubes as templates by a facile microwave-assisted solvothermal synthesis. From the comparisons of their thermoelectric performance and theoretical calculations with simple Bi2Te3 nanostructures, we found that Te/Bi2Te3 hierarchical nanostructures exhibit a higher figure-of-merit due to the optimized reduced Fermi level and enhanced phonon scattering, as well as the suppressed bipolar conduction. This study provides an effective approach to enhance the thermoelectric performance of Bi2Te3-based nanostructures by rationally designing the nanostructures. PMID:27050933

  11. From G Protein-coupled Receptor Structure Resolution to Rational Drug Design*

    PubMed Central

    Jazayeri, Ali; Dias, Joao M.; Marshall, Fiona H.

    2015-01-01

    A number of recent technical solutions have led to significant advances in G protein-coupled receptor (GPCR) structural biology. Apart from a detailed mechanistic view of receptor activation, the new structures have revealed novel ligand binding sites. Together, these insights provide avenues for rational drug design to modulate the activities of these important drug targets. The application of structural data to GPCR drug discovery ushers in an exciting era with the potential to improve existing drugs and discover new ones. In this review, we focus on technical solutions that have accelerated GPCR crystallography as well as some of the salient findings from structures that are relevant to drug discovery. Finally, we outline some of the approaches used in GPCR structure based drug design. PMID:26100628

  12. Rational design of crystalline supermicroporous covalent organic frameworks with triangular topologies.

    PubMed

    Dalapati, Sasanka; Addicoat, Matthew; Jin, Shangbin; Sakurai, Tsuneaki; Gao, Jia; Xu, Hong; Irle, Stephan; Seki, Shu; Jiang, Donglin

    2015-01-01

    Covalent organic frameworks (COFs) are an emerging class of highly ordered porous polymers with many potential applications. They are currently designed and synthesized through hexagonal and tetragonal topologies, limiting the access to and exploration of new structures and properties. Here, we report that a triangular topology can be developed for the rational design and synthesis of a new class of COFs. The triangular topology features small pore sizes down to 12 Å, which is among the smallest pores for COFs reported to date, and high π-column densities of up to 0.25 nm(-2), which exceeds those of supramolecular columnar π-arrays and other COF materials. These crystalline COFs facilitate π-cloud delocalization and are highly conductive, with a hole mobility that is among the highest reported for COFs and polygraphitic ensembles. PMID:26178865

  13. Enhancing thermoelectric performance of Bi2Te3-based nanostructures through rational structure design

    NASA Astrophysics Data System (ADS)

    Hong, Min; Chen, Zhi-Gang; Yang, Lei; Zou, Jin

    2016-04-01

    Nanostructuring has been successfully employed to enhance the thermoelectric performance of Bi2Te3 due to its obtained low thermal conductivity. In order to further reduce the thermal conductivity, we designed a hierarchical nanostructure assembled with well-aligned Bi2Te3 nanoplates using Te nanotubes as templates by a facile microwave-assisted solvothermal synthesis. From the comparisons of their thermoelectric performance and theoretical calculations with simple Bi2Te3 nanostructures, we found that Te/Bi2Te3 hierarchical nanostructures exhibit a higher figure-of-merit due to the optimized reduced Fermi level and enhanced phonon scattering, as well as the suppressed bipolar conduction. This study provides an effective approach to enhance the thermoelectric performance of Bi2Te3-based nanostructures by rationally designing the nanostructures.Nanostructuring has been successfully employed to enhance the thermoelectric performance of Bi2Te3 due to its obtained low thermal conductivity. In order to further reduce the thermal conductivity, we designed a hierarchical nanostructure assembled with well-aligned Bi2Te3 nanoplates using Te nanotubes as templates by a facile microwave-assisted solvothermal synthesis. From the comparisons of their thermoelectric performance and theoretical calculations with simple Bi2Te3 nanostructures, we found that Te/Bi2Te3 hierarchical nanostructures exhibit a higher figure-of-merit due to the optimized reduced Fermi level and enhanced phonon scattering, as well as the suppressed bipolar conduction. This study provides an effective approach to enhance the thermoelectric performance of Bi2Te3-based nanostructures by rationally designing the nanostructures. Electronic supplementary information (ESI) available: XRD patterns, SEM and TEM images of as-synthesized Te nanotubes. See DOI: 10.1039/c6nr00719h

  14. Rational design of small molecule inhibitors targeting the Ras GEF, SOS1

    PubMed Central

    Evelyn, Chris R.; Duan, Xin; Biesiada, Jacek; Seibel, William L.; Meller, Jaroslaw; Zheng, Yi

    2014-01-01

    Summary Ras GTPases regulate intracellular signaling involved in cell proliferation. Elevated Ras signaling activity has been associated with human cancers. Ras activation is catalyzed by guanine-nucleotide exchange factors (GEFs), of which SOS1 is a major member that transduces receptor tyrosine kinase signaling to Ras. We have developed a rational approach coupling virtual screening with experimental screening in identifying small-molecule inhibitors targeting the catalytic site of SOS1 and SOS1-regulated Ras activity. A lead inhibitor, NSC-658497, is found to bind to SOS1, competitively suppresses SOS1-Ras interaction, and dose-dependently inhibits SOS1 GEF activity. Mutagenesis and structure-activity relationship studies map the NSC-658497 site of action to the SOS1 catalytic site, and define the chemical moieties in the inhibitor essential for the activity. NSC-658497 showed dose-dependent efficacy in inhibiting Ras, downstream signaling activities, and associated cell proliferation. These studies establish a proof of principle for rational design of small-molecule inhibitors targeting Ras GEF enzymatic activity. PMID:25455859

  15. Toward Rational Fragment-Based Lead Design without 3D Structures

    PubMed Central

    2012-01-01

    Fragment-based lead discovery (FBLD) has become a prime component of the armamentarium of modern drug design programs. FBLD identifies low molecular weight ligands that weakly bind to important biological targets. Three-dimensional structural information about the binding mode is provided by X-ray crystallography or NMR spectroscopy and is subsequently used to improve the lead compounds. Despite tremendous success rates, FBLD relies on the availability of high-resolution structural information, still a bottleneck in drug discovery programs. To overcome these limitations, we recently demonstrated that the meta-structure approach provides an alternative route to rational lead identification in cases where no 3D structure information about the biological target is available. Combined with information-rich NMR data, this strategy provides valuable information for lead development programs. We demonstrate with several examples the feasibility of the combined NMR and meta-structure approach to devise a rational strategy for fragment evolution without resorting to highly resolved protein complex structures. PMID:22889313

  16. Siberian Snake solenoid for the AGS

    SciTech Connect

    Ratner, L. G.

    1991-01-01

    Recent experiments at the Indiana University Cyclotron Facility (IUCF) have demonstrated that Siberian Snakes'' can be used to preserve the polarization of an accelerated polarized beam in a circular accelerator. Retrofitting full snakes into accelerators such as the Alternating Gradient Synchrotron (AGS) at Brookhaven is almost impossible due to space limitations, but a partial snake that can correct depolarization due to imperfection resonances with 1/20 to 1/30 of a full strength snake seems to present a viable option. We describe such a device for the AGS and give the design criteria in terms of simplicity of accelerator operation and level of achievable polarization. 2 refs., 5 figs., 1 tab.

  17. Rational design of antibodies targeting specific epitopes within intrinsically disordered proteins

    PubMed Central

    Sormanni, Pietro; Aprile, Francesco A.; Vendruscolo, Michele

    2015-01-01

    Antibodies are powerful tools in life sciences research, as well as in diagnostic and therapeutic applications, because of their ability to bind given molecules with high affinity and specificity. Using current methods, however, it is laborious and sometimes difficult to generate antibodies to target specific epitopes within a protein, in particular if these epitopes are not effective antigens. Here we present a method to rationally design antibodies to enable them to bind virtually any chosen disordered epitope in a protein. The procedure consists in the sequence-based design of one or more complementary peptides targeting a selected disordered epitope and the subsequent grafting of such peptides on an antibody scaffold. We illustrate the method by designing six single-domain antibodies to bind different epitopes within three disease-related intrinsically disordered proteins and peptides (α-synuclein, Aβ42, and IAPP). Our results show that all these designed antibodies bind their targets with good affinity and specificity. As an example of an application, we show that one of these antibodies inhibits the aggregation of α-synuclein at substoichiometric concentrations and that binding occurs at the selected epitope. Taken together, these results indicate that the design strategy that we propose makes it possible to obtain antibodies targeting given epitopes in disordered proteins or protein regions. PMID:26216991

  18. Combining different design strategies for rational affinity maturation of the MICA-NKG2D interface

    PubMed Central

    Henager, Samuel H; Hale, Melissa A; Maurice, Nicholas J; Dunnington, Erin C; Swanson, Carter J; Peterson, Megan J; Ban, Joseph J; Culpepper, David J; Davies, Luke D; Sanders, Lisa K; McFarland, Benjamin J

    2012-01-01

    We redesigned residues on the surface of MICA, a protein that binds the homodimeric immunoreceptor NKG2D, to increase binding affinity with a series of rational, incremental changes. A fixed-backbone RosettaDesign protocol scored a set of initial mutations, which we tested by surface plasmon resonance for thermodynamics and kinetics of NKG2D binding, both singly and in combination. We combined the best four mutations at the surface with three affinity-enhancing mutations below the binding interface found with a previous design strategy. After curating design scores with three cross-validated tests, we found a linear relationship between free energy of binding and design score, and to a lesser extent, enthalpy and design score. Multiple mutants bound with substantial subadditivity, but in at least one case full additivity was observed when combining distant mutations. Altogether, combining the best mutations from the two strategies into a septuple mutant enhanced affinity by 50-fold, to 50 nM, demonstrating a simple, effective protocol for affinity enhancement. PMID:22761154

  19. Rational design of metallic nanocavities for resonantly enhanced four-wave mixing

    PubMed Central

    Almeida, Euclides; Prior, Yehiam

    2015-01-01

    Optimizing the shape of nanostructures and nano-antennas for specific optical properties has evolved to be a very fruitful activity. With modern fabrication tools a large variety of possibilities is available for shaping both nanoparticles and nanocavities; in particular nanocavities in thin metal films have emerged as attractive candidates for new metamaterials and strong linear and nonlinear optical systems. Here we rationally design metallic nanocavities to boost their Four-Wave Mixing response by resonating the optical plasmonic resonances with the incoming and generated beams. The linear and nonlinear optical responses as well as the propagation of the electric fields inside the cavities are derived from the solution of Maxwell’s equations by using the 3D finite-differences time domain method. The observed conversion-efficiency of near-infrared to visible light equals or surpasses that of BBO of equivalent thickness. Implications to further optimization for efficient and broadband ultrathin nonlinear optical materials are discussed. PMID:25974175

  20. Rational Design of Multi-Stimuli-Responsive Nanoparticles for Precise Cancer Therapy.

    PubMed

    An, Xiaonan; Zhu, Aijun; Luo, Huanhuan; Ke, Hengte; Chen, Huabing; Zhao, Youliang

    2016-06-28

    Stimuli-responsive nanoparticles with target capacity are of great interest in drug delivery for cancer therapy. However, the challenge is to achieve highly smart release with precise spatiotemporal control for cancer therapy. Herein, we report the preparation and properties of multi-stimuli-responsive nanoparticles through the co-assembly of a 3-arm star quaterpolymer with a near-infrared (NIR) photothermal agent and chemotherapeutic compound. The nanoparticles can exhibit NIR light/pH/reduction-responsive drug release and intracellular drug translocation in cancer cells, which further integrate photoinduced hyperthermia for synergistic anticancer efficiency, thereby leading to tumor ablation without tumor regrowth. Thus, this rational design of nanoparticles with multiple responsiveness represents a versatile strategy to provide smart drug delivery paradigms for cancer therapy. PMID:27285378

  1. In silico rational design of ionic liquids for the exfoliation and dispersion of boron nitride nanosheets.

    PubMed

    García, Gregorio; Atilhan, Mert; Aparicio, Santiago

    2016-01-14

    A requirement for exploiting most of the unique properties of boron-nitride (BN) nanosheets is their isolation from the bulk material. A rational design of task-specific ionic liquids (ILs) through DFT simulations is reported in this work. The applied computational protocol allowed the screening of large IL families, which was carried out bearing in mind the achievement of strong π-π stacking between the anions and BN nanosheets as well as a negative charge transfer from the anion to the surface. The selected ionic liquids yielded strong interaction energies with BN nanosheets and high charge transfer values, while the main features of the ionic liquid are not affected in the presence of nanosheets. DFT simulations provided a detailed picture of the interaction mechanism and useful structure-property relationships in the search of a new ionic liquid for BN exfoliation. PMID:26658819

  2. From empiricism to rational design: a personal perspective of the evolution of vaccine development.

    PubMed

    De Gregorio, Ennio; Rappuoli, Rino

    2014-07-01

    Vaccination, which is the most effective medical intervention that has ever been introduced, originated from the observation that individuals who survived a plague or smallpox would not get the disease twice. To mimic the protective effects of natural infection, Jenner - and later Pasteur - inoculated individuals with attenuated or killed disease-causing agents. This empirical approach inspired a century of vaccine development and the effective prophylaxis of many infectious diseases. From the 1980s, several waves of new technologies have enabled the development of novel vaccines that would not have been possible using the empirical approach. The technological revolution in the field of vaccination is now continuing, and it is delivering novel and safer vaccines. In this Timeline article, we provide our views on the transition from empiricism to rational vaccine design. PMID:24925139

  3. Fibrin-based biomaterials: Modulation of macroscopic properties through rational design at the molecular level

    PubMed Central

    Brown, Ashley C.; Barker, Thomas H.

    2013-01-01

    Fibrinogen is one of the primary components of the coagulation cascade and rapidly forms an insoluble matrix following tissue injury. In addition to its important role in hemostasis, fibrin acts as a scaffold for tissue repair and provides important cues for directing cell phenotype following injury. Because of these properties and the ease of polymerization of the material, fibrin has been widely utilized as a biomaterial for over a century. Modifying the macroscopic properties of fibrin, such as elasticity and porosity, has been somewhat elusive until recently, yet with a molecular-level rational design approach can now be somewhat easily modified through alterations of molecular interactions key to the protein’s polymerization process. This review outlines the biochemistry of fibrin and discusses methods for modification of molecular interactions and their application to fibrin based biomaterials. PMID:24056097

  4. Phenolic melanin precursors provide a rational approach to the design of antitumor agents for melanoma

    SciTech Connect

    Jimbow, K.; Miura, T.; Ito, S.; Ishikawa, K.

    1989-01-01

    A unique biological property of the melanocyte, melanin synthesis may permit a rational approach to design agents for better management of malignant melanoma. This in vivo and in vitro study examined the selective melanocytotoxicity and antimelanoma effects of phenolic compounds, cysteinylphenol (CP), cysteaminylphenol (CAP), and related compounds, and found (1) that both 4-S-CP and 4-S-CAP are melanin precursors, (2) that 4-S-CAP possesses a marked depigmenting potency with selective destruction of melanocytes in black follicles, and (3) a significant inhibition in the protein synthesis and tumor growth of B16 melanoma. Importantly, a whole body autoradiography indicated that these phenolic melanin precursors are selectively incorporated into melanoma tissues after i.p. administration.

  5. Sleeping Beauty transposase structure allows rational design of hyperactive variants for genetic engineering.

    PubMed

    Voigt, Franka; Wiedemann, Lisa; Zuliani, Cecilia; Querques, Irma; Sebe, Attila; Mátés, Lajos; Izsvák, Zsuzsanna; Ivics, Zoltán; Barabas, Orsolya

    2016-01-01

    Sleeping Beauty (SB) is a prominent Tc1/mariner superfamily DNA transposon that provides a popular genome engineering tool in a broad range of organisms. It is mobilized by a transposase enzyme that catalyses DNA cleavage and integration at short specific sequences at the transposon ends. To facilitate SB's applications, here we determine the crystal structure of the transposase catalytic domain and use it to model the SB transposase/transposon end/target DNA complex. Together with biochemical and cell-based transposition assays, our structure reveals mechanistic insights into SB transposition and rationalizes previous hyperactive transposase mutations. Moreover, our data enables us to design two additional hyperactive transposase variants. Our work provides a useful resource and proof-of-concept for structure-based engineering of tailored SB transposases. PMID:27025571

  6. Sleeping Beauty transposase structure allows rational design of hyperactive variants for genetic engineering

    PubMed Central

    Voigt, Franka; Wiedemann, Lisa; Zuliani, Cecilia; Querques, Irma; Sebe, Attila; Mátés, Lajos; Izsvák, Zsuzsanna; Ivics, Zoltán; Barabas, Orsolya

    2016-01-01

    Sleeping Beauty (SB) is a prominent Tc1/mariner superfamily DNA transposon that provides a popular genome engineering tool in a broad range of organisms. It is mobilized by a transposase enzyme that catalyses DNA cleavage and integration at short specific sequences at the transposon ends. To facilitate SB's applications, here we determine the crystal structure of the transposase catalytic domain and use it to model the SB transposase/transposon end/target DNA complex. Together with biochemical and cell-based transposition assays, our structure reveals mechanistic insights into SB transposition and rationalizes previous hyperactive transposase mutations. Moreover, our data enables us to design two additional hyperactive transposase variants. Our work provides a useful resource and proof-of-concept for structure-based engineering of tailored SB transposases. PMID:27025571

  7. Evolving serodiagnostics by rationally designed peptide arrays: the Burkholderia paradigm in Cystic Fibrosis.

    PubMed

    Peri, Claudio; Gori, Alessandro; Gagni, Paola; Sola, Laura; Girelli, Daniela; Sottotetti, Samantha; Cariani, Lisa; Chiari, Marcella; Cretich, Marina; Colombo, Giorgio

    2016-01-01

    Efficient diagnosis of emerging and novel bacterial infections is fundamental to guide decisions on therapeutic treatments. Here, we engineered a novel rational strategy to design peptide microarray platforms, which combines structural and genomic analyses to predict the binding interfaces between diverse protein antigens and antibodies against Burkholderia cepacia complex infections present in the sera of Cystic Fibrosis (CF) patients. The predicted binding interfaces on the antigens are synthesized in the form of isolated peptides and chemically optimized for controlled orientation on the surface. Our platform displays multiple Burkholderia-related epitopes and is shown to diagnose infected individuals even in presence of superinfections caused by other prevalent CF pathogens, with limited cost and time requirements. Moreover, our data point out that the specific patterns determined by combined probe responses might provide a characterization of Burkholderia infections even at the subtype level (genomovars). The method is general and immediately applicable to other bacteria. PMID:27615705

  8. Enhancing the Acyltransferase Activity of Candida antarctica Lipase A by Rational Design.

    PubMed

    Müller, Janett; Sowa, Miriam A; Fredrich, Birte; Brundiek, Henrike; Bornscheuer, Uwe T

    2015-08-17

    A few lipases, such as Candida antarctica lipase A (CAL-A), are known to possess acyltransferase activity. This enables the enzyme to synthesize fatty acid esters from natural oils and alcohols even in the presence of bulk water. Unfortunately, fatty acids are still formed in these reactions as undesired side-products. To reduce the amount of fatty acids, several CAL-A variants were rationally designed based on its crystal structure. These variants were expressed in Escherichia coli and Pichia pastoris, purified, and their acyltransferase/hydrolase activities were investigated by various biocatalytic approaches. Among the investigated variants, mutant Asp122Leu showed a significant decrease in the hydrolytic activity, thus reducing the side-product yield during acylation. As desired, this variant retained wild-type process-relevant features like pH profile and thermostability. PMID:26058745

  9. Improving thermal and detergent stability of Bacillus stearothermophilus neopullulanase by rational enzyme design.

    PubMed

    Ece, Selin; Evran, Serap; Janda, Jan-Oliver; Merkl, Rainer; Sterner, Reinhard

    2015-06-01

    Neopullulanase, a glycosyl hydrolase from Bacillus stearothermophilus (bsNpl), is a potentially valuable enzyme for starch and detergent industries. However, as the protein is not active at elevated temperatures and high surfactant concentrations, we aimed to increase its stability by rational enzyme design. Nine potentially destabilizing cavities were identified in the crystal structure of the enzyme. Based on computational predictions, these cavities were filled by residues with bulkier side chains. The five Asp46Glu, Val239Leu, Val404Leu, Ser407Thr and Ala566Leu exchanges resulted in a drastic stabilization of bsNpl against inactivation by heat and detergents. The catalytic activity of the variants was identical to the wild-type enzyme. PMID:25680359

  10. Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases

    PubMed Central

    Shang, Xun; Marchioni, Fillipo; Sipes, Nisha; Evelyn, Chris R.; Jerabek-Willemsen, Moran; Duhr, Stefan; Seibel, William; Wortman, Matthew; Zheng, Yi

    2012-01-01

    SUMMARY Rho GTPases have been implicated in diverse cellular functions and are potential therapeutic targets. By virtual screening, we have identified a Rho specific inhibitor, Rhosin. Rhosin contains two-aromatic rings tethered by a linker, and it binds to the surface area sandwiching Trp58 of RhoA with a submicromolar Kd and effectively inhibits GEF-catalyzed RhoA activation. In cells Rhosin specifically inhibited RhoA activity and RhoA-mediated cellular function without affecting Cdc42 or Rac1 signaling activities. By suppressing RhoA or RhoC activity Rhosin could inhibit mammary sphere formation by breast cancer cells, suppress invasion of mammary epithelial cells, and induce neurite outgrowth of PC12 cells in synergy with NGF. Thus, the rational designed RhoA subfamily specific small molecule inhibitor is useful for studying the physiological and pathologic roles of Rho GTPase. PMID:22726684

  11. Rational design of DNA-actuated enzyme nanoreactors guided by single molecule analysis

    NASA Astrophysics Data System (ADS)

    Dhakal, Soma; Adendorff, Matthew R.; Liu, Minghui; Yan, Hao; Bathe, Mark; Walter, Nils G.

    2016-01-01

    The control of enzymatic reactions using nanoscale DNA devices offers a powerful application of DNA nanotechnology uniquely derived from actuation. However, previous characterization of enzymatic reaction rates using bulk biochemical assays reported suboptimal function of DNA devices such as tweezers. To gain mechanistic insight into this deficiency and to identify design rules to improve their function, here we exploit the synergy of single molecule imaging and computational modeling to characterize the three-dimensional structures and catalytic functions of DNA tweezer-actuated nanoreactors. Our analysis revealed two important deficiencies - incomplete closure upon actuation and conformational heterogeneity. Upon rational redesign of the Holliday junctions located at their hinge and arms, we found that the DNA tweezers could be more completely and uniformly closed. A novel single molecule enzyme assay was developed to demonstrate that our design improvements yield significant, independent enhancements in the fraction of active enzyme nanoreactors and their individual substrate turnover frequencies. The sequence-level design strategies explored here may aid more broadly in improving the performance of DNA-based nanodevices including biological and chemical sensors.The control of enzymatic reactions using nanoscale DNA devices offers a powerful application of DNA nanotechnology uniquely derived from actuation. However, previous characterization of enzymatic reaction rates using bulk biochemical assays reported suboptimal function of DNA devices such as tweezers. To gain mechanistic insight into this deficiency and to identify design rules to improve their function, here we exploit the synergy of single molecule imaging and computational modeling to characterize the three-dimensional structures and catalytic functions of DNA tweezer-actuated nanoreactors. Our analysis revealed two important deficiencies - incomplete closure upon actuation and conformational

  12. Snake Bite in South Asia: A Review

    PubMed Central

    Alirol, Emilie; Sharma, Sanjib Kumar; Bawaskar, Himmatrao Saluba; Kuch, Ulrich; Chappuis, François

    2010-01-01

    Snake bite is one of the most neglected public health issues in poor rural communities living in the tropics. Because of serious misreporting, the true worldwide burden of snake bite is not known. South Asia is the world's most heavily affected region, due to its high population density, widespread agricultural activities, numerous venomous snake species and lack of functional snake bite control programs. Despite increasing knowledge of snake venoms' composition and mode of action, good understanding of clinical features of envenoming and sufficient production of antivenom by Indian manufacturers, snake bite management remains unsatisfactory in this region. Field diagnostic tests for snake species identification do not exist and treatment mainly relies on the administration of antivenoms that do not cover all of the important venomous snakes of the region. Care-givers need better training and supervision, and national guidelines should be fed by evidence-based data generated by well-designed research studies. Poorly informed rural populations often apply inappropriate first-aid measures and vital time is lost before the victim is transported to a treatment centre, where cost of treatment can constitute an additional hurdle. The deficiency of snake bite management in South Asia is multi-causal and requires joint collaborative efforts from researchers, antivenom manufacturers, policy makers, public health authorities and international funders. PMID:20126271

  13. Rational Design of Peptide Vaccines Against Multiple Types of Human Papillomavirus

    PubMed Central

    Dey, Sumanta; De, Antara; Nandy, Ashesh

    2016-01-01

    Human papillomavirus (HPV) occurs in many types, some of which cause cervical, genital, and other cancers. While vaccination is available against the major cancer-causing HPV types, many others are not covered by these preventive measures. Herein, we present a bioinformatics study for the designing of multivalent peptide vaccines against multiple HPV types as an alternative strategy to the virus-like particle vaccines being used now. Our technique of rational design of peptide vaccines is expected to ensure stability of the vaccine against many cycles of mutational changes, elicit immune response, and negate autoimmune possibilities. Using the L1 capsid protein sequences, we identified several peptides for potential vaccine design for HPV 16, 18, 33, 35, 45, and 11 types. Although there are concerns about the epitope-binding affinities for the peptides identified in this process, the technique indicates possibilities of multivalent, adjuvanted, peptide vaccines against a wider range of HPV types, and tailor-made different combinations of the peptides to address frequency variations of types over different population groups as required for prophylaxis and at lower cost than are in use at the present time. PMID:27279731

  14. Rational design of modular circuits for gene transcription: A test of the bottom-up approach

    PubMed Central

    2010-01-01

    Background Most of synthetic circuits developed so far have been designed by an ad hoc approach, using a small number of components (i.e. LacI, TetR) and a trial and error strategy. We are at the point where an increasing number of modular, inter-changeable and well-characterized components is needed to expand the construction of synthetic devices and to allow a rational approach to the design. Results We used interchangeable modular biological parts to create a set of novel synthetic devices for controlling gene transcription, and we developed a mathematical model of the modular circuits. Model parameters were identified by experimental measurements from a subset of modular combinations. The model revealed an unexpected feature of the lactose repressor system, i.e. a residual binding affinity for the operator site by induced lactose repressor molecules. Once this residual affinity was taken into account, the model properly reproduced the experimental data from the training set. The parameters identified in the training set allowed the prediction of the behavior of networks not included in the identification procedure. Conclusions This study provides new quantitative evidences that the use of independent and well-characterized biological parts and mathematical modeling, what is called a bottom-up approach to the construction of gene networks, can allow the design of new and different devices re-using the same modular parts. PMID:21070658

  15. Cellular Uptake and Localization of Polymyxins in Renal Tubular Cells Using Rationally Designed Fluorescent Probes

    PubMed Central

    Yun, Bo; Azad, Mohammad A. K.; Nowell, Cameron J.; Nation, Roger L.; Thompson, Philip E.; Roberts, Kade D.

    2015-01-01

    Polymyxins are cyclic lipopeptide antibiotics that serve as a last line of defense against Gram-negative bacterial superbugs. However, the extensive accumulation of polymyxins in renal tubular cells can lead to nephrotoxicity, which is the major dose-limiting factor in clinical use. In order to gain further insights into the mechanism of polymyxin-induced nephrotoxicity, we have rationally designed novel fluorescent polymyxin probes to examine the localization of polymyxins in rat renal tubular (NRK-52E) cells. Our design strategy focused on incorporating a dansyl fluorophore at the hydrophobic centers of the polymyxin core structure. To this end, four novel regioselectively labeled monodansylated polymyxin B probes (MIPS-9541, MIPS-9542, MIPS-9543, and MIPS-9544) were designed, synthesized, and screened for their antimicrobial activities and apoptotic effects against rat kidney proximal tubular cells. On the basis of the assessment of antimicrobial activities, cellular uptake, and apoptotic effects on renal tubular cells, incorporation of a dansyl fluorophore at either position 6 or 7 (MIPS-9543 and MIPS-9544, respectively) of the polymyxin core structure appears to be an appropriate strategy for generating representative fluorescent polymyxin probes to be utilized in intracellular imaging and mechanistic studies. Furthermore, confocal imaging experiments utilizing these probes showed evidence of partial colocalization of the polymyxins with both the endoplasmic reticulum and mitochondria in rat renal tubular cells. Our results highlight the value of these new fluorescent polymyxin probes and provide further insights into the mechanism of polymyxin-induced nephrotoxicity. PMID:26392495

  16. A rationally designed A34R mutant oncolytic poxvirus: improved efficacy in peritoneal carcinomatosis.

    PubMed

    Thirunavukarasu, Pragatheeshwar; Sathaiah, Magesh; Gorry, Michael C; O'Malley, Mark E; Ravindranathan, Roshni; Austin, Frances; Thorne, Steven H; Guo, Zong Sheng; Bartlett, David L

    2013-05-01

    Oncolytic poxviruses have demonstrated initial promising results in patients with cancer in clinical trials, yet further improvements are needed. It has been shown that a single point mutation in the A34R gene resulted in the production of more total progeny virus and more extracellular enveloped virus (EEV), a form that can be immune-evasive and with enhanced spread. We have genetically engineered a new oncolytic poxvirus (designated vA34R) by incorporating this mutated A34R gene into a viral backbone (vvDD) which was designed for tumor-selective replication. This rationally designed virus can evade neutralization from antipoxvirus antibodies and is highly cytotoxic to cancer cells. It demonstrates improved spread and increased replication within the peritoneal cavity resulting in improved antitumor effects in a peritoneal carcinomatosis (PC) model of MC38 colon cancer. Impressively, after carrier cell-mediated delivery in the preimmunized host, vA34R displayed high replication in tumor nodules yet low accumulation in normal tissues thus enhancing the therapeutic index leading to 70% long-term cures. These results demonstrate that vA34R gains an enhanced therapeutic index for PC via immune evasion, increased spread, and production of more progeny virus. Thus, vA34R may be a potent oncolytic virus (OV) for patients with PC, even after prior exposure to vaccinia virus (VV). PMID:23439499

  17. Rational protein design: developing next-generation biological therapeutics and nanobiotechnological tools.

    PubMed

    Wilson, Corey J

    2015-01-01

    Proteins are the most functionally diverse macromolecules observed in nature, participating in a broad array of catalytic, biosensing, transport, scaffolding, and regulatory functions. Fittingly, proteins have become one of the most promising nanobiotechnological tools to date, and through the use of recombinant DNA and other laboratory methods we have produced a vast number of biological therapeutics derived from human genes. Our emerging ability to rationally design proteins (e.g., via computational methods) holds the promise of significantly expanding the number and diversity of protein therapies and has opened the gateway to realizing true and uncompromised personalized medicine. In the last decade computational protein design has been transformed from a set of fundamental strategies to stringently test our understanding of the protein structure-function relationship, to practical tools for developing useful biological processes, nano-devices, and novel therapeutics. As protein design strategies improve (i.e., in terms of accuracy and efficiency) clinicians will be able to leverage individual genetic data and biological metrics to develop and deliver personalized protein therapeutics with minimal delay. PMID:25348497

  18. Rational design of Nd(3+)-sensitized multifunctional nanoparticles with highly dominant red emission.

    PubMed

    Xu, Xia; Lei, Pengpeng; Dong, Lile; Liu, Xiuling; Su, Yue; Song, Shuyan; Feng, Jing; Zhang, Hongjie

    2016-05-28

    Controlling excitation and emission wavelengths on demand is very significant in bioimaging. Up-conversion nanoparticles (UCNPs) emit visible light upon near-infrared (NIR) light excitation and are well studied in bioimaging. Red emission is usually preferred to green due to its higher tissue penetration depth in bioimaging. Herein, dominant red emission has been achieved under 808 nm excitation based on the designed α-NaYbF4:Mn(2+)/Er(3+)@NaLuF4:Mn(2+)/Yb(3+)@NaNdF4:Yb(3+)@NaGdF4 (C@S1@S2@S3) nanostructure. The rationally designed interlayer shell NaLuF4:Mn(2+)/Yb(3+) could efficiently filter unwanted energy back-transfer from Er(3+) to Nd(3+) and the outmost shell NaGdF4 could prevent excitation energy from surface-related quenching. The lifetime of (4)F9/2→(4)I15/2 transition of Er(3+) could be as high as 0.7 ms. Moreover, C@S1@S2@S3 UCNPs also possess effective contrast efficiency for both X-ray computed tomography (CT) and magnetic resonance (MR) imaging. The designed multifunctional UCNPs could be used as a potential multimodal bioprobe in bioimaging applications. PMID:27111482

  19. Rational Design of Peptide Vaccines Against Multiple Types of Human Papillomavirus.

    PubMed

    Dey, Sumanta; De, Antara; Nandy, Ashesh

    2016-01-01

    Human papillomavirus (HPV) occurs in many types, some of which cause cervical, genital, and other cancers. While vaccination is available against the major cancer-causing HPV types, many others are not covered by these preventive measures. Herein, we present a bioinformatics study for the designing of multivalent peptide vaccines against multiple HPV types as an alternative strategy to the virus-like particle vaccines being used now. Our technique of rational design of peptide vaccines is expected to ensure stability of the vaccine against many cycles of mutational changes, elicit immune response, and negate autoimmune possibilities. Using the L1 capsid protein sequences, we identified several peptides for potential vaccine design for HPV 16, 18, 33, 35, 45, and 11 types. Although there are concerns about the epitope-binding affinities for the peptides identified in this process, the technique indicates possibilities of multivalent, adjuvanted, peptide vaccines against a wider range of HPV types, and tailor-made different combinations of the peptides to address frequency variations of types over different population groups as required for prophylaxis and at lower cost than are in use at the present time. PMID:27279731

  20. Theory and simulation of DNA-coated colloids: a guide for rational design.

    PubMed

    Angioletti-Uberti, Stefano; Mognetti, Bortolo M; Frenkel, Daan

    2016-03-01

    By exploiting the exquisite selectivity of DNA hybridization, DNA-coated colloids (DNACCs) can be made to self-assemble in a wide variety of structures. The beauty of this system stems largely from its exceptional versatility and from the fact that a proper choice of the grafted DNA sequences yields fine control over the colloidal interactions. Theory and simulations have an important role to play in the optimal design of self assembling DNACCs. At present, the powerful model-based design tools are not widely used, because the theoretical literature is fragmented and the connection between different theories is often not evident. In this Perspective, we aim to discuss the similarities and differences between the different models that have been described in the literature, their underlying assumptions, their strengths and their weaknesses. Using the tools described in the present Review, it should be possible to move towards a more rational design of novel self-assembling structures of DNACCs and, more generally, of systems where ligand-receptor are used to control interactions. PMID:26862595

  1. Rationally designed small molecules targeting the RNA that causes myotonic dystrophy type 1 are potently bioactive.

    PubMed

    Childs-Disney, Jessica L; Hoskins, Jason; Rzuczek, Suzanne G; Thornton, Charles A; Disney, Matthew D

    2012-05-18

    RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expansion of r(CUG) repeats, or r(CUG)(exp), is present in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. r(CUG)(exp) folds into a hairpin with regularly repeating 5'CUG/3'GUC motifs and sequesters muscleblind-like 1 protein (MBNL1). A variety of defects are associated with DM1, including (i) formation of nuclear foci, (ii) decreased translation of DMPK mRNA due to its nuclear retention, and (iii) pre-mRNA splicing defects due to inactivation of MBNL1, which controls the alternative splicing of various pre-mRNAs. Previously, modularly assembled ligands targeting r(CUG)(exp) were designed using information in an RNA motif-ligand database. These studies showed that a bis-benzimidazole (H) binds the 5'CUG/3'GUC motif in r(CUG)(exp.) Therefore, we designed multivalent ligands to bind simultaneously multiple copies of this motif in r(CUG)(exp). Herein, we report that the designed compounds improve DM1-associated defects including improvement of translational and pre-mRNA splicing defects and the disruption of nuclear foci. These studies may establish a foundation to exploit other RNA targets in genomic sequence. PMID:22332923

  2. Rationally Designed Small Molecules Targeting the RNA That Causes Myotonic Dystrophy Type 1 Are Potently Bioactive

    PubMed Central

    Childs-Disney, Jessica L.; Hoskins, Jason; Rzuczek, Suzanne G.; Thornton, Charles A.; Disney, Matthew D.

    2012-01-01

    RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expansion of r(CUG) repeats, or r(CUG)exp, is present in the 3′ untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. r(CUG)exp folds into a hairpin with regularly repeating 5′CUG/3′GUC motifs and sequester muscleblind-like 1 protein (MBNL1). A variety of defects are associated with DM1 including: (i) formation of nuclear foci, (ii) decreased translation of DMPK mRNA due to its nuclear retention, and (iii) pre-mRNA splicing defects due to inactivation of MBNL1, which controls the alternative splicing of various pre-mRNAs. Previously, modularly assembled ligands targeting r(CUG)exp were designed using information in an RNA motif-ligand database. These studies showed that a bis-benzimidazole (H) binds the 5′CUG/3′GUC motif in r(CUG)exp. Therefore, we designed multivalent ligands to bind multiple copies of this motif simultaneously in r(CUG)exp. Herein, we report that the designed compounds improve DM1-associated defects including improvement of translational and pre-mRNA splicing defects and the disruption of nuclear foci. These studies may establish a foundation to exploit other RNA targets in genomic sequence. PMID:22332923

  3. Adapting Rational Unified Process (RUP) approach in designing a secure e-Tendering model

    NASA Astrophysics Data System (ADS)

    Mohd, Haslina; Robie, Muhammad Afdhal Muhammad; Baharom, Fauziah; Darus, Norida Muhd; Saip, Mohamed Ali; Yasin, Azman

    2016-08-01

    e-Tendering is an electronic processing of the tender document via internet and allow tenderer to publish, communicate, access, receive and submit all tender related information and documentation via internet. This study aims to design the e-Tendering system using Rational Unified Process approach. RUP provides a disciplined approach on how to assign tasks and responsibilities within the software development process. RUP has four phases that can assist researchers to adjust the requirements of various projects with different scope, problem and the size of projects. RUP is characterized as a use case driven, architecture centered, iterative and incremental process model. However the scope of this study only focusing on Inception and Elaboration phases as step to develop the model and perform only three of nine workflows (business modeling, requirements, analysis and design). RUP has a strong focus on documents and the activities in the inception and elaboration phases mainly concern the creation of diagrams and writing of textual descriptions. The UML notation and the software program, Star UML are used to support the design of e-Tendering. The e-Tendering design based on the RUP approach can contribute to e-Tendering developers and researchers in e-Tendering domain. In addition, this study also shows that the RUP is one of the best system development methodology that can be used as one of the research methodology in Software Engineering domain related to secured design of any observed application. This methodology has been tested in various studies in certain domains, such as in Simulation-based Decision Support, Security Requirement Engineering, Business Modeling and Secure System Requirement, and so forth. As a conclusion, these studies showed that the RUP one of a good research methodology that can be adapted in any Software Engineering (SE) research domain that required a few artifacts to be generated such as use case modeling, misuse case modeling, activity

  4. Rational design and adaptive management of combination therapies for Hepatitis C virus infection

    SciTech Connect

    Ke, Ruian; Loverdo, Claude; Qi, Hangfei; Sun, Ren; Lloyd-Smith, James O.; Kouyos, Roger Dimitri

    2015-06-30

    Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensate when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design.

  5. Rational design and adaptive management of combination therapies for Hepatitis C virus infection

    DOE PAGESBeta

    Ke, Ruian; Loverdo, Claude; Qi, Hangfei; Sun, Ren; Lloyd-Smith, James O.; Kouyos, Roger Dimitri

    2015-06-30

    Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensatemore » when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design.« less

  6. Rational Design of Biomolecular Templates for Synthesizing Multifunctional Noble Metal Nanoclusters toward Personalized Theranostic Applications.

    PubMed

    Yu, Yong; Mok, Beverly Y L; Loh, Xian Jun; Tan, Yen Nee

    2016-08-01

    Biomolecule-templated or biotemplated metal nanoclusters (NCs) are ultrasmall (<2 nm) metal (Au, Ag) particles stabilized by a certain type of biomolecular template (e.g., peptides, proteins, and DNA). Due to their unique physiochemical properties, biotemplated metal NCs have been widely used in sensing, imaging, delivery and therapy. The overwhelming applications in these individual areas imply the great promise of harnessing biotemplated metal NCs in more advanced biomedical aspects such as theranostics. Although applications of biotemplated metal NCs as theranostic agents are trending, the rational design of biomolecular templates suitable for the synthesis of multifunctional metal NCs for theranostics is comparatively underexplored. This progress report first identifies the essential attributes of biotemplated metal NCs for theranostics by reviewing the state-of-art applications in each of the four modalities of theranostics, namely sensing, imaging, delivery and therapy. To achieve high efficacy in these modalities, we elucidate the design principles underlying the use of biomolecules (proteins, peptides and nucleic acids) to control the NC size, emission color and surface chemistries for post-functionalization of therapeutic moieties. We then propose a unified strategy to engineer biomolecular templates that combine all these modalities to produce multifunctional biotemplated metal NCs that can serve as the next-generation personalized theranostic agents. PMID:27377035

  7. Construction of a rationally designed antibody platform for sequencing-assisted selection.

    PubMed

    Larman, H Benjamin; Xu, George Jing; Pavlova, Natalya N; Elledge, Stephen J

    2012-11-01

    Antibody discovery platforms have become an important source of both therapeutic biomolecules and research reagents. Massively parallel DNA sequencing can be used to assist antibody selection by comprehensively monitoring libraries during selection, thus greatly expanding the power of these systems. We have therefore constructed a rationally designed, fully defined single-chain variable fragment (scFv) library and analysis platform optimized for analysis with short-read deep sequencing. Sequence-defined oligonucleotide libraries encoding three complementarity-determining regions (L3 from the light chain, H2 and H3 from the heavy chain) were synthesized on a programmable microarray and combinatorially cloned into a single scFv framework for molecular display. Our unique complementarity-determining region sequence design optimizes for protein binding by utilizing a hidden Markov model that was trained on all antibody-antigen cocrystal structures in the Protein Data Bank. The resultant ~10(12)-member library was produced in ribosome-display format, and comprehensively analyzed over four rounds of antigen selections by multiplex paired-end Illumina sequencing. The hidden Markov model scFv library generated multiple binders against an emerging cancer antigen and is the basis for a next-generation antibody production platform. PMID:23064642

  8. An approach to rational ligand-design based on a thermodynamic analysis.

    PubMed

    Ui, Mihoko; Tsumoto, Kouhei

    2010-11-01

    Thermodynamic analysis is an effective tool in screening of lead-compounds for development of potential drug candidates. In most cases, a ligand achieve high affinity and specificity to a target protein by means of both favorable enthalpy and entropy terms, which can be reflected in binding profiles of Isothermal Titration Calorimetry (ITC). A favorable enthalpy change suggests the contribution of noncovalent contacts such as hydrogen bonding and van der Waals interaction between a ligand and its target protein. In general, optimization of binding enthalpy is more difficult than that of entropies in ligand-design; therefore, it is desirable to choose firstly a lead-compound based on its binding enthalpic gain. In this paper, we demonstrate the utility of thermodynamic approach to ligand screening using anti-ciguatoxin antibody 10C9 as a model of a target protein which possesses a large hydrophobic pocket. As a result of this screening, we have identified three compounds that could bind to the antigen-binding pocket of 10C9 with a few kcal/mol of favorable binding enthalpy. Comparison of their structure with the proper antigen ciguatoxin CTX3C revealed that 10C9 rigorously identifies their cyclic structure and a characteristic hydroxyl group. ITC measurement might be useful and powerful for a rational ligand screening and the optimization of the ligand; the enthalpic gain is an effective index for ligand-design studies. PMID:21171955

  9. Rational Design of Porous Conjugated Polymers and Roles of Residual Palladium for Photocatalytic Hydrogen Production.

    PubMed

    Li, Lianwei; Cai, Zhengxu; Wu, Qinghe; Lo, Wai-Yip; Zhang, Na; Chen, Lin X; Yu, Luping

    2016-06-22

    Developing highly efficient photocatalyts for water splitting is one of the grand challenges in solar energy conversion. Here, we report the rational design and synthesis of porous conjugated polymer (PCP) that photocatalytically generates hydrogen from water splitting. The design mimics natural photosynthetics systems with conjugated polymer component to harvest photons and the transition metal part to facilitate catalytic activities. A series of PCPs have been synthesized with different light harvesting chromophores and transition metal binding bipyridyl (bpy) sites. The photocatalytic activity of these bpy-containing PCPs can be greatly enhanced due to the improved light absorption, better wettability, local ordering structure, and the improved charge separation process. The PCP made of strong and fully conjugated donor chromophore DBD (M4) shows the highest hydrogen production rate at ∼33 μmol/h. The results indicate that copolymerization between a strong electron donor and weak electron acceptor into the same polymer chain is a useful strategy for developing efficient photocatalysts. This study also reveals that the residual palladium in the PCP networks plays a key role for the catalytic performance. The hydrogen generation activity of PCP photocatalyst can be further enhanced to 164 μmol/h with an apparent quantum yield of 1.8% at 350 nm by loading 2 wt % of extra platinum cocatalyst. PMID:27254306

  10. Rationally Designing Aptamer Sequences with Reduced Affinity for Controlled Sensor Performance

    PubMed Central

    Schoukroun-Barnes, Lauren R.; White, Ryan J.

    2015-01-01

    The relative ease of predicting the secondary structure of nucleic acid sequences lends itself to the design of sequences to perform desired functions. Here, we combine the utility of nucleic acid aptamers with predictable control over the secondary structure to rationally design sequences with controlled affinity towards a target analyte when employed as the recognition element in an electrochemical sensor. Specifically, we present a method to modify an existing high-gain aptamer sequence to create sequences that, when employed in an electrochemical, aptamer-based sensor, exhibit reduced affinity towards a small molecule analyte tobramycin. Sensors fabricated with the high-gain parent sequence saturate at concentrations much below the therapeutic window for tobramycin (7–18 µM). Accordingly, the rationale behind modifying this high-gain sequence to reduce binding affinity was to tune sensor performance for optimal sensitivity in the therapeutic window. Using secondary structure predictions and analysis of the NMR structure of an aminoglycoside RNA aptamer bound to tobramycin, we are able to successfully modify the aptamer sequence to tune the dissociation constants of electrochemical aptamer-based sensors between 0.17 and 3 µM. The guidelines we present represent a general strategy to lessening binding affinity of sensors employing aptamer-modified electrodes. PMID:25835184

  11. Rational design and validation of a vanilloid-sensitive TRPV2 ion channel.

    PubMed

    Yang, Fan; Vu, Simon; Yarov-Yarovoy, Vladimir; Zheng, Jie

    2016-06-28

    Vanilloids activation of TRPV1 represents an excellent model system of ligand-gated ion channels. Recent studies using cryo-electron microcopy (cryo-EM), computational analysis, and functional quantification revealed the location of capsaicin-binding site and critical residues mediating ligand-binding and channel activation. Based on these new findings, here we have successfully introduced high-affinity binding of capsaicin and resiniferatoxin to the vanilloid-insensitive TRPV2 channel, using a rationally designed minimal set of four point mutations (F467S-S498F-L505T-Q525E, termed TRPV2_Quad). We found that binding of resiniferatoxin activates TRPV2_Quad but the ligand-induced open state is relatively unstable, whereas binding of capsaicin to TRPV2_Quad antagonizes resiniferatoxin-induced activation likely through competition for the same binding sites. Using Rosetta-based molecular docking, we observed a common structural mechanism underlying vanilloids activation of TRPV1 and TRPV2_Quad, where the ligand serves as molecular "glue" that bridges the S4-S5 linker to the S1-S4 domain to open these channels. Our analysis revealed that capsaicin failed to activate TRPV2_Quad likely due to structural constraints preventing such bridge formation. These results not only validate our current working model for capsaicin activation of TRPV1 but also should help guide the design of drug candidate compounds for this important pain sensor. PMID:27298359

  12. Rational design and optimization of plasmonic nanoarrays for surface enhanced infrared spectroscopy

    PubMed Central

    Liberman, Vladimir; Adato, Ronen; Jeys, Thomas H.; Saar, Brian G.; Erramilli, Shyamsunder; Altug, Hatice

    2012-01-01

    We present an approach for rational design and optimization of plasmonic arrays for ultrasensitive surface enhanced infrared absorption (SEIRA) spectroscopy of specific protein analytes. Motivated by our previous work that demonstrated sub-attomole detection of surface-bound silk fibroin [Proc. Natl. Acad. Sci. U.S.A. 106, 19227 (2009)], we introduce here a general framework that allows for the numerical optimization of metamaterial sensor designs in order to maximize the absorbance signal. A critical feature of our method is the explicit compensation for the perturbative effects of the analyte's refractive index which alters the resonance frequency and line-shape of the metamaterial response, thereby leading to spectral distortion in SEIRA signatures. As an example, we leverage our method to optimize the geometry of periodic arrays of plasmonic nanoparticles on both Si and CaF2 substrates. The optimal geometries result in a three-order of magnitude absorbance enhancement compared to an unstructured Au layer, with the CaF2 substrate offering an additional factor of three enhancement in absorbance over a traditional Si substrate. The latter improvement arises from increase of near-field intensity over the Au nanobar surface for the lower index substrate. Finally, we perform sensitivity analysis for our optimized arrays to predict the effects of fabrication imperfections. We find that <20% deviation from the optimized absorbance response is readily achievable over large areas with modern nanofabrication techniques. PMID:22714181

  13. Rationally designed donor-acceptor scheme based molecules for applications in opto-electronic devices.

    PubMed

    Subash Sundar, T; Sen, R; Johari, P

    2016-04-01

    Several donor (D)-acceptor (A) based molecules are rationally designed by adopting three different schemes in which the conjugation length, strength of the donor and acceptor moieties, and planarity of the molecules are varied. These variations are made by introducing a π-conjugated linkage unit, terminating the ends of the moieties by different electron donating and accepting functional groups, and fusing the donor and acceptor moieties, respectively. Our DFT and TDDFT based calculations reveal that using the above-mentioned design schemes, the electronic and optical properties of the D-A based molecules can be largely tuned. While introduction of a linkage and fusing of moieties enhance the π-π interaction, addition of electron donating groups (-CH3, -OH, and -NH2) and electron accepting groups (-CF3, -CN, -NO2, and -NH3(+)) varies the strength of the donor and acceptor moieties. These factors lead to modulation of the HOMO and LUMO energy levels and facilitate the engineering of the HOMO-LUMO gap and the optical gap over a wide range of ∼0.7-3.7 eV. Moreover, on the basis of calculated ionization potential and reorganization energy, most of the investigated molecules are predicted to be air stable and to exhibit high electron mobility, with the possibility of the presence of ambipolar characteristics in a few of them. The results of our calculations not only demonstrate the examined molecules to be the potential materials for organic opto-electronic devices, but also establish an understanding of the composition-structure-property correlation, which will provide guidelines for designing and synthesizing new materials of choice. PMID:26972386

  14. Recovery of Red Fluorescent Protein Chromophore Maturation Deficiency through Rational Design

    PubMed Central

    Moore, Matthew M.; Oteng-Pabi, Samuel K.; Pandelieva, Antonia T.; Mayo, Stephen L.; Chica, Roberto A.

    2012-01-01

    Red fluorescent proteins (RFPs) derived from organisms in the class Anthozoa have found widespread application as imaging tools in biological research. For most imaging experiments, RFPs that mature quickly to the red chromophore and produce little or no green chromophore are most useful. In this study, we used rational design to convert a yellow fluorescent mPlum mutant to a red-emitting RFP without reverting any of the mutations causing the maturation deficiency and without altering the red chromophore’s covalent structure. We also created an optimized mPlum mutant (mPlum-E16P) that matures almost exclusively to the red chromophore. Analysis of the structure/function relationships in these proteins revealed two structural characteristics that are important for efficient red chromophore maturation in DsRed-derived RFPs. The first is the presence of a lysine residue at position 70 that is able to interact directly with the chromophore. The second is an absence of non-bonding interactions limiting the conformational flexibility at the peptide backbone that is oxidized during red chromophore formation. Satisfying or improving these structural features in other maturation-deficient RFPs may result in RFPs with faster and more complete maturation to the red chromophore. PMID:23285050

  15. Rational Design of Thermally Stable Novel Biocatalytic Nanomaterials: Enzyme Stability in Restricted Spatial Dimensions

    NASA Astrophysics Data System (ADS)

    Mudhivarthi, Vamsi K.

    Enzyme stability is of intense interest in bio-materials science as biocatalysts, and as sensing platforms. This is essentially because the unique properties of DNA, RNA, PAA can be coupled with the interesting and novel properties of proteins to produce systems with unprecedented control over their properties. In this article, the very first examples of enzyme/NA/inorganic hybrid nanomaterials and enzyme-Polyacrylic acid conjugates will be presented. The basic principles of design, synthesis and control of properties of these hybrid materials will be presented first, and this will be followed by a discussion of selected examples from our recent research findings. Data show that key properties of biological catalysts are improved by the inorganic framework especially when the catalyst is co-embedded with DNA. Several examples of such studies with various enzymes and proteins, including horseradish peroxidase (HRP), glucose oxidase (GO), cytochrome c (Cyt c), met-hemoglobin (Hb) and met-myoglobin (Mb) will be discussed. Additionally, key insights obtained by the standard methods of materials science including XRD, SEM and TEM as well as biochemical, calorimetric and spectroscopic methods will be discussed. Furthermore, improved structure and enhanced activities of the biocatalysts in specific cases will be demonstrated along with the potential stabilization mechanisms. Our hypothesis is that nucleic acids provide an excellent control over the enzyme-solid interactions as well as rational assembly of nanomaterials. These novel nanobiohybrid materials may aid in engineering more effective synthetic materials for gene-delivery, RNA-delivery and drug delivery applications.

  16. Development of bright fluorescent quadracyclic adenine analogues: TDDFT-calculation supported rational design

    PubMed Central

    Foller Larsen, Anders; Dumat, Blaise; Wranne, Moa S.; Lawson, Christopher P.; Preus, Søren; Bood, Mattias; Gradén, Henrik; Marcus Wilhelmsson, L.; Grøtli, Morten

    2015-01-01

    Fluorescent base analogues (FBAs) comprise a family of increasingly important molecules for the investigation of nucleic acid structure and dynamics. We recently reported the quantum chemical calculation supported development of four microenvironment sensitive analogues of the quadracyclic adenine (qA) scaffold, the qANs, with highly promising absorptive and fluorescence properties that were very well predicted by TDDFT calculations. Herein, we report on the efficient synthesis, experimental and theoretical characterization of nine novel quadracyclic adenine derivatives. The brightest derivative, 2-CNqA, displays a 13-fold increased brightness (εΦF = 4500) compared with the parent compound qA and has the additional benefit of being a virtually microenvironment-insensitive fluorophore, making it a suitable candidate for nucleic acid incorporation and use in quantitative FRET and anisotropy experiments. TDDFT calculations, conducted on the nine novel qAs a posteriori, successfully describe the relative fluorescence quantum yield and brightness of all qA derivatives. This observation suggests that the TDDFT-based rational design strategy may be employed for the development of bright fluorophores built up from a common scaffold to reduce the otherwise costly and time-consuming screening process usually required to obtain useful and bright FBAs. PMID:26227585

  17. Rational design of novel cathode materials in solid oxide fuel cells using first-principles simulations

    NASA Astrophysics Data System (ADS)

    Choi, YongMan; Lin, M. C.; Liu, Meilin

    The search for clean and renewable sources of energy represents one of the most vital challenges facing us today. Solid oxide fuel cells (SOFCs) are among the most promising technologies for a clean and secure energy future due to their high energy efficiency and excellent fuel flexibility (e.g., direct utilization of hydrocarbons or renewable fuels). To make SOFCs economically competitive, however, development of new materials for low-temperature operation is essential. Here we report our results on a computational study to achieve rational design of SOFC cathodes with fast oxygen reduction kinetics and rapid ionic transport. Results suggest that surface catalytic properties are strongly correlated with the bulk transport properties in several material systems with the formula of La 0.5Sr 0.5BO 2.75 (where B = Cr, Mn, Fe, or Co). The predictions seem to agree qualitatively with available experimental results on these materials. This computational screening technique may guide us to search for high-efficiency cathode materials for a new generation of SOFCs.

  18. An Integrated Approach for the Rational Design of NanoVectors for Biomedical Imaging and Therapy

    PubMed Central

    Godin, Biana; Driessen, Wouter H.; Proneth, Bettina; Lee, Sei-Young; Srinivasan, Srimeenakshi; Rumbaut, Rolando; Arap, Wadih; Pasqualini, Renata; Ferrari, Mauro; Decuzzi, Paolo

    2013-01-01

    The use of nanoparticles for the early detection, cure and imaging of diseases has been proved already to have enormous potentials in different biomedical fields, as oncology and cardiology. A broad spectrum of nanoparticles are currently under development exhibiting differences in (i) size, ranging from few tens of nanometers to few microns; (ii) shape, from the classical spherical beads to discoidal, hemispherical, cylindrical and conical; (iii) surface functionalization, with a wide range of electrostatic charges and bio-molecule conjugations. Clearly, the library of nanoparticles generated by combining all possible sizes, shapes and surface physico-chemical properties is enormous. With such a complex scenario, an integrated approach is here proposed and described for the rational design of nanoparticle systems (nanovectors) for the intravascular delivery of therapeutic and imaging contrast agents. The proposed integrated approach combines multi-scale/multi-physics mathematical models with in-vitro assays and in-vivo intravital microscopy experiments and aims at identifying the optimal combination of size, shape and surface properties that maximize the nanovectors localization within the diseased microvasculature. PMID:20807601

  19. Staphylococcus aureus in Continuous Culture: A Tool for the Rational Design of Antibiotic Treatment Protocols

    PubMed Central

    Udekwu, Klas I.; Levin, Bruce R.

    2012-01-01

    In vitro measures of the pharmacodynamics of antibiotics that account for the factors anticipated for bacteria in infected patients are central to the rational design of antibiotic treatment protocols. We consider whether or not continuous culture devices are a way to obtain these measures. Staphylococcus aureus PS80 in high-density continuous cultures were exposed to oxacillin, ciprofloxacin, vancomycin, gentamicin, daptomycin and linezolid. Contrary to results from low density retentostats as well as to predictions of traditional PK/MIC ratios, daily dosing with up to 100× MIC did not clear these cultures. The densities of S. aureus in these cultures oscillated with constant amplitude and never fell below 105 CFU per ml. Save for daptomycin “treated” populations, the densities of bacteria in these cultures remained significantly below that of similar antibiotic-free cultures. Although these antibiotics varied in their pharmacodynamic properties there were only modest differences in their mean densities. Mathematical models and experiments suggest that the dominant factor preventing clearance was wall-adhering subpopulations reseeding the planktonic population which can be estimated and corrected for. Continuous cultures provide a way to evaluate the potential efficacy of antibiotic treatment regimes in vitro under conditions that are more clinically realistic and comprehensive than traditional in vitro PK/PD indices. PMID:22911681

  20. Development of bright fluorescent quadracyclic adenine analogues: TDDFT-calculation supported rational design

    NASA Astrophysics Data System (ADS)

    Foller Larsen, Anders; Dumat, Blaise; Wranne, Moa S.; Lawson, Christopher P.; Preus, Søren; Bood, Mattias; Gradén, Henrik; Marcus Wilhelmsson, L.; Grøtli, Morten

    2015-07-01

    Fluorescent base analogues (FBAs) comprise a family of increasingly important molecules for the investigation of nucleic acid structure and dynamics. We recently reported the quantum chemical calculation supported development of four microenvironment sensitive analogues of the quadracyclic adenine (qA) scaffold, the qANs, with highly promising absorptive and fluorescence properties that were very well predicted by TDDFT calculations. Herein, we report on the efficient synthesis, experimental and theoretical characterization of nine novel quadracyclic adenine derivatives. The brightest derivative, 2-CNqA, displays a 13-fold increased brightness (ɛΦF = 4500) compared with the parent compound qA and has the additional benefit of being a virtually microenvironment-insensitive fluorophore, making it a suitable candidate for nucleic acid incorporation and use in quantitative FRET and anisotropy experiments. TDDFT calculations, conducted on the nine novel qAs a posteriori, successfully describe the relative fluorescence quantum yield and brightness of all qA derivatives. This observation suggests that the TDDFT-based rational design strategy may be employed for the development of bright fluorophores built up from a common scaffold to reduce the otherwise costly and time-consuming screening process usually required to obtain useful and bright FBAs.

  1. Engineering of genetic control tools in Synechocystis sp. PCC 6803 using rational design techniques.

    PubMed

    Albers, Stevan C; Gallegos, Victor A; Peebles, Christie A M

    2015-12-20

    Cyanobacteria show promise as photosynthetic microbial factories capable of harnessing sunlight and CO2 to produce valuable end products, but few genetic control tools have been characterized and utilized in these organisms. To develop a suite of control elements capable of gene control at a variety of expression strengths, a library of 10 promoter-constructs were developed and built via rational design techniques by adding individual nucleotides in a step-wise manner within the -10 and -35 cis-acting regions of the tac promoter. This suite produced a dynamic range of expression strength, exhibiting a 78 fold change between the lowest expressing promoter, Psca8- and the highest expressing promoter, Psca3-2 when tested within Synechocystis sp. PCC 6803. Additionally, this study details the construction of a chemically inducible construct for use in Synechocystis that is based on the tac repressor system most commonly used in Escherichia coli. This research demonstrates the construction of a highly expressed inducible promoter that is also capable of high levels of gene repression. Upon chemical induction with IPTG, this same mutant strain was capable of exhibiting an average 24X increase in GFP expression over that of the repressed state. PMID:26450561

  2. Tuning calcite morphology and growth acceleration by a rational design of highly stable protein-mimetics

    NASA Astrophysics Data System (ADS)

    Chen, Chun-Long; Qi, Jiahui; Tao, Jinhui; Zuckermann, Ronald N.; Deyoreo, James J.

    2014-09-01

    In nature, proteins play a significant role in biomineral formation. One of the ultimate goals of bioinspired materials science is to develop highly stable synthetic molecules that mimic the function of these natural proteins by controlling crystal formation. Here, we demonstrate that both the morphology and the degree of acceleration or inhibition observed during growth of calcite in the presence of peptoids can be rationally tuned by balancing the electrostatic and hydrophobic interactions, with hydrophobic interactions playing the dominant role. While either strong electrostatic or hydrophobic interactions inhibit growth and reduces expression of the {104} faces, correlations between peptoid-crystal binding energies and observed changes in calcite growth indicate moderate electrostatic interactions allow peptoids to weakly adsorb while moderate hydrophobic interactions cause disruption of surface-adsorbed water layers, leading to growth acceleration with retained expression of the {104} faces. This study provides fundamental principles for designing peptoids as crystallization promoters, and offers a straightforward screening method based on macroscopic crystal morphology. Because peptoids are sequence-specific, highly stable, and easily synthesized, peptoid-enhanced crystallization offers a broad range of potential applications.

  3. Rationally designed treatment for metastatic colorectal cancer: Current drug development strategies

    PubMed Central

    Spiliopoulou, Pavlina; Arkenau, Hendrik-Tobias

    2014-01-01

    The therapeutic landscape of metastatic colorectal cancer (mCRC) has changed substantially with the emergence of new molecularly targeted agents (MTA) used as single agents or alongside standard chemotherapy. The use of these MTAs extended the overall survival of patients with mCRC to a level that current chemotherapeutics alone could not achieve. In addition, improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC and MTAs have been found to have a significant role here too, as they aid resectability. However, for the majority of patients, mCRC remains an invariably incurable disease necessitating continued courses of combined treatment modalities. During the course of these treatments, either cytotoxic or biological, cancer cells maintain their ability to acquire mitogenic mutations which render them resistant to treatment. Key challenges remain to identify appropriate subsets of patients who will most likely benefit from these new MTAs and effectively select these based on validated biomarkers. Moreover, better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments, so that we can maximise the survivorship of mCRC patients. This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies. PMID:25132745

  4. 25th Anniversary Article: Rational Design and Applications of Hydrogels in Regenerative Medicine

    PubMed Central

    Annabi, Nasim; Tamayol, Ali; Uquillas, Jorge Alfredo; Akbari, Mohsen; Bertassoni, Luiz E.; Cha, Chaenyung; Camci-Unal, Gulden; Dokmeci, Mehmet R.

    2014-01-01

    Hydrogels are hydrophilic polymer-based materials with high water content and physical characteristics that resemble the native extracellular matrix. Because of their remarkable properties, hydrogel systems are used for a wide range of biomedical applications, such as three-dimensional (3D) matrices for tissue engineering, drug-delivery vehicles, composite biomaterials, and as injectable fillers in minimally invasive surgeries. In addition, the rational design of hydrogels with controlled physical and biological properties can be used to modulate cellular functionality and tissue morphogenesis. Here, the development of advanced hydrogels with tunable physiochemical properties is highlighted, with particular emphasis on elastomeric, light-sensitive, composite, and shape-memory hydrogels. Emerging technologies developed over the past decade to control hydrogel architecture are also discussed and a number of potential applications and challenges in the utilization of hydrogels in regenerative medicine are reviewed. It is anticipated that the continued development of sophisticated hydrogels will result in clinical applications that will improve patient care and quality of life. PMID:24741694

  5. Rational design of triazololipopeptides analogs of kisspeptin inducing a long-lasting increase of gonadotropins.

    PubMed

    Beltramo, Massimiliano; Robert, Vincent; Galibert, Mathieu; Madinier, Jean-Baptiste; Marceau, Philippe; Dardente, Hugues; Decourt, Caroline; De Roux, Nicolas; Lomet, Didier; Delmas, Agnès F; Caraty, Alain; Aucagne, Vincent

    2015-04-23

    New potent and selective KISS1R agonists were designed using a combination of rational chemical modifications of the endogenous neuropeptide kisspeptin 10 (KP10). Improved resistance to degradation and presumably reduced renal clearance were obtained by introducing a 1,4-disubstituted 1,2,3-triazole as a proteolysis-resistant amide mimic and a serum albumin-binding motif, respectively. These triazololipopeptides are highly potent full agonists of KISS1R and are >100 selective over the closely related NPFF1R. When injected in ewes with a quiescent reproductive system, the best compound of our series induced a much prolonged increase of luteinizing hormone release compared to KP10 and increased follicle-stimulating hormone plasma concentration. Hence, this KISS1R agonist is a new valuable pharmacological tool to explore the potential of KP system in reproduction control. Furthermore, it represents the first step to develop drugs treating reproductive system disorders due to a reduced activity of the hypothalamo-pituitary-gonadal axis such as delayed puberty, hypothalamic amenorrhea, and hypogonadotropic hypogonadism. PMID:25811530

  6. Surface Termination of M1 Phase and Rational Design of Propane Ammoxidation Catalysts

    SciTech Connect

    Guliants, Vadim

    2015-02-16

    This final report describes major accomplishments in this research project which has demonstrated that the M1 phase is the only crystalline phase required for propane ammoxidation to acrylonitrile and that a surface monolayer terminating the ab planes of the M1 phase is responsible for their activity and selectivity in this reaction. Fundamental studies of the topmost surface chemistry and mechanism of propane ammoxidation over the Mo-V-(Te,Sb)-(Nb,Ta)-O M1 and M2 phases resulted in the development of quantitative understanding of the surface molecular structure – reactivity relationships for this unique catalytic system. These oxides possess unique catalytic properties among mixed metal oxides, because they selectively catalyze three alkane transformation reactions, namely propane ammoxidation to acrylonitrile, propane oxidation to acrylic acid and ethane oxidative dehydrogenation, all of considerable economic significance. Therefore, the larger goal of this research was to expand this catalysis to other alkanes of commercial interest, and more broadly, demonstrate successful approaches to rational design of improved catalysts that can be applied to other selective (amm)oxidation processes.

  7. Rational design and controlled synthesis of Te/Bi2Te3 heterostructure nanostring composites

    NASA Astrophysics Data System (ADS)

    Zhang, Yuzhuo; Chen, Hong; Li, Zhiliang; Huang, Ting; Zheng, Shuqi

    2015-07-01

    Te/Bi2Te3 heterostructure nanostring composites composed of several Bi2Te3 nanoplates, which were perpendicularly strung together by Te nanorod, were rationally designed and synthesized via a facile solvothermal method on a large scale. The X-ray diffraction (XRD) characterization demonstrated that the Bi2Te3 nanoplates were rhombohedral phase and the Te nanorods were trigonal phase. The uniform nanostring morphologies were well characterized by scanning electron microscope (SEM) and transmission electron microscope (TEM). Detailed heterostructures were proved via energy dispersive spectrometer (EDS) and high-resolution transmission electron microscope (HRTEM). The morphology transformation from Bi2Te3 nanoplates to Te/Bi2Te3 heterostructure nanostrings could be controlled by adjusting the ratio of bismuth oxide to tellurium oxide. NaOH, serving as catalytic reduction agent and morphology controlling agent, played an important role in the synthesis of Te/Bi2Te3 heterostructure nanostrings. The reaction mechanism was also proposed to explain the formation process of the composites and the specific function of reagents in this reaction system.

  8. Rational Design of Cathode Structure for High Rate Performance Lithium-Sulfur Batteries.

    PubMed

    Chen, Hongwei; Wang, Changhong; Dai, Yafei; Qiu, Shengqiang; Yang, Jinlong; Lu, Wei; Chen, Liwei

    2015-08-12

    Practical applications of Li-S batteries require not only high specific capacities and long cycle lifetimes but also high rate performance. We report a rationally designed Li-S cathode, which consists of a freestanding composite thin film assembled from S nanoparticles, reduced graphene oxide (rGO), and a multifunctional additive poly(anthraquinonyl sulfide) (PAQS). The S nanoparticles provide a high initial specific capacity, and the layered and porous rGO structure provides electron and ion transport paths and restricts polysulfide shuttling. PAQS is not only a highly efficient sulfide trapping agent but also an excellent Li(+) conductor, which benefits the battery reaction kinetics at a high rate. The resulting cathode exhibits an initial specific capacity of 1255 mAh g(-1) with a decay rate as low as 0.046% per cycles over 1200 cycles. Importantly, it displays a reversible capacity of 615 mAh g(-1) when discharged at a high rate of 8 C (13.744 A g(-1)). PMID:26148126

  9. Tuning calcite morphology and growth acceleration by a rational design of highly stable protein-mimetics

    SciTech Connect

    Chen, Chunlong; Qi, Jiahui; Tao, Jinhui; Zuckermann, Ronald; De Yoreo, James J.

    2014-09-05

    In nature, proteins play a significant role in biomineral formation. One of the ultimate goals of bioinspired materials science is to develop highly stable synthetic molecules that mimic the function of these natural proteins by controlling crystal formation. Here, we demonstrate that both the morphology and the degree of acceleration or inhibition observed during growth of calcite in the presence of peptoids can be rationally tuned by balancing the electrostatic interactions (EI) and hydrophobic interactions (HI), with HI playing the dominant role. While either strong EI or HI inhibit growth and suppress (104) face expression, correlations between peptoid-crystal binding energies and observed changes in calcite growth indicate moderate EI allow peptoids to weakly adsorb while moderate HI cause disruption of surface-adsorbed water layers, leading to growth acceleration with retained expression of (104) faces. This study provides fundamental principles for designing peptoids as crystallization promoters, and offers a straightforward screening method based on macroscopic crystal morphology. Because peptoids are sequence-specific, highly stable, and easily synthesized, peptoid-enhanced crystallization offers a broad range of potential applications.

  10. Biomimetics: From Bioinformatics to Rational Design of Dendrimers as Gene Carriers

    PubMed Central

    Araya-Durán, Ingrid; Varas-Concha, Ignacio; Almonacid, Daniel Eduardo; González-Nilo, Fernando Danilo

    2015-01-01

    Biomimetics, or the use of principles of Nature for developing new materials, is a paradigm that could help Nanomedicine tremendously. One of the current challenges in Nanomedicine is the rational design of new efficient and safer gene carriers. Poly(amidoamine) (PAMAM) dendrimers are a well-known class of nanoparticles, extensively used as non-viral nucleic acid carriers, due to their positively charged end-groups. Yet, there are still several aspects that can be improved for their successful application in in vitro and in vivo systems, including their affinity for nucleic acids as well as lowering their cytotoxicity. In the search of new functional groups that could be used as new dendrimer-reactive groups, we followed a biomimetic approach to determine the amino acids with highest prevalence in protein-DNA interactions. Then we introduced them individually as terminal groups of dendrimers, generating a new class of nanoparticles. Molecular dynamics studies of two systems: PAMAM-Arg and PAMAM-Lys were also performed in order to describe the formation of complexes with DNA. Results confirmed that the introduction of amino acids as terminal groups in a dendrimer increases their affinity for DNA and the interactions in the complexes were characterized at atomic level. We end up by briefly discussing additional modifications that can be made to PAMAM dendrimers to turned them into promising new gene carriers. PMID:26382062

  11. Rational design of metal-organic electronic devices: A computational perspective

    NASA Astrophysics Data System (ADS)

    Chilukuri, Bhaskar

    engineers to choose the appropriate metal electrodes considering the chemical interactions at the interface. Additionally, the calculations performed on the interfaces provided valuable insight into binding energies, charge redistribution, change in the energy levels, dipole formation, etc., which are important parameters to consider while fabricating an electronic device. The research described in this dissertation highlights the application of unique computational modeling methods at different levels of theory to guide the experimental chemists and device engineers toward a rational design of transition metal based electronic devices with low cost and high performance.

  12. Rational risk-based decision support for drinking water well managers by optimized monitoring designs

    NASA Astrophysics Data System (ADS)

    Enzenhöfer, R.; Geiges, A.; Nowak, W.

    2011-12-01

    Advection-based well-head protection zones are commonly used to manage the contamination risk of drinking water wells. Considering the insufficient knowledge about hazards and transport properties within the catchment, current Water Safety Plans recommend that catchment managers and stakeholders know, control and monitor all possible hazards within the catchments and perform rational risk-based decisions. Our goal is to supply catchment managers with the required probabilistic risk information, and to generate tools that allow for optimal and rational allocation of resources between improved monitoring versus extended safety margins and risk mitigation measures. To support risk managers with the indispensable information, we address the epistemic uncertainty of advective-dispersive solute transport and well vulnerability (Enzenhoefer et al., 2011) within a stochastic simulation framework. Our framework can separate between uncertainty of contaminant location and actual dilution of peak concentrations by resolving heterogeneity with high-resolution Monte-Carlo simulation. To keep computational costs low, we solve the reverse temporal moment transport equation. Only in post-processing, we recover the time-dependent solute breakthrough curves and the deduced well vulnerability criteria from temporal moments by non-linear optimization. Our first step towards optimal risk management is optimal positioning of sampling locations and optimal choice of data types to reduce best the epistemic prediction uncertainty for well-head delineation, using the cross-bred Likelihood Uncertainty Estimator (CLUE, Leube et al., 2011) for optimal sampling design. Better monitoring leads to more reliable and realistic protection zones and thus helps catchment managers to better justify smaller, yet conservative safety margins. In order to allow an optimal choice in sampling strategies, we compare the trade-off in monitoring versus the delineation costs by accounting for ill

  13. Coupling molecular dynamics simulations with experiments for the rational design of indolicidin-analogous antimicrobial peptides.

    PubMed

    Tsai, Ching-Wei; Hsu, Ning-Yi; Wang, Chang-Hsu; Lu, Chia-Yu; Chang, Yung; Tsai, Hui-Hsu Gavin; Ruaan, Rouh-Chyu

    2009-09-25

    Antimicrobial peptides (AMPs) have attracted much interest in recent years because of their potential use as new-generation antibiotics. Indolicidin (IL) is a 13-residue cationic AMP that is effective against a broad spectrum of bacteria, fungi, and even viruses. Unfortunately, its high hemolytic activity retards its clinical applications. In this study, we adopted molecular dynamics (MD) simulations as an aid toward the rational design of IL analogues exhibiting high antimicrobial activity but low hemolysis. We employed long-timescale, multi-trajectory all-atom MD simulations to investigate the interactions of the peptide IL with model membranes. The lipid bilayer formed by the zwitterionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) was chosen as the model erythrocyte membrane; lipid bilayers formed from a mixture of POPC and the negatively charged 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol were chosen to model bacterial membranes. MD simulations with a total simulation time of up to 4 micros revealed the mechanisms of the processes of IL adsorption onto and insertion into the membranes. The packing order of these lipid bilayers presumably correlated to the membrane stability upon IL adsorption and insertion. We used the degree of local membrane thinning and the reduction in the order parameter of the acyl chains of the lipids to characterize the membrane stability. The order of the mixed 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol/POPC lipid bilayer reduced significantly upon the adsorption of IL. On the other hand, although the order of the pure-POPC lipid bilayer was perturbed slightly during the adsorption stage, the value was reduced more dramatically upon the insertion of IL into the membrane's hydrophobic region. The results imply that enhancing IL adsorption on the microbial membrane may amplify its antimicrobial activity, while the degree of hemolysis may be reduced through inhibition of IL insertion into the hydrophobic region

  14. Rational design of the gram-scale synthesis of nearly monodisperse semiconductor nanocrystals

    PubMed Central

    2011-01-01

    We address two aspects of general interest for the chemical synthesis of colloidal semiconductor nanocrystals: (1) the rational design of the synthesis protocol aiming at the optimization of the reaction parameters in a minimum number of experiments; (2) the transfer of the procedure to the gram scale, while maintaining a low size distribution and maximizing the reaction yield. Concerning the first point, the design-of-experiment (DOE) method has been applied to the synthesis of colloidal CdSe nanocrystals. We demonstrate that 16 experiments, analyzed by means of a Taguchi L16 table, are sufficient to optimize the reaction parameters for controlling the mean size of the nanocrystals in a large range while keeping the size distribution narrow (5-10%). The DOE method strongly reduces the number of experiments necessary for the optimization as compared to trial-and-error approaches. Furthermore, the Taguchi table analysis reveals the degree of influence of each reaction parameter investigated (e.g., the nature and concentration of reagents, the solvent, the reaction temperature) and indicates the interactions between them. On the basis of these results, the synthesis has been scaled up by a factor of 20. Using a 2-L batch reactor combined with a high-throughput peristaltic pump, different-sized samples of CdSe nanocrystals with yields of 2-3 g per synthesis have been produced without sacrificing the narrow size distribution. In a similar setup, the gram-scale synthesis of CdSe/CdS/ZnS core/shell/shell nanocrystals exhibiting a fluorescence quantum yield of 81% and excellent resistance of the photoluminescence in presence of a fluorescent quencher (aromatic thiol) has been achieved. PACS: 81.20.Ka, 81.07.Bc, 78.67.Bf PMID:21791060

  15. Rational Concept for Designing Vapor-Liquid-Solid Growth of Single Crystalline Metal Oxide Nanowires.

    PubMed

    Klamchuen, Annop; Suzuki, Masaru; Nagashima, Kazuki; Yoshida, Hideto; Kanai, Masaki; Zhuge, Fuwei; He, Yong; Meng, Gang; Kai, Shoichi; Takeda, Seiji; Kawai, Tomoji; Yanagida, Takeshi

    2015-10-14

    Metal oxide nanowires hold great promise for various device applications due to their unique and robust physical properties in air and/or water and also due to their abundance on Earth. Vapor-liquid-solid (VLS) growth of metal oxide nanowires offers the high controllability of their diameters and spatial positions. In addition, VLS growth has applicability to axial and/or radial heterostructures, which are not attainable by other nanowire growth methods. However, material species available for the VLS growth of metal oxide nanowires are substantially limited even though the variety of material species, which has fascinating physical properties, is the most interesting feature of metal oxides. Here we demonstrate a rational design for the VLS growth of various metal oxide nanowires, based on the "material flux window". This material flux window describes the concept of VLS nanowire growth within a limited material flux range, where nucleation preferentially occurs only at a liquid-solid interface. Although the material flux was previously thought to affect primarily the growth rate, we experimentally and theoretically demonstrate that the material flux is the important experimental variable for the VLS growth of metal oxide nanowires. On the basis of the material flux window concept, we discover novel metal oxide nanowires, composed of MnO, CaO, Sm2O3, NiO, and Eu2O3, which were previously impossible to form via the VLS route. The newly grown NiO nanowires exhibited stable memristive properties superior to conventional polycrystalline devices due to the single crystallinity. Thus, this VLS design route offers a useful guideline for the discovery of single crystalline nanowires that are composed of functional metal oxide materials. PMID:26372675

  16. Rational and Modular Design of Potent Ligands Targeting the RNA that Causes Myotonic Dystrophy 2

    PubMed Central

    Lee, Melissa M.; Pushechnikov, Alexei; Disney, Matthew D.

    2009-01-01

    Most ligands targeting RNA are identified through screening a therapeutic target for binding members of a ligand library. A potential alternative way to construct RNA binders is through rational design using information about the RNA motifs ligands prefer to bind. Herein, we describe such an approach to design modularly assembled ligands targeting the RNA that causes myotonic dystrophy type 2 (DM2), a currently untreatable disease. A previous study identified that 6′-N-5-hexynoate kanamycin A (1) prefers to bind 2×2 nucleotide, pyrimidine-rich RNA internal loops. Multiple copies of such loops were found in the RNA hairpin that causes DM2. The 1 ligand was then modularly displayed on a peptoid scaffold with varied number and spacing to target several internal loops simultaneously. Modularly assembled ligands were tested for binding to a series of RNAs and for inhibiting the formation of the toxic DM2 RNA-muscleblind protein (MBNL-1) interaction. The most potent ligand displays three 1 modules, each separated by four spacing submonomers, and inhibits the formation of the RNA-protein complex with an IC50 of 25 nM. This ligand is higher affinity and more specific for binding DM2 RNA than MBNL-1. It binds the DM2 RNA at least 20-times more tightly than related RNAs and 15-fold more tightly than MBNL-1. A related control peptoid displaying 6′-N-5-hexynoate neamine (2) is >100-fold less potent at inhibiting the RNA-protein interaction and binds to DM2 RNA >125-fold more weakly. Uptake studies into a mouse myoblast cell line also show that the most potent ligand is cell permeable. PMID:19348464

  17. Intensive mutagenesis of the nisin hinge leads to the rational design of enhanced derivatives.

    PubMed

    Healy, Brian; Field, Des; O'Connor, Paula M; Hill, Colin; Cotter, Paul D; Ross, R Paul

    2013-01-01

    Nisin A is the most extensively studied lantibiotic and has been used as a preservative by the food industry since 1953. This 34 amino acid peptide contains three dehydrated amino acids and five thioether rings. These rings, resulting from one lanthionine and four methyllanthionine bridges, confer the peptide with its unique structure. Nisin A has two mechanisms of action, with the N-terminal domain of the peptide inhibiting cell wall synthesis through lipid II binding and the C-terminal domain responsible for pore-formation. The focus of this study is the three amino acid 'hinge' region (N 20, M 21 and K 22) which separates these two domains and allows for conformational flexibility. As all lantibiotics are gene encoded, novel variants can be generated through manipulation of the corresponding gene. A number of derivatives in which the hinge region was altered have previously been shown to possess enhanced antimicrobial activity. Here we take this approach further by employing simultaneous, indiscriminate site-saturation mutagenesis of all three hinge residues to create a novel bank of nisin derivative producers. Screening of this bank revealed that producers of peptides with hinge regions consisting of AAK, NAI and SLS displayed enhanced bioactivity against a variety of targets. These and other results suggested a preference for small, chiral amino acids within the hinge region, leading to the design and creation of producers of peptides with hinges consisting of AAA and SAA. These producers, and the corresponding peptides, exhibited enhanced bioactivity against Lactococcus lactis HP, Streptococcus agalactiae ATCC 13813, Mycobacterium smegmatis MC2155 and Staphylococcus aureus RF122 and thus represent the first example of nisin derivatives that possess enhanced activity as a consequence of rational design. PMID:24244524

  18. Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein–Ligand Complexes

    PubMed Central

    2015-01-01

    Multipolar interactions involving fluorine and the protein backbone have been frequently observed in protein–ligand complexes. Such fluorine–backbone interactions may substantially contribute to the high affinity of small molecule inhibitors. Here we found that introduction of trifluoromethyl groups into two different sites in the thienopyrimidine class of menin–MLL inhibitors considerably improved their inhibitory activity. In both cases, trifluoromethyl groups are engaged in short interactions with the backbone of menin. In order to understand the effect of fluorine, we synthesized a series of analogues by systematically changing the number of fluorine atoms, and we determined high-resolution crystal structures of the complexes with menin. We found that introduction of fluorine at favorable geometry for interactions with backbone carbonyls may improve the activity of menin–MLL inhibitors as much as 5- to 10-fold. In order to facilitate the design of multipolar fluorine–backbone interactions in protein–ligand complexes, we developed a computational algorithm named FMAP, which calculates fluorophilic sites in proximity to the protein backbone. We demonstrated that FMAP could be used to rationalize improvement in the activity of known protein inhibitors upon introduction of fluorine. Furthermore, FMAP may also represent a valuable tool for designing new fluorine substitutions and support ligand optimization in drug discovery projects. Analysis of the menin–MLL inhibitor complexes revealed that the backbone in secondary structures is particularly accessible to the interactions with fluorine. Considering that secondary structure elements are frequently exposed at protein interfaces, we postulate that multipolar fluorine–backbone interactions may represent a particularly attractive approach to improve inhibitors of protein–protein interactions. PMID:26288158

  19. Dangerous snakes, deadly snakes and medically important snakes

    PubMed Central

    2013-01-01

    This correspondence argues that the dangerousness of a venomous snake species is not solely determined by the venom characteristics or the lethality of the snake, and recognizes that medical importance comprises a key variable as well. The medical importance of a snake is determined by several factors – including frequency of medical attention after a bite, local or systemic envenomation provoked by the bite, fatal bites, long term consequences, availability of antivenom therapy as well as the size of the population at risk – that may vary from one region to another. PMID:24099013

  20. Rational design of on-chip refractive index sensors based on lattice plasmon resonances (Presentation Recording)

    NASA Astrophysics Data System (ADS)

    Lin, Linhan; Zheng, Yuebing

    2015-08-01

    Lattice plasmon resonances (LPRs), which originate from the plasmonic-photonic coupling in gold or silver nanoparticle arrays, possess ultra-narrow linewidth by suppressing the radiative damping and provide the possibility to develop the plasmonic sensors with high figure of merit (FOM). However, the plasmonic-photonic coupling is greatly suppressed when the nanoparticles are immobilized on substrates because the diffraction orders are cut off at the nanoparticle-substrate interfaces. Here, we develop the rational design of LPR structures for the high-performance, on-chip plasmonic sensors based on both orthogonal and parallel coupling. Our finite-difference time-domain simulations in the core/shell SiO2/Au nanocylinder arrays (NCAs) reveal that new modes of localized surface plasmon resonances (LSPRs) show up when the aspect ratio of the NCAs is increased. The height-induced LSPRs couple with the superstrate diffraction orders to generate the robust LPRs in asymmetric environment. The high wavelength sensitivity and narrow linewidth in these LPRs lead to the plasmonic sensors with high FOM and high signal-to-noise ratio (SNR). Wide working wavelengths from visible to near-infrared are also achieved by tuning the parameters of the NCAs. Moreover, the wide detection range of refractive index is obtained in the parallel LPR structure. The electromagnetic field distributions in the NCAs demonstrate the height-enabled tunability of the plasmonic "hot spots" at the sub-nanoparticles resolution and the coupling between these "hot spots" with the superstrate diffraction waves, which are responsible for the high performance LPRs-based on-chip refractive index sensors.

  1. Toward the rational design of protein kinase casein kinase-2 inhibitors.

    PubMed

    Sarno, Stefania; Moro, Stefano; Meggio, Flavio; Zagotto, Giuseppe; Dal Ben, Diego; Ghisellini, Paola; Battistutta, Roberto; Zanotti, Giuseppe; Pinna, Lorenzo A

    2002-01-01

    Casein kinase-2 (CK2) probably is the most pleiotropic member of the protein kinase family, with more than 200 substrates known to date. Unlike the great majority of protein kinases, which are tightly regulated enzymes, CK2 is endowed with high constitutive activity, a feature that is suspected to underlie its oncogenic potential and possible implication in viral infections. This makes CK2 an attractive target for anti-neoplastic and antiviral drugs. Here, we present an overview of our present knowledge about CK2 inhibitors, with special reference to the information drawn from two recently solved crystal structures of CK2alpha in complex with emodin and with 4,5,6,7-tetrabromo-2-azabenzimidazole (TBB), this latter being the most specific CK2 inhibitor known to date. A comparison with a series of anthraquinone and xanthenone derivatives highlights the crucial relevance of the hydroxyl group at position 3 for inhibition by emodin, and discloses the possibility of increasing the inhibitory potency by placing an electron withdrawing group at position 5. We also present mutational data corroborating the relevance of two hydrophobic residues unique to CK2, Val66 and Ile174, for the interactions with emodin and TBB, but not with the flavonoid inhibitors quercetin and fisetin. In particular, the CK2alpha mutant V66A displays 27- and 11-fold higher IC(50) values with emodin and TBB, respectively, as compared with the wild-type, while the IC(50) value with quercetin is unchanged. The data presented pave the road toward the rational design of more potent and selective inhibitors of CK2 and the generation of CK2 mutants refractory to inhibition, useful to probe the implication of CK2 in specific cellular functions. PMID:12191608

  2. SNAKE CALIBRATION IN RHIC.

    SciTech Connect

    RANJBAR,V.; BAI,M.; LUCCIO,A.; MACKAY,W.W.; ROSER,T.; LEET,S.Y.

    2002-06-02

    A proper understanding of the response of the spin orientation due to the currents in the four helices which make up each snake is necessary to control spin tune, avoid snake resonances and facilitate the operation of the RHIC spin flipper. The effect of the helical dipole snakes in RHIC is to rotate the spin orientation an angle {mu} about an axis at an angle {phi} in the horizontal plane. With two snakes the combined effect gives rise to a spin precession frequency which is determined by the {mu} and {phi} angles at each snake. Depolarization or spin flipping can occur when this spin tune is near an external driving frequency. We employed the RHIC spin flipper in this way to determine the spin tune and thus verify spin tune predictions based upon previous field measurements of the snake. We also considered the response of snake resonances locations to spin tune as another way of verifying spin tune predictions.

  3. Rational Ligand Design for U(VI) and Pu(IV)

    SciTech Connect

    Szigethy, Geza

    2009-08-12

    Nuclear power is an attractive alternative to hydrocarbon-based energy production at a time when moving away from carbon-producing processes is widely accepted as a significant developmental need. Hence, the radioactive actinide power sources for this industry are necessarily becoming more widespread, which is accompanied by the increased risk of exposure to both biological and environmental systems. This, in turn, requires the development of technology designed to remove such radioactive threats efficiently and selectively from contaminated material, whether that be contained nuclear waste streams or the human body. Raymond and coworkers (University of California, Berkeley) have for decades investigated the interaction of biologically-inspired, hard Lewis-base ligands with high-valent, early-actinide cations. It has been established that such ligands bind strongly to the hard Lewis-acidic early actinides, and many poly-bidentate ligands have been developed and shown to be effective chelators of actinide contaminants in vivo. Work reported herein explores the effect of ligand geometry on the linear U(IV) dioxo dication (uranyl, UO2 2+). The goal is to utilize rational ligand design to develop ligands that exhibit shape selectivity towards linear dioxo cations and provides thermodynamically favorable binding interactions. The uranyl complexes with a series of tetradentate 3-hydroxy-pyridin-2-one (3,2-HOPO) ligands were studied in both the crystalline state as well as in solution. Despite significant geometric differences, the uranyl affinities of these ligands vary only slightly but are better than DTPA, the only FDA-approved chelation therapy for actinide contamination. The terepthalamide (TAM) moiety was combined into tris-beidentate ligands with 1,2- and 3,2-HOPO moieties were combined into hexadentate ligands whose structural preferences and solution thermodynamics were measured with the uranyl cation. In addition to achieving coordinative

  4. Study of spin resonances in the accelerators with snakes

    SciTech Connect

    Lee, S.Y.

    1988-01-01

    Spin resonances in the circular accelerators with snakes are studied to understand the nature of snake resonances. We analyze the effect of snake configuration, and the snake superperiod on the resonance. Defining the critical resonance strength epsilon/sub c/ as the maximum tolerable resonance strength without losing the beam polarization after passing through the resonance, we found that epsilon/sub c/ is a sensitive function of the snake configuration, the snake superperiod at the first order snake resonance, the higher order snake resonance conditions and the spin matching condition. Under properly designed snake configuration, the critical resonance strength epsilon/sub c/ is found to vary linearly with N/sub S/ as = (1/..pi..)sin/sup /minus/1/(/vert bar/cos ..pi nu../sub z//vert bar//sup /1/2//)N/sub S/, where ..nu../sub z/ and N/sub S/ are the betatron tune and the number of snakes respectively. We also study the effect of overlapping intrinsic and imperfection resonances. The imperfection resonance should be corrected to a magnitude of insignificance (e.g., epsilonless than or equal to0.1 for two snakes case) to maintain proper polarization. 23 refs., 25 figs.

  5. Rational design of therapeutic mAbs against aggregation through protein engineering and incorporation of glycosylation motifs applied to bevacizumab.

    PubMed

    Courtois, Fabienne; Agrawal, Neeraj J; Lauer, Timothy M; Trout, Bernhardt L

    2016-01-01

    The aggregation of biotherapeutics is a major hindrance to the development of successful drug candidates; however, the propensity to aggregate is often identified too late in the development phase to permit modification to the protein's sequence. Incorporating rational design for the stability of proteins in early discovery has numerous benefits. We engineered out aggregation-prone regions on the Fab domain of a therapeutic monoclonal antibody, bevacizumab, to rationally design a biobetter drug candidate. With the purpose of stabilizing bevacizumab with respect to aggregation, 2 strategies were undertaken: single point mutations of aggregation-prone residues and engineering a glycosylation site near aggregation-prone residues to mask these residues with a carbohydrate moiety. Both of these approaches lead to comparable decreases in aggregation, with an up to 4-fold reduction in monomer loss. These single mutations and the new glycosylation pattern of the Fab domain do not modify binding to the target. Biobetters with increased stability against aggregation can therefore be generated in a rational manner, by either removing or masking the aggregation-prone region or crowding out protein-protein interactions. PMID:26514585

  6. Impact of regional variation in Bothrops asper snake venom on the design of antivenoms: integrating antivenomics and neutralization approaches.

    PubMed

    Gutiérrez, José María; Sanz, Libia; Flores-Díaz, Marietta; Figueroa, Lucía; Madrigal, Marvin; Herrera, María; Villalta, Mauren; León, Guillermo; Estrada, Ricardo; Borges, Adolfo; Alape-Girón, Alberto; Calvete, Juan J

    2010-01-01

    Intraspecific snake venom variations have implications in the preparation of venom pools for the generation of antivenoms. The impact of such variation in the cross-reactivity of antivenoms against Bothrops asper venom was assessed by comparing two commercial and four experimental antivenoms. All antivenoms showed similar immunorecognition pattern toward the venoms from adult and neonate specimens. They completely immunodepleted most P-III snake venom metalloproteinases (SVMPs), l-amino acid oxidases, serine proteinases, DC fragments, cysteine-rich secretory proteins (CRISPs), and C-type lectin-like proteins, and partially immunodepleted medium-sized disintegrins, phospholipases A(2) (PLA(2)s), some serine proteinases, and P-I SVMPs. Although all antivenoms abrogated the lethal, hemorrhagic, coagulant, proteinase, and PLA(2) venoms activities, monospecific experimental antivenoms were more effective than the polyspecific experimental antivenom. In addition, the commercial antivenoms, produced in horses subjected to repeated immunization cycles, showed higher neutralization than experimental polyspecific antivenom, produced by a single round of immunization. Overall, a conspicuous pattern of cross-neutralization was evident for all effects by all antivenoms, and monospecific antivenoms raised against venom from the Caribbean population were effective against venom from the Pacific population, indicating that geographic variations in venom proteomes of B. asper from Costa Rica do not result in overt variations in immunological cross-reactivity between antivenoms. PMID:19911849

  7. Rationally Designed Interfacial Peptides Are Efficient In Vitro Inhibitors of HIV-1 Capsid Assembly with Antiviral Activity

    PubMed Central

    Bocanegra, Rebeca; Nevot, María; Doménech, Rosa; López, Inmaculada; Abián, Olga; Rodríguez-Huete, Alicia; Cavasotto, Claudio N.; Velázquez-Campoy, Adrián; Gómez, Javier; Martínez, Miguel Ángel; Neira, José Luis; Mateu, Mauricio G.

    2011-01-01

    Virus capsid assembly constitutes an attractive target for the development of antiviral therapies; a few experimental inhibitors of this process for HIV-1 and other viruses have been identified by screening compounds or by selection from chemical libraries. As a different, novel approach we have undertaken the rational design of peptides that could act as competitive assembly inhibitors by mimicking capsid structural elements involved in intersubunit interfaces. Several discrete interfaces involved in formation of the mature HIV-1 capsid through polymerization of the capsid protein CA were targeted. We had previously designed a peptide, CAC1, that represents CA helix 9 (a major part of the dimerization interface) and binds the CA C-terminal domain in solution. Here we have mapped the binding site of CAC1, and shown that it substantially overlaps with the CA dimerization interface. We have also rationally modified CAC1 to increase its solubility and CA-binding affinity, and designed four additional peptides that represent CA helical segments involved in other CA interfaces. We found that peptides CAC1, its derivative CAC1M, and H8 (representing CA helix 8) were able to efficiently inhibit the in vitro assembly of the mature HIV-1 capsid. Cocktails of several peptides, including CAC1 or CAC1M plus H8 or CAI (a previously discovered inhibitor of CA polymerization), or CAC1M+H8+CAI, also abolished capsid assembly, even when every peptide was used at lower, sub-inhibitory doses. To provide a preliminary proof that these designed capsid assembly inhibitors could eventually serve as lead compounds for development of anti-HIV-1 agents, they were transported into cultured cells using a cell-penetrating peptide, and tested for antiviral activity. Peptide cocktails that drastically inhibited capsid assembly in vitro were also able to efficiently inhibit HIV-1 infection ex vivo. This study validates a novel, entirely rational approach for the design of capsid assembly

  8. Testing the limits of rational design by engineering pH sensitivity into membrane-active peptides.

    PubMed

    Wiedman, Gregory; Wimley, William C; Hristova, Kalina

    2015-04-01

    In this work, we sought to rationally design membrane-active peptides that are triggered by low pH to form macromolecular-sized pores in lipid bilayers. Such peptides could have broad utility in biotechnology and in nanomedicine as cancer therapeutics or drug delivery vehicles that promote release of macromolecules from endosomes. Our approach to rational design was to combine the properties of a pH-independent peptide, MelP5, which forms large pores allowing passage of macromolecules, with the properties of two pH-dependent membrane-active peptides, pHlip and GALA. We created two hybrid sequences, MelP5_Δ4 and MelP5_Δ6, by using the distribution of acidic residues on pHlip and GALA as a guide to insert acidic amino acids into the amphipathic helix of MelP5. We show that the new peptides bind to lipid bilayers and acquire secondary structure in a pH-dependent manner. The peptides also destabilize bilayers in a pH-dependent manner, such that lipid vesicles release the small molecules ANTS/DPX at low pH only. Thus, we were successful in designing pH-triggered pore-forming peptides. However, no macromolecular release was observed under any conditions. Therefore, we abolished the unique macromolecular poration properties of MelP5 by introducing pH sensitivity into its sequence. We conclude that the properties of pHlip, GALA, and MelP5 are additive, but only partially so. We propose that this lack of additivity is a limitation in the rational design of novel membrane-active peptides, and that high-throughput approaches to discovery will be critical for continued progress in the field. PMID:25572997

  9. Trapping the arboreal snake Boiga irregularis

    USGS Publications Warehouse

    Rodda, G.H.; Rondeau, R.J.; Fritts, T.H.; Maughan, O.E.

    1992-01-01

    The snake Boiga irregularis, an exotic on Guam, has eliminated the majority of the native vertebrates there. We tested traps designed to control this arboreal snake during three periods of 20-41 days in 1988 and 1989. The relative trapping successes with different baits and trap configurations indicated that this snake will not readily push through a visually obstructed entrance. However, under some conditions, 80% of the snakes escaped from traps lacking a physical blockage at the entrance. Live bait was more successful than odoriferous bait alone, and odoriferous guide ropes that led to trap entrances did not enhance capture rates. These findings corroborate laboratory experiments indicating an unusually strong dependence on visual cues in this highly successful nocturnal predator.

  10. Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics

    PubMed Central

    Philipp, Jenny; Künze, Georg; Wodtke, Robert; Löser, Reik; Fahmy, Karim; Pisabarro, M. Teresa

    2016-01-01

    Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB) in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1), which are relevant for its interaction with interleukin-10 (IL-10) has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands. PMID:27123592

  11. Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics.

    PubMed

    Ruiz-Gómez, Gloria; Hawkins, John C; Philipp, Jenny; Künze, Georg; Wodtke, Robert; Löser, Reik; Fahmy, Karim; Pisabarro, M Teresa

    2016-01-01

    Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB) in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1), which are relevant for its interaction with interleukin-10 (IL-10) has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands. PMID:27123592

  12. Snaking through Science.

    ERIC Educational Resources Information Center

    Chattin, Sam S.

    1983-01-01

    Suggestions are provided for using animals (particularly snakes) as the focus of studies and activities in the science classroom. For example, cages with animals can serve as a learning center on various aspects of the animal. A list of suggestions for the care and feeding of snakes is provided. (JN)

  13. ACCELERATION OF POLARIZED BEAMS USING MULTIPLE STRONG PARTIAL SIBERIAN SNAKES.

    SciTech Connect

    ROSER,T.AHRENS,L.BAI,M.ET AL.

    2004-07-05

    Acceleration of polarized protons in the energy range of 5 to 25 GeV is particularly difficult since depolarizing spin resonances are strong enough to cause significant depolarization but full Siberian snakes cause intolerably large orbit excursions. Using a 20-30% partial Siberian snake both imperfection and intrinsic resonances can be overcome. Such a strong partial Siberian snake was designed for the Brookhaven AGS using a dual pitch helical superconducting dipole. Multiple strong partial snakes are also discussed for spin matching at beam injection and extraction.

  14. Elementary Mode Analysis for the Rational Design of Efficient Succinate Conversion from Glycerol by Escherichia coli

    PubMed Central

    Chen, Zhen; Liu, Hongjuan; Zhang, Jianan; Liu, Dehua

    2010-01-01

    By integrating the restriction of oxygen and redox sensing/regulatory system, elementary mode analysis was used to predict the metabolic potential of glycerol for succinate production by E. coli under either anaerobic or aerobic conditions. It was found that although the theoretical maximum succinate yields under both anaerobic and aerobic conditions are 1.0 mol/mol glycerol, the aerobic condition was considered to be more favorable for succinate production. Although increase of the oxygen concentration would reduce the succinate yield, the calculation suggests that controlling the molar fraction of oxygen to be under 0.65 mol/mol would be beneficial for increasing the succinate productivity. Based on the elementary mode analysis, the rational genetic modification strategies for efficient succinate production under aerobic and anaerobic conditions were obtained, respectively. Overexpressing the phosphoenolpyruvate carboxylase or heterogonous pyruvate carboxylase is considered to be the most efficient strategy to increase the succinate yield. PMID:20886007

  15. A key role for galectin-1 in sprouting angiogenesis revealed by novel rationally designed antibodies.

    PubMed

    van Beijnum, Judy R; Thijssen, Victor L; Läppchen, Tilman; Wong, Tse J; Verel, Iris; Engbersen, Maurits; Schulkens, Iris A; Rossin, Raffaella; Grüll, Holger; Griffioen, Arjan W; Nowak-Sliwinska, Patrycja

    2016-08-15

    Galectins are carbohydrate binding proteins that function in many key cellular processes. We have previously demonstrated that galectins are essential for tumor angiogenesis and their expression is associated with disease progression. Targeting galectins is therefore a potential anti-angiogenic and anti-cancer strategy. Here, we used a rational approach to generate antibodies against a specific member of this conserved protein family, i.e. galectin-1. We characterized two novel mouse monoclonal antibodies that specifically react with galectin-1 in human, mouse and chicken. We demonstrate that these antibodies are excellent tools to study galectin-1 expression and function in a broad array of biological systems. In a potential diagnostic application, radiolabeled antibodies showed specific targeting of galectin-1 positive tumors. In a therapeutic setting, the antibodies inhibited sprouting angiogenesis in vitro and in vivo, underscoring the key function of galectin-1 in this process. PMID:27062254

  16. [Hygienic characteristics of daily ration, designed for military servicemen doing call-up military service].

    PubMed

    Smagulov, N K; Mukhametzhanov, A M

    2016-01-01

    The article gives the hygienic characteristics of the daily diet of soldiers doing call-up military service. The object of study--military servicemen aged 18-22 years doing call-up military service. The material of the study data was obtained from a continuous cross-sectional study of dietary intake among military personnel. Investigation pointed out that consumption of nutrients and energy value of the surveyed military personnel was broadly in accordance with recommended physiological requirements for nutrients and energy for this age group. However; despite the adequacy of energy supply, showed signs of imbalance on the nutrients of rations provided in the military establishment. Structure of consumption of products is not in full compliance with the existing recommendations of the Kazakh academy of Nutrition. PMID:27120954

  17. A Rationally Designed Connector for Assembly of Protein-Functionalized DNA Nanostructures.

    PubMed

    Koßmann, Katja J; Ziegler, Cornelia; Angelin, Alessandro; Meyer, Rebecca; Skoupi, Marc; Rabe, Kersten S; Niemeyer, Christof M

    2016-06-16

    We report on the rational engineering of the binding interface of the self-ligating HaloTag protein to generate an optimized linker for DNA nanostructures. Five amino acids positioned around the active-site entry channel for the chlorohexyl ligand (CH) of the HaloTag protein were exchanged for positively charged lysine amino acids to produce the HOB (halo-based oligonucleotide binder) protein. HOB was genetically fused with the enzyme cytochrome P450 BM3, as well as with BMR, the separated reductase domain of BM3. The resulting HOB-fusion proteins revealed significantly improved rates in ligation with CH-modified oligonucleotides and DNA origami nanostructures. These results suggest that the efficient self-assembly of protein-decorated DNA structures can be greatly improved by fine-tuning of the electrostatic interactions between proteins and the negatively charged nucleic acid nanostructures. PMID:26972311

  18. Toward rational design of organic dye sensitized solar cells (DSSCs): an application to the TA-St-CA dye.

    PubMed

    Mohammadi, Narges; Mahon, Peter J; Wang, Feng

    2013-03-01

    A computer aided rational design has been performed on TA-St-CA dye sensitizer in order to improve the desirable properties for new organic dye sensitized solar cell (DSSC). A number of electron-donating (ED) and electron-withdrawing (EW) units based on Dewar's rules are substituted into the π-conjugated oligo-phenylenevinylene bridge of the reference TA-St-CA dye. The effects of these alternations on the molecular structures and the electron absorption spectra are calculated using time-dependant density functional theory (TDDFT). It is found that chemical modifications using electron donating (ED) substitutions exhibit advantages over the electron withdrawing (EW) substitutes to reduce the HOMO-LUMO energy gap as well as the electron distribution of the frontier orbitals of the new dyes. Dewar's rule is a useful guideline for rational design of new dye sensitizers with desired HOMO-LUMO gap. The impact on the optical spectra of new dyes are, however, less significant. PMID:23353583

  19. Protein engineering of Bacillus acidopullulyticus pullulanase for enhanced thermostability using in silico data driven rational design methods.

    PubMed

    Chen, Ana; Li, Yamei; Nie, Jianqi; McNeil, Brian; Jeffrey, Laura; Yang, Yankun; Bai, Zhonghu

    2015-10-01

    Thermostability has been considered as a requirement in the starch processing industry to maintain high catalytic activity of pullulanase under high temperatures. Four data driven rational design methods (B-FITTER, proline theory, PoPMuSiC-2.1, and sequence consensus approach) were adopted to identify the key residue potential links with thermostability, and 39 residues of Bacillus acidopullulyticus pullulanase were chosen as mutagenesis targets. Single mutagenesis followed by combined mutagenesis resulted in the best mutant E518I-S662R-Q706P, which exhibited an 11-fold half-life improvement at 60 °C and a 9.5 °C increase in Tm. The optimum temperature of the mutant increased from 60 to 65 °C. Fluorescence spectroscopy results demonstrated that the tertiary structure of the mutant enzyme was more compact than that of the wild-type (WT) enzyme. Structural change analysis revealed that the increase in thermostability was most probably caused by a combination of lower stability free-energy and higher hydrophobicity of E518I, more hydrogen bonds of S662R, and higher rigidity of Q706P compared with the WT. The findings demonstrated the effectiveness of combined data-driven rational design approaches in engineering an industrial enzyme to improve thermostability. PMID:26215347

  20. Hierarchical N-Doped Carbon as CO2 Adsorbent with High CO2 Selectivity from Rationally Designed Polypyrrole Precursor.

    PubMed

    To, John W F; He, Jiajun; Mei, Jianguo; Haghpanah, Reza; Chen, Zheng; Kurosawa, Tadanori; Chen, Shucheng; Bae, Won-Gyu; Pan, Lijia; Tok, Jeffrey B-H; Wilcox, Jennifer; Bao, Zhenan

    2016-01-27

    Carbon capture and sequestration from point sources is an important component in the CO2 emission mitigation portfolio. In particular, sorbents with both high capacity and selectivity are required for reducing the cost of carbon capture. Although physisorbents have the advantage of low energy consumption for regeneration, it remains a challenge to obtain both high capacity and sufficient CO2/N2 selectivity at the same time. Here, we report the controlled synthesis of a novel N-doped hierarchical carbon that exhibits record-high Henry's law CO2/N2 selectivity among physisorptive carbons while having a high CO2 adsorption capacity. Specifically, our synthesis involves the rational design of a modified pyrrole molecule that can co-assemble with the soft Pluronic template via hydrogen bonding and electrostatic interactions to give rise to mesopores followed by carbonization. The low-temperature carbonization and activation processes allow for the development of ultrasmall pores (d < 0.5 nm) and preservation of nitrogen moieties, essential for enhanced CO2 affinity. Furthermore, our described work provides a strategy to initiate developments of rationally designed porous conjugated polymer structures and carbon-based materials for various potential applications. PMID:26717034

  1. Homicidal Snake Bite in Children.

    PubMed

    Paulis, Melad G; Faheem, Ayman L

    2016-03-01

    Snake bites are common in many regions of the world. Snake envenomation is relatively uncommon in Egypt; such unfortunate events usually attract much publicity. Snake bite is almost only accidental, occurring in urban areas and desert. Few cases were reported to commit suicide by snake. Homicidal snake poisoning is so rare. It was known in ancient world by executing capital punishment by throwing the victim into a pit full of snakes. Another way was to ask the victim to put his hand inside a small basket harboring a deadly snake. Killing a victim by direct snake bite is so rare. There was one reported case where an old couple was killed by snake bite. Here is the first reported case of killing three children by snake bite. It appeared that the diagnosis of such cases is so difficult and depended mainly on the circumstantial evidences. PMID:27404632

  2. Rational design for multifunctional non-liposomal lipid-based nanocarriers for cancer management: theory to practice

    PubMed Central

    2013-01-01

    Nanomedicines have gained more and more attention in cancer therapy thanks to their ability to enhance the tumour accumulation and the intracellular uptake of drugs while reducing their inactivation and toxicity. In parallel, nanocarriers have been successfully employed as diagnostic tools increasing imaging resolution holding great promises both in preclinical research and in clinical settings. Lipid-based nanocarriers are a class of biocompatible and biodegradable vehicles that provide advanced delivery of therapeutic and imaging agents, improving pharmacokinetic profile and safety. One of most promising engineering challenges is the design of innovative and versatile multifunctional targeted nanotechnologies for cancer treatment and diagnosis. This review aims to highlight rational approaches to design multifunctional non liposomal lipid-based nanocarriers providing an update of literature in this field. PMID:24564841

  3. Rational design of a binary metal alloy for chemical vapour deposition growth of uniform single-layer graphene.

    PubMed

    Dai, Boya; Fu, Lei; Zou, Zhiyu; Wang, Min; Xu, Haitao; Wang, Sheng; Liu, Zhongfan

    2011-01-01

    Controlled growth of high-quality graphene is still the bottleneck of practical applications. The widely used chemical vapour deposition process generally suffers from an uncontrollable carbon precipitation effect that leads to inhomogeneous growth and strong correlation to the growth conditions. Here we report the rational design of a binary metal alloy that effectively suppresses the carbon precipitation process and activates a self-limited growth mechanism for homogeneous monolayer graphene. As demonstrated by an Ni-Mo alloy, the designed binary alloy contains an active catalyst component for carbon source decomposition and graphene growth and a black hole counterpart for trapping the dissolved carbons and forming stable metal carbides. This type of process engineering has been used to grow strictly single-layer graphene with 100% surface coverage and excellent tolerance to variations in growth conditions. With simplicity, scalability and a very large growth window, the presented approach may facilitate graphene research and industrial applications. PMID:22045001

  4. Improved detection of botulinum type E by rational design of a new peptide substrate for endopeptidase-mass spectrometry assay.

    PubMed

    Rosen, Osnat; Feldberg, Liron; Gura, Sigalit; Zichel, Ran

    2014-07-01

    Botulinum neurotoxins (BoNTs) are the most toxic substances known to humans. Endopeptidase-mass spectrometry (Endopep-MS) is used as a specific and rapid in vitro assay to detect BoNTs. In this assay, immunocaptured toxin cleaves a serotype-specific peptide substrate, and the cleavage products are then detected by MS. To further improve the sensitivity of the assay, we report here the rational design of a new substrate peptide for the detection of botulinum neurotoxin type E (BoNT/E). Our strategy was based on previously reported structural interactions integrated with analysis method efficiency considerations. Integration of the newly designed substrate has led to a more than one order of magnitude increased sensitivity of the assay. PMID:24721293

  5. Designing of skull defect implants using C1 rational cubic Bezier and offset curves

    NASA Astrophysics Data System (ADS)

    Mohamed, Najihah; Majid, Ahmad Abd; Piah, Abd Rahni Mt; Rajion, Zainul Ahmad

    2015-05-01

    Some of the reasons to construct skull implant are due to head trauma after an accident or an injury or an infection or because of tumor invasion or when autogenous bone is not suitable for replacement after a decompressive craniectomy (DC). The main objective of our study is to develop a simple method to redesign missing parts of the skull. The procedure begins with segmentation, data approximation, and estimation process of the outer wall by a C1 continuous curve. Its offset curve is used to generate the inner wall. A metaheuristic algorithm, called harmony search (HS) is a derivative-free real parameter optimization algorithm inspired from the musical improvisation process of searching for a perfect state of harmony. In this study, data approximation by a rational cubic Bézier function uses HS to optimize position of middle points and value of the weights. All the phases contribute significantly in making our proposed technique automated. Graphical examples of several postoperative skulls are displayed to show the effectiveness of our proposed method.

  6. Rational Design of Methodology-Independent Metal Parameters Using a Nonbonded Dummy Model.

    PubMed

    Jiang, Yang; Zhang, Haiyang; Tan, Tianwei

    2016-07-12

    A nonbonded dummy model for metal ions is highly imperative for the computation of complex biological systems with for instance multiple metal centers. Here we present nonbonded dummy parameters of 11 divalent metallic cations, namely, Mg(2+), V(2+), Cr(2+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Zn(2+), Cd(2+), Sn(2+), and Hg(2+), that are optimized to be compatible with three widely used water models (TIP3P, SPC/E, and TIP4P-EW). The three sets of metal parameters reproduce simultaneously the solvation free energies (ΔGsol), the ion-oxygen distance in the first solvation shell (IOD), and coordination numbers (CN) in explicit water with a relative error less than 1%. The main sources of errors to ΔGsol that arise from the boundary conditions and treatment of electrostatic interactions are corrected rationally, which ensures the independence of the proposed parameters on the methodology used in the calculation. This work will be of great value for the computational study of metal-containing biological systems. PMID:27182744

  7. Activity improvement of a Kluyveromyces lactis aldo-keto reductase KlAKR via rational design.

    PubMed

    Luo, Xi; Wang, Ya-Jun; Shen, Wei; Zheng, Yu-Guo

    2016-04-20

    Optically pure t-butyl 6-cyano-(3R, 5R)-dihydroxyhexanoate ((R)-1b) is the key chiral precursor for atorvastatin calcium, the most widely used cholesterol-lowering drug. Wild-type aldo-keto reductase KlAKR from Kluyveromyces lactis has ideal diastereoselectivity toward t-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate (1a, dep>99.5%) but poor activity. A rational engineering was used to improve the KlAKR activity. Based on homology modeling and molecular docking, two amino acid residues (295 and 296) were selected as mutation sites, and two rounds of site-saturation mutagenesis were performed. Among the mutants, KlAKR-Y295W/W296L exhibited the highest catalytic efficiency (kcat/Km) toward 1a up to 12.37s(-1)mM(-1), which was 11.25-fold higher than that of wild-type KlAKR. Moreover, the majority of mutations have no negative impact on stereoselectivity. Using KlAKR-Y295W/W296L coupled with Exiguobacterium sibiricum glucose dehydrogenase (EsGDH) for cofactor regeneration, (R)-1b was accumulated up to 162.7mM with dep value above 99.5%. KlAKR-Y295W/W296L represents a robust tool for (R)-1b synthesis. PMID:26959479

  8. Physics of icing and rational design of surfaces with extraordinary icephobicity.

    PubMed

    Schutzius, Thomas M; Jung, Stefan; Maitra, Tanmoy; Eberle, Patric; Antonini, Carlo; Stamatopoulos, Christos; Poulikakos, Dimos

    2015-05-01

    Icing of surfaces is commonplace in nature and technology, affecting everyday life and sometimes causing catastrophic events. Understanding (and counteracting) surface icing brings with it significant scientific challenges that requires interdisciplinary knowledge from diverse scientific fields such as nucleation thermodynamics and heat transfer, fluid dynamics, surface chemistry, and surface nanoengineering. Here we discuss key aspects and findings related to the physics of ice formation on surfaces and show how such knowledge could be employed to rationally develop surfaces with extreme resistance to icing (extraordinary icephobicity). Although superhydrophobic surfaces with micro-, nano-, or (often biomimetic) hierarchical roughnesses have shown in laboratory settings (under certain conditions) excellent repellency and low adhesion to water down to temperatures near or below the freezing point, extreme icephobicity necessitates additional important functionalities. Other approaches, such as lubricant-impregnated surfaces, exhibit both advantages and serious limitations with respect to icing. In all, a clear path toward passive surfaces with extreme resistance to ice formation remains a challenge, but it is one well worth undertaking. Equally important to potential applications is scalable surface manufacturing and the ability of icephobic surfaces to perform reliably and sustainably outside the laboratory under adverse conditions. Surfaces should possess mechanical and chemical stability, and they should be thermally resilient. Such issues and related research directions are also addressed in this article. PMID:25346213

  9. Converting bulk sugars into prebiotics: semi-rational design of a transglucosylase with controlled selectivity.

    PubMed

    Verhaeghe, Tom; De Winter, Karel; Berland, Magali; De Vreese, Rob; D'hooghe, Matthias; Offmann, Bernard; Desmet, Tom

    2016-03-01

    Despite the growing importance of prebiotics in nutrition and gastroenterology, their structural variety is currently still very limited. The lack of straightforward procedures to gain new products in sufficient amounts often hampers application testing and further development. Although the enzyme sucrose phosphorylase can be used to produce the rare disaccharide kojibiose (α-1,2-glucobiose) from the bulk sugars sucrose and glucose, the target compound is only a side product that is difficult to isolate. Accordingly, for this biocatalyst to become economically attractive, the formation of other glucobioses should be avoided and therefore we applied semi-rational mutagenesis and low-throughput screening, which resulted in a double mutant (L341I_Q345S) with a selectivity of 95% for kojibiose. That way, an efficient and scalable production process with a yield of 74% could be established, and with a simple yeast treatment and crystallization step over a hundred grams of highly pure kojibiose (>99.5%) was obtained. PMID:26858011

  10. Disentangling electron tunneling and protein dynamics of cytochrome c through a rationally designed surface mutation.

    PubMed

    Alvarez-Paggi, Damián; Meister, Wiebke; Kuhlmann, Uwe; Weidinger, Inez; Tenger, Katalin; Zimányi, László; Rákhely, Gábor; Hildebrandt, Peter; Murgida, Daniel H

    2013-05-23

    Nonexponential distance dependence of the apparent electron-transfer (ET) rate has been reported for a variety of redox proteins immobilized on biocompatible electrodes, thus posing a physicochemical challenge of possible physiological relevance. We have recently proposed that this behavior may arise not only from the structural and dynamical complexity of the redox proteins but also from their interplay with strong electric fields present in the experimental setups and in vivo (J. Am Chem. Soc. 2010, 132, 5769-5778). Therefore, protein dynamics are finely controlled by the energetics of both specific contacts and the interaction between the protein's dipole moment and the interfacial electric fields. In turn, protein dynamics may govern electron-transfer kinetics through reorientation from low to high donor-acceptor electronic coupling orientations. Here we present a combined computational and experimental study of WT cytochrome c and the surface mutant K87C adsorbed on electrodes coated with self-assembled monolayers (SAMs) of varying thickness (i.e., variable strength of the interfacial electric field). Replacement of the positively charged K87 by a neutral amino acid allowed us to disentangle protein dynamics and electron tunneling from the reaction kinetics and to rationalize the anomalous distance dependence in terms of (at least) two populations of distinct average electronic couplings. Thus, it was possible to recover the exponential distance dependence expected from ET theory. These results pave the way for gaining further insight into the parameters that control protein electron transfer. PMID:23611698

  11. A retrospective study of use of polyvalent anti-snake venom and risk factors for mortality from snake bite in a tertiary care setting

    PubMed Central

    Pore, Shraddha M.; Ramanand, Sunita J.; Patil, Praveenkumar T.; Gore, Alka D.; Pawar, Mayur P.; Gaidhankar, Smita L.; Ghanghas, Ravi R.

    2015-01-01

    Aims: Envenomation with poisonous snakes is associated with considerable morbidity and mortality. The present study was undertaken with the objectives of assessing anti-snake venom (ASV) use, early adverse reactions to ASV, premedication and clinical outcomes in snake bite patients. Association of various risk factors (age, gender, dose of ASV, time gap between snake bite and ASV administration, use of mechanical ventilation and type of snake bite) with mortality was also assessed. Settings and Design: This retrospective study was conducted at two Tertiary Care Teaching Hospitals. Subjects and Methods: The medical records of 176 patients of snake bite with documented use of ASV were retrospectively analyzed to retrieve relevant data. Statistical Analysis: Descriptive statistics was used to express results about ASV use, early adverse reactions to ASV, premedication and clinical outcomes. Univariate and multivariate analysis was performed to find out significant risk factors associated with mortality. Results: The main indication for ASV was vasculotoxic snake bite (75%) followed by neurotoxic snake bite (16%). Mean dose of ASV was 18.63 ± 14.52 vials. Prophylactic premedication with corticosteroids alone or in combination with antihistaminic was used in more than 70% patients. Early adverse reactions to ASV were seen in 4% patients. Neurotoxic snake bite was a significant risk factor associated with mortality in multivariate analysis. Conclusions: Neurotoxic snake bite is an independent predictor of mortality in snake bite patients. Currently used polyvalent ASV may be less effective in treating neurotoxic snake bite. PMID:26069363

  12. Reviewing Ligand-Based Rational Drug Design: The Search for an ATP Synthase Inhibitor

    PubMed Central

    Lee, Chia-Hsien; Huang, Hsuan-Cheng; Juan, Hsueh-Fen

    2011-01-01

    Following major advances in the field of medicinal chemistry, novel drugs can now be designed systematically, instead of relying on old trial and error approaches. Current drug design strategies can be classified as being either ligand- or structure-based depending on the design process. In this paper, by describing the search for an ATP synthase inhibitor, we review two frequently used approaches in ligand-based drug design: The pharmacophore model and the quantitative structure-activity relationship (QSAR) method. Moreover, since ATP synthase ligands are potentially useful drugs in cancer therapy, pharmacophore models were constructed to pave the way for novel inhibitor designs. PMID:21954360

  13. Rational design and validation of an anti-protein kinase C active-state specific antibody based on conformational changes

    PubMed Central

    Pena, Darlene Aparecida; Andrade, Victor Piana de; Silva, Gabriela Ávila Fernandes; Neves, José Ivanildo; Oliveira, Paulo Sergio Lopes de; Alves, Maria Julia Manso; Devi, Lakshmi A.; Schechtman, Deborah

    2016-01-01

    Protein kinase C (PKC) plays a regulatory role in key pathways in cancer. However, since phosphorylation is a step for classical PKC (cPKC) maturation and does not correlate with activation, there is a lack of tools to detect active PKC in tissue samples. Here, a structure-based rational approach was used to select a peptide to generate an antibody that distinguishes active from inactive cPKC. A peptide conserved in all cPKCs, C2Cat, was chosen since modeling studies based on a crystal structure of PKCβ showed that it is localized at the interface between the C2 and catalytic domains of cPKCs in an inactive kinase. Anti-C2Cat recognizes active cPKCs at least two-fold better than inactive kinase in ELISA and immunoprecipitation assays, and detects the temporal dynamics of cPKC activation upon receptor or phorbol stimulation. Furthermore, the antibody is able to detect active PKC in human tissue. Higher levels of active cPKC were observed in the more aggressive triple negative breast cancer tumors as compared to the less aggressive estrogen receptor positive tumors. Thus, this antibody represents a reliable, hitherto unavailable and a valuable tool to study PKC activation in cells and tissues. Similar structure-based rational design strategies can be broadly applied to obtain active-state specific antibodies for other signal transduction molecules. PMID:26911897

  14. Rational design of thermostable vaccines by engineered peptide-induced virus self-biomineralization under physiological conditions.

    PubMed

    Wang, Guangchuan; Cao, Rui-Yuan; Chen, Rong; Mo, Lijuan; Han, Jian-Feng; Wang, Xiaoyu; Xu, Xurong; Jiang, Tao; Deng, Yong-Qiang; Lyu, Ke; Zhu, Shun-Ya; Qin, E-De; Tang, Ruikang; Qin, Cheng-Feng

    2013-05-01

    The development of vaccines against infectious diseases represents one of the most important contributions to medical science. However, vaccine-preventable diseases still cause millions of deaths each year due to the thermal instability and poor efficacy of vaccines. Using the human enterovirus type 71 vaccine strain as a model, we suggest a combined, rational design approach to improve the thermostability and immunogenicity of live vaccines by self-biomineralization. The biomimetic nucleating peptides are rationally integrated onto the capsid of enterovirus type 71 by reverse genetics so that calcium phosphate mineralization can be biologically induced onto vaccine surfaces under physiological conditions, generating a mineral exterior. This engineered self-biomineralized virus was characterized in detail for its unique structural, virological, and chemical properties. Analogous to many exteriors, the mineral coating confers some new properties on enclosed vaccines. The self-biomineralized vaccine can be stored at 26 °C for more than 9 d and at 37 °C for approximately 1 wk. Both in vitro and in vivo experiments demonstrate that this engineered vaccine can be used efficiently after heat treatment or ambient temperature storage, which reduces the dependence on a cold chain. Such a combination of genetic technology and biomineralization provides an economic solution for current vaccination programs, especially in developing countries that lack expensive refrigeration infrastructures. PMID:23589862

  15. Rational design of thermostable vaccines by engineered peptide-induced virus self-biomineralization under physiological conditions

    PubMed Central

    Wang, Guangchuan; Cao, Rui-Yuan; Chen, Rong; Mo, Lijuan; Han, Jian-Feng; Wang, Xiaoyu; Xu, Xurong; Jiang, Tao; Deng, Yong-Qiang; Lyu, Ke; Zhu, Shun-Ya; Tang, Ruikang; Qin, Cheng-Feng

    2013-01-01

    The development of vaccines against infectious diseases represents one of the most important contributions to medical science. However, vaccine-preventable diseases still cause millions of deaths each year due to the thermal instability and poor efficacy of vaccines. Using the human enterovirus type 71 vaccine strain as a model, we suggest a combined, rational design approach to improve the thermostability and immunogenicity of live vaccines by self-biomineralization. The biomimetic nucleating peptides are rationally integrated onto the capsid of enterovirus type 71 by reverse genetics so that calcium phosphate mineralization can be biologically induced onto vaccine surfaces under physiological conditions, generating a mineral exterior. This engineered self-biomineralized virus was characterized in detail for its unique structural, virological, and chemical properties. Analogous to many exteriors, the mineral coating confers some new properties on enclosed vaccines. The self-biomineralized vaccine can be stored at 26 °C for more than 9 d and at 37 °C for approximately 1 wk. Both in vitro and in vivo experiments demonstrate that this engineered vaccine can be used efficiently after heat treatment or ambient temperature storage, which reduces the dependence on a cold chain. Such a combination of genetic technology and biomineralization provides an economic solution for current vaccination programs, especially in developing countries that lack expensive refrigeration infrastructures. PMID:23589862

  16. Rational design and validation of an anti-protein kinase C active-state specific antibody based on conformational changes.

    PubMed

    Pena, Darlene Aparecida; Andrade, Victor Piana de; Silva, Gabriela Ávila Fernandes; Neves, José Ivanildo; Oliveira, Paulo Sergio Lopes de; Alves, Maria Julia Manso; Devi, Lakshmi A; Schechtman, Deborah

    2016-01-01

    Protein kinase C (PKC) plays a regulatory role in key pathways in cancer. However, since phosphorylation is a step for classical PKC (cPKC) maturation and does not correlate with activation, there is a lack of tools to detect active PKC in tissue samples. Here, a structure-based rational approach was used to select a peptide to generate an antibody that distinguishes active from inactive cPKC. A peptide conserved in all cPKCs, C2Cat, was chosen since modeling studies based on a crystal structure of PKCβ showed that it is localized at the interface between the C2 and catalytic domains of cPKCs in an inactive kinase. Anti-C2Cat recognizes active cPKCs at least two-fold better than inactive kinase in ELISA and immunoprecipitation assays, and detects the temporal dynamics of cPKC activation upon receptor or phorbol stimulation. Furthermore, the antibody is able to detect active PKC in human tissue. Higher levels of active cPKC were observed in the more aggressive triple negative breast cancer tumors as compared to the less aggressive estrogen receptor positive tumors. Thus, this antibody represents a reliable, hitherto unavailable and a valuable tool to study PKC activation in cells and tissues. Similar structure-based rational design strategies can be broadly applied to obtain active-state specific antibodies for other signal transduction molecules. PMID:26911897

  17. Rational design of broad spectrum antibacterial activity based on a clinically relevant enoyl-acyl carrier protein (ACP) reductase inhibitor.

    PubMed

    Schiebel, Johannes; Chang, Andrew; Shah, Sonam; Lu, Yang; Liu, Li; Pan, Pan; Hirschbeck, Maria W; Tareilus, Mona; Eltschkner, Sandra; Yu, Weixuan; Cummings, Jason E; Knudson, Susan E; Bommineni, Gopal R; Walker, Stephen G; Slayden, Richard A; Sotriffer, Christoph A; Tonge, Peter J; Kisker, Caroline

    2014-06-01

    Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors, including CG400549. Based on these structures, we rationalize the 65-fold reduced affinity of CG400549 toward Escherichia coli versus S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms. PMID:24739388

  18. Rational design of an efficient, genetically encodable, protein-encased singlet oxygen photosensitizer.

    PubMed

    Westberg, Michael; Holmegaard, Lotte; Pimenta, Frederico M; Etzerodt, Michael; Ogilby, Peter R

    2015-02-01

    Singlet oxygen, O(2)(a(1)Δ(g)), plays a key role in many processes of cell signaling. Limitations in mechanistic studies of such processes are generally associated with the difficulty of controlling the amount and location of O(2)(a(1)Δ(g)) production in or on a cell. As such, there is great need for a system that (a) selectively produces O(2)(a(1)Δ(g)) in appreciable and accurately quantifiable yields and (b) can be localized in a specific place at the suborganelle level. A genetically encodable, protein-encased photosensitizer is one way to achieve this goal. Through a systematic and rational approach involving mutations to a LOV2 protein that binds the chromophore flavin mononucleotide (FMN), we have developed a promising photosensitizer that overcomes many of the problems that affect related systems currently in use. Specifically, by decreasing the extent of hydrogen bonding between FMN and a specific amino acid residue in the local protein environment, we decrease the susceptibility of FMN to undesired photoinitiated electron-transfer reactions that kinetically compete with O(2)(a(1)Δ(g)) production. As a consequence, our protein-encased FMN system produces O(2)(a(1)Δ(g)) with the uniquely large quantum efficiency of 0.25 ± 0.03. We have also quantified other key photophysical parameters that characterize this sensitizer system, including unprecedented H(2)O/D(2)O solvent isotope effects on the O(2)(a(1)Δ(g)) formation kinetics and yields. As such, our results facilitate future systematic developments in this field. PMID:25575190

  19. The Promiscuity of [beta]-Strand Pairing Allows for Rational Design of [beta]-Sheet Face Inversion

    SciTech Connect

    Makabe, Koki; Koide, Shohei

    2009-06-17

    Recent studies suggest the dominant role of main-chain H-bond formation in specifying {beta}-sheet topology. Its essentially sequence-independent nature implies a large degree of freedom in designing {beta}-sheet-based nanomaterials. Here we show rational design of {beta}-sheet face inversions by incremental deletions of {beta}-strands from the single-layer {beta}-sheet of Borrelia outer surface protein A. We show that a {beta}-sheet structure can be maintained when a large number of native contacts are removed and that one can design large-scale conformational transitions of a {beta}-sheet such as face inversion by exploiting the promiscuity of strand-strand interactions. High-resolution X-ray crystal structures confirmed the success of the design and supported the importance of main-chain H-bonds in determining {beta}-sheet topology. This work suggests a simple but effective strategy for designing and controlling nanomaterials based on {beta}-rich peptide self-assemblies.

  20. Snake Filament Eruption

    NASA Video Gallery

    A very long solar filament that had been snaking around the Sun erupted on Dec. 6, 2010 with a flourish. NASA's Solar Dynamics Observatory (SDO) caught the action in dramatic detail in extreme ultr...

  1. Rational designed bipolar, conjugated polymer-DNA composite beacon for the sensitive detection of proteins and ions.

    PubMed

    Jia, Yongmei; Zuo, Xiaolei; Lou, Xiaoding; Miao, Mao; Cheng, Yong; Min, Xuehong; Li, Xinchun; Xia, Fan

    2015-04-01

    Nature owns remarkable capabilities in sensing target molecules, while the artificial biosensor lags far behind nature. Inspired by nature, we devise a new sensing platform that can specifically bind the molecules and synchronously initiate a specific signal response. We rationally designed a type of bipolar probe that is comprised of a hydrophilic DNA part and a hydrophobic conjugated polymer (CP) unit. In aqueous solution, they can form micelles with a hydrophobic CP core and a hydrophilic DNA shell. The aggregation-caused quenching suppresses the fluorescence of CP. Adding telomerase, the hydropathical profile of the bipolar probes is drastically regulated that results in the collapse of micelles and liberates fluorescence simultaneously. The probe has been used in both mimic systems and real urine samples (38 samples). We achieve sensitive and specific detection of telomerase and obtain clearly classification for normal people and cancer patients. It can also be used in a signal off sensor that is used to detect mercury ions. PMID:25694029

  2. Rational Design Synthesis and Evaluation of New Selective Inhibitors of Microbial Class II (Zinc Dependent) Fructose Bis-phosphate Aldolases

    SciTech Connect

    R Daher; M Coincon; M Fonvielle; P Gest; M Guerin; M Jackson; J Sygusch; M Therisod

    2011-12-31

    We report the synthesis and biochemical evaluation of several selective inhibitors of class II (zinc dependent) fructose bis-phosphate aldolases (Fba). The products were designed as transition-state analogues of the catalyzed reaction, structurally related to the substrate fructose bis-phosphate (or sedoheptulose bis-phosphate) and based on an N-substituted hydroxamic acid, as a chelator of the zinc ion present in active site. The compounds synthesized were tested on class II Fbas from various pathogenic microorganisms and, by comparison, on a mammalian class I Fba. The best inhibitor shows Ki against class II Fbas from various pathogens in the nM range, with very high selectivity (up to 105). Structural analyses of inhibitors in complex with aldolases rationalize and corroborate the enzymatic kinetics results. These inhibitors represent lead compounds for the preparation of new synthetic antibiotics, notably for tuberculosis prophylaxis.

  3. Rational design of a protein that binds integrin αvβ3 outside the ligand binding site

    PubMed Central

    Turaga, Ravi Chakra; Yin, Lu; Yang, Jenny J.; Lee, Hsiauwei; Ivanov, Ivaylo; Yan, Chunli; Yang, Hua; Grossniklaus, Hans E.; Wang, Siming; Ma, Cheng; Sun, Li; Liu, Zhi-Ren

    2016-01-01

    Integrin αvβ3 expression is altered in various diseases and has been proposed as a drug target. Here we use a rational design approach to develop a therapeutic protein, which we call ProAgio, that binds to integrin αvβ3 outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin αvβ3-expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin αvβ3. ProAgio also has anti-angiogenic activity and strongly inhibits growth of tumour xenografts, but does not affect the established vasculature. Toxicity analyses demonstrate that ProAgio is not toxic to mice. Our study reports a new integrin-targeting agent with a unique mechanism of action, and provides a template for the development of integrin-targeting therapeutics. PMID:27241473

  4. One-pot synthesis of MWW zeolite nanosheets using a rationally designed organic structure-directing agent

    PubMed Central

    Luo, Helen Y.; Michaelis, Vladimir K.; Hodges, Sydney; Griffin, Robert G.

    2015-01-01

    A new material MIT-1 comprised of delaminated MWW zeolite nanosheets is synthesized in one-pot using a rationally designed organic structure-directing agent (OSDA). The OSDA is comprised of a hydrophilic head segment that resembles the OSDA used to synthesize the zeolite precursor MCM22(P), a hydrophobic tail segment that resembles the swelling agent used to swell MCM22(P), and a di-quaternary ammonium linker that connects both segments. MIT-1 features high crystallinity and surface areas exceeding 500 m2g−1, and can be synthesized over a wide synthesis window that includes Si/Al ratios ranging from 13 to 67. Characterization data reveal high mesoporosity and acid strength with no detectable amorphous silica phases. Compared to MCM-22 and MCM-56, MIT-1 shows a three-fold increase in catalytic activity for the Friedel-Crafts alkylation of benzene with benzyl alcohol. PMID:26478803

  5. Rational design of a protein that binds integrin αvβ3 outside the ligand binding site.

    PubMed

    Turaga, Ravi Chakra; Yin, Lu; Yang, Jenny J; Lee, Hsiauwei; Ivanov, Ivaylo; Yan, Chunli; Yang, Hua; Grossniklaus, Hans E; Wang, Siming; Ma, Cheng; Sun, Li; Liu, Zhi-Ren

    2016-01-01

    Integrin αvβ3 expression is altered in various diseases and has been proposed as a drug target. Here we use a rational design approach to develop a therapeutic protein, which we call ProAgio, that binds to integrin αvβ3 outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin αvβ3-expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin αvβ3. ProAgio also has anti-angiogenic activity and strongly inhibits growth of tumour xenografts, but does not affect the established vasculature. Toxicity analyses demonstrate that ProAgio is not toxic to mice. Our study reports a new integrin-targeting agent with a unique mechanism of action, and provides a template for the development of integrin-targeting therapeutics. PMID:27241473

  6. Rational Design of a Second Generation Catalyst for Preparation of Allylsilanes Using the Silyl-Heck Reaction

    PubMed Central

    2015-01-01

    Using rational ligand design, we have developed of a second-generation ligand, bis(3,5-di-tert-butylphenyl)(tert-butyl)phosphine, for the preparation of allylsilanes using the palladium-catalyzed silyl-Heck reaction. This new ligand provides nearly complete suppression of starting material alkene isomerization that was observed with our first-generation catalyst, providing vastly improved yields of allylsilanes from simple alkene starting materials. The studies quantifying the electronic and steric properties of the new ligand are described. Finally, we report an X-ray crystal structure of a palladium complex resulting from the oxidative addition of Me3SiI using an analogous ligand that provides significant insight into the nature of the catalytic system. PMID:25003502

  7. Rational Design of Diketopyrrolopyrrole-Based Small Molecules as Donating Materials for Organic Solar Cells

    PubMed Central

    Jin, Ruifa; Wang, Kai

    2015-01-01

    A series of diketopyrrolopyrrole-based small molecules have been designed to explore their optical, electronic, and charge transport properties as organic solar cell (OSCs) materials. The calculation results showed that the designed molecules can lower the band gap and extend the absorption spectrum towards longer wavelengths. The designed molecules own the large longest wavelength of absorption spectra, the oscillator strength, and absorption region values. The optical, electronic, and charge transport properties of the designed molecules are affected by the introduction of different π-bridges and end groups. We have also predicted the mobility of the designed molecule with the lowest total energies. Our results reveal that the designed molecules are expected to be promising candidates for OSC materials. Additionally, the designed molecules are expected to be promising candidates for electron and/or hole transport materials. On the basis of our results, we suggest that molecules under investigation are suitable donors for [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) and its derivatives as acceptors of OSCs. PMID:26343640

  8. Rational Design of Diketopyrrolopyrrole-Based Small Moleculesas Donating Materials for Organic Solar Cells.

    PubMed

    Jin, Ruifa; Wang, Kai

    2015-01-01

    A series of diketopyrrolopyrrole-based small molecules have been designed to explore their optical, electronic, and charge transport properties as organic solar cell(OSCs) materials. The calculation results showed that the designed molecules can lower the band gap and extend the absorption spectrum towards longer wavelengths.The designed molecules own the large longest wavelength of absorption spectra,the oscillator strength, and absorption region values. The optical, electronic, and charge transport properties of the designed molecules are affected by the introduction of different π-bridges and end groups. We have also predicted the mobility of the designed molecule with the lowest total energies. Our results reveal that the designed molecules are expected to be promising candidates for OSC materials. Additionally, the designed molecules are expected to be promising candidates for electron and/or hole transport materials. On the basis of our results, we suggest that molecules under investigation are suitable donors for[6,6]-phenyl-C61-butyric acid methyl ester (PCBM) and its derivatives as acceptors of OSCs. PMID:26343640

  9. Rational Design of Bioelectrochemically Multifunctional Film with Oxidase, Ferrocene, and Graphene Oxide for Development of in Vivo Electrochemical Biosensors.

    PubMed

    Wang, Xiuyun; Li, Qian; Xu, Jingjing; Wu, Shuo; Xiao, Tongfang; Hao, Jie; Yu, Ping; Mao, Lanqun

    2016-06-01

    This study demonstrates a new strategy to develop in vivo electrochemical biosensors through rational design and simple formation of bioelectrochemically multifunctional film (BMF). The BMF is rationally designed by first efficiently incorporating oxidase, ferrocene mediator, and graphene oxide into polymaleimidostyrene/polystyrene (PMS/PS) matrix to form a homogeneous mixture and then simply formed by drop-coating the mixture onto solid conducting substrate. By using the as-formed BMF, electrochemical biosensors could be constructed with a technical simplicity and high reproducibility. To illustrate the BMF-based biosensors for in vivo applications, we directly couple the biosensors to in vivo microdialysis to establish an online electrochemical system (OECS) for in vivo monitoring of glucose in rat auditory cortex during salicylate-induced tinnitus model. The OECS with the BMF-based biosensor as the detector shows a linear response toward glucose within a concentration range from 50 to 500 μM with a detection limit of 10 μM (S/N = 3). Additionally, the OECS is stable and does not suffer from the interference from the electroactive species endogenously coexisting in the brain microdialysate. With the BMF-based OECS, the basal level of glucose in the microdialysate continuously sampled from rat auditory cortex is determined to be 120 ± 10 μM (n = 5). After the rats were administrated with salicylate to induce transient tinnitus, the microdialysate glucose concentration in the rat auditory cortex remarkably increased to 433 ± 190 μM (n = 5) at the time point of 1.5 h. This study essentially offers a new, technically simple and reproducible approach to development of in vivo electrochemical biosensors, which is envisaged to be relatively useful for understanding of the molecular basis of brain functions. PMID:27146343

  10. Model-based rational feedback controller design for closed-loop deep brain stimulation of Parkinson's disease

    NASA Astrophysics Data System (ADS)

    Gorzelic, P.; Schiff, S. J.; Sinha, A.

    2013-04-01

    Objective. To explore the use of classical feedback control methods to achieve an improved deep brain stimulation (DBS) algorithm for application to Parkinson's disease (PD). Approach. A computational model of PD dynamics was employed to develop model-based rational feedback controller design. The restoration of thalamocortical relay capabilities to patients suffering from PD is formulated as a feedback control problem with the DBS waveform serving as the control input. Two high-level control strategies are tested: one that is driven by an online estimate of thalamic reliability, and another that acts to eliminate substantial decreases in the inhibition from the globus pallidus interna (GPi) to the thalamus. Control laws inspired by traditional proportional-integral-derivative (PID) methodology are prescribed for each strategy and simulated on this computational model of the basal ganglia network. Main Results. For control based upon thalamic reliability, a strategy of frequency proportional control with proportional bias delivered the optimal control achieved for a given energy expenditure. In comparison, control based upon synaptic inhibitory output from the GPi performed very well in comparison with those of reliability-based control, with considerable further reduction in energy expenditure relative to that of open-loop DBS. The best controller performance was amplitude proportional with derivative control and integral bias, which is full PID control. We demonstrated how optimizing the three components of PID control is feasible in this setting, although the complexity of these optimization functions argues for adaptive methods in implementation. Significance. Our findings point to the potential value of model-based rational design of feedback controllers for Parkinson's disease.

  11. Standby Gasoline Rationing Plan

    SciTech Connect

    1980-06-01

    The final rules adopted by the President for a Standby Gasoline Rationing Plan are presented. The plan provides that eligibility for ration allotments will be determined primarily on the basis of motor vehicle registrations, taking into account historical differences in the use of gasoline among states. The regulations also provide authority for supplemental allotments to firms so that their allotment will equal a specified percentage of gasoline use during a base period. Priority classifications, i.e., agriculture, defense, etc., are established to assure adequate gasoline supplies for designated essential services. Ration rights must be provided by end-users to their suppliers for each gallon sold. DOE will regulate the distribution of gasoline at the wholesale level according to the transfer by suppliers of redeemed ration rights and the gasoline allocation regulations. Ration rights are transferable. A ration banking system is created to facilitate transfers of ration rights. Each state will be provided with a reserve of ration rights to provide for hardship needs and to alleviate inequities. (DC)

  12. Rational Design of Fluorescent Phthalazinone Derivatives for One- and Two-Photon Imaging.

    PubMed

    Yang, Lingfei; Zhu, Yuanjun; Shui, Mengyang; Zhou, Tongliang; Cai, Yuanbo; Wang, Wei; Xu, Fengrong; Niu, Yan; Wang, Chao; Zhang, Jun-Long; Xu, Ping; Yuan, Lan; Liang, Lei

    2016-08-22

    Phthalazinone derivatives were designed as optical probes for one- and two-photon fluorescence microscopy imaging. The design strategy involves stepwise extension and modification of pyridazinone by 1) expansion of pyridazinone to phthalazinone, a larger conjugated system, as the electron acceptor, 2) coupling of electron-donating aromatic groups such as N,N-diethylaminophenyl, thienyl, naphthyl, and quinolyl to the phthalazinone, and 3) anchoring of an alkyl chain to the phthalazinone with various terminal substituents such as triphenylphosphonio, morpholino, triethylammonio, N-methylimidazolio, pyrrolidino, and piperidino. Theoretical calculations were utilized to verify the initial design. The desired fluorescent probes were synthesized by two different routes in considerable yields. Twenty-two phthalazinone derivatives were synthesized and their photophysical properties were measured. Selected compounds were applied in cell imaging, and valuable information was obtained. Furthermore, the designed compounds showed excellent performance in two-photon microscopic imaging of mouse brain slices. PMID:27440529

  13. DEVELOPMENT OF A RATIONALLY BASED DESIGN PROTOCOL FOR THE ULTRAVIOLET LIGHT DISINFECTION PROCESS

    EPA Science Inventory

    A protocol is demonstrated for the design and evaluation of ultraviolet (UV) disinfection systems based on a mathematical model. The disinfection model incorporates the system's physical dimensions, the residence time distribution of the reactor and dispersion characteristics, th...

  14. Combined Bioinformatic and Rational Design Approach To Develop Antimicrobial Peptides against Mycobacterium tuberculosis.

    PubMed

    Pearson, C Seth; Kloos, Zachary; Murray, Brian; Tabe, Ebot; Gupta, Monica; Kwak, Jun Ha; Karande, Pankaj; McDonough, Kathleen A; Belfort, Georges

    2016-05-01

    Drug-resistant pathogens are a growing problem, and novel strategies are needed to combat this threat. Among the most significant of these resistant pathogens is Mycobacterium tuberculosis, which is an unusually difficult microbial target due to its complex membrane. Here, we design peptides for specific activity against M. tuberculosis using a combination of "database filtering" bioinformatics, protein engineering, and de novo design. Several variants of these peptides are structurally characterized to validate the design process. The designed peptides exhibit potent activity (MIC values as low as 4 μM) against M. tuberculosis and also exhibit broad activity against a host of other clinically relevant pathogenic bacteria such as Gram-positive bacteria (Streptococcus) and Gram-negative bacteria (Escherichia coli). They also display excellent selectivity, with low cytotoxicity against cultured macrophages and lung epithelial cells. These first-generation antimicrobial peptides serve as a platform for the design of antibiotics and for investigating structure-activity relationships in the context of the M. tuberculosis membrane. The antimicrobial peptide design strategy is expected to be generalizable for any pathogen for which an activity database can be created. PMID:26902758

  15. Rational Mutagenesis to Support Structure-based Drug Design: MAPKAP Kinase 2 as a Case Study

    SciTech Connect

    M Argiriadi; S Sousa; D Banach; D Marcotte; T Xiang; M Tomlinson; M Demers; C Harris; S Kwak; et al.

    2011-12-31

    Structure-based drug design (SBDD) can provide valuable guidance to drug discovery programs. Robust construct design and expression, protein purification and characterization, protein crystallization, and high-resolution diffraction are all needed for rapid, iterative inhibitor design. We describe here robust methods to support SBDD on an oral anti-cytokine drug target, human MAPKAP kinase 2 (MK2). Our goal was to obtain useful diffraction data with a large number of chemically diverse lead compounds. Although MK2 structures and structural methods have been reported previously, reproducibility was low and improved methods were needed. Our construct design strategy had four tactics: N- and C-terminal variations; entropy-reducing surface mutations; activation loop deletions; and pseudoactivation mutations. Generic, high-throughput methods for cloning and expression were coupled with automated liquid dispensing for the rapid testing of crystallization conditions with minimal sample requirements. Initial results led to development of a novel, customized robotic crystallization screen that yielded MK2/inhibitor complex crystals under many conditions in seven crystal forms. In all, 44 MK2 constructs were generated, {approx}500 crystals were tested for diffraction, and {approx}30 structures were determined, delivering high-impact structural data to support our MK2 drug design effort. Key lessons included setting reasonable criteria for construct performance and prioritization, a willingness to design and use customized crystallization screens, and, crucially, initiation of high-throughput construct exploration very early in the drug discovery process.

  16. Roles of glutamates and metal ions in a rationally designed nitric oxide reductase based on myoglobin

    SciTech Connect

    Lin, Y.W.; Robinson, H.; Yeung, N.; Gao, Y.-G.; Miner, K. D.; Tian, S.; Lu, Y.

    2010-05-11

    A structural and functional model of bacterial nitric oxide reductase (NOR) has been designed by introducing two glutamates (Glu) and three histidines (His) in sperm whale myoglobin. X-ray structural data indicate that the three His and one Glu (V68E) residues bind iron, mimicking the putative FeB site in NOR, while the second Glu (I107E) interacts with a water molecule and forms a hydrogen bonding network in the designed protein. Unlike the first Glu (V68E), which lowered the heme reduction potential by {approx}110 mV, the second Glu has little effect on the heme potential, suggesting that the negatively charged Glu has a different role in redox tuning. More importantly, introducing the second Glu resulted in a {approx}100% increase in NOR activity, suggesting the importance of a hydrogen bonding network in facilitating proton delivery during NOR reactivity. In addition, EPR and X-ray structural studies indicate that the designed protein binds iron, copper, or zinc in the FeB site, each with different effects on the structures and NOR activities, suggesting that both redox activity and an intermediate five-coordinate heme-NO species are important for high NOR activity. The designed protein offers an excellent model for NOR and demonstrates the power of using designed proteins as a simpler and more well-defined system to address important chemical and biological issues.

  17. Roles of Glutamates and Metal ions in a Rationally Designed Nitric Oxide Reductase Based on Myoglobin

    SciTech Connect

    Y Lin; N Yeung; Y Gao; K Miner; S Tian; H Robinson; Y Lu

    2011-12-31

    A structural and functional model of bacterial nitric oxide reductase (NOR) has been designed by introducing two glutamates (Glu) and three histidines (His) in sperm whale myoglobin. X-ray structural data indicate that the three His and one Glu (V68E) residues bind iron, mimicking the putative FeB site in NOR, while the second Glu (I107E) interacts with a water molecule and forms a hydrogen bonding network in the designed protein. Unlike the first Glu (V68E), which lowered the heme reduction potential by {approx}110 mV, the second Glu has little effect on the heme potential, suggesting that the negatively charged Glu has a different role in redox tuning. More importantly, introducing the second Glu resulted in a {approx}100% increase in NOR activity, suggesting the importance of a hydrogen bonding network in facilitating proton delivery during NOR reactivity. In addition, EPR and X-ray structural studies indicate that the designed protein binds iron, copper, or zinc in the FeB site, each with different effects on the structures and NOR activities, suggesting that both redox activity and an intermediate five-coordinate heme-NO species are important for high NOR activity. The designed protein offers an excellent model for NOR and demonstrates the power of using designed proteins as a simpler and more well-defined system to address important chemical and biological issues.

  18. Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts

    PubMed Central

    Disney, Matthew D.

    2013-01-01

    RNA is an important yet vastly underexploited target for small molecule chemical probes or lead therapeutics. Small molecules have been used successfully to modulate the function of the bacterial ribosome, viral RNAs and riboswitches. These RNAs are either highly expressed or can be targeted using substrate mimicry, a mainstay in the design of enzyme inhibitors. However, most cellular RNAs are neither highly expressed nor have a lead small molecule inhibitor, a significant challenge for drug discovery efforts. Herein, I describe the design of small molecules targeting expanded repeating transcripts that cause myotonic muscular dystrophy (DM). These test cases illustrate the challenges of designing small molecules that target RNA and the advantages of targeting repeating transcripts. Lastly, I discuss how small molecules might be more advantageous than oligonucleotides for targeting RNA. PMID:23939337

  19. Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts.

    PubMed

    Disney, Matthew D

    2013-12-01

    RNA is an important yet vastly underexploited target for small molecule chemical probes or lead therapeutics. Small molecules have been used successfully to modulate the function of the bacterial ribosome, viral RNAs and riboswitches. These RNAs are either highly expressed or can be targeted using substrate mimicry, a mainstay in the design of enzyme inhibitors. However, most cellular RNAs are neither highly expressed nor have a lead small molecule inhibitor, a significant challenge for drug discovery efforts. Herein, I describe the design of small molecules targeting expanded repeating transcripts that cause myotonic muscular dystrophy (DM). These test cases illustrate the challenges of designing small molecules that target RNA and the advantages of targeting repeating transcripts. Lastly, I discuss how small molecules might be more advantageous than oligonucleotides for targeting RNA. PMID:23939337

  20. Rational design, synthesis, and verification of affinity ligands to a protein surface cleft

    PubMed Central

    Baumann, Herbert; Öhrman, Sara; Shinohara, Yasuro; Ersoy, Oguz; Choudhury, Devapriya; Axén, Andreas; Tedebark, Ulf; Carredano, Enrique

    2003-01-01

    The structure-based design, synthesis, and screening of a glucuronic acid scaffold library of affinity ligands directed toward the catalytic cleft on porcine pancreas α-amylase are presented. The design was based on the simulated docking to the enzyme active site of 53 aryl glycosides from the Available Chemicals Directory (ACD) selected by in silico screening. Twenty-three compounds were selected for synthesis and screened in solution for binding toward α-amylase using nuclear magnetic resonance techniques. The designed molecules include a handle outside of the binding site to allow their attachment to various surfaces with minimal loss of binding activity. After initial screening in solution, one affinity ligand was selected, immobilized to Sepharose (Amersham Biosciences), and evaluated as a chromatographic probe. A column packed with ligand-coupled Sepharose specifically retained the enzyme, which could be eluted by a known inhibitor. PMID:12649437

  1. Approaching rational epitope vaccine design for hepatitis C virus with meta-server and multivalent scaffolding

    NASA Astrophysics Data System (ADS)

    He, Linling; Cheng, Yushao; Kong, Leopold; Azadnia, Parisa; Giang, Erick; Kim, Justin; Wood, Malcolm R.; Wilson, Ian A.; Law, Mansun; Zhu, Jiang

    2015-08-01

    Development of a prophylactic vaccine against hepatitis C virus (HCV) has been hampered by the extraordinary viral diversity and the poor host immune response. Scaffolding, by grafting an epitope onto a heterologous protein scaffold, offers a possible solution to epitope vaccine design. In this study, we designed and characterized epitope vaccine antigens for the antigenic sites of HCV envelope glycoproteins E1 (residues 314-324) and E2 (residues 412-423), for which neutralizing antibody-bound structures are available. We first combined six structural alignment algorithms in a “scaffolding meta-server” to search for diverse scaffolds that can structurally accommodate the HCV epitopes. For each antigenic site, ten scaffolds were selected for computational design, and the resulting epitope scaffolds were analyzed using structure-scoring functions and molecular dynamics simulation. We experimentally confirmed that three E1 and five E2 epitope scaffolds bound to their respective neutralizing antibodies, but with different kinetics. We then investigated a “multivalent scaffolding” approach by displaying 24 copies of an epitope scaffold on a self-assembling nanoparticle, which markedly increased the avidity of antibody binding. Our study thus demonstrates the utility of a multi-scale scaffolding strategy in epitope vaccine design and provides promising HCV immunogens for further assessment in vivo.

  2. Computational Protein Engineering: Bridging the Gap between Rational Design and Laboratory Evolution

    PubMed Central

    Barrozo, Alexandre; Borstnar, Rok; Marloie, Gaël; Kamerlin, Shina Caroline Lynn

    2012-01-01

    Enzymes are tremendously proficient catalysts, which can be used as extracellular catalysts for a whole host of processes, from chemical synthesis to the generation of novel biofuels. For them to be more amenable to the needs of biotechnology, however, it is often necessary to be able to manipulate their physico-chemical properties in an efficient and streamlined manner, and, ideally, to be able to train them to catalyze completely new reactions. Recent years have seen an explosion of interest in different approaches to achieve this, both in the laboratory, and in silico. There remains, however, a gap between current approaches to computational enzyme design, which have primarily focused on the early stages of the design process, and laboratory evolution, which is an extremely powerful tool for enzyme redesign, but will always be limited by the vastness of sequence space combined with the low frequency for desirable mutations. This review discusses different approaches towards computational enzyme design and demonstrates how combining newly developed screening approaches that can rapidly predict potential mutation “hotspots” with approaches that can quantitatively and reliably dissect the catalytic step can bridge the gap that currently exists between computational enzyme design and laboratory evolution studies. PMID:23202907

  3. Approaching rational epitope vaccine design for hepatitis C virus with meta-server and multivalent scaffolding

    PubMed Central

    He, Linling; Cheng, Yushao; Kong, Leopold; Azadnia, Parisa; Giang, Erick; Kim, Justin; Wood, Malcolm R.; Wilson, Ian A.; Law, Mansun; Zhu, Jiang

    2015-01-01

    Development of a prophylactic vaccine against hepatitis C virus (HCV) has been hampered by the extraordinary viral diversity and the poor host immune response. Scaffolding, by grafting an epitope onto a heterologous protein scaffold, offers a possible solution to epitope vaccine design. In this study, we designed and characterized epitope vaccine antigens for the antigenic sites of HCV envelope glycoproteins E1 (residues 314–324) and E2 (residues 412–423), for which neutralizing antibody-bound structures are available. We first combined six structural alignment algorithms in a “scaffolding meta-server” to search for diverse scaffolds that can structurally accommodate the HCV epitopes. For each antigenic site, ten scaffolds were selected for computational design, and the resulting epitope scaffolds were analyzed using structure-scoring functions and molecular dynamics simulation. We experimentally confirmed that three E1 and five E2 epitope scaffolds bound to their respective neutralizing antibodies, but with different kinetics. We then investigated a “multivalent scaffolding” approach by displaying 24 copies of an epitope scaffold on a self-assembling nanoparticle, which markedly increased the avidity of antibody binding. Our study thus demonstrates the utility of a multi-scale scaffolding strategy in epitope vaccine design and provides promising HCV immunogens for further assessment in vivo. PMID:26238798

  4. Peer Mentoring in Long-Term Care: Rational, Design, and Retention

    ERIC Educational Resources Information Center

    Hegeman, Carol; Hoskinson, Debi; Munro, Heather; Maiden, Patricia; Pillemer, Karl

    2007-01-01

    This article describes two successful peer-mentoring programs designed to improve the quality of care in nursing homes and retention rates among direct care staff. The first program, "Growing Strong Roots," examined CNA retention rates and the second program, "Peer Mentoring for Long Term Charge Nurses," examined RN and LPN retention rates. These…

  5. Rational design of alpha-helical tandem repeat proteins with closed architectures

    PubMed Central

    Doyle, Lindsey; Hallinan, Jazmine; Bolduc, Jill; Parmeggiani, Fabio; Baker, David; Stoddard, Barry L.; Bradley, Philip

    2015-01-01

    Tandem repeat proteins, which are formed by repetition of modular units of protein sequence and structure, play important biological roles as macromolecular binding and scaffolding domains, enzymes, and building blocks for the assembly of fibrous materials1,2. The modular nature of repeat proteins enables the rapid construction and diversification of extended binding surfaces by duplication and recombination of simple building blocks3,4. The overall architecture of tandem repeat protein structures – which is dictated by the internal geometry and local packing of the repeat building blocks – is highly diverse, ranging from extended, super-helical folds that bind peptide, DNA, and RNA partners5–9, to closed and compact conformations with internal cavities suitable for small molecule binding and catalysis10. Here we report the development and validation of computational methods for de novo design of tandem repeat protein architectures driven purely by geometric criteria defining the inter-repeat geometry, without reference to the sequences and structures of existing repeat protein families. We have applied these methods to design a series of closed alpha-solenoid11 repeat structures (alpha-toroids) in which the inter-repeat packing geometry is constrained so as to juxtapose the N- and C-termini; several of these designed structures have been validated by X-ray crystallography. Unlike previous approaches to tandem repeat protein engineering12–20, our design procedure does not rely on template sequence or structural information taken from natural repeat proteins and hence can produce structures unlike those seen in nature. As an example, we have successfully designed and validated closed alpha-solenoid repeats with a left-handed helical architecture that – to our knowledge – is not yet present in the protein structure database21. PMID:26675735

  6. Rational design of α-helical tandem repeat proteins with closed architectures.

    PubMed

    Doyle, Lindsey; Hallinan, Jazmine; Bolduc, Jill; Parmeggiani, Fabio; Baker, David; Stoddard, Barry L; Bradley, Philip

    2015-12-24

    Tandem repeat proteins, which are formed by repetition of modular units of protein sequence and structure, play important biological roles as macromolecular binding and scaffolding domains, enzymes, and building blocks for the assembly of fibrous materials. The modular nature of repeat proteins enables the rapid construction and diversification of extended binding surfaces by duplication and recombination of simple building blocks. The overall architecture of tandem repeat protein structures--which is dictated by the internal geometry and local packing of the repeat building blocks--is highly diverse, ranging from extended, super-helical folds that bind peptide, DNA, and RNA partners, to closed and compact conformations with internal cavities suitable for small molecule binding and catalysis. Here we report the development and validation of computational methods for de novo design of tandem repeat protein architectures driven purely by geometric criteria defining the inter-repeat geometry, without reference to the sequences and structures of existing repeat protein families. We have applied these methods to design a series of closed α-solenoid repeat structures (α-toroids) in which the inter-repeat packing geometry is constrained so as to juxtapose the amino (N) and carboxy (C) termini; several of these designed structures have been validated by X-ray crystallography. Unlike previous approaches to tandem repeat protein engineering, our design procedure does not rely on template sequence or structural information taken from natural repeat proteins and hence can produce structures unlike those seen in nature. As an example, we have successfully designed and validated closed α-solenoid repeats with a left-handed helical architecture that--to our knowledge--is not yet present in the protein structure database. PMID:26675735

  7. Stability and solubility engineering of the EphB4 tyrosine kinase catalytic domain using a rationally designed synthetic library.

    PubMed

    Overman, R C; Green, I; Truman, C M; Read, J A; Embrey, K J; McAlister, M S B; Attwood, T K

    2013-10-01

    The inability to generate soluble, correctly folded recombinant protein is often a barrier to successful structural and functional studies. Access to affordable synthetic genes has, however, made it possible to design, make and test many more variants of a target protein to identify suitable constructs. We have used rational design and gene synthesis to create a controlled randomised library of the EphB4 receptor tyrosine kinase, with the aim of obtaining soluble, purifiable and active catalytic domain material at multi-milligram levels in Escherichia coli. Three main parameters were tested in designing the library--construct length, functional mutations and stability grafting. These variables were combined to generate a total of 9720 possible variants. The screening of 480 clones generated a 3% hit rate, with a purifiable solubility of up to 15 mg/L for some EphB4 constructs that was largely independent of construct length. Sequencing of the positive clones revealed a pair of hydrophobic core mutations that were key to obtaining soluble material. A minimal kinase domain construct containing these two mutations exhibited a +4.5°C increase in thermal stability over the wild-type protein. These approaches will be broadly applicable for solubility engineering of many different protein target classes. Atomic coordinates and structural factors have been deposited in PDB under the accession 2yn8 (EphB4 HP + staurosporine). PMID:23840071

  8. Rational design of ultrastable and reversibly photoswitchable fluorescent proteins for super-resolution imaging of the bacterial periplasm

    PubMed Central

    El Khatib, Mariam; Martins, Alexandre; Bourgeois, Dominique; Colletier, Jacques-Philippe; Adam, Virgile

    2016-01-01

    Phototransformable fluorescent proteins are central to several nanoscopy approaches. As yet however, there is no available variant allowing super-resolution imaging in cell compartments that maintain oxidative conditions. Here, we report the rational design of two reversibly switchable fluorescent proteins able to fold and photoswitch in the bacterial periplasm, rsFolder and rsFolder2. rsFolder was designed by hybridisation of Superfolder-GFP with rsEGFP2, and inherited the fast folding properties of the former together with the rapid switching of the latter, but at the cost of a reduced switching contrast. Structural characterisation of the switching mechanisms of rsFolder and rsEGFP2 revealed different scenarios for chromophore cis-trans isomerisation and allowed designing rsFolder2, a variant of rsFolder that exhibits improved switching contrast and is amenable to RESOLFT nanoscopy. The rsFolders can be efficiently expressed in the E. coli periplasm, opening the door to the nanoscale investigation of proteins localised in hitherto non-observable cellular compartments. PMID:26732634

  9. Rational design of ultrastable and reversibly photoswitchable fluorescent proteins for super-resolution imaging of the bacterial periplasm.

    PubMed

    El Khatib, Mariam; Martins, Alexandre; Bourgeois, Dominique; Colletier, Jacques-Philippe; Adam, Virgile

    2016-01-01

    Phototransformable fluorescent proteins are central to several nanoscopy approaches. As yet however, there is no available variant allowing super-resolution imaging in cell compartments that maintain oxidative conditions. Here, we report the rational design of two reversibly switchable fluorescent proteins able to fold and photoswitch in the bacterial periplasm, rsFolder and rsFolder2. rsFolder was designed by hybridisation of Superfolder-GFP with rsEGFP2, and inherited the fast folding properties of the former together with the rapid switching of the latter, but at the cost of a reduced switching contrast. Structural characterisation of the switching mechanisms of rsFolder and rsEGFP2 revealed different scenarios for chromophore cis-trans isomerisation and allowed designing rsFolder2, a variant of rsFolder that exhibits improved switching contrast and is amenable to RESOLFT nanoscopy. The rsFolders can be efficiently expressed in the E. coli periplasm, opening the door to the nanoscale investigation of proteins localised in hitherto non-observable cellular compartments. PMID:26732634

  10. A rational design for the separation of metallic and semiconducting single-walled carbon nanotubes using a magnetic field

    NASA Astrophysics Data System (ADS)

    Luo, Chengzhi; Wan, Da; Jia, Junji; Li, Delong; Pan, Chunxu; Liao, Lei

    2016-06-01

    The separation of metallic (m-) and semiconducting (s-) single-walled carbon nanotubes (SWNTs) without causing contamination and damage is a major challenge for SWNT-based devices. As a facile and nondestructive tool, the use of a magnetic field could be an ideal strategy to separate m-/s-SWNTs, based on the difference of magnetic susceptibilities. Here, we designed a novel magnetic field-assisted floating catalyst chemical vapor deposition system to separate m-/s-SWNTs. Briefly, m-SWNTs are attracted toward the magnetic pole, leaving s-SWNTs on the substrate. By using this strategy, s-SWNTs with a purity of 99% could be obtained, which is enough to construct high-performance transistors with a mobility of 230 cm2 V-1 s-1 and an on/off ratio of 106. We also established a model to quantitatively calculate the percentage of m-SWNTs on the substrate and this model shows a good match with the experimental data. Furthermore, our rational design also provides a new avenue for the growth of SWNTs with specific chirality and manipulated arrangement due to the difference of magnetic susceptibilities between different diameters, chiralities, and types.The separation of metallic (m-) and semiconducting (s-) single-walled carbon nanotubes (SWNTs) without causing contamination and damage is a major challenge for SWNT-based devices. As a facile and nondestructive tool, the use of a magnetic field could be an ideal strategy to separate m-/s-SWNTs, based on the difference of magnetic susceptibilities. Here, we designed a novel magnetic field-assisted floating catalyst chemical vapor deposition system to separate m-/s-SWNTs. Briefly, m-SWNTs are attracted toward the magnetic pole, leaving s-SWNTs on the substrate. By using this strategy, s-SWNTs with a purity of 99% could be obtained, which is enough to construct high-performance transistors with a mobility of 230 cm2 V-1 s-1 and an on/off ratio of 106. We also established a model to quantitatively calculate the percentage of m

  11. Rationally designed fluorescently labeled sulfate-binding protein mutants: evaluation in the development of a sensing system for sulfate

    NASA Technical Reports Server (NTRS)

    Shrestha, Suresh; Salins, Lyndon L E.; Mark Ensor, C.; Daunert, Sylvia

    2002-01-01

    Periplasmic binding proteins from E. coli undergo large conformational changes upon binding their respective ligands. By attaching a fluorescent probe at rationally selected unique sites on the protein, these conformational changes in the protein can be monitored by measuring the changes in fluorescence intensity of the probe which allow the development of reagentless sensing systems for their corresponding ligands. In this work, we evaluated several sites on bacterial periplasmic sulfate-binding protein (SBP) for attachment of a fluorescent probe and rationally designed a reagentless sensing system for sulfate. Eight different mutants of SBP were prepared by employing the polymerase chain reaction (PCR) to introduce a unique cysteine residue at a specific location on the protein. The sites Gly55, Ser90, Ser129, Ala140, Leu145, Ser171, Val181, and Gly186 were chosen for mutagenesis by studying the three-dimensional X-ray crystal structure of SBP. An environment-sensitive fluorescent probe (MDCC) was then attached site-specifically to the protein through the sulfhydryl group of the unique cysteine residue introduced. Each fluorescent probe-conjugated SBP mutant was characterized in terms of its fluorescence properties and Ser171 was determined to be the best site for the attachment of the fluorescent probe that would allow for the development of a reagentless sensing system for sulfate. Three different environment-sensitive fluorescent probes (1,5-IAEDANS, MDCC, and acylodan) were studied with the SBP171 mutant protein. A calibration curve for sulfate was constructed using the labeled protein and relating the change in the fluorescence intensity with the amount of sulfate present in the sample. The detection limit for sulfate was found to be in the submicromolar range using this system. The selectivity of the sensing system was demonstrated by evaluating its response to other anions. A fast and selective sensing system with detection limits for sulfate in the

  12. Discovery of highly potent novel antifungal azoles by structure-based rational design.

    PubMed

    Wang, Wenya; Sheng, Chunquan; Che, Xiaoying; Ji, Haitao; Cao, Yongbing; Miao, Zhenyuan; Yao, Jianzhong; Zhang, Wannian

    2009-10-15

    On the basis of the active site of lanosterol 14alpha-demethylase from Candida albicans (CACYP51), a series of new azoles were designed and synthesized. All the new azoles show excellent in vitro activity against most of the tested pathogenic fungi, which represent a class of promising leads for the development of novel antifungal agents. The MIC(80) value of compounds 8c, 8i and 8n against C. albicans is 0.001 microg/mL, indicating that these compounds are more potent than fluconazole, itraconazole and voriconazole. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CACYP51 through hydrophobic, van der Waals and hydrogen-bonding interactions. PMID:19748782

  13. Rationally designed fluorogenic protease reporter visualizes spatiotemporal dynamics of apoptosis in vivo

    PubMed Central

    Piggott, Beverly J.; Makhijani, Kalpana; Yu, Dan; Jan, Yuh Nung; Shu, Xiaokun

    2015-01-01

    Fluorescence resonance energy transfer-based reporters have been widely used in imaging cell signaling; however, their in vivo application has been handicapped because of poor signal. Although fluorogenic reporters overcome this problem, no such reporter of proteases has been demonstrated for in vivo imaging. Now we have redesigned an infrared fluorescent protein so that its chromophore incorporation is regulated by protease activity. Upon protease activation, the infrared fluorogenic protease reporter becomes fluorescent with no requirement of exogenous cofactor. To demonstrate biological applications, we have designed an infrared fluorogenic executioner-caspase reporter, which reveals spatiotemporal coordination between cell apoptosis and embryonic morphogenesis, as well as dynamics of apoptosis during tumorigenesis in Drosophila. The designed scaffold may be used to engineer reporters of other proteases with specific cleavage sequence. PMID:25733847

  14. Rational design of metal ion sequestering agents. 1998 annual progress report

    SciTech Connect

    Raymond, K.N.

    1998-06-01

    'This project addresses fundamental issues and requirements in developing hazardous metal ion separation technologies needed in the treatment and disposal of radioactive and chemical toxic waste. It encompasses the synthesis of new agents, followed by their characterization and evaluation, with the aim to optimize their metal ion sequestering properties for use in applied technologies. This research is focused on the following key areas: (1) basic design and synthesis of new metal ion specific sequestering ligands; (2) structural and thermodynamic investigations of these ligands and their complexes formed with the targeted metal ions; and (3) development of sequestering agents and their incorporation into systems designed to be prototypes of inexpensive and highly effective materials for hazardous metal ion decontamination. Basic studies of the sequestration of relevant toxic metals are required in order to develop processes that will treat effluents sufficiently well to allow direct release into the environment and minimize the production of secondary wastes.'

  15. Enhanced Photoelectrochemical Performance from Rationally Designed Anatase/Rutile TiO2 Heterostructures.

    PubMed

    Cao, Fengren; Xiong, Jie; Wu, Fangli; Liu, Qiong; Shi, Zhiwei; Yu, Yanhao; Wang, Xudong; Li, Liang

    2016-05-18

    In a photoelectrochemical (PEC) cell for water splitting, the critical issue is charge separation and transport, which is usually completed by designing semiconductor heterojunctions. TiO2 anatase-rutile mixed junctions could largely improve photocatalytic properties, but impairs PEC water splitting performance. We designed and prepared two types of TiO2 heterostructures with the anatase thin film and rutile nanowire phases organized in different sequences. The two types of heterostructures were used as PEC photoanodes for water splitting and demonstrated completely opposite results. Rutile nanowires on anatase film demonstrated enhanced photocurrent density and onset potential, whereas strong negative performance was obtained from anatase film on rutile nanowire structures. The mechanism was investigated by photoresponse, light absorption and reflectance, and electrochemical impedance spectra. This work revealed the significant role of phase sequence in performance gain of anatase-rutile TiO2 heterostructured PEC photoanodes. PMID:27136708

  16. Rational design of a bisphenol A aptamer selective surface-enhanced Raman scattering nanoprobe.

    PubMed

    Marks, Haley L; Pishko, Michael V; Jackson, George W; Coté, Gerard L

    2014-12-01

    Surface-enhanced Raman scattering (SERS) optical nanoprobes offer a number of advantages for ultrasensitive analyte detection. These functionalized colloidal nanoparticles are a multifunctional assay component. providing a platform for conjugation to spectral tags, stabilizing polymers, and biorecognition elements such as aptamers or antibodies. We demonstrate the design and characterization of a SERS-active nanoprobe and investigate the nanoparticles' biorecognition capabilities for use in a competitive binding assay. Specifically, the nanoprobe is designed for the quantification of bisphenol A (BPA) levels in the blood after human exposure to the toxin in food and beverage plastic packaging. The nanoprobes demonstrated specific affinity to a BPA aptamer with a dissociation constant Kd of 54 nM, and provided a dose-dependent SERS spectra with a limit of detection of 3 nM. Our conjugation approach shows the versatility of colloidal nanoparticles in assay development, acting as detectable spectral tagging elements and biologically active ligands concurrently. PMID:25329684

  17. Rational Design of a Bisphenol A Aptamer Selective Surface-Enhanced Raman Scattering Nanoprobe

    PubMed Central

    2015-01-01

    Surface-enhanced Raman scattering (SERS) optical nanoprobes offer a number of advantages for ultrasensitive analyte detection. These functionalized colloidal nanoparticles are a multifunctional assay component. providing a platform for conjugation to spectral tags, stabilizing polymers, and biorecognition elements such as aptamers or antibodies. We demonstrate the design and characterization of a SERS-active nanoprobe and investigate the nanoparticles’ biorecognition capabilities for use in a competitive binding assay. Specifically, the nanoprobe is designed for the quantification of bisphenol A (BPA) levels in the blood after human exposure to the toxin in food and beverage plastic packaging. The nanoprobes demonstrated specific affinity to a BPA aptamer with a dissociation constant Kd of 54 nM, and provided a dose-dependent SERS spectra with a limit of detection of 3 nM. Our conjugation approach shows the versatility of colloidal nanoparticles in assay development, acting as detectable spectral tagging elements and biologically active ligands concurrently. PMID:25329684

  18. Rational design, synthesis and in vitro evaluation of allylidene hydrazinecarboximidamide derivatives as BACE-1 inhibitors.

    PubMed

    Jain, Priti; Wadhwa, Pankaj K; Rohilla, Shilpa; Jadhav, Hemant R

    2016-01-01

    BACE-1 (β-secretase) is considered to be one of the promising targets for treatment of Alzheimer's disease as it catalyzes the rate limiting step of Aβ-42 production. Herein, we report a novel class of allylidene hydrazinecarboximidamide derivatives as moderately potent BACE-1 inhibitors, having aminoguanidine substitution on allyl linker with two aromatic groups on either side. A library of derivatives was designed based on the docking studies, synthesized and evaluated for BACE-1 inhibition in vitro. The designed ligands displayed interactions with the catalytic aspartate dyad through guanidinium functionality. Further, the aromatic rings placed on either side of the linker occupied S1 and S3 active site regions contributing to the activity. These ligands were also predicted to follow Lipinski rule and cross blood brain barrier. Compound 2.21, having high docking score, was found to be most active with IC50 of 6.423μM indicating good correlation with docking prediction. PMID:26614409

  19. Bacterial signaling systems as platforms for rational design of new generations of biosensors.

    PubMed

    Checa, Susana K; Zurbriggen, Matias D; Soncini, Fernando C

    2012-10-01

    Bacterial signal-responsive regulatory circuits have been employed as platform to design and construct whole-cell bacterial biosensors for reporting toxicity. A new generation of biosensors with improved performance and a wide application range has emerged after the application of synthetic biology concepts to biosensor design. Site-directed mutagenesis, directed evolution and domain swapping were applied to upgrade signal detection or to create novel sensor modules. Rewiring of the genetic circuits allows improving the determinations and reduces the heterogeneity of the response between individual reporter cells. Moreover, the assembly of natural or engineered modules to biosensor platforms provides innovative outputs, expanding the range of application of these devises, from monitoring toxics and bioremediation to killing targeted cells. PMID:22658939

  20. Enhanced Luminance of Electrochemical Cells with a Rationally Designed Ionic Iridium Complex and an Ionic Additive.

    PubMed

    Suhr, Kristin J; Bastatas, Lyndon D; Shen, Yulong; Mitchell, Lauren A; Holliday, Bradley J; Slinker, Jason D

    2016-04-13

    Light-emitting electrochemical cells (LEECs) offer the potential for high efficiency operation from an inexpensive device. However, long turn-on times and low luminance under steady-state operation are longstanding LEEC issues. Here, we present a single-layer LEEC with a custom-designed iridium(III) complex and a lithium salt additive for enhanced device performance. These devices display reduced response times, modest lifetimes, and peak luminances as high as 5500 cd/m(2), 80% higher than a comparable device from an unoptimized complex and 50% higher than the salt-free device. Improved device efficiency suggests that salt addition balances space charge effects at the interfaces. Extrapolation suggests favorable half-lives of 120 ± 10 h at 1000 cd/m(2) and 3800 ± 400 h at 100 cd/m(2). Overall, complex design and device engineering produce competitive LEECs from simple, single-layer architectures. PMID:27023074

  1. Rational design of reversible and irreversible cysteine sulfenic acid-targeted linear C-nucleophiles.

    PubMed

    Gupta, Vinayak; Carroll, Kate S

    2016-02-16

    Concerns about off-target effects has motivated the development of reversible covalent inhibition strategies for targeting cysteine. However, such strategies have not been reported for the unique cysteine oxoform, sulfenic acid. Herein, we have designed and identified linear C-nucleophiles that react selectively with cysteine sulfenic acid. The resulting thioether adducts exhibit reversibility ranging from minutes to days under reducing conditions, showing the feasibility of tuning C-nucleophile reactivity across a wide range of time scales. PMID:26878905

  2. Rational design of dynamic ammonium salt catalysts towards more flexible and selective function

    PubMed Central

    Ishihara, Kazuaki

    2009-01-01

    This review focuses on the development of dynamic ammonium salt catalysis for selective organic transformations conducted in our laboratory since 2002. Several important concepts in designing of catalysts are described with some examples. In particular, the practial synthesis of chiral 1,1′-binaphthyl-2,2′-disulfonic acid (BINSA) and its application in chiral ammonium salt catalysis for the enantioselective direct Mannich-type reaction are described. PMID:19838010

  3. Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

    SciTech Connect

    Thompson, Scott K.; Washburn, David G.; Frazee, James S.; Madauss, Kevin P.; Hoang, Tram H.; Lapinski, Leahann; Grygielko, Eugene T.; Glace, Lindsay E.; Trizna, Walter; Williams, Shawn P.; Duraiswami, Chaya; Bray, Jeffrey D.; Laping, Nicholas J.

    2010-09-03

    Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

  4. Molding Phonon Flow with Symmetry: Rational Design of Hypersonic Phononic Crystals

    NASA Astrophysics Data System (ADS)

    Koh, Cheong Yang; Thomas, Edwin L.

    2009-03-01

    Phononic crystals structured at appropriate length scales allow control over the flow of phonons, leading to new possibilities in applications such as heat-management, sound isolation and even energy transfer and conversion. Symmetry provides a unified framework for the interpretation 1D to 3D phononic band structures, allowing utilization of a common set of principles for designing band structures of phononic crystals as well as actual purposeful defects such as waveguide location and boundary termination in finite devices. In this work, we explore the band structure properties of phononic crystals with non-symmorphic space groups, as well as those having quasi-crystalline approximants. We demonstrate gap opening abilities from both anti-crossing and Bragg scattering, as well as unique features like ``sticking'' bands. Symmetry concepts are also powerful means to tune the density of states of the structures. Importantly, we fabricate various theoretical designs and measure their experimental dispersion diagrams for comparison with theoretical calculation. This affords an elegant approach toward a design blueprint for fabricating phononic structures for applications such as opto-acoustic coupling.

  5. Computer-aided rational design of novel EBF analogues with an aromatic ring.

    PubMed

    Wang, Shanshan; Sun, Yufeng; Du, Shaoqing; Qin, Yaoguo; Duan, Hongxia; Yang, Xinling

    2016-06-01

    Odorant binding proteins (OBPs) are important in insect olfactory recognition. These proteins bind specifically to insect semiochemicals and induce their seeking, mating, and alarm behaviors. Molecular docking and molecular dynamics simulations were performed to provide computational insight into the interaction mode between AgamOBP7 and novel (E)-β-farnesene (EBF) analogues with an aromatic ring. The ligand-binding cavity in OBP7 was found to be mostly hydrophobic due to the presence of several nonpolar residues. The interactions between the EBF analogues and the hydrophobic residues in the binding cavity increased in strength as the distance between them decreased. The EBF analogues with an N-methyl formamide or ester linkage had higher docking scores than those with an amide linkage. Moreover, delocalized π-π and electrostatic interactions were found to contribute significantly to the binding between the ligand benzene ring and nearby protein residues. To design new compounds with higher activity, four EBF analogues D1-D4 with a benzene ring were synthesized and evaluated based on their docking scores and binding affinities. D2, which had an N-methyl formamide group linkage, exhibited stronger binding than D1, which had an amide linkage. D4 exhibited particularly strong binding due to multiple hydrophobic interactions with the protein. This study provides crucial foundations for designing novel EBF analogues based on the OBP structure. Graphical abstract The design strategy of new EBF analogues based on the OBP7 structure. PMID:27251400

  6. Rational design of charge transport molecules for blue organic light emitting devices

    NASA Astrophysics Data System (ADS)

    Padmaperuma, Asanga; Cosimbescu, Lelia; Koech, Phillip; Polikarpov, Evgueni; Swensen, James; Gaspar, Daniel

    2012-02-01

    The efficiency and stability of blue OLEDs continue to be the primary roadblock to developing organic solid-state white lighting as well as power efficient displays. It is generally accepted that such high quantum efficiency can be achieved with the use of organometallic phosphor doped OLEDs. The transport layers can be designed to increase the carrier density as a way to reduce the drive voltage. We have developed a comprehensive library of charge transporting molecules using combination of theoretical modeling and experimental evidence. Our work focuses on using chemical structure design and computational methods to develop host, transport, emitter, and blocking materials for high efficiency blue OLEDs, along with device architectures to take advantage of these new materials. Through chemical modification of materials we are able to influence both the charge balance and emission efficiency of OLEDs, and understand the influence of the location of photon emission in OLEDs as a function of minor chemical modifications of host and electron transport materials. Design rules, structure-property relationships and results from state of the art OLEDs will be presented.

  7. Cancer Drug Delivery: Considerations in the Rational Design of Nanosized Bioconjugates

    PubMed Central

    2015-01-01

    In order to efficiently deliver anticancer agents to tumors, biocompatible nanoparticles or bioconjugates, including antibody–drug conjugates (ADCs), have recently been designed, synthesized, and tested, some even in clinical trials. Controlled delivery can be enhanced by changing specific design characteristics of the bioconjugate such as its size, the nature of the payload, and the surface features. The delivery of macromolecular drugs to cancers largely relies on the leaky nature of the tumor vasculature compared with healthy vessels in normal organs. When administered intravenously, macromolecular bioconjugates and nanosized agents tend to circulate for prolonged times, unless they are small enough to be excreted by the kidney or stealthy enough to evade the macrophage phagocytic system (MPS), formerly the reticulo-endothelial system (RES). Therefore, macromolecular bioconjugates and nanosized agents with long circulation times leak preferentially into tumor tissue through permeable tumor vessels and are then retained in the tumor bed due to reduced lymphatic drainage. This process is known as the enhanced permeability and retention (EPR) effect. However, success of cancer drug delivery only relying on the EPR effect is still limited. To cure cancer patients, further improvement of drug delivery is required by both designing superior agents and enhancing EPR effects. In this Review, we describe the basis of macromolecular or nanosized bioconjugate delivery into cancer tissue and discuss current diagnostic methods for evaluating leakiness of the tumor vasculature. Then, we discuss methods to augment conventional “permeability and retention” effects for macromolecular or nanosized bioconjugates in cancer tissue. PMID:25385142

  8. Multi-terrain locomotor interactions in flying snakes

    NASA Astrophysics Data System (ADS)

    Yeaton, Isaac; Baumgardner, Grant; Ross, Shane; Socha, John

    Arboreal snakes of the genus Chrysopelea are the only known snakes to glide. To execute aerial locomotion, a snake uses one of several stereotyped jumps from a tree into the air, while simultaneously flattening its body into an aerodynamically favorable shape. Large amplitude traveling waves are propagated posteriorly during the stable glide, while landing involves body wrapping, passive body compression, and energy absorption through compliance in the landing substrate to dissipate the accumulated kinetic energy from the glide. In all of these locomotor events, from interacting with cylindrical branches, falling through the air, grasping compliant tree branches and leaves, to landing on solid ground, snakes appropriate the same body morphology and perhaps the same basic neural mechanisms. Here we discuss our use of computational models and animal experiments to understand how flying snakes interact with and locomote on and through multiple media, potentially providing principles for legless locomotor designs. Supported by NSF 1351322.

  9. Research on Snake-Like Robot with Controllable Scales

    NASA Astrophysics Data System (ADS)

    Chen, Kailin; Zhao, Yuting; Chen, Shuping

    The purpose of this paper is to propose a new structure for a snake-like robot. This type of snake-like robot is different from the normal snake-like robot because it has lots of controllable scales which have a large role in helping moving. Besides, a new form of robot gait named as linear motion mode is developed based on theoretical analysis for the new mechanical structure. Through simulation and analysis in simmechanics of matlab, we proved the validity of theories about the motion mode of snake-like robot. The proposed machine construction and control method for the designed motion is verified experimentally by the independent developed snake robot.

  10. Observation of snake resonances at Relativistic Heavy Ion Collider

    SciTech Connect

    Bai, M.; Ahrens, L.; Alekseev, I.G.; Alessi, J.; et al

    2010-09-27

    The Siberian snakes are powerful tools in preserving polarization in high energy accelerators has been demonstrated at the Brookhaven Relativistic Heavy Ion Collider (RHIC). Equipped with two full Siberian snakes in each ring, polarization is preserved during acceleration from injection to 100 GeV. However, the Siberian snakes also introduce a new set of depolarization resonances, i.e. snake resonances as first discovered by Lee and Tepikian. The intrinsic spin resonances above 100 GeV are about a factor of two stronger than those below 100 GeV which raises the challenge to preserve the polarization up to 250 GeV. In 2009, polarized protons collided for the first time at the RHIC design store energy of 250 GeV. This paper presents the experimental measurements of snake resonances at RHIC. The plan for avoiding these resonances is also presented.

  11. 50 CFR 226.205 - Critical habitat for Snake River sockeye salmon, Snake River fall chinook salmon, and Snake River...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies of the USGS publication and maps may be... 50 Wildlife and Fisheries 7 2010-10-01 2010-10-01 false Critical habitat for Snake River sockeye... ADMINISTRATION, DEPARTMENT OF COMMERCE MARINE MAMMALS DESIGNATED CRITICAL HABITAT § 226.205 Critical habitat...

  12. 50 CFR 226.205 - Critical habitat for Snake River sockeye salmon, Snake River fall chinook salmon, and Snake River...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies of the USGS publication and maps may be... 50 Wildlife and Fisheries 9 2011-10-01 2011-10-01 false Critical habitat for Snake River sockeye... ADMINISTRATION, DEPARTMENT OF COMMERCE MARINE MAMMALS DESIGNATED CRITICAL HABITAT § 226.205 Critical habitat...

  13. 50 CFR 226.205 - Critical habitat for Snake River sockeye salmon, Snake River fall chinook salmon, and Snake River...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies of the USGS publication and maps may be... 50 Wildlife and Fisheries 10 2014-10-01 2014-10-01 false Critical habitat for Snake River sockeye... ADMINISTRATION, DEPARTMENT OF COMMERCE MARINE MAMMALS DESIGNATED CRITICAL HABITAT § 226.205 Critical habitat...

  14. Restricting HIV-1 pathways for escape using rationally designed anti–HIV-1 antibodies

    PubMed Central

    Klein, Florian; Horwitz, Joshua A.; Halper-Stromberg, Ariel; Sather, D. Noah; Marcovecchio, Paola M.; Lee, Terri; West, Anthony P.; Gao, Han; Seaman, Michael S.; Stamatatos, Leonidas; Nussenzweig, Michel C.; Bjorkman, Pamela J.

    2013-01-01

    Recently identified broadly neutralizing antibodies (bNAbs) that potently neutralize most HIV-1 strains are key to potential antibody-based therapeutic approaches to combat HIV/AIDS in the absence of an effective vaccine. Increasing bNAb potencies and resistance to common routes of HIV-1 escape through mutation would facilitate their use as therapeutics. We previously used structure-based design to create the bNAb NIH45-46G54W, which exhibits superior potency and/or breadth compared with other bNAbs. We report new, more effective NIH45-46G54W variants designed using analyses of the NIH45-46–gp120 complex structure and sequences of NIH45-46G54W–resistant HIV-1 strains. One variant, 45-46m2, neutralizes 96% of HIV-1 strains in a cross-clade panel and viruses isolated from an HIV-infected individual that are resistant to all other known bNAbs, making it the single most broad and potent anti–HIV-1 antibody to date. A description of its mechanism is presented based on a 45-46m2–gp120 crystal structure. A second variant, 45-46m7, designed to thwart HIV-1 resistance to NIH45-46G54W arising from mutations in a gp120 consensus sequence, targets a common route of HIV-1 escape. In combination, 45-46m2 and 45-46m7 reduce the possible routes for the evolution of fit viral escape mutants in HIV-1YU-2–infected humanized mice, with viremic control exhibited when a third antibody, 10–1074, was added to the combination. PMID:23712429

  15. Rational design, preparation, and characterization of a therapeutic enzyme mutant with improved stability and function for cocaine detoxification.

    PubMed

    Fang, Lei; Chow, K Martin; Hou, Shurong; Xue, Liu; Chen, Xiabin; Rodgers, David W; Zheng, Fang; Zhan, Chang-Guo

    2014-08-15

    Cocaine esterase (CocE) is known as the most efficient natural enzyme for cocaine hydrolysis. The major obstacle to the clinical application of wild-type CocE is the thermoinstability with a half-life of only ∼12 min at 37 °C. The previously designed T172R/G173Q mutant (denoted as enzyme E172-173) with an improved in vitro half-life of ∼6 h at 37 °C is currently in clinical trial Phase II for cocaine overdose treatment. Through molecular modeling and dynamics simulation, we designed and characterized a promising new mutant of E172-173 with extra L196C/I301C mutations (denoted as enzyme E196-301) to produce cross-subunit disulfide bonds that stabilize the dimer structure. The cross-subunit disulfide bonds were confirmed by X-ray diffraction. The designed L196C/I301C mutations have not only considerably extended the in vitro half-life at 37 °C to >100 days, but also significantly improved the catalytic efficiency against cocaine by ∼150%. In addition, the thermostable E196-301 can be PEGylated to significantly prolong the residence time in mice. The PEGylated E196-301 can fully protect mice from a lethal dose of cocaine (180 mg/kg, LD100) for at least 3 days, with an average protection time of ∼94h. This is the longest in vivo protection of mice from the lethal dose of cocaine demonstrated within all studies using an exogenous enzyme reported so far. Hence, E196-301 may be developed to become a more valuable therapeutic enzyme for cocaine abuse treatment, and it demonstrates that a general design strategy and protocol to simultaneously improve both the stability and function are feasible for rational protein drug design. PMID:24919140

  16. Rational Design, Synthesis and Evaluation of Coumarin Derivatives as Protein-protein Interaction Inhibitors.

    PubMed

    De Luca, Laura; Agharbaoui, Fatima E; Gitto, Rosaria; Buemi, Maria Rosa; Christ, Frauke; Debyser, Zeger; Ferro, Stefania

    2016-09-01

    Herein we describe the design and synthesis of a new series of coumarin derivatives searching for novel HIV-1 integrase (IN) allosteric inhibitors. All new obtained compounds were tested in order to evaluate their ability to inhibit the interaction between the HIV-1 IN enzyme and the nuclear protein lens epithelium growth factor LEDGF/p75. A combined approach of docking and molecular dynamic simulations has been applied to clarify the activity of the new compounds. Specifically, the binding free energies by using the method of molecular mechanics-generalized Born surface area (MM-GBSA) was calculated, whereas hydrogen bond occupancies were monitored throughout simulations methods. PMID:27546050

  17. Spectromicroscopic insights for rational design of redox-based memristive devices.

    PubMed

    Baeumer, Christoph; Schmitz, Christoph; Ramadan, Amr H H; Du, Hongchu; Skaja, Katharina; Feyer, Vitaliy; Müller, Philipp; Arndt, Benedikt; Jia, Chun-Lin; Mayer, Joachim; De Souza, Roger A; Michael Schneider, Claus; Waser, Rainer; Dittmann, Regina

    2015-01-01

    The demand for highly scalable, low-power devices for data storage and logic operations is strongly stimulating research into resistive switching as a novel concept for future non-volatile memory devices. To meet technological requirements, it is imperative to have a set of material design rules based on fundamental material physics, but deriving such rules is proving challenging. Here, we elucidate both switching mechanism and failure mechanism in the valence-change model material SrTiO3, and on this basis we derive a design rule for failure-resistant devices. Spectromicroscopy reveals that the resistance change during device operation and failure is indeed caused by nanoscale oxygen migration resulting in localized valence changes between Ti(4+) and Ti(3+). While fast reoxidation typically results in retention failure in SrTiO3, local phase separation within the switching filament stabilizes the retention. Mimicking this phase separation by intentionally introducing retention-stabilization layers with slow oxygen transport improves retention times considerably. PMID:26477940

  18. Rational design of self-assembly pathways for complex multicomponent structures.

    PubMed

    Jacobs, William M; Reinhardt, Aleks; Frenkel, Daan

    2015-05-19

    The field of complex self-assembly is moving toward the design of multiparticle structures consisting of thousands of distinct building blocks. To exploit the potential benefits of structures with such "addressable complexity," we need to understand the factors that optimize the yield and the kinetics of self-assembly. Here we use a simple theoretical method to explain the key features responsible for the unexpected success of DNA-brick experiments, which are currently the only demonstration of reliable self-assembly with such a large number of components. Simulations confirm that our theory accurately predicts the narrow temperature window in which error-free assembly can occur. Even more strikingly, our theory predicts that correct assembly of the complete structure may require a time-dependent experimental protocol. Furthermore, we predict that low coordination numbers result in nonclassical nucleation behavior, which we find to be essential for achieving optimal nucleation kinetics under mild growth conditions. We also show that, rather surprisingly, the use of heterogeneous bond energies improves the nucleation kinetics and in fact appears to be necessary for assembling certain intricate 3D structures. This observation makes it possible to sculpt nucleation pathways by tuning the distribution of interaction strengths. These insights not only suggest how to improve the design of structures based on DNA bricks, but also point the way toward the creation of a much wider class of chemical or colloidal structures with addressable complexity. PMID:25941388

  19. Rational design of tryptophan-rich antimicrobial peptides with enhanced antimicrobial activities and specificities.

    PubMed

    Yu, Hui-Yuan; Huang, Kuo-Chun; Yip, Bak-Sau; Tu, Chih-Hsiang; Chen, Heng-Li; Cheng, Hsi-Tsung; Cheng, Jya-Wei

    2010-11-01

    Trp-rich antimicrobial peptides play important roles in the host innate defense mechanism of many plants and animals. A series of short Trp-rich peptides derived from the C-terminal region of Bothrops asper myothoxin II, a Lys49 phospholipase A(2) (PLA(2)), were found to reproduce the antimicrobial activities of their parent molecule. Of these peptides, KKWRWWLKALAKK-designated PEM-2-was found to display improved activity against both Gram-positive and Gram-negative bacteria. To improve the antimicrobial activity of PEM-2 for potential clinical applications further, we determined the solution structure of PEM-2 bound to membrane-mimetic dodecylphosphocholine (DPC) micelles by two-dimensional NMR methods. The DPC micelle-bound structure of PEM-2 adopts an α-helical conformation and the positively charged residues are clustered together to form a hydrophilic patch. The surface electrostatic potential map indicates that two of the three tryptophan residues are packed against the peptide backbone and form a hydrophobic face with Leu7, Ala9, and Leu10. A variety of biophysical and biochemical experiments, including circular dichroism, fluorescence spectroscopy, and microcalorimetry, were used to show that PEM-2 interacted with negatively charged phospholipid vesicles and efficiently induced dye release from these vesicles, suggesting that the antimicrobial activity of PEM-2 could be due to interactions with bacterial membranes. Potent analogues of PEM-2 with enhanced antimicrobial and less pronounced hemolytic activities were designed with the aid of these structural studies. PMID:20865718

  20. Spectromicroscopic insights for rational design of redox-based memristive devices

    NASA Astrophysics Data System (ADS)

    Baeumer, Christoph; Schmitz, Christoph; Ramadan, Amr H. H.; Du, Hongchu; Skaja, Katharina; Feyer, Vitaliy; Müller, Philipp; Arndt, Benedikt; Jia, Chun-Lin; Mayer, Joachim; de Souza, Roger A.; Michael Schneider, Claus; Waser, Rainer; Dittmann, Regina

    2015-10-01

    The demand for highly scalable, low-power devices for data storage and logic operations is strongly stimulating research into resistive switching as a novel concept for future non-volatile memory devices. To meet technological requirements, it is imperative to have a set of material design rules based on fundamental material physics, but deriving such rules is proving challenging. Here, we elucidate both switching mechanism and failure mechanism in the valence-change model material SrTiO3, and on this basis we derive a design rule for failure-resistant devices. Spectromicroscopy reveals that the resistance change during device operation and failure is indeed caused by nanoscale oxygen migration resulting in localized valence changes between Ti4+ and Ti3+. While fast reoxidation typically results in retention failure in SrTiO3, local phase separation within the switching filament stabilizes the retention. Mimicking this phase separation by intentionally introducing retention-stabilization layers with slow oxygen transport improves retention times considerably.

  1. Spectromicroscopic insights for rational design of redox-based memristive devices

    PubMed Central

    Baeumer, Christoph; Schmitz, Christoph; Ramadan, Amr H. H.; Du, Hongchu; Skaja, Katharina; Feyer, Vitaliy; Müller, Philipp; Arndt, Benedikt; Jia, Chun-Lin; Mayer, Joachim; De Souza, Roger A.; Michael Schneider, Claus; Waser, Rainer; Dittmann, Regina

    2015-01-01

    The demand for highly scalable, low-power devices for data storage and logic operations is strongly stimulating research into resistive switching as a novel concept for future non-volatile memory devices. To meet technological requirements, it is imperative to have a set of material design rules based on fundamental material physics, but deriving such rules is proving challenging. Here, we elucidate both switching mechanism and failure mechanism in the valence-change model material SrTiO3, and on this basis we derive a design rule for failure-resistant devices. Spectromicroscopy reveals that the resistance change during device operation and failure is indeed caused by nanoscale oxygen migration resulting in localized valence changes between Ti4+ and Ti3+. While fast reoxidation typically results in retention failure in SrTiO3, local phase separation within the switching filament stabilizes the retention. Mimicking this phase separation by intentionally introducing retention-stabilization layers with slow oxygen transport improves retention times considerably. PMID:26477940

  2. Current progress in Structure-Based Rational Drug Design marks a new mindset in drug discovery.

    PubMed

    Lounnas, Valère; Ritschel, Tina; Kelder, Jan; McGuire, Ross; Bywater, Robert P; Foloppe, Nicolas

    2013-01-01

    The past decade has witnessed a paradigm shift in preclinical drug discovery with structure-based drug design (SBDD) making a comeback while high-throughput screening (HTS) methods have continued to generate disappointing results. There is a deficit of information between identified hits and the many criteria that must be fulfilled in parallel to convert them into preclinical candidates that have a real chance to become a drug. This gap can be bridged by investigating the interactions between the ligands and their receptors. Accurate calculations of the free energy of binding are still elusive; however progresses were made with respect to how one may deal with the versatile role of water. A corpus of knowledge combining X-ray structures, bioinformatics and molecular modeling techniques now allows drug designers to routinely produce receptor homology models of increasing quality. These models serve as a basis to establish and validate efficient rationales used to tailor and/or screen virtual libraries with enhanced chances of obtaining hits. Many case reports of successful SBDD show how synergy can be gained from the combined use of several techniques. The role of SBDD with respect to two different classes of widely investigated pharmaceutical targets: (a) protein kinases (PK) and (b) G-protein coupled receptors (GPCR) is discussed. Throughout these examples prototypical situations covering the current possibilities and limitations of SBDD are presented. PMID:24688704

  3. Case-control study on uveal melanoma (RIFA): rational and design

    PubMed Central

    Schmidt-Pokrzywniak, Andrea; Jöckel, Karl-Heinz; Bornfeld, Norbert; Stang, Andreas

    2004-01-01

    Background Although a rare disease, uveal melanoma is the most common primary intraocular malignancy in adults, with an incidence rate of up to 1.0 per 100,000 persons per year in Europe. Only a few consistent risk factors have been identified for this disease. We present the study design of an ongoing incident case-control study on uveal melanoma (acronym: RIFA study) that focuses on radiofrequency radiation as transmitted by radio sets and wireless telephones, occupational risk factors, phenotypical characteristics, and UV radiation. Methods/Design We conduct a case-control study to identify the role of different exposures in the development of uveal melanoma. The cases of uveal melanoma were identified at the Division of Ophthalmology, University of Essen, a referral centre for tumours of the eye. We recruit three control groups: population controls, controls sampled from those ophthalmologists who referred cases to the Division of Ophthalmology, University of Duisburg-Essen, and sibling controls. For each case the controls are matched on sex and age (five year groups), except for sibling controls. The data are collected from the study participants by short self-administered questionnaire and by telephone interview. During and at the end of the field phase, the data are quality-checked. To estimate the effect of exposures on uveal melanoma risk, we will use conditional logistic regression that accounts for the matching factors and allows to control for potential confounding. PMID:15318944

  4. Functionalized Single-Walled Carbon Nanotubes as Rationally Designed Vehicles for Tumor-Targeted Drug Delivery

    SciTech Connect

    Chen,J.; Wong,S.; Chen, S.; Zhao, X.; Kuznetsova, L.V.; and Ojima, I.

    2008-11-14

    A novel single-walled carbon nanotube (SWNT)-based tumor-targeted drug delivery system (DDS) has been developed, which consists of a functionalized SWNT linked to tumor-targeting modules as well as prodrug modules. There are three key features of this nanoscale DDS: (a) use of functionalized SWNTs as a biocompatible platform for the delivery of therapeutic drugs or diagnostics, (b) conjugation of prodrug modules of an anticancer agent (taxoid with a cleavable linker) that is activated to its cytotoxic form inside the tumor cells upon internalization and in situ drug release, and (c) attachment of tumor-recognition modules (biotin and a spacer) to the nanotube surface. To prove the efficacy of this DDS, three fluorescent and fluorogenic molecular probes were designed, synthesized, characterized, and subjected to the analysis of the receptor-mediated endocytosis and drug release inside the cancer cells (L1210FR leukemia cell line) by means of confocal fluorescence microscopy. The specificity and cytotoxicity of the conjugate have also been assessed and compared with L1210 and human noncancerous cell lines. Then, it has unambiguously been proven that this tumor-targeting DDS works exactly as designed and shows high potency toward specific cancer cell lines, thereby forming a solid foundation for further development.

  5. Rational design of self-assembly pathways for complex multicomponent structures

    PubMed Central

    Jacobs, William M.; Reinhardt, Aleks; Frenkel, Daan

    2015-01-01

    The field of complex self-assembly is moving toward the design of multiparticle structures consisting of thousands of distinct building blocks. To exploit the potential benefits of structures with such “addressable complexity,” we need to understand the factors that optimize the yield and the kinetics of self-assembly. Here we use a simple theoretical method to explain the key features responsible for the unexpected success of DNA-brick experiments, which are currently the only demonstration of reliable self-assembly with such a large number of components. Simulations confirm that our theory accurately predicts the narrow temperature window in which error-free assembly can occur. Even more strikingly, our theory predicts that correct assembly of the complete structure may require a time-dependent experimental protocol. Furthermore, we predict that low coordination numbers result in nonclassical nucleation behavior, which we find to be essential for achieving optimal nucleation kinetics under mild growth conditions. We also show that, rather surprisingly, the use of heterogeneous bond energies improves the nucleation kinetics and in fact appears to be necessary for assembling certain intricate 3D structures. This observation makes it possible to sculpt nucleation pathways by tuning the distribution of interaction strengths. These insights not only suggest how to improve the design of structures based on DNA bricks, but also point the way toward the creation of a much wider class of chemical or colloidal structures with addressable complexity. PMID:25941388

  6. Rational Design of Potent and Selective Inhibitors of an Epoxide Hydrolase Virulence Factor from Pseudomonas aeruginosa.

    PubMed

    Kitamura, Seiya; Hvorecny, Kelli L; Niu, Jun; Hammock, Bruce D; Madden, Dean R; Morisseau, Christophe

    2016-05-26

    The virulence factor cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif) is secreted by Pseudomonas aeruginosa and is the founding member of a distinct class of epoxide hydrolases (EHs) that triggers the catalysis-dependent degradation of the CFTR. We describe here the development of a series of potent and selective Cif inhibitors by structure-based drug design. Initial screening revealed 1a (KB2115), a thyroid hormone analog, as a lead compound with low micromolar potency. Structural requirements for potency were systematically probed, and interactions between Cif and 1a were characterized by X-ray crystallography. On the basis of these data, new compounds were designed to yield additional hydrogen bonding with residues of the Cif active site. From this effort, three compounds were identified that are 10-fold more potent toward Cif than our first-generation inhibitors and have no detectable thyroid hormone-like activity. These inhibitors will be useful tools to study the pathological role of Cif and have the potential for clinical application. PMID:27120257

  7. Nanocarriers for photodynamic therapy-rational formulation design and medium-scale manufacture.

    PubMed

    Villa Nova, Mônica; Janas, Christine; Schmidt, Mike; Ulshoefer, Thomas; Gräfe, Susanna; Schiffmann, Susanne; de Bruin, Natasja; Wiehe, Arno; Albrecht, Volker; Parnham, Michael J; Luciano Bruschi, Marcos; Wacker, Matthias G

    2015-08-01

    The development and manufacture of novel nanocarriers for drug delivery has proved challenging with regards to scale-up and pharmaceutical quality. Polymeric nanocarriers composed of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-PEG) were prepared and the photosensitizer meso-tetrakis(3-hydroxyphenyl) chlorin (mTHPC) was effectively encapsulated. Furthermore, the interplay of various process and formulation parameters and their impact on the most important product specifications were investigated by using a factorial design and a central composite design in a microfluidic manufacturing process. These nanoparticles for intravenous administration with a size of 97 ± 0.13 nm, narrow size distribution, and an encapsulation efficiency of more than 80% were produced at high throughput. In vitro stability and in vitro drug release testing were applied for quality control purposes. Finally, the toxicity of the photosensitizer was tested in vitro. The cytotoxicity was successfully reduced while the efficacy of the formulation was maintained. First observations using in vivo imaging suggest effective distribution of the nanocarrier system after injection into rodents. Thus, further in vivo testing of the beneficial effects of nanoencapsulation into the matrix system and its formulation will be considered for the delivery of mTHPC to tumor tissues during photodynamic therapy. PMID:26123822

  8. Rational design of partial agonists for the muscarinic m1 acetylcholine receptor.

    PubMed

    Chen, Xinyu; Klöckner, Jessika; Holze, Janine; Zimmermann, Cornelia; Seemann, Wiebke K; Schrage, Ramona; Bock, Andreas; Mohr, Klaus; Tränkle, Christian; Holzgrabe, Ulrike; Decker, Michael

    2015-01-22

    Aiming to design partial agonists for a G-protein-coupled receptor based on dynamic ligand binding, we synthesized three different series of bipharmacophoric ligands composed of the orthosteric building blocks iperoxo and 1 linked to allosteric modulators (BQCA-derived compounds, BQCAd; TBPB-derived compound, TBPBd). Their interactions were studied with the human muscarinic acetylcholine M1-receptor (hM1) with respect to receptor binding and Gq-protein signaling. Results demonstrate that iperoxo/BQCAd (2, 3) and 1/BQCAd hybrids (4) act as M1 partial agonists, whereas 1/TBPBd hybrids (5) did not activate M1-receptors. Among the iperoxo/BQCAd-hybrids, spacer length in conjunction with the pattern of substitution tuned efficacy. Most interestingly, a model of dynamic ligand binding revealed that the spacer length of 2a and 3a controlled the probability of switch between the inactive purely allosteric and the active bitopic orthosteric/allosteric binding pose. In summary, dynamic ligand binding can be exploited in M1 receptors to design partial agonists with graded efficacy. PMID:25478907

  9. Use of Organosilicon Compounds towards the Rational Design of Antiparasitic and Antiviral Drugs

    PubMed Central

    Déléris, Gérard

    1995-01-01

    One of the major problems met for the conception of antiviral or antiparasitic drugs is to reach a high level of selectivity towards the pathogenic agent versus the host. We shall describe two synthetic approaches where main group organometallics have been used towards this goal. A series of nucleoside sila-analogues was synthesized as potential therapeutic agents designed to inhibit HIV Reverse Transcriptase. In a second approach novel organosilicon derivatives have been synthesized as mimics of antisense oligonucleotides. Infectious agents, namely viruses or parasites, more or less use cellular machinery. Therefore therapeutic agents must interfere with biochemical mechanisms or possess high affinity towards specific molecular cellular components, to reach selectivity. We thought that main group organometallics could show many advantages for designing biologically active molecules in this field. They allow a high synthetic flexibility for the modulations of physico-chemical properties and they show a mechanistic behaviour which may be close to the one of several heteroelements present in living organisms such as sulfur or phosphorus. We tried to use this approach towards two directions involving the synthesis of organosilicon derivatives i.e: -the synthesis of organosilicon derivatives as inhibitors of HIV Reverse Transcriptase, -the synthesis of organosilicon precursors of modified antisense oligonucleotides. PMID:18472760

  10. Hairpin Ribozyme Genes Curtail Alcohol Drinking: from Rational Design to in vivo Effects in the Rat.

    PubMed

    Sapag, Amalia; Irrazábal, Thergiory; Lobos-González, Lorena; Muñoz-Brauning, Carlos R; Quintanilla, María Elena; Tampier, Lutske

    2016-01-01

    Ribozyme genes were designed to reduce voluntary alcohol drinking in a rat model of alcohol dependence. Acetaldehyde generated from alcohol in the liver is metabolized by the mitochondrial aldehyde dehydrogenase (ALDH2) such that diminishing ALDH2 activity leads to the aversive effects of blood acetaldehyde upon alcohol intake. A stepwise approach was followed to design genes encoding ribozymes targeted to the rat ALDH2 mRNA. In vitro studies of accessibility to oligonucleotides identified suitable target sites in the mRNA, one of which fulfilled hammerhead and hairpin ribozyme requirements (CGGUC). Ribozyme genes delivered in plasmid constructs were tested in rat cells in culture. While the hairpin ribozyme reduced ALDH2 activity 56% by cleavage and blockade (P < 0.0001), the hammerhead ribozyme elicited minor effects by blockade. The hairpin ribozyme was tested in vivo by adenoviral gene delivery to UChB alcohol drinker rats. Ethanol intake was curtailed 47% for 34 days (P < 0.0001), while blood acetaldehyde more than doubled upon ethanol administration and ALDH2 activity dropped 25% in liver homogenates, not affecting other ALDH isoforms. Thus, hairpin ribozymes targeted to 16 nt in the ALDH2 mRNA provide durable and specific effects in vivo, representing an improvement on previous work and encouraging development of gene therapy for alcoholism. PMID:27404720

  11. Engineering phage materials with desired peptide display: rational design sustained through natural selection.

    PubMed

    Merzlyak, Anna; Lee, Seung-Wuk

    2009-12-01

    Genetic engineering of phage provides novel opportunities to build various nanomaterials by displaying functional peptide motifs on its surface coat protein. However, any genetic modifications of phage coat proteins must be able to accommodate their many biological roles in the phage replication process. To express functional but inherently unfavorable peptide motifs on major coat protein pVIII, we devised a novel genetic conjugation method to circumvent bacterial biological censorship. Constraining the designed peptides among the degenerate flanking residues, we obtained a pVIII library of phage that retained the desired sequences yet could navigate through the phage replication process due to the naturally selected flanking residues. Further, we systematically analyzed the biochemical and size-related compensation mechanisms of the pVIII expressed peptides by constructing four chemically diverse (His, Trp, Glu, Lys) partial library series. Described genetic conjugation methodology can serve to improve the design of engineered phage and allow further exploitation of these particles as functional nanobiomaterials for various applications. PMID:19842621

  12. Current progress in Structure-Based Rational Drug Design marks a new mindset in drug discovery

    PubMed Central

    Lounnas, Valère; Ritschel, Tina; Kelder, Jan; McGuire, Ross; Bywater, Robert P.; Foloppe, Nicolas

    2013-01-01

    The past decade has witnessed a paradigm shift in preclinical drug discovery with structure-based drug design (SBDD) making a comeback while high-throughput screening (HTS) methods have continued to generate disappointing results. There is a deficit of information between identified hits and the many criteria that must be fulfilled in parallel to convert them into preclinical candidates that have a real chance to become a drug. This gap can be bridged by investigating the interactions between the ligands and their receptors. Accurate calculations of the free energy of binding are still elusive; however progresses were made with respect to how one may deal with the versatile role of water. A corpus of knowledge combining X-ray structures, bioinformatics and molecular modeling techniques now allows drug designers to routinely produce receptor homology models of increasing quality. These models serve as a basis to establish and validate efficient rationales used to tailor and/or screen virtual libraries with enhanced chances of obtaining hits. Many case reports of successful SBDD show how synergy can be gained from the combined use of several techniques. The role of SBDD with respect to two different classes of widely investigated pharmaceutical targets: (a) protein kinases (PK) and (b) G-protein coupled receptors (GPCR) is discussed. Throughout these examples prototypical situations covering the current possibilities and limitations of SBDD are presented. PMID:24688704

  13. Rational design of biaryl pharmacophore inserted noscapine derivatives as potent tubulin binding anticancer agents.

    PubMed

    Santoshi, Seneha; Manchukonda, Naresh Kumar; Suri, Charu; Sharma, Manya; Sridhar, Balasubramanian; Joseph, Silja; Lopus, Manu; Kantevari, Srinivas; Baitharu, Iswar; Naik, Pradeep Kumar

    2015-03-01

    We have strategically designed a series of noscapine derivatives by inserting biaryl pharmacophore (a major structural constituent of many of the microtubule-targeting natural anticancer compounds) onto the scaffold structure of noscapine. Molecular interaction of these derivatives with α,β-tubulin heterodimer was investigated by molecular docking, molecular dynamics simulation, and binding free energy calculation. The predictive binding affinity indicates that the newly designed noscapinoids bind to tubulin with a greater affinity. The predictive binding free energy (ΔG(bind, pred)) of these derivatives (ranging from -5.568 to -5.970 kcal/mol) based on linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model showed improved binding affinity with tubulin compared to the lead compound, natural α-noscapine (-5.505 kcal/mol). Guided by the computational findings, these new biaryl type α-noscapine congeners were synthesized from 9-bromo-α-noscapine using optimized Suzuki reaction conditions for further experimental evaluation. The derivatives showed improved inhibition of the proliferation of human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human lung adenocarcinoma cells (A549), compared to natural noscapine. The cell cycle analysis in MCF-7 further revealed that these compounds alter the cell cycle profile and cause mitotic arrest at G2/M phase more strongly than noscapine. Tubulin binding assay revealed higher binding affinity to tubulin, as suggested by dissociation constant (Kd) of 126 ± 5.0 µM for 5a, 107 ± 5.0 µM for 5c, 70 ± 4.0 µM for 5d, and 68 ± 6.0 µM for 5e compared to noscapine (Kd of 152 ± 1.0 µM). In fact, the experimentally determined value of ΔG(bind, expt) (calculated from the Kd value) are consistent with the predicted value of ΔG(bind, pred) calculated based on LIE-SGB. Based on these results, one of the derivative 5e of this series was used for further

  14. Rational design of efficient electrode–electrolyte interfaces for solid-state energy storage using ion soft landing

    PubMed Central

    Prabhakaran, Venkateshkumar; Mehdi, B. Layla; Ditto, Jeffrey J.; Engelhard, Mark H.; Wang, Bingbing; Gunaratne, K. Don D.; Johnson, David C.; Browning, Nigel D.; Johnson, Grant E.; Laskin, Julia

    2016-01-01

    The rational design of improved electrode–electrolyte interfaces (EEI) for energy storage is critically dependent on a molecular-level understanding of ionic interactions and nanoscale phenomena. The presence of non-redox active species at EEI has been shown to strongly influence Faradaic efficiency and long-term operational stability during energy storage processes. Herein, we achieve substantially higher performance and long-term stability of EEI prepared with highly dispersed discrete redox-active cluster anions (50 ng of pure ∼0.75 nm size molybdenum polyoxometalate (POM) anions on 25 μg (∼0.2 wt%) carbon nanotube (CNT) electrodes) by complete elimination of strongly coordinating non-redox species through ion soft landing (SL). Electron microscopy provides atomically resolved images of a uniform distribution of individual POM species soft landed directly on complex technologically relevant CNT electrodes. In this context, SL is established as a versatile approach for the controlled design of novel surfaces for both fundamental and applied research in energy storage. PMID:27097686

  15. Design rules for rational control of polymer glass formation behavior and mechanical properties with small molecular additives

    NASA Astrophysics Data System (ADS)

    Mangalara, Jayachandra Hari; Simmons, David

    Small molecule additives have long been employed to tune polymers' glass formation, mechanical and transport properties. For example, plasticizers are commonly employed to suppress polymer Tg and soften the glassy state, while antiplasticizers, which stiffen the glassy state of a polymer while suppressing its Tg, are employed to enhance protein and tissue preservation in sugar glasses. Recent literature indicates that additives can have a wide range of possible effects, but all of these have not been clearly understood and well appreciated. Here we employ molecular dynamics simulations to establish design rules for the selection of small molecule additives with size, molecular stiffness, and interaction energy chosen to achieve targeted effects on polymer properties. We furthermore find that a given additive's effect on a polymer's Tg can be predicted from its Debye-Waller factor via a function previously found to describe nanoconfinement effects on the glass transition. These results emphasize the potential for a new generation of targeted molecular additives to contribute to more targeted rational design of polymers. We acknowledge the Keck Foundation and the Ohio Supercomputing Center for financial and computational support of this effort, respectively.

  16. Rational design, synthesis and biological evaluation of modular fluorogenic substrates with high affinity and selectivity for PTP1B.

    PubMed

    Sanchini, Silvano; Perruccio, Francesca; Piizzi, Grazia

    2014-05-01

    Protein-tyrosine phosphatase 1B (PTP1B) is a key regulatory enzyme in several signal transduction pathways, and its upregulation has been associated with type-2 diabetes, obesity and cancer. Selective determination of the functional significance of PTP1B remains a major challenge because the activity of this crucial enzyme is currently evaluated through the use of fluorescent probes that lack selectivity and are limited to biochemical assays. Here we describe the rational design, synthesis and biological evaluation of new modular PTP1B fluorogenic substrates. The self-immolative 4-hydroxybenzyl alcohol has been used as a key component for the design of phosphotyrosine mimics linked to a latent chromophore, which is released through an enzyme-initiated domino reaction. Preliminary biological investigations showed that, by optimising the stereoelectronic properties and the binding interactions at the enzyme active site, it is possible to achieve substrates with high affinity and promising selectivity. Due to their modular nature, the synthesised fluorogenic probes represent versatile tools; customisation of the different subunits could widen the scope of these probes to a broader range of in vitro assays. Finally, these studies elucidate the critical role played by Asp181 in the PTP1B-catalysed dephosphorylation mechanism: disruption of the native conformation of this key amino acid residue on the WDP loop yields fluorogenic inhibitors, rather than substrates. For this reason, our studies also represent a step forward for the development of improved PTP1B noncovalent inhibitors. PMID:24719298

  17. Rational design of a low-affinity peptide for the detection of cystatin C in a fast homogeneous immunoassay.

    PubMed

    Dobslaff, Kristin; Zscharnack, Kristin; Kreisig, Thomas; Zuchner, Thole

    2016-02-01

    Immunoassays play an essential role in current research and diagnostics resulting in a variety of detection principles. Thereby, homogeneous assays are often used for a fast signal response as demanded for example in point-of-care diagnostics. These systems often rely on a competitive assay design where the sample analyte and the corresponding dye-labeled substance are competing for binding sites on an antibody present in limited amounts. Due to the similar affinities of the antibody towards the sample analyte and the competitor, both sensitivity and assay time are limited. As a consequence, a competitor with a slightly reduced affinity towards the antibody can potentially overcome these drawbacks. Here, we present the rational design of a low-affinity peptide (donor peptide) as a specific analyte competitor for a FRET-based homogeneous immunoassay for the analysis of the protein cystatin C. Thereby, the strategy of peptide-induced antibody generation was combined with the selective variation of the immunization sequence in order to achieve a lower affinity towards the antibody. We could show that shortened donor peptides improved the resulting quenching efficiency in the immunoassay. In addition, the substitution of small hydrophobic amino acids by those with a higher steric demand appeared to be the most promising strategy providing a fast assay response for cystatin C of only 90 s. PMID:26403846

  18. Rational design of efficient electrode-electrolyte interfaces for solid-state energy storage using ion soft landing

    NASA Astrophysics Data System (ADS)

    Prabhakaran, Venkateshkumar; Mehdi, B. Layla; Ditto, Jeffrey J.; Engelhard, Mark H.; Wang, Bingbing; Gunaratne, K. Don D.; Johnson, David C.; Browning, Nigel D.; Johnson, Grant E.; Laskin, Julia

    2016-04-01

    The rational design of improved electrode-electrolyte interfaces (EEI) for energy storage is critically dependent on a molecular-level understanding of ionic interactions and nanoscale phenomena. The presence of non-redox active species at EEI has been shown to strongly influence Faradaic efficiency and long-term operational stability during energy storage processes. Herein, we achieve substantially higher performance and long-term stability of EEI prepared with highly dispersed discrete redox-active cluster anions (50 ng of pure ~0.75 nm size molybdenum polyoxometalate (POM) anions on 25 μg (~0.2 wt%) carbon nanotube (CNT) electrodes) by complete elimination of strongly coordinating non-redox species through ion soft landing (SL). Electron microscopy provides atomically resolved images of a uniform distribution of individual POM species soft landed directly on complex technologically relevant CNT electrodes. In this context, SL is established as a versatile approach for the controlled design of novel surfaces for both fundamental and applied research in energy storage.

  19. 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

  20. 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

  1. Semi-Rational Design of Geobacillus stearothermophilus L-Lactate Dehydrogenase to Access Various Chiral α-Hydroxy Acids.

    PubMed

    Aslan, Aşkın Sevinç; Birmingham, William R; Karagüler, Nevin Gül; Turner, Nicholas J; Binay, Barış

    2016-06-01

    Chiral α-hydroxy acids (AHAs) are rapidly becoming important synthetic building blocks, in particular for the production of pharmaceuticals and other fine chemicals. Chiral compounds of a variety of functionalities are now often derived using enzymes, and L-lactate dehydrogenase from the thermophilic organism Geobacillus stearothermophilus (bsLDH) has the potential to be employed for the industrial synthesis of chiral α-hydroxy acids. Despite the thorough characterization of this enzyme, generation of variants with high activity on non-natural substrates has remained difficult and therefore limits the use of bsLDH in industry. Here, we present the engineering of bsLDH using semi-rational design as a method of focusing screening in a small and smart library for novel biocatalysts. In this study, six mutant libraries were designed in an effort to expand the substrate range of bsLDH. The eight variants identified as having enhanced activity toward the selected α-keto acids belonged to the same library, which targeted two positions simultaneously. These new variants now may be useful biocatalysts for chiral synthesis of α-hydroxy acids. PMID:26852025

  2. Rational design of efficient electrode-electrolyte interfaces for solid-state energy storage using ion soft landing.

    PubMed

    Prabhakaran, Venkateshkumar; Mehdi, B Layla; Ditto, Jeffrey J; Engelhard, Mark H; Wang, Bingbing; Gunaratne, K Don D; Johnson, David C; Browning, Nigel D; Johnson, Grant E; Laskin, Julia

    2016-01-01

    The rational design of improved electrode-electrolyte interfaces (EEI) for energy storage is critically dependent on a molecular-level understanding of ionic interactions and nanoscale phenomena. The presence of non-redox active species at EEI has been shown to strongly influence Faradaic efficiency and long-term operational stability during energy storage processes. Herein, we achieve substantially higher performance and long-term stability of EEI prepared with highly dispersed discrete redox-active cluster anions (50 ng of pure ∼0.75 nm size molybdenum polyoxometalate (POM) anions on 25 μg (∼0.2 wt%) carbon nanotube (CNT) electrodes) by complete elimination of strongly coordinating non-redox species through ion soft landing (SL). Electron microscopy provides atomically resolved images of a uniform distribution of individual POM species soft landed directly on complex technologically relevant CNT electrodes. In this context, SL is established as a versatile approach for the controlled design of novel surfaces for both fundamental and applied research in energy storage. PMID:27097686

  3. Neutralizing antibody and functional mapping of Bacillus anthracis protective antigen-The first step toward a rationally designed anthrax vaccine.

    PubMed

    McComb, Ryan C; Martchenko, Mikhail

    2016-01-01

    Anthrax is defined by the Centers for Disease Control and Prevention as a Category A pathogen for its potential use as a bioweapon. Current prevention treatments include Anthrax Vaccine Adsorbed (AVA). AVA is an undefined formulation of Bacillus anthracis culture supernatant adsorbed to aluminum hydroxide. It has an onerous vaccination schedule, is slow and cumbersome to produce and is slightly reactogenic. Next-generation vaccines are focused on producing recombinant forms of anthrax toxin in a well-defined formulation but these vaccines have been shown to lose potency as they are stored. In addition, studies have shown that a proportion of the antibody response against these vaccines is focused on non-functional, non-neutralizing regions of the anthrax toxin while some essential functional regions are shielded from eliciting an antibody response. Rational vaccinology is a developing field that focuses on designing vaccine antigens based on structural information provided by neutralizing antibody epitope mapping, crystal structure analysis, and functional mapping through amino acid mutations. This information provides an opportunity to design antigens that target only functionally important and conserved regions of a pathogen in order to make a more optimal vaccine product. This review provides an overview of the literature related to functional and neutralizing antibody epitope mapping of the Protective Antigen (PA) component of anthrax toxin. PMID:26611201

  4. A rational design for the separation of metallic and semiconducting single-walled carbon nanotubes using a magnetic field.

    PubMed

    Luo, Chengzhi; Wan, Da; Jia, Junji; Li, Delong; Pan, Chunxu; Liao, Lei

    2016-07-14

    The separation of metallic (m-) and semiconducting (s-) single-walled carbon nanotubes (SWNTs) without causing contamination and damage is a major challenge for SWNT-based devices. As a facile and nondestructive tool, the use of a magnetic field could be an ideal strategy to separate m-/s-SWNTs, based on the difference of magnetic susceptibilities. Here, we designed a novel magnetic field-assisted floating catalyst chemical vapor deposition system to separate m-/s-SWNTs. Briefly, m-SWNTs are attracted toward the magnetic pole, leaving s-SWNTs on the substrate. By using this strategy, s-SWNTs with a purity of 99% could be obtained, which is enough to construct high-performance transistors with a mobility of 230 cm(2) V(-1) s(-1) and an on/off ratio of 10(6). We also established a model to quantitatively calculate the percentage of m-SWNTs on the substrate and this model shows a good match with the experimental data. Furthermore, our rational design also provides a new avenue for the growth of SWNTs with specific chirality and manipulated arrangement due to the difference of magnetic susceptibilities between different diameters, chiralities, and types. PMID:27315328

  5. Structure-based rational design, synthesis and antifungal activity of oxime-containing azole derivatives.

    PubMed

    Xu, Yulan; Sheng, Chunquan; Wang, Wenya; Che, Xiaoying; Cao, Yongbing; Dong, Guoqiang; Wang, Shengzheng; Ji, Haitao; Miao, Zhenyuan; Yao, Jianzhong; Zhang, Wannian

    2010-05-01

    In an attempt to find novel azole antifungal agents with improved activity and broader spectrum, computer modeling was used to design a series of new azoles with piperidin-4-one O-substituted oxime side chains. Molecular docking studies revealed that they formed hydrophobic and hydrogen-bonding interactions with lanosterol 14alpha-demethylase of Candida albicans (CACYP51). In vitro antifungal assay indicates that most of the synthesized compounds showed good activity against tested fungal pathogens. In comparison with fluconazole, itraconazole and voriconazole, several compounds (such as 10c, 10e, and 10i) show more potent antifungal activity and broader spectrum, suggesting that they are promising leads for the development of novel antifungal agents. PMID:20362444

  6. The rational design of a peptide-based hydrogel responsive to H2S.

    PubMed

    Peltier, Raoul; Chen, Ganchao; Lei, Haipeng; Zhang, Mei; Gao, Liqian; Lee, Su Seong; Wang, Zuankai; Sun, Hongyan

    2015-12-18

    The development of hydrogels that are responsive to external stimuli in a well-controlled manner is important for numerous biomedical applications. Herein we reported the first example of a hydrogel responsive to hydrogen sulphide (H2S). H2S is an important gasotransmitter whose deregulation has been associated with a number of pathological conditions. Our hydrogel design is based on the functionalization of an ultrashort hydrogelating peptide sequence with an azidobenzyl moiety, which was reported to react with H2S selectively under physiological conditions. The resulting peptide was able to produce hydrogels at a concentration as low as 0.1 wt%. It could then be fully degraded in the presence of excess H2S. We envision that the novel hydrogel developed in this study may provide useful tools for biomedical research. PMID:26463661

  7. Biobased building blocks for the rational design of renewable block polymers.

    PubMed

    Holmberg, Angela L; Reno, Kaleigh H; Wool, Richard P; Epps, Thomas H

    2014-10-14

    Block polymers (BPs) derived from biomass (biobased) are necessary components of a sustainable future that relies minimally on petroleum-based plastics for applications ranging from thermoplastic elastomers and pressure-sensitive adhesives to blend compatibilizers. To facilitate their adoption, renewable BPs must be affordable, durable, processable, versatile, and reasonably benign. Their desirability further depends on the relative sustainability of the renewable resources and the methods employed in the monomer and polymer syntheses. Various strategies allow these BPs' characteristics to be tuned and enhanced for commercial applications, and many of these techniques also can be applied to manipulate the wide-ranging mechanical and thermal properties of biobased and self-assembling block polymers. From feedstock to application, this review article highlights promising renewable BPs, plus their material and assembly properties, in support of de novo design strategies that could revolutionize material sustainability. PMID:25131385

  8. Quantum Chemical-Based Protocol for the Rational Design of Covalent Inhibitors.

    PubMed

    Schirmeister, Tanja; Kesselring, Jochen; Jung, Sascha; Schneider, Thomas H; Weickert, Anastasia; Becker, Johannes; Lee, Wook; Bamberger, Denise; Wich, Peter R; Distler, Ute; Tenzer, Stefan; Johé, Patrick; Hellmich, Ute A; Engels, Bernd

    2016-07-13

    We propose a structure-based protocol for the development of customized covalent inhibitors. Starting from a known inhibitor, in the first and second steps appropriate substituents of the warhead are selected on the basis of quantum mechanical (QM) computations and hybrid approaches combining QM with molecular mechanics (QM/MM). In the third step the recognition unit is optimized using docking approaches for the noncovalent complex. These predictions are finally verified by QM/MM or molecular dynamic simulations. The applicability of our approach is successfully demonstrated by the design of reversible covalent vinylsulfone-based inhibitors for rhodesain. The examples show that our approach is sufficiently accurate to identify compounds with the desired properties but also to exclude nonpromising ones. PMID:27347738

  9. Identification of SENP1 inhibitors through in silico screening and rational drug design.

    PubMed

    Zhao, Yaxue; Wang, Zhongli; Zhang, Jianchen; Zhou, Huchen

    2016-10-21

    The small ubiquitin-related modifier (SUMO)-specific proteases (SENPs) catalyze the deconjugation of SUMO from their substrate proteins. SENP1 which is the most studied isoform is closely related to many cancers such as prostate cancer and colon cancer, thus representing a potential therapeutic target for cancer treatment. In the present study, we identified eleven SENP1 inhibitors representing a variety of scaffolds through in silico screening. Based on these scaffolds, a series of new compounds were designed and synthesized in order to improve their SENP1 inhibitory potency. As a result, compounds with IC50 as low as 3.5 μM (compound 13m) were obtained and a preliminary structure-activity relationship was discussed. PMID:27344494

  10. Rational Design of Glycomimetic Compounds Targeting the Saccharomyces cerevisiae Transglycosylase Gas2.

    PubMed

    Delso, Ignacio; Valero-González, Jessika; Marca, Eduardo; Tejero, Tomás; Hurtado-Guerrero, Ramón; Merino, Pedro

    2016-02-01

    The transglycosylase Saccharomyces cerevisiae Gas2 (ScGas2) belongs to a large family of enzymes that are key players in yeast cell wall remodeling. Despite its biologic importance, no studies on the synthesis of substrate-based compounds as potential inhibitors have been reported. We have synthesized a series of docking-guided glycomimetics that were evaluated by fluorescence spectroscopy and saturation-transfer difference (STD) NMR experiments, revealing that a minimum of three glucose units linked via a β-(1,3) linkage are required for achieving molecular recognition at the binding donor site. The binding mode of our compounds is further supported by STD-NMR experiments using the active site-mutants Y107Q and Y244Q. Our results are important for both understanding of ScGas2-substrate interactions and setting up the basis for future design of glycomimetics as new antifungal agents. PMID:26280762

  11. Rational design of fluorescent membrane probes for apoptosis based on 3-hydroxyflavone

    NASA Astrophysics Data System (ADS)

    Darwich, Zeinab; Kucherak, Oleksandr A.; Kreder, Rémy; Richert, Ludovic; Vauchelles, Romain; Mély, Yves; Klymchenko, Andrey S.

    2013-06-01

    Environment-sensitive probes constitute powerful tools for monitoring changes in the physico-chemical properties of cell plasma membranes. Among these probes, 3-hydroxyflavone probes are of great interest due to their dual emission and ratiometric response. Here, three probes derived from the parent F2N12S were designed, characterized and applied to monitor the membrane changes occurring during apoptosis. These three probes were designed to orient the dye vertically in the membrane. They differ by the length of their alkyl chains (from 4 to 8 carbons), which were included to optimize their affinity to the lipid membranes. Among these three probes, the one with medium chain length (hexyl) showed the best affinity to model and cell membranes, while the one with the longest alkyl chains (octyl) did not efficiently stain the membranes, probably due to aggregation. The new probes were found to be more sensitive than F2N12S to both the lipid phase and surface charge in lipid vesicles and to loss of lipid order in cell plasma membranes after cholesterol extraction. The one with the shortest (butyl) chains was found to be the most sensitive to apoptosis, while the one with medium-length (hexyl) chains was the brightest. Interestingly, apoptosis induced by different agents led to similar spectroscopic effects to those produced by the loss of lipid order and change in the surface charge, confirming that apoptosis decreases the lipid order and increases the negative surface charge in the outer leaflet of cell membranes. In conclusion, these studies report the relationship between the probe structures and their sensitivity to lipid order, surface charge and apoptosis and propose new probes for membrane research.

  12. Snakes: An Integrated Unit Plan.

    ERIC Educational Resources Information Center

    Lawrence, Lisa

    This document presents an integrated unit plan on snakes targeting second grade students. Objectives of the unit include developing concepts of living things, understanding the contribution and importance of snakes to the environment, and making connections between different disciplines. The unit integrates the topic of snakes into the areas of…

  13. The Role of Flexibility in the Rational Design of Modularly Assembled Ligands Targeting the RNAs that Cause the Myotonic Dystrophies

    PubMed Central

    Lee, Melissa M.; Pushechnikov, Alexei; Childs-Disney, Jessica L.

    2010-01-01

    Modularly assembled ligands were designed to target the RNAs that cause two currently untreatable neuromuscular disorders, myotonic dystrophy types 1 (DM1) and 2 (DM2). DM1 is caused by an expanded repeating sequence of CUG, and DM2 is caused by expanded CCUG repeats. Both are present in non-coding regions and fold into hairpins with either repeating 1×1 nucleotide UU (DM1) or 2×2 nucleotide 5′CU/3′UC (DM2) internal loops separated by two GC pairs. The repeats are toxic because they sequester the RNA splicing regulator Muscleblind-like 1 protein (MBNL1). Rational design of ligands targeting these RNAs was enabled by a database of RNA motif-ligand partners compiled using Two-Dimensional Combinatorial Screening (2DCS). One 2DCS study found that the 6″-azido-kanamycin A module binds internal loops similar to those found in DM1 and DM2. In order to further enhance affinity, the ligand was assembled on a peptoid backbone to precisely control the valency and the distance between ligand modules. Designed compounds are more potent and specific binders to the toxic RNAs than MBNL1 and inhibit the formation of the RNA-protein complexes with nanomolar IC50’s. This study shows that three important factors govern potent inhibition: (1) the surface area sequestered by the assembled ligands; (2) the spacing between ligand modules since a longer distance is required to target DM2 RNAs than DM1 RNAs; and, (3) flexibility in the modular assembly scaffold used to display the RNA-binding module. These results have impacts on the general design of assembled ligands targeting RNAs present in genomic sequence. PMID:20058255

  14. Rational Catalyst Design of Titanium-Silica Materials Aided by Site-Specific Titration Tools

    NASA Astrophysics Data System (ADS)

    Eaton, Todd Robert

    between particle and crystal size, as obtained from XRD. In the course of establishing these relationships we've gained the knowledge of how to control TiO x structure, which enables the design of new and better catalysts. Understanding the synthesis-structure-function relationships allow for the design of a tandem photo/thermocatalytic reaction system for producing and consuming H2O2. By partially overcoating a TiO 2 photocatalyst with a ˜2 nm silica layer we observe a 56-fold rate improvement compared to bare-TiO2 for H2O2 synthesis from the proton-assisted reduction of O2. Addition of metal-SiO2 thermocatalysts (metal=Ti, Nb, or Ta) with sites needed for H2O2 activation creates a tandem system wherein the H2O2 produced in situ is utilized for alkene epoxidation. Compared to a thermocatalytic-only system, the tandem system accelerates epoxidation for cis-cyclooctene(11x faster), styrene(20x) and 1-octene(30x). This approach demonstrates a means for epoxidation with O2 that avoids H2O2 purification and transport, simplifies the total process, provides new opportunities for control by independent H2O2 production and consumption in the same reactor, and enhances rates relative to thermocatalytic-only epoxidation by intimately coupling H2O2 generation and consumption. Critically, establishment of titanium-silica synthesis-structure-function relationships enables the design of new catalysts and systems that are less energy- and material-intensive, leading towards more sustainable chemistry.

  15. Electromagnetic modelling and rational design of GLAD thin films for optical applications

    NASA Astrophysics Data System (ADS)

    Leontyev, Viktor A.

    This thesis presents a theoretical study of columnar films, fabricated by glancing angle deposition (GLAD), as photonic bandgap structures and metamaterials with predictable dielectric and magnetic response. Glancing angle deposition (GLAD) employs extremely oblique vapour incidence and computerized substrate motion to produce nanocolumns with a variety of shapes. Columns grow in random or periodic arrays and may be periodic in one, two, or three dimensions. The films' optical properties were studied using finite-difference time-domain and finite-difference frequency-domain methods, as well as effective medium theories, with support from experimental research. A large part of the thesis is devoted to column arrays with subwavelength intercolumnar distance and periodically modulated column shape. Among them, s-shaped columns were designed as polarizers for linearly polarized light. Simulations have shown a competitive effect from two structural anisotropy sources, causing a band gap suppression for one of two linear polarizations, and high polarizing ability. Simulations were compared to the measurements with a very good agreement in spectral response. Subwavelength column arrays were further explored as anisotropic interference mirrors with omnidirectional reflection bands. Index graded vertical post films were designed, having up to four times wider reflection bands than in the isotropic analogs. Band gap properties of 3D periodic GLAD columns were studied on the example of square-spiral photonic crystals. A significant influence of column cross-section was shown, that currently prevents fabrication of square spirals with a 3D band gap in the visible range. Inverted square-spiral films have better performance, which is further improved by material redistribution along the spiral. Lastly, this work studies the effective dielectric response of porous columnar films with metal particles. Characteristic matrix formalism was combined with finite-difference modelling to

  16. Rational design of redox mediators for advanced Li–O2 batteries

    NASA Astrophysics Data System (ADS)

    Lim, Hee-Dae; Lee, Byungju; Zheng, Yongping; Hong, Jihyun; Kim, Jinsoo; Gwon, Hyeokjo; Ko, Youngmin; Lee, Minah; Cho, Kyeongjae; Kang, Kisuk

    2016-06-01

    The discovery of effective catalysts is an important step towards achieving Li–O2 batteries with long cycle life and high round-trip efficiency. Soluble-type catalysts or redox mediators (RMs) possess great advantages over conventional solid catalysts, generally exhibiting much higher efficiency. Here, we select a series of organic RM candidates as a model system to identify the key descriptor in determining the catalytic activities and stabilities in Li–O2 cells. It is revealed that the level of ionization energies, readily available parameters from a database of the molecules, can serve such a role when comparing with the formation energy of Li2O2 and the highest occupied molecular orbital energy of the electrolyte. It is demonstrated that they are critical in reducing the overpotential and improving the stability of Li–O2 cells, respectively. Accordingly, we propose a general principle for designing feasible catalysts and report a RM, dimethylphenazine, with a remarkably low overpotential and high stability.

  17. Rationally designed molecularly imprinted polymers for selective extraction of methocarbamol from human plasma.

    PubMed

    Gholivand, Mohammad Bagher; Khodadadian, Mehdi

    2011-09-15

    Molecularly imprinted polymers (MIPs) with high selectivity toward methocarbamol have been computationally designed and synthesized based on the general non-covalent molecular imprinting approach. A virtual library consisting of 18 functional monomers was built and possible interactions between the template and functional monomers were investigated using a semiempirical approach. The monomers with the highest binding scores were then considered for additional calculations using a more accurate quantum mechanical (QM) calculation exploiting the density functional theory (DFT) at B3LYP/6-31G(d,p) level. The cosmo polarizable continuum model (CPCM) was also used to simulate the polymerization solvent. On the basis of computational results, acrylic acid (AA) and tetrahydrofuran (THF) were found to be the best choices of functional monomer and polymerization solvent, respectively. MIPs were then synthesized by the precipitation polymerization method and used as selective adsorbents to develop a molecularly imprinted solid-phase extraction (MISPE) procedure before quantitative analysis. After MISPE the drug could be determined either by differential pulse voltammetry (DPV), on a glassy carbon electrode modified with multiwalled-carbon nanotubes (GC/MWNT), or high performance chromatography (HPLC) with UV detection. A comparative study between MISPE-DPV and MISPE-HPLC-UV was performed. The MISPE-DPV was more sensitive but both techniques showed similar accuracy and precision. PMID:21807239

  18. Rational design and validation of a Tip60 histone acetyltransferase inhibitor

    NASA Astrophysics Data System (ADS)

    Gao, Chunxia; Bourke, Emer; Scobie, Martin; Famme, Melina Arcos; Koolmeister, Tobias; Helleday, Thomas; Eriksson, Leif A.; Lowndes, Noel F.; Brown, James A. L.

    2014-06-01

    Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer.

  19. Rational design of allosteric regulation of homoserine dehydrogenase by a nonnatural inhibitor L-lysine.

    PubMed

    Chen, Zhen; Rappert, Sugima; Zeng, An-Ping

    2015-02-20

    Allosteric proteins, which can sense different signals, are interesting biological parts for synthetic biology. In particular, the design of an artificial allosteric enzyme to sense an unnatural signal is both challenging and highly desired, for example, for a precise and dynamical control of fluxes of growth-essential but byproduct pathways in metabolic engineering of industrial microorganisms. In this work, we used homoserine dehydrogenase (HSDH) of Corynebacterium glutamicum, which is naturally allosterically regulated by threonine and isoleucine, as an example to demonstrate the feasibility of reengineering an allosteric enzyme to respond to an unnatural inhibitor L-lysine. For this purpose, the natural threonine binding sites of HSD were first predicted and verified by mutagenesis experiments. The threonine binding sites were then engineered to a lysine binding pocket. The reengineered HSD only responds to lysine inhibition but not to threonine. This is a significant step toward the construction of artificial molecular circuits for dynamic control of growth-essential byproduct formation pathway for lysine biosynthesis. PMID:24344690

  20. Rationally designed peptidomimetic modulators of aβ toxicity in Alzheimer's disease.

    PubMed

    Rajasekhar, K; Suresh, S N; Manjithaya, Ravi; Govindaraju, T

    2015-01-01

    Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21st century. The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the β-amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process may act as therapeutic agents for the treatment of the disease. Use of recognition unit based peptidomimetics as inhibitors are a promising approach, as they exhibit greater protease stability compared to natural peptides. Here, we present peptidomimetic inhibitors of Aβ aggregation designed based on the KLVFF (P1) sequence that is known to bind Aβ aggregates. We improved inhibition efficiency of P1 by introducing multiple hydrogen bond donor-acceptor moieties (thymine/barbiturate) at the N-terminal (P2 and P3), and blood serum stability by modifying the backbone by incorporating sarcosine (N-methylglycine) units at alternate positions (P4 and P5). The peptidomimetics showed moderate to good activity in both inhibition and dissolution of Aβ aggregates as depicted by thioflavin assay, circular dichroism (CD) measurements and microscopy (TEM). The activity of P4 and P5 were studied in a yeast cell model showing Aβ toxicity. P4 and P5 could rescue yeast cells from Aβ toxicity and Aβ aggregates were cleared by the process of autophagy. PMID:25633824

  1. Rational Design of Potent Antagonists to the Human Growth Hormone Receptor

    NASA Astrophysics Data System (ADS)

    Fuh, Germaine; Cunningham, Brian C.; Fukunaga, Rikiro; Nagata, Shigekazu; Goeddel, David V.; Wells, James A.

    1992-06-01

    A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially-a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.

  2. G3 Assisted Rational Design of Chemical Sensor Array Using Carbonitrile Neutral Receptors

    PubMed Central

    Rosli, Ahmad Nazmi; Bakar, Maizathul Akmam Abu; Manan, Ninie Suhana Abdul; Woi, Pei Meng; Lee, Vannajan Sanghiran; Zain, Sharifuddin Md; Ahmad, Mohd Rais; Alias, Yatimah

    2013-01-01

    Combined computational and experimental strategies for the systematic design of chemical sensor arrays using carbonitrile neutral receptors are presented. Binding energies of acetonitrile, n-pentylcarbonitrile and malononitrile with Ca(II), Mg(II), Be(II) and H+ have been investigated with the B3LYP, G3, CBS-QB3, G4 and MQZVP methods, showing a general trend H+ > Be(II) > Mg(II) > Ca(II). Hydrogen bonding, donor-acceptor and cation-lone pair electron simple models were employed in evaluating the performance of computational methods. Mg(II) is bound to acetonitrile in water by 12.5 kcal/mol, and in the gas phase the receptor is more strongly bound by 33.3 kcal/mol to Mg(II) compared to Ca(II). Interaction of bound cations with carbonitrile reduces the energies of the MOs involved in the proposed σ-p conjugated network. The planar malononitrile-Be(II) complex possibly involves a π-network with a cationic methylene carbon. Fabricated potentiometric chemical sensors show distinct signal patterns that can be exploited in sensor array applications. PMID:24129020

  3. Protein-Support Interactions for Rationally Designed Bilirubin Oxidase Based Cathode: A Computational Study.

    PubMed

    Matanovic, Ivana; Babanova, Sofia; Chavez, Madelaine Seow; Atanassov, Plamen

    2016-04-21

    An example of biocathode based on bilirubin oxidase (BOx) was used to demonstrate how density functional theory can be combined with docking simulations in order to study the interface interactions between the enzyme and specifically designed electrode surface. The electrode surface was modified through the adsorption of bilirubin, the natural substrate for BOx, and the prepared electrode was electrochemically characterized using potentiostatic measurements. The experimentally determined current densities showed that the presence of bilirubin led to significant improvement of the cathode operation. On the basis of the computationally calculated binding energies of bilirubin to the graphene support and BOx and the analysis of the positioning of bilirubin relative to the support and T1 Cu atom of the enzyme, we hypothesize that the bilirubin serves as a geometric and electronic extension of the support. The computational results further confirm that the modification of the electrode surface with bilirubin provides an optimal orientation of BOx toward the support but also show that bilirubin facilitates the interfacial electron transfer by decreasing the distance between the electrode surface and the T1 Cu atom. PMID:27015361

  4. Rationally designed porous polystyrene encapsulated zirconium phosphate nanocomposite for highly efficient fluoride uptake in waters

    PubMed Central

    Zhang, Qingrui; Du, Qing; Jiao, Tifeng; Zhang, Zhaoxiang; Wang, Sufeng; Sun, Qina; Gao, Faming

    2013-01-01

    Fluoride pollution in waters has engulfed worldwide regions and an excess of fluoride intake always causes skeletal fluorosis. Herein, a novel hybrid nanomaterial ZrP-MPN was fabricated for fluoride retention by encapsulating nano-ZrP onto macroporous polystyrene materials modified with quaternary ammonium groups. The as-obtained materials exhibited favorable removal of fluoride ions from aqueous solution in presence of common anions (SO42−/NO3−/Cl−) at high contents. Moreover outstanding sorption properties were also detected by involving series of commercial adsorbents (AA/magnetite/GFH/manganese sands) as references. Such satisfactory performances might be ascribed to the structural design of nanocomposite. (1) the CH2N+(CH3)3Cl groups enhances sorption diffusion and preconcentration in sorbent phase theoretically based on Donnan membrane principle; (2) the embedded ZrP nanoparticles also devotes to the efficient adsorption capacities due to its size-dependent specific properties. Additionally, the exhausted ZrP-MPN could be regenerated readily by alkaline solution. Thus, ZrP-MPN was a promising material for fluoride retention in waters. PMID:23989688

  5. Rational design of dendrimer/lipid nanoassemblies in drug delivery for cancer chemotherapy

    NASA Astrophysics Data System (ADS)

    Sun, Qihang

    Nanocarriers can minimize the side effects and improve therapeutic efficacy of anticancer drugs. Although some success has been achieved via active or passive drug delivery to tumor cells, the known nanocarriers are far from satisfying therapeutic efficacy expectations. This is because they usually fail in one of the four crucial requirements, that is, to retain drug in blood circulation but release it reliably in tumor cells and to be stealthy in transport in circulation and tumor tissue but sticky upon arrival at the tumor cell. Therefore, the goal of this work is to fabricate nanoassemblies of dendrimers and lipids to address all these challenges. Particularly, nanoassemblies designed and prepared in this work are illustrated to improve the tumor tissue penetration. Examples of dendrimers synthesized in this work are water-insoluble, pH-dependent water-insoluble and water-soluble biodegradable polyester dendrimers. These dendrimers are shown to be encapsulated by commonly used fusogenic and long-circulating lipids to form reliable nanoassemblies. The dendrimer/lipid nanocarriers are used to demonstrate a cascade drug delivery. They are expected to be stable in circulation, due to their appropriately large size, but to release the drug-loaded dendrimers in tumor tissue. The released dendrimers carrying drugs are much smaller and hence expected to have a much deeper penetration throughout the tumor tissue.

  6. pH sensitive silica nanotubes as rationally designed vehicles for NSAIDs delivery.

    PubMed

    Sousa, Célia T; Nunes, Cláudia; Proença, Mariana P; Leitão, Diana C; Lima, José L F C; Reis, Salette; Araújo, João P; Lúcio, Marlene

    2012-06-01

    A novel pH-sensitive drug delivery system based on functionalized silica nanotubes was developed for the incorporation of non-steroidal anti-inflammatory drugs (NSAIDs), aimed at a tailored drug release in acidic conditions characteristic of inflamed tissues. Silica nanotubes (SNTs) were synthesized by a nanoporous alumina template assisted sol-gel method. Inner surfaces were physically and chemically modified to improve both the functionalization and subsequent incorporation of the drug. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and transmission electron microscopy (TEM) were used to characterize the designed nanocarriers and their functionalization. To achieve the highest degree of functionalization, three types of aminosilanes were tested and calcination conditions were optimized. APTES was shown to be the most effective aminosilane regarding the functionalization of the SNTs' inner surface and an adequate calcination temperature (220°C) was found to attain mechanical stability without compromising functionalization efficiency. Finally, the incorporation of naproxen into the nanotubes was accessed by fluorescence measurements and drug release studies were performed, revealing that the electrostatic linkage ensures effective release of the drug in the acidic pH typical of inflamed cells, while maintaining the SNT-drug conjugates stable at the typical bloodstream pH. PMID:22366067

  7. Rational design of berberine-based FtsZ inhibitors with broad-spectrum antibacterial activity.

    PubMed

    Sun, Ning; Chan, Fung-Yi; Lu, Yu-Jing; Neves, Marco A C; Lui, Hok-Kiu; Wang, Yong; Chow, Ka-Yan; Chan, Kin-Fai; Yan, Siu-Cheong; Leung, Yun-Chung; Abagyan, Ruben; Chan, Tak-Hang; Wong, Kwok-Yin

    2014-01-01

    Inhibition of the functional activity of Filamenting temperature-sensitive mutant Z (FtsZ) protein, an essential and highly conserved bacterial cytokinesis protein, is a promising approach for the development of a new class of antibacterial agents. Berberine, a benzylisoquinoline alkaloid widely used in traditional Chinese and native American medicines for its antimicrobial properties, has been recently reported to inhibit FtsZ. Using a combination of in silico structure-based design and in vitro biological assays, 9-phenoxyalkyl berberine derivatives were identified as potent FtsZ inhibitors. Compared to the parent compound berberine, the derivatives showed a significant enhancement of antibacterial activity against clinically relevant bacteria, and an improved potency against the GTPase activity and polymerization of FtsZ. The most potent compound 2 strongly inhibited the proliferation of Gram-positive bacteria, including methicillin-resistant S. aureus and vancomycin-resistant E. faecium, with MIC values between 2 and 4 µg/mL, and was active against the Gram-negative E. coli and K. pneumoniae, with MIC values of 32 and 64 µg/mL respectively. The compound perturbed the formation of cytokinetic Z-ring in E. coli. Also, the compound interfered with in vitro polymerization of S. aureus FtsZ. Taken together, the chemical modification of berberine with 9-phenoxyalkyl substituent groups greatly improved the antibacterial activity via targeting FtsZ. PMID:24824618

  8. Rational Design of Berberine-Based FtsZ Inhibitors with Broad-Spectrum Antibacterial Activity

    PubMed Central

    Sun, Ning; Chan, Fung-Yi; Lu, Yu-Jing; Neves, Marco A. C.; Lui, Hok-Kiu; Wang, Yong; Chow, Ka-Yan; Chan, Kin-Fai; Yan, Siu-Cheong; Leung, Yun-Chung; Abagyan, Ruben; Chan, Tak-Hang; Wong, Kwok-Yin

    2014-01-01

    Inhibition of the functional activity of Filamenting temperature-sensitive mutant Z (FtsZ) protein, an essential and highly conserved bacterial cytokinesis protein, is a promising approach for the development of a new class of antibacterial agents. Berberine, a benzylisoquinoline alkaloid widely used in traditional Chinese and native American medicines for its antimicrobial properties, has been recently reported to inhibit FtsZ. Using a combination of in silico structure-based design and in vitro biological assays, 9-phenoxyalkyl berberine derivatives were identified as potent FtsZ inhibitors. Compared to the parent compound berberine, the derivatives showed a significant enhancement of antibacterial activity against clinically relevant bacteria, and an improved potency against the GTPase activity and polymerization of FtsZ. The most potent compound 2 strongly inhibited the proliferation of Gram-positive bacteria, including methicillin-resistant S. aureus and vancomycin-resistant E. faecium, with MIC values between 2 and 4 µg/mL, and was active against the Gram-negative E. coli and K. pneumoniae, with MIC values of 32 and 64 µg/mL respectively. The compound perturbed the formation of cytokinetic Z-ring in E. coli. Also, the compound interfered with in vitro polymerization of S. aureus FtsZ. Taken together, the chemical modification of berberine with 9-phenoxyalkyl substituent groups greatly improved the antibacterial activity via targeting FtsZ. PMID:24824618

  9. A rational approach towards the design of chitosan-based nanoparticles obtained by ionotropic gelation.

    PubMed

    Kleine-Brueggeney, H; Zorzi, G K; Fecker, T; El Gueddari, N E; Moerschbacher, B M; Goycoolea, F M

    2015-11-01

    Chitosan is a linear aminopolysaccharide that has been widely used for the formation of chitosan-based nanoparticles by ionic gelation with sodium tripolyphosphate (TPP). Often, the experimental design used to obtain these systems does not take into consideration important variables, such as the degree of acetylation (DA) and the molecular weight (Mw) of chitosan. In this work, we studied the formation of chitosan-TPP nanoparticles with chitosan samples of varying DA and Mw (DA0 ∼ 0-47% and Mw ∼ 2.5-282 kDa). We addressed the influence the degree of space occupancy and the degree of crosslinking on the physical properties of chitosan-TPP nanoparticles. Nanoparticles that comprised chitosan of DA ∼ 0-21.7% behaved differently than those made of chitosan of DA ∼ 34.7-47%. We attributed these differences to the polymer conformation and chain flexibility of the distinct chitosans in solution. Moreover, chitosan of high Mw were found to have a stronger preference for incorporating into the formed nanoparticles than do low-Mw ones, as determined by SEC-HPLC. These results open new perspectives to understand the formation of chitosan nanoparticles by the ionic gelation technique. PMID:26241921

  10. Rational design and validation of a Tip60 histone acetyltransferase inhibitor

    PubMed Central

    Gao, Chunxia; Bourke, Emer; Scobie, Martin; Famme, Melina Arcos; Koolmeister, Tobias; Helleday, Thomas; Eriksson, Leif A.; Lowndes, Noel F.; Brown, James A. L.

    2014-01-01

    Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer. PMID:24947938

  11. New mimetic peptides inhibitors of Αβ aggregation. Molecular guidance for rational drug design.

    PubMed

    Barrera Guisasola, Exequiel E; Andujar, Sebastián A; Hubin, Ellen; Broersen, Kerensa; Kraan, Ivonne M; Méndez, Luciana; Delpiccolo, Carina M L; Masman, Marcelo F; Rodríguez, Ana M; Enriz, Ricardo D

    2015-05-01

    A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer's disease. For the molecular dynamics simulations, we used an Aβ42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of our Aβ42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands. PMID:25805447

  12. Towards the rational design of organic/inorganic interface for solid supported CO2 capture

    NASA Astrophysics Data System (ADS)

    He, Feng

    Monoethanolamine (MEA, HO(CH2)2NH2) aqueous solution based CO2 capture is the current technology used to mitigate power plants' green house gas emission. Solid based CO2 capture technique is regarded as a promising alternative, because it is more cost-effective and environmentally friendly than the solution based technique. Recently, solid-supported CO2 capture on MEA modified TiO 2 powders has been demonstrated [1]. It is believed that the main reaction pathway involved in solid-supported amine based CO2 capture is similar to the reaction in the amine solution, where the amine group reacts with CO2 to form carbamate (--NHCOO--). From the previous work on the MEA/TiO2 (110) system [2], it is found that MEA covered rutile TiO2 (110) did not capture CO 2. The main reaction pathway in this system was blocked because the amine group attached to the surface. In order to design a functional system, we proposed two possible mechanisms to free --NH2 from rutile TiO2 (110) surface. In this work, we investigated one of our six candidates, the 3-Amino-1-propanol (3AP, HO(CH2) 3NH2) molecule. The classical reactive force field (ReaxFF) [3] method has been employed to investigate the 3AP/TiO2 (110) system with emphasis on binding configurations and binding energies. We found that the amine group of 3AP did not attach to the rutile TiO2 (110) surface, indicating the CO2 capture capability of the 3AP/TiO 2 (110) system, which was confirmed by our experimental collaborators [4].

  13. Computational ligand-based rational design: Role of conformational sampling and force fields in model development

    PubMed Central

    Shim, Jihyun; MacKerell, Alexander D.

    2011-01-01

    A significant number of drug discovery efforts are based on natural products or high throughput screens from which compounds showing potential therapeutic effects are identified without knowledge of the target molecule or its 3D structure. In such cases computational ligand-based drug design (LBDD) can accelerate the drug discovery processes. LBDD is a general approach to elucidate the relationship of a compound's structure and physicochemical attributes to its biological activity. The resulting structure-activity relationship (SAR) may then act as the basis for the prediction of compounds with improved biological attributes. LBDD methods range from pharmacophore models identifying essential features of ligands responsible for their activity, quantitative structure-activity relationships (QSAR) yielding quantitative estimates of activities based on physiochemical properties, and to similarity searching, which explores compounds with similar properties as well as various combinations of the above. A number of recent LBDD approaches involve the use of multiple conformations of the ligands being studied. One of the basic components to generate multiple conformations in LBDD is molecular mechanics (MM), which apply an empirical energy function to relate conformation to energies and forces. The collection of conformations for ligands is then combined with functional data using methods ranging from regression analysis to neural networks, from which the SAR is determined. Accordingly, for effective application of LBDD for SAR determinations it is important that the compounds be accurately modelled such that the appropriate range of conformations accessible to the ligands is identified. Such accurate modelling is largely based on use of the appropriate empirical force field for the molecules being investigated and the approaches used to generate the conformations. The present chapter includes a brief overview of currently used SAR methods in LBDD followed by a more

  14. Improvements in Rational Design Strategies of Inulin Derivative Polycation for siRNA Delivery.

    PubMed

    Sardo, Carla; Craparo, Emanuela Fabiola; Porsio, Barbara; Giammona, Gaetano; Cavallaro, Gennara

    2016-07-11

    The advances of short interfering RNA (siRNA)-mediated therapy provide a powerful option for the treatment of many diseases, including cancer, by silencing the expression of targeted genes involved in the progression of the pathology. On this regard, a new pH-responsive polycation derived from inulin, Inulin-g-imidazole-g-diethylenetriamine (INU-IMI-DETA), was designed and employed to produce INU-IMI-DETA/siRNA "Inulin COmplex Nanoaggregates" (ICONs). The experimental results showed that INU-IMI-DETA exhibited strong cationic characteristics and high solubility in the pH range 3-5 and self-aggregation triggered by pH increase and physiological salt concentration. INU-IMI-DETA showed as well a high buffering capacity in the endosomal pH range of 7.4-5.1. In the concentration range between 25 and 1000 μg/mL INU-IMI-DETA had no cytotoxic effect on breast cancer cells (MCF-7) and no lytic effect on human red blood cells. ICONs were prepared by two-step procedure involving complexation and precipitation into DPBS buffer (pH 7.4) to produce siRNA-loaded nanoaggregates with minimized surface charge and suitable size for parenteral administration. Bafilomycin A1 inhibited transfection on MCF-7 cells, indicating that the protonation of the imidazole groups in the endolysosome pathway favors the escape of the system from endolysosomal compartment, increasing the amount of siRNA that can reach the cytoplasm. PMID:27238382

  15. Enhancement and investigation of second-order nonlinearity through rational design and organic synthesis

    NASA Astrophysics Data System (ADS)

    Davies, Joshua A.

    2009-12-01

    Since the turn of the century, continued research in the field of organic electrooptics (EO) has led to an enormous amount of progress in terms of bulk second-order nonlinear optical response. However, as of late, fundamental research in chromophore structure-property relationships and optimization of molecular hyperpolarizability through new approaches certainly does not get the consideration it is warranted despite having a significant contribution to the present success in the realm of EO. Guided through the use of sophisticated quantum mechanical modeling and classic design paradigms, materials were engineered in an attempt to further increase first-order hyperpolarizability (beta) above and beyond state-of-the-art materials through the use of novel heteroaryl-based electron donors and acceptors. The unprecedented degree of polarization in these neutral ground state chromophores, which resulted from lower ionization potentials and aromaticities, was extensively explored, both analytically and theoretically. In one new class of chromophores, an increase in electron-donor strength was off-set by the resistivity towards polarization caused by the divinylthienyl bridge. This led to an excellent balance in asymmetry and polarizability, and thus large beta. However, when these heteroaryl donors were incorporated into ring-locked tetraene bridges, the strong electron-donors were believed to have polarized the highly efficient bridges beyond optimal beta. Finally, ground work has been laid out for the application of all-optical, and optically assisted poling of a class of second generation, high beta, azo-based chromophores as an alternate means of improving poling induced order.

  16. Rational design, synthesis, and DNA binding properties of novel sequence-selective peptidyl congeners of ametantrone.

    PubMed

    Gianoncelli, Alessandra; Basili, Serena; Scalabrin, Matteo; Sosic, Alice; Moro, Stefano; Zagotto, Giuseppe; Palumbo, Manlio; Gresh, Nohad; Gatto, Barbara

    2010-07-01

    Natural and synthetic compounds characterized by an anthraquinone nucleus represent an important class of anti-neoplastic agents, the mechanism of action of which is related to intercalation into DNA. Ametantrone (AM) is a synthetic 9,10-anthracenedione bearing two (hydroxyethylamino)ethylamino residues at positions 1 and 4; along with other anthraquinones and anthracyclines, it shares a polycyclic intercalating moiety and charged side chains that stabilize DNA binding. All these drugs elicit adverse side effects, which represent a challenge for antitumor chemotherapy. In the present work the structure of AM was augmented with appropriate groups that target well-defined base pairs in the major groove. These should endow AM with DNA sequence selectivity. We describe the rationale for the synthesis and the evaluation of activity of a new series of compounds in which the planar anthraquinone is conjugated at positions 1 and 4 through the side chains of AM or other bioisosteric linkers to appropriate dipeptides. The designed novel AM derivatives were shown to selectively stabilize two oligonucleotide duplexes that both have a palindromic GC-rich hexanucleotide core, but their stabilizing effects on a random DNA sequence was negligible. In the case of the most effective compound, the 1,4-bis-[Gly-(L-Lys)] derivative of AM, the experimental results confirm the predictions of earlier theoretical computations. In contrast, AM had equal stabilizing effects on all three sequences and showed no preferential binding. This novel peptide derivative can be classified as a strong binder regarding the sequences that it selectively targets, possibly opening the exploitation of less cytotoxic conjugates of AM to the targeted treatment of oncological and viral diseases. PMID:20458714

  17. Rational design of self-cleaving pre-tRNA-ribonuclease P RNA conjugates.

    PubMed

    Frank, D N; Harris, M E; Pace, N R

    1994-09-01

    Ribonuclease P (RNaseP) generates the mature 5' end of tRNAs by removing 5'leader sequences from pre-tRNAs. In vitro, the RNA subunit is sufficient to catalyze this reaction and is therefore a ribozyme. The kinetic analysis of RNase P-mediated catalysis is complicated because product release is normally rate-limiting. Furthermore, the intermolecular nature of the cleavage reaction precludes many applications of in vitro selection schemes to the analysis of RNaseP. To examine and manipulate the RNase P function more effectively, we designed a pair of ribozymes in which the RNase P RNA is covalently linked to a pre-tRNA substrate. To facilitate intramolecular cleavage, pre-tRNA molecules were tethered to circulatory permuted RNaseP RNA molecules at nucleotides implicated in substrate binding. These "active-site-tethered" pre-tRNA-RNaseP RNA conjugates undergo accurate and efficient self-cleavage in vitro, with first-order reaction rates equivalent to the rate of the chemical step of the native RNase P reaction. Unlike most ribozymes, RNase P recognizes its substrate through tertiary RNA-RNA interactions, rather than through extensive Watson-Crick base-pairing. However, the development of the active-site-tethered conjugates has led us to create a sequence-specific endonuclease, termed Endo.P. In the Endo.P configuration, the 3'half of the pre-tRNA acceptor stem binds exogenous RNA substrates via Watson-Crick base-pairing; the bound substrate is subsequently cleaved at the predicted site. The demonstration of sequence-specific cleavage by Endo.P expands the potential of RNase P and its derivatives as reagents in gene therapy. PMID:8075082

  18. Computational ligand-based rational design: Role of conformational sampling and force fields in model development.

    PubMed

    Shim, Jihyun; Mackerell, Alexander D

    2011-05-01

    A significant number of drug discovery efforts are based on natural products or high throughput screens from which compounds showing potential therapeutic effects are identified without knowledge of the target molecule or its 3D structure. In such cases computational ligand-based drug design (LBDD) can accelerate the drug discovery processes. LBDD is a general approach to elucidate the relationship of a compound's structure and physicochemical attributes to its biological activity. The resulting structure-activity relationship (SAR) may then act as the basis for the prediction of compounds with improved biological attributes. LBDD methods range from pharmacophore models identifying essential features of ligands responsible for their activity, quantitative structure-activity relationships (QSAR) yielding quantitative estimates of activities based on physiochemical properties, and to similarity searching, which explores compounds with similar properties as well as various combinations of the above. A number of recent LBDD approaches involve the use of multiple conformations of the ligands being studied. One of the basic components to generate multiple conformations in LBDD is molecular mechanics (MM), which apply an empirical energy function to relate conformation to energies and forces. The collection of conformations for ligands is then combined with functional data using methods ranging from regression analysis to neural networks, from which the SAR is determined. Accordingly, for effective application of LBDD for SAR determinations it is important that the compounds be accurately modelled such that the appropriate range of conformations accessible to the ligands is identified. Such accurate modelling is largely based on use of the appropriate empirical force field for the molecules being investigated and the approaches used to generate the conformations. The present chapter includes a brief overview of currently used SAR methods in LBDD followed by a more

  19. Structural basis of glycogen branching enzyme deficiency and pharmacologic rescue by rational peptide design

    PubMed Central

    Froese, D. Sean; Michaeli, Amit; McCorvie, Thomas J.; Krojer, Tobias; Sasi, Meitav; Melaev, Esther; Goldblum, Amiram; Zatsepin, Maria; Lossos, Alexander; Álvarez, Rafael; Escribá, Pablo V.; Minassian, Berge A.; von Delft, Frank; Kakhlon, Or; Yue, Wyatt W.

    2015-01-01

    Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. Mutations in the GBE1 gene lead to the heterogeneous early-onset glycogen storage disorder type IV (GSDIV) or the late-onset adult polyglucosan body disease (APBD). To better understand this essential enzyme, we crystallized human GBE1 in the apo form, and in complex with a tetra- or hepta-saccharide. The GBE1 structure reveals a conserved amylase core that houses the active centre for the branching reaction and harbours almost all GSDIV and APBD mutations. A non-catalytic binding cleft, proximal to the site of the common APBD mutation p.Y329S, was found to bind the tetra- and hepta-saccharides and may represent a higher-affinity site employed to anchor the complex glycogen substrate for the branching reaction. Expression of recombinant GBE1-p.Y329S resulted in drastically reduced protein yield and solubility compared with wild type, suggesting this disease allele causes protein misfolding and may be amenable to small molecule stabilization. To explore this, we generated a structural model of GBE1-p.Y329S and designed peptides ab initio to stabilize the mutation. As proof-of-principle, we evaluated treatment of one tetra-peptide, Leu-Thr-Lys-Glu, in APBD patient cells. We demonstrate intracellular transport of this peptide, its binding and stabilization of GBE1-p.Y329S, and 2-fold increased mutant enzymatic activity compared with untreated patient cells. Together, our data provide the rationale and starting point for the screening of small molecule chaperones, which could become novel therapies for this disease. PMID:26199317

  20. Rational design and characterization of D-Phe-Pro-D-Arg-derived direct thrombin inhibitors.

    PubMed

    Figueiredo, Ana C; Clement, Cristina C; Zakia, Sheuli; Gingold, Julian; Philipp, Manfred; Pereira, Pedro J B

    2012-01-01

    The tremendous social and economic impact of thrombotic disorders, together with the considerable risks associated to the currently available therapies, prompt for the development of more efficient and safer anticoagulants. Novel peptide-based thrombin inhibitors were identified using in silico structure-based design and further validated in vitro. The best candidate compounds contained both L- and D-amino acids, with the general sequence D-Phe(P3)-Pro(P2)-D-Arg(P1)-P1'-CONH₂. The P1' position was scanned with L- and D-isomers of natural or unnatural amino acids, covering the major chemical classes. The most potent non-covalent and proteolysis-resistant inhibitors contain small hydrophobic or polar amino acids (Gly, Ala, Ser, Cys, Thr) at the P1' position. The lead tetrapeptide, D-Phe-Pro-D-Arg-D-Thr-CONH₂, competitively inhibits α-thrombin's cleavage of the S2238 chromogenic substrate with a K(i) of 0.92 µM. In order to understand the molecular details of their inhibitory action, the three-dimensional structure of three peptides (with P1' L-isoleucine (fPrI), L-cysteine (fPrC) or D-threonine (fPrt)) in complex with human α-thrombin were determined by X-ray crystallography. All the inhibitors bind in a substrate-like orientation to the active site of the enzyme. The contacts established between the D-Arg residue in position P1 and thrombin are similar to those observed for the L-isomer in other substrates and inhibitors. However, fPrC and fPrt disrupt the active site His57-Ser195 hydrogen bond, while the combination of a P1 D-Arg and a bulkier P1' residue in fPrI induce an unfavorable geometry for the nucleophilic attack of the scissile bond by the catalytic serine. The experimental models explain the observed relative potency of the inhibitors, as well as their stability to proteolysis. Moreover, the newly identified direct thrombin inhibitors provide a novel pharmacophore platform for developing antithrombotic agents by exploring the conformational

  1. Rational Design of Iron Oxide Nanoparticles as Targeted Nanomedicines for Cancer Therapy

    NASA Astrophysics Data System (ADS)

    Kievit, Forrest M.

    2011-07-01

    Nanotechnology provides a flexible platform for the development of effective therapeutic nanomaterials that can interact specifically with a target in a biological system and provoke a desired biological response. Of the nanomaterials studied, superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as one of top candidates for cancer therapy due to their intrinsic superparamagnetism that enables non-invasive magnetic resonance imaging (MRI) and biodegradability favorable for in vivo application. This dissertation is aimed at development of SPION-based nanomedicines to overcome the current limitations in cancer therapy. These limitations include non-specificity of therapy which can harm healthy tissue, the difficulty in delivering nucleic acids for gene therapy, the formation of drug resistance, and the inability to detect and treat micrometastases. First, a SPION-based non-viral gene delivery vehicle was developed through functionalization of the SPION core with a co-polymer designed to provide stable binding of DNA and low toxicity which showed excellent gene delivery in vitro and in vivo. This SPION-based non-viral gene delivery vehicle was then activated with a targeting agent to improve gene delivery throughout a xenograft tumor of brain cancer. It was found that targeting did not promote the accumulation of SPIONs at the tumor site, but rather improved the distribution of SPIONs throughout the tumor so a higher proportion of cells received treatment. Next, the high surface area of SPIONs was utilized for loading large amounts of drug which was shown to overcome the multidrug resistance acquired by many cancer cells. Drug bound to SPIONs showed significantly higher multidrug resistant cell uptake as compared to free drug which translated into improved cell kill. Also, an antibody activated SPION was developed and was shown to be able to target micrometastases in a transgenic animal model of metastatic breast cancer. These SPION-based nanomedicines

  2. A rational design approach to nanostructured catalysts for the oxidation of carbon monoxide

    NASA Astrophysics Data System (ADS)

    Karwacki, Christopher

    zirconia readily dissociates adsorbed water on the most active and stable crystal structures (111) compared to other metal oxides, such as the common anatase (101) form of titania. Also, the support must provide a source of activated oxygen as a means to oxidize intermediate carbonates with CO 2 formation. The role of the support is to provide lattice oxygen in an activated state (O2-) for oxidation of adsorbed CO the Au NP:support interface. Furthermore, the primary interest is the energy associated Au NP in proximity to the support surface. Advancing the understanding of this region is believed to be crucial to the future design of active nanostructured materials that function under ambient conditions. The proposed model involves a structure consisting of properly sized and highly dispersed Au NP supported on a hydroxylated form of nanocrystalline zirconia. This type of zirconia is in a highly polymorphic form consisting of aggregates of small crystals less than 10 nm. The structure is highly porous, containing undercoordinated zirconium atoms, and provides an environment for rapid dissociation of molecular water. In this research and in collaboration with Mogilevsky et al., 37 I introduce a novel method for quantifying the surface concentration of two major forms of hydroxide that form on zirconia. Furthermore, in this research I show how both the porosity of the zirconia support and the size of the crystalline aggregates affect the type and surface concentration of hydroxyl groups. This relationship is thus directly related to the oxidation activity of the catalyst consisting of Au NP supported on hydroxylated ZrO 2. These phenomena are exemplified by a reduction in structural porosity and surface hydroxyl groups with increasing temperature treatments of the zirconia support. Gold NP and ZrO2 supports were extended to studies that included interactions with activated carbons. This work was done on the premise that graphitic carbons, based on their tunable porosities

  3. Rational Emotive Education

    ERIC Educational Resources Information Center

    Knaus, William

    1977-01-01

    Rational Emotive Education--an outgrowth of theories developed by Albert Ellis--is a teaching design of mental health concepts and problem-solving activities designed to help students to approach and cope with their problems through experiential learning, via a structured, thematic sequence of emotive education lessons. (MJB)

  4. A kinetic study on the reduction of CO2 by frustrated Lewis pairs: from understanding to rational design.

    PubMed

    Liu, Lei; Vankova, Nina; Heine, Thomas

    2016-02-01

    Carbon dioxide (CO2) is known as one of the major reasons for global warming. On the other hand, CO2 is considered as an abundant carbon source. Therefore, transformation of CO2 into target chemicals nowadays is of great interest. Recently, a concept of so-called "frustrated Lewis pairs" (FLPs) has been proposed. Such FLPs show unusual reactivity, such as hydrogen activation and the reduction of CO2. In this study, by means of density functional theory (DFT) and ab initio calculations, we conduct a kinetic survey on the reduction of CO2 by a series of FLPs. We investigate the relationship between the electronic structures and kinetic properties. The kinetic properties include: (1) reaction energy barriers, (2) the structural properties of the associated transition states (TSs), and (3) the natural charge population in these TSs. Our results indicate that there is a systematic relationship between the electronic structures and the kinetic properties, and, as a rule of thumb, similar activation barriers for both individual reactions are needed for best performance. The derived relationship can be used not only to rationalize the published experimental results, but also to assist the future design of more efficient Lewis acid-base pairs as metal-free catalysts for the reduction of CO2. PMID:26751729

  5. Directed in vitro evolution of reporter genes based on semi-rational design and high-throughput screening.

    PubMed

    Xiong, Ai-Sheng; Yao, Quan-Hong; Peng, Ri-He; Cheng, Zong-Ming

    2010-01-01

    Marker genes, such as gusA, lacZ, and gfp, have been applied comprehensively in biological studies. Directed in vitro evolution provides a powerful tool for modifying genes and for studying gene structure, expression, and function. Here, we describe a strategy for directed in vitro evolution of reporter genes based on semi-rational design and high-throughput screening. The protocol involves two processes of DNA shuffling and screening. The first DNA shuffling and screening process involves eight steps: (1) amplifying the target gene by PCR, (2) cutting the product into random fragments with DNase I, (3) purification of 50-100 bp fragments, (4) reassembly of the fragments in a primerless PCR, (5) amplification of the reassembled product by primer PCR, (6) cloning into expression vector, (7) transformation of E. coli by electroporation, and (8) screening the target mutants using a nitrocellulose filter. The second DNA shuffling and screening process also involves the same eight steps, except that degenerate oligonucleotide primers are based on the sequence of the selected mutant. PMID:20676989

  6. Cell-penetrating conjugates of coproporphyrins with oligoarginine peptides: rational design and application for sensing intracellular O2.

    PubMed

    Dmitriev, Ruslan I; Ropiak, Honorata M; Ponomarev, Gelii V; Yashunsky, Dmitri V; Papkovsky, Dmitri B

    2011-12-21

    A panel of phosphorescent oligoarginine conjugates of tetracarboxylic Pt(II)-coproporphyrin I dye (PtCP), monosubstituted with long peptides or tetra-substituted with short peptides and having different linkers and peripheral groups, is described. Their photophysical properties, cell loading efficiency, and mechanisms of transport into the cell were investigated and compared. The conjugates were seen to rely on endocytotic mechanisms of cell entry, which are different from that of the unconjugated oligoarginine peptide, and show diverse patterns of intracellular distribution. On the basis of this study, the tetra-substituted PtCP conjugate displaying whole cell distribution was selected for the sensing of intracellular O(2). This probe has been tested in biological experiments on a fluorescence plate reader, including the monitoring of in situ oxygenation of respiring cells and their responses to metabolic stimulation. Similar conjugates of the phosphorescent Pd(II)-coprorphyrin and fluorescent coproporphyrin-ketone were also synthesized and assessed for the sensing of low levels intracellular O(2) and ratiometric pH-sensing, respectively. The results produced and the structure-activity relationships determined can facilitate the rational design of new bioconjugates of porphyrin dyes tailored to specific applications. PMID:22035070

  7. Rational Design of ZnO:H/ZnO Bilayer Structure for High-Performance Thin-Film Transistors.

    PubMed

    Abliz, Ablat; Huang, Chun-Wei; Wang, Jingli; Xu, Lei; Liao, Lei; Xiao, Xiangheng; Wu, Wen-Wei; Fan, Zhiyong; Jiang, Changzhong; Li, Jinchai; Guo, Shishang; Liu, Chuansheng; Guo, Tailiang

    2016-03-01

    The intriguing properties of zinc oxide-based semiconductors are being extensively studied as they are attractive alternatives to current silicon-based semiconductors for applications in transparent and flexible electronics. Although they have promising properties, significant improvements on performance and electrical reliability of ZnO-based thin film transistors (TFTs) should be achieved before they can be applied widely in practical applications. This work demonstrates a rational and elegant design of TFT, composed of poly crystalline ZnO:H/ZnO bilayer structure without using other metal elements for doping. The field-effect mobility and gate bias stability of the bilayer structured devices have been improved. In this device structure, the hydrogenated ultrathin ZnO:H active layer (∼3 nm) could provide suitable carrier concentration and decrease the interface trap density, while thick pure-ZnO layer could control channel conductance. Based on this novel structure, a high field-effect mobility of 42.6 cm(2) V(-1) s(-1), a high on/off current ratio of 10(8) and a small subthreshold swing of 0.13 V dec(-1) have been achieved. Additionally, the bias stress stability of the bilayer structured devices is enhanced compared to the simple single channel layer ZnO device. These results suggest that the bilayer ZnO:H/ZnO TFTs have a great potential for low-cost thin-film electronics. PMID:26977526

  8. Facile synthesis of optical microcavities by a rationally designed anodization approach: tailoring photonic signals by nanopore structure.

    PubMed

    Wang, Ye; Chen, Yuting; Kumeria, Tushar; Ding, Fuyuan; Evdokiou, Andreas; Losic, Dusan; Santos, Abel

    2015-05-13

    Structural engineering of porous anodic aluminum oxide (AAO) nanostructures by anodization has been extensively studied in the past two decades. However, the transition of this technique into the fabrication of AAO-based one-dimensional photonic crystal is still challenging. Herein, we report for the first time on the fabrication of AAO optical microcavities by a rationally designed anodization approach. In our study, two feasible methods are used to fabricate microcavities with tunable resonance peak across the visible and near-infrared spectra. Distributed Bragg reflector (DBR) nanostructures are first fabricated by pulse anodization approach, in which the anodization voltage was periodically manipulated to achieve pseudosinusoidal modulation of the effective refractive index gradient along the depth of the AAO nanostructures. Microcavities were created by creating a nanoporous layer of constant porosity between two AAO-DBR nanostructures, and by introducing a shift of the phase of the porosity gradient along the depth of AAO. The position of the resonance peak in these microcavities can be linearly tuned by means of the duration of the high voltage anodization. These optical nanostructures are sensitive to alterations of the effective media inside the nanopores. The AAO microcavity shows a central wavelength shift of 2.58 ± 0.37 nm when exposed to water vapor. Our research highlights the feasibility of anodization technique to fabricate AAO-based photonic nanostructures for advanced sensing applications. PMID:25901537

  9. Rational design, synthesis, and application of a new receptor for the molecular recognition of tricarboxylate salts in aqueous media.

    PubMed

    Frontera, Antonio; Morey, Jeroni; Oliver, Antonia; Piña, M Neus; Quiñonero, David; Costa, Antoni; Ballester, Pablo; Deyà, Pere M; Anslyn, Eric V

    2006-09-15

    A rational design of a tripodal receptor for the molecular recognition of tricarboxylate salts in aqueous media, based on squaramide, has been performed using high-level DFT calculations (RI-BP86/SVP level of theory) in solution using the COSMO treatment, including some preliminary ab initio calculations at the higher RI-MP2/TZVP level of theory, comparing the ability of squaramide to bind carboxylate salts with two widely used guanidinium salts. The tripodal receptor has been synthesized using a new methodology that has been recently reported by some of us, and its capability of recognizing several mono-, di-, and tricarboxylate salts has been studied experimentally by means of microcalorimetry experiments in a very high competitive media, H(2)O:EtOH 1:3. These experiments give enthalpic and entropic data, which are unfortunately scarce in the literature of molecular recognition of anions. Finally, a fluorimetric ensemble of the receptor with fluorescein has been found to be useful for the fluorimetric determination of zinc citrate in a commercial toothpaste using competition assays. PMID:16958511

  10. Rational design of carbonitrile-carboxaldehyde cation receptor models: probing the nature of the heteroatom-metal interaction.

    PubMed

    Rosli, Ahmad Nazmi; Abu Bakar, Maizathul Akmam; Lee, Vannajan Sanghiran; Zain, Sharifuddin Md; Ahmad, Mohd Rais; Abdul Manan, Ninie Suhana; Alias, Yatimah; Woi, Pei Meng

    2014-09-01

    In this work, hybrid functional and G4 methods were employed in the rational design of carbonitrile-carboxaldehyde receptor models for cation recognition. Electron-sharing and ionic interactions between the models and the cations were analyzed utilizing the concepts of overlap population, atomic valence, electrostatic potential, and CHELPG charge in order to elucidate the nature of the heteroatom-metal interaction, the N versus O disparity, and the effect of pH. Receptor fragment models from ionomycin were employed to rationalize the selection of receptor models for discriminating group I cations and enhancing the selectivity for Mg(II) rather than Ca(II), and to examine the effects of keto-enol forms and negatively charged sites. The changes in geometries, overlap population, metal valence, and CHELPG charge upon solvation in heptane medium as compared to the gas phase were negligible. The optimized geometries reveal that the interaction between group II cations and the keto, enol, and enolate forms of 2-cyanoethanal causes 12 % bending of the C-C-N angle from linearity. Overlap populations show that the electron-sharing interaction favors group II cations but that the same mechanism allows Li(I) to compete. The total spin of Li(I) is 17 % greater than that of Ca(II), but the G4 binding energies of the two are separated by more than 50 kcal/mol, favoring group II cations, which may eliminate interference from Li(I). 1,2-Dicyanoethylene, which has only one form, shows similar characteristics. CHELPG analysis shows that Mg(II) transfers 25 and 18 % of its positive charge to 2-cyanoethanal enolate and 1,2-dicyanoethylene, respectively. Hydrogen atoms receive most of the positive charge in both receptors, but the N-termini exhibit strikingly different characteristics. Electrostatic potential contour profiles were found to be in good agreement with the atomic charge distributions. The application of uncharged 1,3-dicarbonyl and 2-cyanocarbonyl receptors and a judicious

  11. 50 CFR 226.205 - Critical habitat for Snake River sockeye salmon, Snake River fall chinook salmon, and Snake River...

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies of the USGS publication and maps may be... salmon, Snake River fall chinook salmon, and Snake River spring/summer chinook salmon. 226.205 Section... Snake River sockeye salmon, Snake River fall chinook salmon, and Snake River spring/summer...

  12. 50 CFR 226.205 - Critical habitat for Snake River sockeye salmon, Snake River fall chinook salmon, and Snake River...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies of the USGS publication and maps may be... salmon, Snake River fall chinook salmon, and Snake River spring/summer chinook salmon. 226.205 Section... Snake River sockeye salmon, Snake River fall chinook salmon, and Snake River spring/summer...

  13. HYDROGEN INITIATIVE: AN INTEGRATED APPROACH TOWARD RATIONAL NANOCATALYST DESIGN FOR HYDROGEN PRODUCTION. Technical Report-Year 1

    SciTech Connect

    Vlachos, Dionisios G; Buttrey, Douglas J; Lauterbach, Jochen

    2007-03-29

    The overall objective of this grant is to develop a rational framework for the discovery of low cost, robust, and active nano-catalysts that will enable efficient hydrogen production. Our approach will be the first demonstration of integrated multiscale model, nano-catalyst synthesis, and nanoscale characterization assisted high throughput experimentation (HTE). We will initially demonstrate our approach with ammonia decomposition on noble metal catalysts. Our research focuses on many elements of the Hydrogen Initiative in the Focus Area of “Design of Catalysts at the Nanoscale’. It combines high-throughput screening methods with various nanostructure synthesis protocols, advanced measurements, novel in situ and ex situ characterization techniques, and multiscale theory, modeling and simulation. This project directly addresses several of the long-term goals of the DOE/BES program. In particular, new nanoscale catalytic materials will be synthesized, characterized and modeled for the production of hydrogen from ammonia and a computational framework will be developed for efficient extraction of information from experimental data and for rational design of catalysts whose impact goes well beyond the proposed hydrogen production project. In the first year of the grant, we have carried out HTE screening using a 16 parallel microreactor coupled with an FTIR analysis system. We screened nearly twenty single metals and several bimetallic catalysts as a function of temperature, catalyst loading, inlet composition, and temperature (order of 400 experiments). We have found that Ru is the best single metal catalyst and no better catalysts were found among the library of bimetallics we have created so far. Furthermore, we have investigated promoting effects (i.e., K, Cs, and Ba) of the Ru catalyst. We have found that K is the dominant promoter of increased Ru activity. Response surface experimental design has led to substantial improvements of the Ru catalyst with promotion

  14. Confucian Rationalism

    ERIC Educational Resources Information Center

    Lam, Chi-Ming

    2014-01-01

    Nowadays, there is still a widely held view that the Chinese and Western modes of thought are quite distinct from each other. In particular, the Chinese mode of thought derived from Confucianism is considered as comparatively less rational than the Western one. In this article, I first argue that although the analogical mode of argumentation,…

  15. Rational design of a fluorescent sensor to simultaneously determine both the enantiomeric composition and the concentration of chiral functional amines.

    PubMed

    Wen, Kaili; Yu, Shanshan; Huang, Zeng; Chen, Liming; Xiao, Meng; Yu, Xiaoqi; Pu, Lin

    2015-04-01

    A fluorescent molecular probe, a 1,1'-bi-2-naphthol (BINOL)-based bis(naphthylimine) compound (R)-4, is designed to exhibit very different fluorescent responses at two emission wavelengths toward a variety of chiral functional amines including diamines, amino alcohols, and amino acids. At one emission wavelength (λ1), it shows high sensitivity toward the substrates, and at another wavelength (λ2), it shows high enantioselectivity. This is the first rational design of such a dual responsive fluorescent sensor which can be used to simultaneously determine both the concentration and the enantiomeric composition of functional chiral amines by one fluorescent measurement. This strategy is potentially generally applicable for the construction of sensors for rapid assay of structurally diverse chiral substrates. When (R)-4 is treated with various chiral functional amines in the presence of Zn(OAc)2, its 2-naphthylamine units are displaced off to show large fluorescent enhancement at λ1 = 427 nm (I1) due to the restored emission of 2-naphthylamine. The combination of the remaining chiral binaphthyl unit with the chiral substrates leads to highly enantioselective fluorescent enhancement at λ2 > 500 nm (I2). Since I1 is only concentration dependent but independent of the chiral configuration, it allows the determination of the substrate concentration. The highly enantioselective I2 allows the determination of the enantiomeric composition. Thus, using one fluorescent probe with one fluorescent measurement, both the concentration and the enantiomeric composition are determined. The dual responsive mechanism of (R)-4 is studied by using various spectroscopic methods including fluorescence, UV-vis, NMR, and mass analyses. PMID:25790271

  16. Rational formulation design.

    PubMed

    Lane, M E; Hadgraft, J; Oliveira, G; Vieira, R; Mohammed, D; Hirata, K

    2012-12-01

    To be efficacious and to satisfy the requirements for claim substantiation, a cosmetic formulation must achieve effective targeting of an active in the skin. Although the basic principles governing the skin permeation and disposition of molecules have been known for many years, attention has been far less focused on the role of the vehicle, particularly at cosmetically relevant doses. In this article, we discuss the necessity to understand the fate of the formulation components as well as the active once applied onto skin. Recent data confirm that the residence time of the formulation constituents can have a profound impact on the fate of the active. Approaches to identify the ideal vehicle for skin delivery are considered critically, specifically the recent work on 'formulating for efficacy' (FFE) by the late Johann Wiechers. Essentially, FFE aims to match the active with the optimal vehicle for skin delivery based on matching polarity/solubility values of the trinity of skin, active and vehicle. The emerging importance of techniques that provide insight to how the vehicle distributes in and on skin is highlighted. PMID:22882873

  17. Where Galactic Snakes Live

    NASA Technical Reports Server (NTRS)

    2006-01-01

    This infrared image from NASA's Spitzer Space Telescope shows what astronomers are referring to as a 'snake' (upper left) and its surrounding stormy environment. The sinuous object is actually the core of a thick, sooty cloud large enough to swallow dozens of solar systems. In fact, astronomers say the 'snake's belly' may be harboring beastly stars in the process of forming.

    The galactic creepy crawler to the right of the snake is another thick cloud core, in which additional burgeoning massive stars might be lurking. The colorful regions below the two cloud cores are less dense cloud material, in which dust has been heated by starlight and glows with infrared light. Yellow and orange dots throughout the image are monstrous developing stars; the red star on the 'belly' of the snake is 20 to 50 times as massive as our sun. The blue dots are foreground stars.

    The red ball at the bottom left is a 'supernova remnant,' the remains of massive star that died in a fiery blast. Astronomers speculate that radiation and winds from the star before it died, in addition to a shock wave created when it exploded, might have played a role in creating the snake.

    Spitzer was able to spot the two black cloud cores using its heat-seeking infrared vision. The objects are hiding in the dusty plane of our Milky Way galaxy, invisible to optical telescopes. Because their heat, or infrared light, can sneak through the dust, they first showed up in infrared images from past missions. The cloud cores are so thick with dust that if you were to somehow transport yourself into the middle of them, you would see nothing but black, not even a star in the sky. Now, that's spooky!

    Spitzer's new view of the region provides the best look yet at the massive embryonic stars hiding inside the snake. Astronomers say these observations will ultimately help them better understand how massive stars form. By studying the clustering and range of masses of the stellar embryos, they hope

  18. Fear the serpent: A psychometric study of snake phobia.

    PubMed

    Polák, Jakub; Sedláčková, Kristýna; Nácar, David; Landová, Eva; Frynta, Daniel

    2016-08-30

    Millions of people worldwide suffer from specific phobias. Almost any stimulus may trigger a phobic reaction, but snakes are among the most feared objects. Half of the population feel anxious about snakes and 2-3% meet the diagnostic criteria for snake phobia. Despite such a high ratio, only one instrument is commonly used, the Snake Questionnaire (SNAQ). The aim of this study was to develop a standardized Czech translation, describe its psychometric properties and analyze the distribution of snake fears. In a counter-balanced design 755 respondents were asked to complete the English and Czech SNAQ (first or last) with a 2-3 month delay; 300 of them completed both instruments. We found excellent test-retest reliability (0.94), although the total scores differed significantly when the English version was administered first. The mean score was 5.80 and Generalized Linear Models revealed significant effects of sex and field of study (women and people with no biology education scored higher than men and biologists). A cut-off point for snake phobia as derived from a previous study identified 2.6% of the subjects as phobic. Finally, the score distribution was similar to other countries supporting the view that fear of snakes is universal. PMID:27280527

  19. Rationally designed graphene-nanotube 3D architectures with a seamless nodal junction for efficient energy conversion and storage

    PubMed Central

    Xue, Yuhua; Ding, Yong; Niu, Jianbing; Xia, Zhenhai; Roy, Ajit; Chen, Hao; Qu, Jia; Wang, Zhong Lin; Dai, Liming

    2015-01-01

    One-dimensional (1D) carbon nanotubes (CNTs) and 2D single-atomic layer graphene have superior thermal, electrical, and mechanical properties. However, these nanomaterials exhibit poor out-of-plane properties due to the weak van der Waals interaction in the transverse direction between graphitic layers. Recent theoretical studies indicate that rationally designed 3D architectures could have desirable out-of-plane properties while maintaining in-plane properties by growing CNTs and graphene into 3D architectures with a seamless nodal junction. However, the experimental realization of seamlessly-bonded architectures remains a challenge. We developed a strategy of creating 3D graphene-CNT hollow fibers with radially aligned CNTs (RACNTs) seamlessly sheathed by a cylindrical graphene layer through a one-step chemical vapor deposition using an anodized aluminum wire template. By controlling the aluminum wire diameter and anodization time, the length of the RACNTs and diameter of the graphene hollow fiber can be tuned, enabling efficient energy conversion and storage. These fibers, with a controllable surface area, meso-/micropores, and superior electrical properties, are excellent electrode materials for all-solid-state wire-shaped supercapacitors with poly(vinyl alcohol)/H2SO4 as the electrolyte and binder, exhibiting a surface-specific capacitance of 89.4 mF/cm2 and length-specific capacitance up to 23.9 mF/cm, — one to four times the corresponding record-high capacities reported for other fiber-like supercapacitors. Dye-sensitized solar cells, fabricated using the fiber as a counter electrode, showed a power conversion efficiency of 6.8% and outperformed their counterparts with an expensive Pt wire counter electrode by a factor of 2.5. These novel fiber-shaped graphene-RACNT energy conversion and storage devices are so flexible they can be woven into fabrics as power sources. PMID:26601246

  20. Rationally designed graphene-nanotube 3D architectures with a seamless nodal junction for efficient energy conversion and storage.

    PubMed

    Xue, Yuhua; Ding, Yong; Niu, Jianbing; Xia, Zhenhai; Roy, Ajit; Chen, Hao; Qu, Jia; Wang, Zhong Lin; Dai, Liming

    2015-09-01

    One-dimensional (1D) carbon nanotubes (CNTs) and 2D single-atomic layer graphene have superior thermal, electrical, and mechanical properties. However, these nanomaterials exhibit poor out-of-plane properties due to the weak van der Waals interaction in the transverse direction between graphitic layers. Recent theoretical studies indicate that rationally designed 3D architectures could have desirable out-of-plane properties while maintaining in-plane properties by growing CNTs and graphene into 3D architectures with a seamless nodal junction. However, the experimental realization of seamlessly-bonded architectures remains a challenge. We developed a strategy of creating 3D graphene-CNT hollow fibers with radially aligned CNTs (RACNTs) seamlessly sheathed by a cylindrical graphene layer through a one-step chemical vapor deposition using an anodized aluminum wire template. By controlling the aluminum wire diameter and anodization time, the length of the RACNTs and diameter of the graphene hollow fiber can be tuned, enabling efficient energy conversion and storage. These fibers, with a controllable surface area, meso-/micropores, and superior electrical properties, are excellent electrode materials for all-solid-state wire-shaped supercapacitors with poly(vinyl alcohol)/H2SO4 as the electrolyte and binder, exhibiting a surface-specific capacitance of 89.4 mF/cm(2) and length-specific capacitance up to 23.9 mF/cm, - one to four times the corresponding record-high capacities reported for other fiber-like supercapacitors. Dye-sensitized solar cells, fabricated using the fiber as a counter electrode, showed a power conversion efficiency of 6.8% and outperformed their counterparts with an expensive Pt wire counter electrode by a factor of 2.5. These novel fiber-shaped graphene-RACNT energy conversion and storage devices are so flexible they can be woven into fabrics as power sources. PMID:26601246

  1. Site-Directed Mutagenesis of a Hyperthermophilic Endoglucanase Cel12B from Thermotoga maritima Based on Rational Design

    PubMed Central

    Zhang, Jinfeng; Shi, Hao; Xu, Linyu; Zhu, Xiaoyan; Li, Xiangqian

    2015-01-01

    To meet the demand for the application of high activity and thermostable cellulases in the production of new-generation bioethanol from nongrain-cellulose sources, a hyperthermostable β-1,4-endoglucase Cel12B from Thermotoga maritima was selected for further modification by gene site-directed mutagenesis method in the present study, based on homology modeling and rational design. As a result, two recombinant enzymes showed significant improvement in enzyme activity by 77% and 87%, respectively, higher than the parental enzyme TmCel12B. Furthermore, the two mutants could retain 80% and 90.5% of their initial activity after incubation at 80°C for 8 h, while only 45% for 5 h to TmCel12B. The Km and Vmax of the two recombinant enzymes were 1.97±0.05 mM, 4.23±0.15 μmol·mg-1·min-1 of TmCel12B-E225H-K207G-D37V, and 2.97±0.12 mM, 3.15±0.21 μmol·mg-1·min-1 of TmCel12B-E225H-K207G, respectively, when using CMC-Na as the substrate. The roles of the mutation sites were also analyzed and evaluated in terms of electron density, hydrophobicity of the modeled protein structures. The recombinant enzymes may be used in the hydrolysis of cellulose at higher temperature in the future. It was concluded that the gene mutagenesis approach of a certain active residues may effectively improve the performance of cellulases for the industrial applications and contribute to the study the thermostable mechanism of thermophilic enzymes. PMID:26218520

  2. Facet-dependent stripping behavior of Cu2O microcrystals toward lead ions: a rational design for the determination of lead ions.

    PubMed

    Liu, Zhong-Gang; Sun, Yu-Feng; Chen, Wen-Kai; Kong, Yuan; Jin, Zhen; Chen, Xing; Zheng, Xiao; Liu, Jin-Huai; Huang, Xing-Jiu; Yu, Shu-Hong

    2015-06-01

    Facet-dependent stripping behavior in the determination of Pb(II): Well-defined Cu2O microcrystals with different structures show facet-dependent electrochemical behaviors toward heavy metal ions. This provides an important insight into the understanding the efficiency of facet-dependent properties of microcrystals on electroanalytical performance for the rational design of electrochemical analytical techniques for efficient detection of heavy metal ions. PMID:25630388

  3. Reproductive strategies in snakes.

    PubMed Central

    Shine, Richard

    2003-01-01

    Snakes of both sexes display remarkable flexibility and diversity in their reproductive tactics. Many features of reproduction in female snakes (such as reproductive mode and frequency, seasonality and multiple mating) allow flexible maternal control. For example, females can manipulate not only the genotypes of their offspring (through mate choice or enhanced sperm competition) but also the phenotypes of their offspring (through allocation 'decisions', behavioural and physiological thermoregulation, and nest-site selection). Reliance on stored energy ('capital') to fuel breeding results in low frequencies of female reproduction and, in extreme cases, semelparity. A sophisticated vomeronasal system not only allows male snakes to locate reproductive females by following scent trails, but also facilitates pheromonally mediated mate choice by males. Male-male rivalry takes diverse forms, including female mimicry and mate guarding; combat bouts impose strong selection for large body size in males of some species. Intraspecific (geographical) variation and phenotypic plasticity in a wide array of reproductive traits (offspring size and number; reproductive frequency; incidence of multiple mating; male tactics such as mate guarding and combat; mate choice criteria) provide exceptional opportunities for future studies. PMID:12803888

  4. Snakes Have Feelings, Too: Elements of a Camp Snake Program.

    ERIC Educational Resources Information Center

    Allen, Robert Ross

    2001-01-01

    A camp snake program can help campers overcome their fear of snakes, and people cannot truly enjoy nature when they carry a phobia about any one part of it. It can also help overcome prejudice by teaching truth and respect, instilling compassion, and helping campers develop empathy. Advice on catching, handling, identifying, keeping, and feeding…

  5. Rationalization: A Bibliography.

    ERIC Educational Resources Information Center

    Pedrini, D. T.; Pedrini, Bonnie C.

    Rationalization was studied by Sigmund Freud and was specifically labeled by Ernest Jones. Rationalization ought to be differentiated from rational, rationality, logical analysis, etc. On the one hand, rationalization is considered a defense mechanism, on the other hand, rationality is not. Haan has done much work with self-report inventories and…

  6. Rational design, synthesis, and biological evaluation of lactam-bridged gramicidin A analogues: discovery of a low-hemolytic antibacterial peptide.

    PubMed

    Mao, Ji; Kuranaga, Takefumi; Hamamoto, Hiroshi; Sekimizu, Kazuhisa; Inoue, Masayuki

    2015-03-01

    A linear peptide, gramicidin A (GA), folds into a β(6.3) -helix, functions as an ion channel in the cell membrane, and exerts antibacterial activity. Herein we describe the rational design, synthesis, and biological evaluation of lactam-bridged GA analogues. The GA analogue with a 27-membered macrolactam was found to adopt a stable β(6.3) -helical conformation and exhibits higher ion-exchange activity than GA. Furthermore, this GA analogue retains the potent antibiotic activity of GA, but its hemolytic activity and toxicity toward mammalian cells are significantly lower than those of GA. This study thus dissociates the antibacterial and hemolytic/cytotoxic activities of GA, and charts a rational path forward for the development of new ion-channel-based antibiotics. PMID:25510221

  7. Quantum snake walk on graphs

    SciTech Connect

    Rosmanis, Ansis

    2011-02-15

    I introduce a continuous-time quantum walk on graphs called the quantum snake walk, the basis states of which are fixed-length paths (snakes) in the underlying graph. First, I analyze the quantum snake walk on the line, and I show that, even though most states stay localized throughout the evolution, there are specific states that most likely move on the line as wave packets with momentum inversely proportional to the length of the snake. Next, I discuss how an algorithm based on the quantum snake walk might potentially be able to solve an extended version of the glued trees problem, which asks to find a path connecting both roots of the glued trees graph. To the best of my knowledge, no efficient quantum algorithm solving this problem is known yet.

  8. Snake bite: pit vipers.

    PubMed

    Peterson, Michael E

    2006-11-01

    Pit vipers are the largest group of venomous snakes in the United States and are involved in an estimated 150,000 bites annually of dogs and cats. The severity of any pit viper bite is related to the volume and toxicity of the venom injected as well as the location of the bite, which may influence the rate of venom uptake. The toxicity of rattlesnake venom varies widely. It is possible for pit vipers' venom to be strictly neurotoxic with virtually no local signs of envenomation. Venom consists of 90% water and has a minimum of 10 enzymes and 3 to 12 nonenzymatic proteins and peptides in any individual snake. The onset of clinical signs after envenomation may be delayed for several hours. The presence of fang marks does not indicate that envenomation has occurred, only that a bite has taken place. Systemic clinical manifestations encompass a wide variety of problems including pain, weakness, dizziness, nausea, severe hypotension, and thrombocytopenia. The victim's clotting abnormalities largely depend upon the species of snake involved. Venom induced thrombocytopenia occurs in approximately 30% of envenomations. Many first aid measures have been advocated for pit viper bite victims, none has been shown to prevent morbidity or mortality. Current recommendations for first aid in the field are to keep the victim calm, keep the bite site below heart level if possible, and transport the victim to a veterinary medical facility for primary medical intervention. The patient should be hospitalized and monitored closely for a minimum of 8 hours for the onset of signs of envenomation. The only proven specific therapy against pit viper envenomation is the administration of antivenin. The dosage of antivenin needed is calculated relative to the amount of venom injected, the body mass of the victim, and the bite site. The average dosage in dogs and cats is 1 to 2 vials of antivenin. PMID:17265901

  9. Rational design of sub-parts per million specific gas sensors array based on metal nanoparticles decorated nanowire enhancement-mode transistors.

    PubMed

    Zou, Xuming; Wang, Jingli; Liu, Xingqiang; Wang, Chunlan; Jiang, Ying; Wang, Yong; Xiao, Xiangheng; Ho, Johnny C; Li, Jinchai; Jiang, Changzhong; Fang, Ying; Liu, Wei; Liao, Lei

    2013-07-10

    "One key to one lock" hybrid sensor configuration is rationally designed and demonstrated as a direct effective route for the target-gas-specific, highly sensitive, and promptly responsive chemical gas sensing for room temperature operation in a complex ambient background. The design concept is based on three criteria: (i) quasi-one-dimensional metal oxide nanostructures as the sensing platform which exhibits good electron mobility and chemical and thermal stability; (ii) deep enhancement-mode field-effect transistors (E-mode FETs) with appropriate threshold voltages to suppress the nonspecific sensitivity to all gases (decouple the selectivity and sensitivity away from nanowires); (iii) metal nanoparticle decoration onto the nanostructure surface to introduce the gas specific selectivity and sensitivity to the sensing platform. In this work, using Mg-doped In2O3 nanowire E-mode FET sensor arrays decorated with various discrete metal nanoparticles (i.e., Au, Ag, and Pt) as illustrative prototypes here further confirms the feasibility of this design. Particularly, the Au decorated sensor arrays exhibit more than 3 orders of magnitude response to the exposure of 100 ppm CO among a mixture of gases at room temperature. The corresponding response time and detection limit are as low as ∼4 s and ∼500 ppb, respectively. All of these could have important implications for this "one key to one lock" hybrid sensor configuration which potentially open up a rational avenue to the design of advanced-generation chemical sensors with unprecedented selectivity and sensitivity. PMID:23796312

  10. Self-assembling magnetic "snakes"

    SciTech Connect

    2010-01-01

    Nickel particles float peacefully in a liquid medium until a giant snake seems to swim by and snatch several particles up, adding to its own mass. The self-assembled "snakes" act like biological systems, but they are not alive and are driven by a magnetic field. The research may someday offer some insight into the organization of life itself. Read more at Wired: http://www.wired.com/wiredscience/2009/03/snakes/ Research and video by Alex Snezhko and Igor Aronson, Argonne National Laboratory.

  11. ENGINEERING OF THE AGS SNAKE COIL ASSEMBLY.

    SciTech Connect

    ANERELLA,M.GUPTA,R.KOVACH,P.MARONE,A.PLATE,S.POWER,K.SCHMALZLE,J.WILLEN,E.

    2003-05-12

    A 30% Snake superconducting magnet is proposed to maintain polarization in the AGS proton beam, the magnetic design of which is described elsewhere. The required helical coils for this magnet push the limits of the technology developed for the RHIC Snake coils. First, fields must be provided with differing pitch along the length of the magnet. To accomplish this, a new 3-D CAD system (''Pro/Engineer'' from PTC), which uses parametric techniques to enable fast iterations, has been employed. Revised magnetic field calculations are then based on the output of the mechanical model. Changes are made in turn to the model on the basis of those field calculations. To ensure that accuracy is maintained, the final solid model is imported directly into the CNC machine programming software, rather than by the use of graphics translating software. Next, due to the large coil size and magnetic field, there was concern whether the structure could contain the coil forces. A finite element analysis was performed, using the 3-D model, to ensure that the stresses and deflections were acceptable. Finally, a method was developed using ultrasonic energy to improve conductor placement during coil winding, in an effort to minimize electrical shorts due to conductor misplacement, a problem that occurred in the RHIC helical coil program. Each of these activities represents a significant improvement in technology over that which was used previously for the RHIC snake coils.

  12. Spin rotators and split Siberian Snakes

    SciTech Connect

    Roser, Thomas

    1994-03-01

    The study of spin effects in the collision of polarized high energy beams requires flexible and compact spin rotators to manipulate the beam polarization direction. Design criteria and specific examples are presented for high energy, orbit transparent spin rotators ranging from small angle rotators to be used for the excitation of spin resonances to large angle rotators to be used as Siberian Snakes. It is shown that all the requirements for spin rotators can be met with a simple 6-magnet spin rotator design, for which a complete continuous solution is presented.

  13. Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents That Target and Modulate Multiple Facets of Alzheimer’s Disease

    PubMed Central

    Lee, Sanghyun; Zheng, Xueyun; Krishnamoorthy, Janarthanan; Savelieff, Masha G.; Park, Hyun Min; Brender, Jeffrey R.; Kim, Jin Hoon; Derrick, Jeffrey S.; Kochi, Akiko; Lee, Hyuck Jin; Kim, Cheal; Ramamoorthy, Ayyalusamy; Bowers, Michael T.; Lim, Mi Hee

    2014-01-01

    Alzheimer’s disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress. We report a novel compound (ML) prototype of a rationally designed molecule obtained by integrating structural elements for Aβ aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single molecule. Chemical, biochemical, ion mobility mass spectrometric, and NMR studies indicate that the compound ML targets metal-free and metal-bound Aβ (metal–Aβ) species, suppresses Aβ aggregation in vitro, and diminishes toxicity induced by Aβ and metal-treated Aβ in living cells. Comparison of ML to its structural moieties (i.e., 4-(dimethylamino)phenol (DAP) and (8-aminoquinolin-2-yl)methanol (1)) for reactivity with Aβ and metal–Aβ suggests the synergy of incorporating structural components for both metal chelation and Aβ interaction. Moreover, ML is water-soluble and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, we demonstrate that a rational structure-based design strategy can generate a small molecule that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity. PMID:24397771

  14. Rational design of anatase TiO2 architecture with hierarchical nanotubes and hollow microspheres for high-performance dye-sensitized solar cells

    NASA Astrophysics Data System (ADS)

    Gu, Jiuwang; Khan, Javid; Chai, Zhisheng; Yuan, Yufei; Yu, Xiang; Liu, Pengyi; Wu, Mingmei; Mai, Wenjie

    2016-01-01

    Large surface area, sufficient light-harvesting and superior electron transport property are the major factors for an ideal photoanode of dye-sensitized solar cells (DSSCs), which requires rational design of the nanoarchitectures and smart integration of state-of-the-art technologies. In this work, a 3D anatase TiO2 architecture consisting of vertically aligned 1D hierarchical TiO2 nanotubes (NTs) with ultra-dense branches (HTNTs, bottom layer) and 0D hollow TiO2 microspheres with rough surface (HTS, top layer) is first successfully constructed on transparent conductive fluorine-doped tin oxide glass through a series of facile processes. When used as photoanodes, the DSSCs achieve a very large short-current density of 19.46 mA cm-2 and a high overall power conversion efficiency of 8.38%. The remarkable photovoltaic performance is predominantly ascribed to the enhanced charge transport capacity of the NTs (function as the electron highway), the large surface area of the branches (act as the electron branch lines), the pronounced light harvesting efficiency of the HTS (serve as the light scattering centers), and the engineered intimate interfaces between all of them (minimize the recombination effect). Our work demonstrates a possibility of fabricating superior photoanodes for high-performance DSSCs by rational design of nanoarchitectures and smart integration of multi-functional components.

  15. A Rationally Designed Nitrogen-Rich Metal-Organic Framework and Its Exceptionally High CO2 and H2 Uptake Capability

    PubMed Central

    Wang, Xiao-Jun; Li, Pei-Zhou; Chen, Yifei; Zhang, Quan; Zhang, Huacheng; Chan, Xiu Xiang; Ganguly, Rakesh; Li, Yongxin; Jiang, Jianwen; Zhao, Yanli

    2013-01-01

    On the way towards a sustainable low-carbon future, the design and construction of chemical or physical adsorbents for CO2 capture and clean energy storage are vital technology. The incorporation of accessible nitrogen-donor sites into the pore walls of porous adsorbents can dramatically affect the CO2 uptake capacity and selectivity on account of the dipole-quadrupole interactions between the polarizable CO2 molecule and the accessible nitrogen site. In the present work, a nitrogen-rich rth-type metal-organic framework (MOF) was constructed based on rational design and careful synthesis. The MOF presents exceptionally high uptake capacity not only for CO2 but also for H2, which is attributed to favorable interactions between the gas molecules and the nitrogen-rich triazole units of the MOF proved by both experimental measurements and theoretical molecular simulations. PMID:23359632

  16. A Rationally Designed Nitrogen-Rich Metal-Organic Framework and Its Exceptionally High CO2 and H2 Uptake Capability

    NASA Astrophysics Data System (ADS)

    Wang, Xiao-Jun; Li, Pei-Zhou; Chen, Yifei; Zhang, Quan; Zhang, Huacheng; Chan, Xiu Xiang; Ganguly, Rakesh; Li, Yongxin; Jiang, Jianwen; Zhao, Yanli

    2013-01-01

    On the way towards a sustainable low-carbon future, the design and construction of chemical or physical adsorbents for CO2 capture and clean energy storage are vital technology. The incorporation of accessible nitrogen-donor sites into the pore walls of porous adsorbents can dramatically affect the CO2 uptake capacity and selectivity on account of the dipole-quadrupole interactions between the polarizable CO2 molecule and the accessible nitrogen site. In the present work, a nitrogen-rich rth-type metal-organic framework (MOF) was constructed based on rational design and careful synthesis. The MOF presents exceptionally high uptake capacity not only for CO2 but also for H2, which is attributed to favorable interactions between the gas molecules and the nitrogen-rich triazole units of the MOF proved by both experimental measurements and theoretical molecular simulations.

  17. Development of Snake Fungal Disease after Experimental Challenge with Ophidiomyces ophiodiicola in Cottonmouths (Agkistrodon piscivorous)

    PubMed Central

    Allender, Matthew C.; Baker, Sarah; Wylie, Daniel; Loper, Daniel; Dreslik, Michael J.; Phillips, Christopher A.; Maddox, Carol; Driskell, Elizabeth A.

    2015-01-01

    Snake fungal disease (SFD) is a clinical syndrome associated with dermatitis, myositis, osteomyelitis, and pneumonia in several species of free-ranging snakes in the US. The causative agent has been suggested as Ophidiomyces ophiodiicola, but other agents may contribute to the syndrome and the pathogenesis is not understood. To understand the role of O. ophiodiicola in SFD, a cottonmouth snake model of SFD was designed. Five cottonmouths (Agkistrodon piscivorous) were experimentally challenged by nasolabial pit inoculation with a pure culture of O. ophiodiicola. Development of skin lesions or facial swelling at the site of inoculation was observed in all snakes. Twice weekly swabs of the inoculation site revealed variable presence of O. ophiodiicola DNA by qPCR in all five inoculated snakes for 3 to 58 days post-inoculation; nasolabial flushes were not a useful sampling method for detection. Inoculated snakes had a 40% mortality rate. All inoculated snakes had microscopic lesions unilaterally on the side of the swabbed nasolabial pit, including erosions to ulcerations and heterophilic dermatitis. All signs were consistent with SFD; however, the severity of lesions varied in individual snakes, and fungal hyphae were only observed in 3 of 5 inoculated snakes. These three snakes correlated with post-mortem tissue qPCR evidence of O. ophiodiicola. The findings of this study conclude that O. ophiodiicola inoculation in a cottonmouth snake model leads to disease similar to SFD, although lesion severity and the fungal load are quite variable within the model. Future studies may utilize this model to further understand the pathogenesis of this disease and develop management strategies that mitigate disease effects, but investigation of other models with less variability may be warranted. PMID:26469977

  18. Rationally re-designed mutation of NAD-independent l-lactate dehydrogenase: high optical resolution of racemic mandelic acid by the engineered Escherichia coli

    PubMed Central

    2012-01-01

    Background NAD-independent l-lactate dehydrogenase (l-iLDH) from Pseudomonas stutzeri SDM can potentially be used for the kinetic resolution of small aliphatic 2-hydroxycarboxylic acids. However, this enzyme showed rather low activity towards aromatic 2-hydroxycarboxylic acids. Results Val-108 of l-iLDH was changed to Ala by rationally site-directed mutagenesis. The l-iLDH mutant exhibited much higher activity than wide-type l-iLDH towards l-mandelate, an aromatic 2-hydroxycarboxylic acid. Using the engineered Escherichia coli expressing the mutant l-iLDH as a biocatalyst, 40 g·L-1 of dl-mandelic acid was converted to 20.1 g·L-1 of d-mandelic acid (enantiomeric purity higher than 99.5%) and 19.3 g·L-1 of benzoylformic acid. Conclusions A new biocatalyst with high catalytic efficiency toward an unnatural substrate was constructed by rationally re-design mutagenesis. Two building block intermediates (optically pure d-mandelic acid and benzoylformic acid) were efficiently produced by the one-pot biotransformation system. PMID:23176608

  19. Managed care and efficient rationing.

    PubMed

    Rosenthal, Meredith B; Newhouse, Joseph P

    2002-01-01

    Widespread dissatisfaction with managed care has led to calls for major reform and consumer protection. Although some have concluded that managed care backlash is simply a result of too much rationing, we propose an alternative view that focuses on the nature of services eliminated by managed care. In particular, we point out that managed care rations services largely without regard to consumer preferences. We question whether managed care's emphasis on supply-side control of moral hazard is consistent with the principles of efficient rationing. Further research on the nature of provider and consumer rationing decisions is needed to inform the design of supply-side and demand-side incentives that will lead to an efficient allocation of services. PMID:12148660

  20. Rational Design of Disulfide Bonds Increases Thermostability of a Mesophilic 1,3-1,4-β-Glucanase from Bacillus terquilensis

    PubMed Central

    Xu, Xin; Li, Qi

    2016-01-01

    1,3–1,4-β-glucanase is an important biocatalyst in brewing industry and animal feed industry, while its low thermostability often reduces its application performance. In this study, the thermostability of a mesophilic β-glucanase from Bacillus terquilensis was enhanced by rational design and engineering of disulfide bonds in the protein structure. Protein spatial configuration was analyzed to pre-exclude the residues pairs which negatively conflicted with the protein structure and ensure the contact of catalytic center. The changes in protein overall and local flexibility among the wild-type enzyme and the designated mutants were predicted to select the potential disulfide bonds for enhancement of thermostability. Two residue pairs (N31C-T187C and P102C-N125C) were chosen as engineering targets and both of them were proved to significantly enhance the protein thermostability. After combinational mutagenesis, the double mutant N31C-T187C/P102C-N125C showed a 48.3% increase in half-life value at 60°C and a 4.1°C rise in melting temperature (Tm) compared to wild-type enzyme. The catalytic property of N31C-T187C/P102C-N125C mutant was similar to that of wild-type enzyme. Interestingly, the optimal pH of double mutant was shifted from pH6.5 to pH6.0, which could also increase its industrial application. By comparison with mutants with single-Cys substitutions, the introduction of disulfide bonds and the induced new hydrogen bonds were proved to result in both local and overall rigidification and should be responsible for the improved thermostability. Therefore, the introduction of disulfide bonds for thermostability improvement could be rationally and highly-effectively designed by combination with spatial configuration analysis and molecular dynamics simulation. PMID:27100881

  1. ISOB: A Database of Indigenous Snake Species of Bangladesh with respective known venom composition

    PubMed Central

    Roly, Zahida Yesmin; Hakim, Md Abdul; Zahan, ASM Shahriar; Hossain, M Monzur; Reza, Md Abu

    2015-01-01

    At present there is no well structured database available for the venomous snakes and venom composition of snakes in the world although venom has immense importance in biomedical research. Searching for a specific venom component from NCBI, PDB or public databases is troublesome, because they contain huge amount of data entries. Therefore, we created a database named “ISOB” which is a web accessible unique secondary database that represents the first online available bioinformatics resource showing venom composition of snakes. This database provides a comprehensive overview of seventy-eight indigenous snake species covering description of snakes supplemented with structural information of the relevant individual available venom proteins. We strongly believe that this database will contribute significantly in the field of bioinformatics, environmental research, proteomics, drug development and rationale drug designing. Availability The database is freely available at http://www.snakebd.com/ PMID:25848172

  2. The burrowing origin of modern snakes

    PubMed Central

    Yi, Hongyu; Norell, Mark A.

    2015-01-01

    Modern snakes probably originated as habitat specialists, but it controversial unclear whether they were ancestrally terrestrial burrowers or marine swimmers. We used x-ray virtual models of the inner ear to predict the habit of Dinilysia patagonica, a stem snake closely related to the origin of modern snakes. Previous work has shown that modern snakes perceive substrate vibrations via their inner ear. Our data show that D. patagonica and modern burrowing squamates share a unique spherical vestibule in the inner ear, as compared with swimmers and habitat generalists. We built predictive models for snake habit based on their vestibular shape, which estimated D. patagonica and the hypothetical ancestor of crown snakes as burrowers with high probabilities. This study provides an extensive comparative data set to test fossoriality quantitatively in stem snakes, and it shows that burrowing was predominant in the lineages leading to modern crown snakes. PMID:26702436

  3. [Constitutional requirements of rationing].

    PubMed

    Kluth, Winfried

    2008-01-01

    Rationing is an emotive issue in the field of public health. This complicates the rational discourse, which is indispensable for analyzing the rationing conditions as set out by constitutional law and which requires manifold differentiation and consideration that shall briefly be outlined in the following short contribution. Of central significance is the distinction between indirect and direct rationing as well as the reference to the essential responsibility of legislators for rationing decisions. PMID:19004184

  4. Energy Scaling of Spin Tune due to RHIC Snakes

    SciTech Connect

    MacKay,W.W.

    2009-01-02

    For a ring like RHIC with two full Siberian snakes on opposite sides of the ring, the spin tune for a flat orbit will be 1/2 if the snake rotation axes are perpendicular, {Delta}{phi} = {phi}{sub 9}-{phi}{sub 3} = {pi}/2. Here {phi}{sup 9} and {phi}{sub 3} are respectively the direction of the rotation axes of the 9 o'clock and 3 o'clock snakes relative to the design trajectory as shown in Figure 1. If the two snakes are slightly detuned by the same amount such that the rotation axes are no longer perpendicular, then the deviation of the closed-orbit spin tune {nu}{sub 0} from 1/2 is given by {Delta}{nu}{sub 0} {approx_equal} ({Delta}{mu}){sup 2}/4{pi} cosG{gamma}{pi} - 2{Delta}{phi}/{pi} {approx_equal} 2{Delta}{phi}/180{sup o} with G{gamma} at a half integer, and where {Delta}{mu} is the deviation of snake rotation angle from 180{sup o}. It should be noted that there is a sign ambiguity in {Delta}{mu}{sub 0} since a spin tune of 0.495 is also a spin tune of 0.505, depending on the direction taken along the stable spin axis. In order to understand the effect of energy scaling on the snake axis direction, I have integrated the trajectory and spin rotation through a model of a RHIC snake (bi9-snk7) and found the energy (U) dependence of the snake axis angle {phi}{sub 9} and rotation angle {mu} as shown. A {approx_equal} p{sup -2} scaling of errors is typical in helical snakes. To first order, the orbit excursion drops as p{sup -1} and the spin precessions about transverse fields increase as {gamma} giving an approximate cancellation with energy, so we do not expect much change during the field ramp. The next order term which comes in is primarily proportional to p{sup -2}; although naively one might expect a slight effect inversely proportional to the velocity since {gamma}/p {proportional_to} c/{nu} {approx_equal} 1 + 1/2{gamma}{sup 2}.

  5. Study of the design and analytical properties of the lethality neutralization assay used to estimate antivenom potency against Bothrops asper snake venom.

    PubMed

    Solano, Gabriela; Segura, Alvaro; Herrera, María; Gómez, Aarón; Villalta, Mauren; Gutiérrez, José María; León, Guillermo

    2010-09-01

    The lethality neutralization assay performed in mice is the standard recommended by the World Health Organization to estimate antivenom potency. The interpretation of its results without considering its analytical capacity may lead to erroneous conclusions. Therefore, laboratories that manufacture or control antivenoms must demonstrate the appropriateness of their models. A study of the method used at Instituto Clodomiro Picado, Costa Rica, to estimate the potency of antivenoms against Bothrops asper snake venom was performed. Results show that venom doses ranging from 2 to 6 Median Lethal Doses (LD50) are appropriate to be used as challenge in this test. Variables such as the injection route, number of mice used per venom/antivenom level, and weight of the animals are critical in the estimation of the Median Effective Dose (ED50), whereas incubation time is not. The assay has an acceptable selectivity, linearity, and limits of detection and quantification. Accuracy of the lethality neutralization assay, expressed as percentage recovery, was between 71% and 127%. Intermediate precision, expressed as relative standard deviation, was < or = 17%. It is concluded that the analytical characteristics of this assay are adequate enough to prove product compliance and to have statistical control over an industrial line of antivenom serial production. PMID:20638298

  6. Diagnostic uses of snake venom.

    PubMed

    Marsh, N A

    2001-01-01

    Snake venom toxins are invaluable for the assay of coagulation factors and for the study of haemostasis generally. Thrombin-like enzymes (SVTLE) are used for fibrinogen and fibrinogen breakdown product assays as well as detecting dysfibrinogenaemias. Since SVTLE are not inhibited by heparin, they can be used for assaying antithrombin III in samples containing heparin. Snake venom prothrombin activators are utilised in prothrombin assays, whilst Russell's viper venom (RVV) can be used to assay clotting factors V, VII, X and lupus anticoagulants (LA). Activators from the taipan, Australian brown snake and saw-scaled viper have also been used to assay LA. Protein C (PC) and activated PC (APC) resistance can be measured by means of RVV, Protac (from Southern copperhead snake venom) and STA-Staclot (from Crotalus viridis helleri) whilst von Willebrand factor can be studied with Botrocetin (Bothrops jararaca). Finally, snake venom C-type lectins and metalloproteinase disintegrins are being used to study platelet glycoprotein receptors and show great potential for use in the routine coagulation laboratory. PMID:11910187

  7. Rational Design, Synthesis, and Preliminary Structure-Activity Relationships of α-Substituted-2-Phenylcyclopropane Carboxylic Acids as Inhibitors of Salmonella typhimurium O-Acetylserine Sulfhydrylase.

    PubMed

    Pieroni, Marco; Annunziato, Giannamaria; Beato, Claudia; Wouters, Randy; Benoni, Roberto; Campanini, Barbara; Pertinhez, Thelma A; Bettati, Stefano; Mozzarelli, Andrea; Costantino, Gabriele

    2016-03-24

    Cysteine is a building block for several biomolecules that are crucial for living organisms. The last step of cysteine biosynthesis is catalyzed by O-acetylserine sulfydrylase (OASS), a highly conserved pyridoxal 5'-phosphate (PLP)-dependent enzyme, present in different isoforms in bacteria, plants, and nematodes, but absent in mammals. Beside the biosynthesis of cysteine, OASS exerts a series of "moonlighting" activities in bacteria, such as transcriptional regulation, contact-dependent growth inhibition, swarming motility, and induction of antibiotic resistance. Therefore, the discovery of molecules capable of inhibiting OASS would be a valuable tool to unravel how this protein affects the physiology of unicellular organisms. As a continuation of our efforts toward the synthesis of OASS inhibitors, in this work we have used a combination of computational and spectroscopic approaches to rationally design, synthesize, and test a series of substituted 2-phenylcyclopropane carboxylic acids that bind to the two S. typhymurium OASS isoforms at nanomolar concentrations. PMID:26894308

  8. Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics.

    PubMed

    Luz, John Gately; Antonysamy, Stephen; Kuklish, Steven L; Condon, Bradley; Lee, Matthew R; Allison, Dagart; Yu, Xiao-Peng; Chandrasekhar, Srinivasan; Backer, Ryan; Zhang, Aiping; Russell, Marijane; Chang, Shawn S; Harvey, Anita; Sloan, Ashley V; Fisher, Matthew J

    2015-06-11

    Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E2 (PGE2) from prostaglandin H2 (PGH2). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH2 synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure-activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies. PMID:25961169

  9. 33 CFR 117.1058 - Snake River.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Snake River. 117.1058 Section 117... OPERATION REGULATIONS Specific Requirements Washington § 117.1058 Snake River. (a) The draw of the Burlington Northern Santa Fe railroad bridge across the Snake River at mile 1.5 between Pasco and Burbank...

  10. 33 CFR 117.1058 - Snake River.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Snake River. 117.1058 Section 117... OPERATION REGULATIONS Specific Requirements Washington § 117.1058 Snake River. (a) The draw of the Burlington Northern Santa Fe railroad bridge across the Snake River at mile 1.5 between Pasco and Burbank...

  11. 33 CFR 117.331 - Snake Creek.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false Snake Creek. 117.331 Section 117.331 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Florida § 117.331 Snake Creek. The draw of the Snake...

  12. Coyotes Are Afraid of Little Snakes.

    ERIC Educational Resources Information Center

    Weewish Tree, 1979

    1979-01-01

    Wichita tale of a contest between Coyote and Small Snake to see whose teeth are strongest. They bite each other, and soon big, strong Coyote is dead from the poisoned bite of the tiny snake. Explains why, from that time onward, coyotes have been afraid of little snakes. (DS)

  13. 33 CFR 117.331 - Snake Creek.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Snake Creek. 117.331 Section 117.331 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Florida § 117.331 Snake Creek. The draw of the Snake...

  14. 33 CFR 117.331 - Snake Creek.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Snake Creek. 117.331 Section 117.331 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Florida § 117.331 Snake Creek. The draw of the Snake...

  15. 33 CFR 117.331 - Snake Creek.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Snake Creek. 117.331 Section 117.331 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Florida § 117.331 Snake Creek. The draw of the Snake...

  16. 33 CFR 117.331 - Snake Creek.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Snake Creek. 117.331 Section 117.331 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Florida § 117.331 Snake Creek. The draw of the Snake...

  17. The Egg-Eating Snake, Introductory Problem, Explorations in Biology.

    ERIC Educational Resources Information Center

    Mid-Continent Regional Educational Lab., Inc., Kansas City, MO.

    The booklet is designed as an introduction to a series of topics which use the same format, and which are published separately. A series of photographs of a snake eating an egg are used to ask students to identify a puzzling event that they would want to investigate if they were biologists. A scrambled programed text format is used to direct…

  18. Rational design of carboxyl groups perpendicularly attached to a graphene sheet: a platform for enhanced biosensing applications.

    PubMed

    Bonanni, Alessandra; Chua, Chun Kiang; Pumera, Martin

    2014-01-01

    Graphene oxide (GO)-based materials offer great potential for biofunctionalization with applications ranging from biosensing to drug delivery. Such biofunctionalization utilizes specific functional groups, typically a carboxyl moiety, as anchoring points for biomolecule. However, due to the fact that the exact chemical structure of GO is still largely unknown and poorly defined (it was postulated to consist of various oxygen-containing groups, such as epoxy, hydroxyl, carboxyl, carbonyl, and peroxy in varying ratios), it is challenging to fabricate highly biofunctionalized GO surfaces. The predominant anchoring sites (i.e., carboxyl groups) are mainly present as terminal groups on the edges of GO sheets and thus account for only a fraction of the oxygen-containing groups on GO. Herein, we suggest a direct solution to the long-standing problem of limited abundance of carboxyl groups on GO; GO was first reduced to graphene and consequently modified with only carboxyl groups grafted perpendicularly to its surface by a rational synthesis using free-radical addition of isobutyronitrile with subsequent hydrolysis. Such grafted graphene oxide can contain a high amount of carboxyl groups for consequent biofunctionalization, at which the extent of grafting is limited only by the number of carbon atoms in the graphene plane; in contrast, the abundance of carboxyl groups on "classical" GO is limited by the amount of terminal carbon atoms. Such a graphene platform embedded with perpendicularly grafted carboxyl groups was characterized in detail by X-ray photoelectron spectroscopy, cyclic voltammetry, and electrochemical impedance spectroscopy, and its application was exemplified with single-nucleotide polymorphism detection. It was found that the removal of oxygen functionalities after the chemical reduction enhanced the electron-transfer rate of the graphene. More importantly, the introduction of carboxyl groups promoted a more efficient immobilization of DNA probes on the

  19. Rational design of liposomal drug delivery systems, a review: Combined experimental and computational studies of lipid membranes, liposomes and their PEGylation.

    PubMed

    Bunker, Alex; Magarkar, Aniket; Viitala, Tapani

    2016-10-01

    Combined experimental and computational studies of lipid membranes and liposomes, with the aim to attain mechanistic understanding, result in a synergy that makes possible the rational design of liposomal drug delivery system (LDS) based therapies. The LDS is the leading form of nanoscale drug delivery platform, an avenue in drug research, known as "nanomedicine", that holds the promise to transcend the current paradigm of drug development that has led to diminishing returns. Unfortunately this field of research has, so far, been far more successful in generating publications than new drug therapies. This partly results from the trial and error based methodologies used. We discuss experimental techniques capable of obtaining mechanistic insight into LDS structure and behavior. Insight obtained purely experimentally is, however, limited; computational modeling using molecular dynamics simulation can provide insight not otherwise available. We review computational research, that makes use of the multiscale modeling paradigm, simulating the phospholipid membrane with all atom resolution and the entire liposome with coarse grained models. We discuss in greater detail the computational modeling of liposome PEGylation. Overall, we wish to convey the power that lies in the combined use of experimental and computational methodologies; we hope to provide a roadmap for the rational design of LDS based therapies. Computational modeling is able to provide mechanistic insight that explains the context of experimental results and can also take the lead and inspire new directions for experimental research into LDS development. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Róg. PMID:26915693

  20. Physical Characterization of Tobramycin Inhalation Powder: I. Rational Design of a Stable Engineered-Particle Formulation for Delivery to the Lungs.

    PubMed

    Miller, Danforth P; Tan, Trixie; Tarara, Thomas E; Nakamura, John; Malcolmson, Richard J; Weers, Jeffry G

    2015-08-01

    A spray-dried engineered particle formulation, Tobramycin Inhalation Powder (TIP), was designed through rational selection of formulation composition and process parameters. This PulmoSphere powder comprises small, porous particles with a high drug load. As a drug/device combination, TOBI Podhaler enables delivery of high doses of drug per inhalation, a feature critical for dry powder delivery of anti-infectives for treatment of cystic fibrosis. The objective of this work was to characterize TIP on both the particle and molecular levels using multiple orthogonal physical characterization techniques. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), electron spectroscopy for chemical analysis (ESCA), and Raman measurements show that a TIP particle consists of two phases: amorphous, glassy tobramycin sulfate with a glass transition temperature of about 100 °C and a gel-phase phospholipid (DSPC) with a gel-to-liquid-crystal transition temperature of about 80 °C. This was by design and constituted a rational formulation approach to provide Tg and Tm values that are well above the temperatures used for long-term storage of TIP. Raman and ESCA data provide support for a core/shell particle architecture of TIP. Particle surfaces are enriched with a porous, hydrophobic coating that reduces cohesive forces, improving powder fluidization and dispersibility. The excellent aerosol dispersibility of TIP enables highly efficient delivery of fine particles to the respiratory tract. Collectively, particle engineering has enabled development of TOBI Podhaler, an approved inhaled drug product that meaningfully reduces the treatment burden to cystic fibrosis patients worldwide. PMID:26052676

  1. Using Magnetic Stir Bars To Determine Digestive Passage Rate in an Ectotherm, the Garter Snake.

    ERIC Educational Resources Information Center

    Temple, John G.

    2002-01-01

    Details how students, working under the guidance of an instructor, design an experiment to test the relationship of temperature and digestive passage rate in garter snakes. Allows students to formulate and test hypotheses. (DDR)

  2. Considerations in the rational design and conduct of phase I/II pediatric clinical trials: avoiding the problems and pitfalls.

    PubMed

    Abdel-Rahman, S M; Reed, M D; Wells, T G; Kearns, G L

    2007-04-01

    Over the past decade, there has been a heightened awareness of the need to include children in the drug development process. With this awareness has come an expansion of the infrastructure for conducting studies in children and an increase in the sponsorship of pediatric clinical trials. However, the growth in pediatric research has, in many cases, not been accompanied by an increase in the involvement of trained pediatric investigators when it comes to trial design and/or interpretation. Pediatric phase I/II protocols continue to span a spectrum from those that are carefully constructed to those that are poorly designed. This paper highlights the basic elements of phase I/II protocols that merit unique consideration when the clinical trial involves children. Illustrations are provided from our experience, which highlight problems that may arise when trials are not designed with the pediatric patient in mind. PMID:17329988

  3. Multiple Partial Siberian Snakes in the AGS

    SciTech Connect

    Takano, J.; Ahrens, L. A.; Bai, M.; Brown, K.; Courant, E. D.; Gardner, C. J.; Glenn, J. W.; Huang, H.; Luccio, A. U.; MacKay, W. W.; Okamura, M.; Roser, T.; Tepikian, S.; Tsoupas, N.; Yip, K.; Zelenski, A.; Zeno, K.; Hattori, T.; Lin, F.

    2007-06-13

    Polarized protons are accelerated up to 24.3 GeV in the Alternating Gradient Synchrotron (AGS) at Brookhaven National Laboratory (BNL). To accelerate the beam with preserving the polarization, two different types of helical dipole partial Siberian snake have been installed to the AGS. One is a superconducting magnet (Cold Snake, CSNK), and the other is a normal conducting one (Warm Snake, WSNK). With these snake magnets, the polarization at the AGS extraction achieved 65%. However, the AGS has spin mismatches at the injection and extraction. This description shows calculated results to have better spin matching with using two or three snakes.

  4. Snake venom toxins: toxicity and medicinal applications.

    PubMed

    Chan, Yau Sang; Cheung, Randy Chi Fai; Xia, Lixin; Wong, Jack Ho; Ng, Tzi Bun; Chan, Wai Yee

    2016-07-01

    Snake venoms are complex mixtures of small molecules and peptides/proteins, and most of them display certain kinds of bioactivities. They include neurotoxic, cytotoxic, cardiotoxic, myotoxic, and many different enzymatic activities. Snake envenomation is a significant health issue as millions of snakebites are reported annually. A large number of people are injured and die due to snake venom poisoning. However, several fatal snake venom toxins have found potential uses as diagnostic tools, therapeutic agent, or drug leads. In this review, different non-enzymatically active snake venom toxins which have potential therapeutic properties such as antitumor, antimicrobial, anticoagulating, and analgesic activities will be discussed. PMID:27245678

  5. Solving rational matrix equations in the state space with applications to computer-aided control-system design

    NASA Technical Reports Server (NTRS)

    Packard, A. K.; Sastry, S. S.

    1986-01-01

    A method of solving a class of linear matrix equations over various rings is proposed, using results from linear geometric control theory. An algorithm, successfully implemented, is presented, along with non-trivial numerical examples. Applications of the method to the algebraic control system design methodology are discussed.

  6. Rational Design of High-Number dsDNA Fragments Based on Thermodynamics for the Construction of Full-Length Genes in a Single Reaction

    PubMed Central

    Birla, Bhagyashree S.; Chou, Hui-Hsien

    2015-01-01

    Gene synthesis is frequently used in modern molecular biology research either to create novel genes or to obtain natural genes when the synthesis approach is more flexible and reliable than cloning. DNA chemical synthesis has limits on both its length and yield, thus full-length genes have to be hierarchically constructed from synthesized DNA fragments. Gibson Assembly and its derivatives are the simplest methods to assemble multiple double-stranded DNA fragments. Currently, up to 12 dsDNA fragments can be assembled at once with Gibson Assembly according to its vendor. In practice, the number of dsDNA fragments that can be assembled in a single reaction are much lower. We have developed a rational design method for gene construction that allows high-number dsDNA fragments to be assembled into full-length genes in a single reaction. Using this new design method and a modified version of the Gibson Assembly protocol, we have assembled 3 different genes from up to 45 dsDNA fragments at once. Our design method uses the thermodynamic analysis software Picky that identifies all unique junctions in a gene where consecutive DNA fragments are specifically made to connect to each other. Our novel method is generally applicable to most gene sequences, and can improve both the efficiency and cost of gene assembly. PMID:26716828

  7. Rational Design of a GFP-Based Fluorogenic Caspase Reporter for Imaging Apoptosis In Vivo.

    PubMed

    To, Tsz-Leung; Schepis, Antonino; Ruiz-González, Rubén; Zhang, Qiang; Yu, Dan; Dong, Zhiqiang; Coughlin, Shaun R; Shu, Xiaokun

    2016-07-21

    Fluorescence resonance energy transfer-based executioner caspase reporters using GFP are important tools for imaging apoptosis. While these reporters are useful for imaging apoptosis in cultured cells, their in vivo application has been handicapped by poor signal to noise. Here, we report the design and characterization of a GFP-based fluorogenic protease reporter, dubbed ZipGFP. ZipGFP-based TEV protease reporter increased fluorescence 10-fold after activation by protease. A ZipGFP-based executioner caspase reporter visualized apoptosis in live zebrafish embryos with spatiotemporal resolution. Thus, the ZipGFP-based caspase reporter may be useful for monitoring apoptosis during animal development and for designing reporters of proteases beyond the executioner caspases. PMID:27447051

  8. Species identification from dried snake venom.

    PubMed

    Singh, Chandra S; Gaur, Ajay; Sreenivas, Ara; Singh, Lalji

    2012-05-01

    Illegal trade in snake parts has increased enormously. In spite of strict protection under wildlife act, a large number of snakes are being killed ruthlessly in India for venom and skin. Here, an interesting case involving confiscation of crystallized dried snake venom and subsequent DNA-based species identification is reported. The analysis using the universal primers for cytochrome b region of the mitochondrial DNA revealed that the venom was extracted from an Indian cobra (Naja naja). On the basis of this report, the forwarding authority booked a case in the court of law against the accused for illegal hunting of an endangered venomous snake and smuggling of snake venom. This approach thus has immense potential for rapid identification of snake species facing endangerment because of illegal trade. This is also the first report of DNA isolation from dried snake venom for species identification. PMID:22268640

  9. Rational Design of a Multiepitope Vaccine Encoding T-Lymphocyte Epitopes for Treatment of Chronic Hepatitis B Virus Infections▿

    PubMed Central

    Depla, Erik; Van der Aa, Annegret; Livingston, Brian D.; Crimi, Claire; Allosery, Koen; De Brabandere, Veronique; Krakover, Jonathan; Murthy, Sidharta; Huang, Manley; Power, Scott; Babé, Lilia; Dahlberg, Carol; McKinney, Denise; Sette, Alessandro; Southwood, Scott; Philip, Ramilla; Newman, Mark J.; Meheus, Lydie

    2008-01-01

    Protein sequences from multiple hepatitis B virus (HBV) isolates were analyzed for the presence of amino acid motifs characteristic of cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte (HTL) epitopes with the goal of identifying conserved epitopes suitable for use in a therapeutic vaccine. Specifically, sequences bearing HLA-A1, -A2, -A3, -A24, -B7, and -DR supertype binding motifs were identified, synthesized as peptides, and tested for binding to soluble HLA. The immunogenicity of peptides that bound with moderate to high affinity subsequently was assessed using HLA transgenic mice (CTL) and HLA cross-reacting H-2bxd (BALB/c × C57BL/6J) mice (HTL). Through this process, 30 CTL and 16 HTL epitopes were selected as a set that would be the most useful for vaccine design, based on epitope conservation among HBV sequences and HLA-based predicted population coverage in diverse ethnic groups. A plasmid DNA-based vaccine encoding the epitopes as a single gene product, with each epitope separated by spacer residues to enhance appropriate epitope processing, was designed. Immunogenicity testing in mice demonstrated the induction of multiple CTL and HTL responses. Furthermore, as a complementary approach, mass spectrometry allowed the identification of correctly processed and major histocompatibility complex-presented epitopes from human cells transfected with the DNA plasmid. A heterologous prime-boost immunization with the plasmid DNA and a recombinant MVA gave further enhancement of the immune responses. Thus, a multiepitope therapeutic vaccine candidate capable of stimulating those cellular immune responses thought to be essential for controlling and clearing HBV infection was successfully designed and evaluated in vitro and in HLA transgenic mice. PMID:17942551

  10. Rationing medical education.

    PubMed

    Walsh, Kieran

    2016-03-01

    The purpose of this paper is to discuss the role of rationing in medical education. Medical education is expensive and there is a limit to that which governments, funders or individuals can spend on it. Rationing involves the allocation of resources that are limited. This paper discussed the pros and cons of the application of rationing to medical education and the different forms of rationing that could be applied. Even though some stakeholders in medical education might be taken aback at the prospect of rationing, the truth is that rationing has always occurred in one form or another in medical education and in healthcare more broadly. Different types of rationing exist in healthcare professional education. For example rationing may be implicit or explicit or may be based on macro-allocation or micro-allocation decisions. Funding can be distributed equally among learners, or according to the needs of individual learners, or to ensure that overall usefulness is maximised. One final option is to allow the market to operate freely and to decide in that way. These principles of rationing can apply to individual learners or to institutions or departments or learning modes. Rationing is occurring in medical education, even though it might be implicit. It is worth giving consideration to methods of rationing and to make thinking about rationing more explicit. PMID:27358649

  11. A rational design for improving the trypsin resistance of aflatoxin-detoxifizyme (ADTZ) based on molecular structure evaluation.

    PubMed

    Qiu, Yuxin; Wu, Xiyang; Xie, Chunfang; Hu, Yadong; Liu, Daling; Ma, Yi; Yao, Dongsheng

    2016-05-01

    The resistance of feed enzymes against proteases is crucial in livestock farming. In this study, the trypsin resistance of aflatoxin-detoxifizyme (ADTZ) is improved. ADTZ possesses 72 lys/arg residue sites, 45 of which are scattered on the outermost layers of the molecule (RSA≧25%). These 45 lys/arg sites could be target sites for trypsin hydrolysis. By considering shape-matching (including physical and secondary bond interactions) and the "induced fit-effect", we hypothesized that some of these lys/arg sites are vulnerable to trypsin. A protein-protein docking simulation method was used to avoid the massive computational requirements and to address the intricacy of selecting candidate sites, as candidate site selection is affected by space displacement. Optimal mutants (K244Q/K213C/K270T and R356E/K357T/R623C) were predicted by computational design with protein folding energy analysis and molecular dynamics simulations. A trypsin digestion assay was performed, and the mutants displayed much higher stability against trypsin hydrolysis compared to the native enzyme. Moreover, temperature- and pH-activity profiles revealed that the designed mutations did not affect the catalytic activity of the enzyme. PMID:26992797

  12. Molecular Dynamics (MD) Simulation Directed Rational Design of Inhibitors Targeting Drug-Resistant Mutants of Influenza A Virus M2

    PubMed Central

    Wang, Jun; Ma, Chunlong; Fiorin, Giacomo; Carnevale, Vincenzo; Wang, Tuo; Hu, Fanghao; Lamb, Robert A.; Pinto, Lawrence H.; Hong, Mei; Klein, Michael L.; DeGrado, William F.

    2012-01-01

    Influenza A virus M2 (A/M2) forms a homotetrameric proton selective channel in the viral membrane. It has been the drug targets of antiviral drugs such as amantadine and rimantadine. However, most of the current virulent influenza A viruses carry drug resistant mutations alongside the drug binding site, such as S31N, V27A, and L26F etc., each of which might be dominant in a given flu season. Among these mutations, the V27A mutation was prevalent among transmissible viruses under drug selection pressure. Until now, V27A has not been successfully targeted by small molecule inhibitors, despite years of extensive medicinal chemistry research efforts and high throughput screening. Guided by molecular dynamics (MD) simulation of drug binding and the influence of drug binding on the dynamics of A/M2 from earlier experimental studies, we designed a series of potent spirane amine inhibitors targeting not only WT, but also both A/M2-27A and L26F mutants with IC50s similar to that seen for amantadine's inhibition of the WT channel. The potencies of these inhibitors were further demonstrated in experimental binding and plaque reduction assays. These results demonstrate the power of MD simulations to probe the mechanism of drug binding as well as the ability to guide design of inhibitors of targets that had previously appeared to be undruggable. PMID:21744829

  13. Theoretical investigations on maleimide and its indolyl derivatives: Rational drug design approach for PKCβII inhibitors

    NASA Astrophysics Data System (ADS)

    Grewal, Baljinder K.; Sobhia, M. Elizabeth

    2012-12-01

    Protein kinase C βII (PKCβII) is preferentially activated during the hyperglycemic state and is associated with various diabetic complications. Hence its inhibition would be one of the ways to treat the diabetic complications. Maleimide constitutes the important moiety of PKCβII inhibitors, however till date no study on the significance of maleimide toward PKCβII inhibition is performed. Present report endeavors to study the electronic properties of maleimide with relevance to PKCβII inhibition. In the crystal structure of PKCβII, maleimide moiety of co-crystallized ligand 2-methyl-1H-indol-3-yl-BIM-1 is reported to form 3H-bonds, to reckon the importance of these H-bonds "H-bond interaction energy" was calculated using the ONIOM method, taking into consideration only the single point energy of the protein-ligand structure. New class of PKCβII inhibitors are designed based on above studies result and comparative analysis of rings similar to maleimide on the basis of various quantum chemical descriptors. The designed molecule showed good potency, binding interactions and scores in docking and ONIOM single point energy study.

  14. Spin Motion Near Snake Resonances

    SciTech Connect

    Barber, D. P.; Vogt, M.

    2007-06-13

    We give a brief account of on-going work on the loss of polarisation during acceleration close to so-called snake resonances in proton storage rings. We show that within the model studied here the polarisation can be preserved if the rate of acceleration is low enough.

  15. Tolerance of Snakes to Hypergravity

    NASA Technical Reports Server (NTRS)

    Lillywhite, H. B.; Ballard, R. E.; Hargens, A. R.

    1994-01-01

    Sensitivity of carotid blood flow to +Gz (head-to-tail) acceleration was studied in six species of snakes hypothesized to show varied adaptive cardiovascular responses to gravity. Blood flow in the proximal carotid artery was measured in 15 snakes before, during and following stepwise increments of +0.25Gz force produced on a 2.4 m diameter centrifuge. During centrifugation each snake was confined to a straight position within an individually- fitted acrylic tube with the head facing the center of rotation. We measured the centrifugal force at the tail of the snake in order to quantify the maximum intensity of force gradient promoting antero-posterior pooling of blood. Tolerance to increased gravity was quantified as the acceleration force at which carotid blood flow ceased. This parameter varied according to the gravitational adaptation of species defined by their ecology and behavior. At the extremes, carotid blood flow decreased in response to increasing gravity and approached zero near +1Gz in aquatic and ground-dwelling species, whereas in climbing species carotid flow was maintained at forces in excess of +2Gz. Surprisingly, tolerant (arboreal) species withstood hypergravic forces of +2 to +3 G. for periods up to 1 h without cessation of carotid blood flow or apparent loss of consciousness. Data suggest that relatively tight skin of the tolerant species provides a natural antigravity suit which is of prime importance in counteracting Gz stress on blood circulation.

  16. Synthesis and extraction studies with a rationally designed diamide ligand selective to actinide(iv) pertinent to the plutonium uranium redox extraction process.

    PubMed

    Sharma, Shikha; Panja, Surajit; Bhattacharyya, Arunasis; Dhami, Prem S; Gandhi, Preetam M; Ghosh, Sunil K

    2016-05-01

    A new class of conformationally constrained oxa-bridged tricyclo-dicarboxamide (OTDA) ligand was rationally designed for the selective extraction of tetravalent actinides pertinent to the Plutonium Uranium Redox EXtraction (PUREX) process. Two of the designed diamide ligands were synthesized and extraction studies were performed for Pu(iv) from HNO3 medium. The mechanism of extraction was investigated by studying various parameters such as feed HNO3, NaNO3 and OTDA concentrations. The nature of the extracted species was found to be [Pu(NO3)4(OTDA)]. One of the OTDA ligands was elaborately tested and showed the selective extraction of Pu(iv) and Np(iv) over other actinide species, viz., U(vi), Np(v), Am(iii), lanthanides and fission products contained in a nuclear waste from the PUREX process. DFT calculations predicted the charge density on each of the coordinating 'O' atoms of OTDA supporting its high Pu(iv) selectivity over other ions studied and also provided the energy optimized structure of OTDA and its Pu(iv) complex. PMID:27054892

  17. A de novo NADPH generation pathway for improving lysine production of Corynebacterium glutamicum by rational design of the coenzyme specificity of glyceraldehyde 3-phosphate dehydrogenase.

    PubMed

    Bommareddy, Rajesh Reddy; Chen, Zhen; Rappert, Sugima; Zeng, An-Ping

    2014-09-01

    Engineering the cofactor availability is a common strategy of metabolic engineering to improve the production of many industrially important compounds. In this work, a de novo NADPH generation pathway is proposed by altering the coenzyme specificity of a native NAD-dependent glyceraldehyde 3-phosphate dehydrogenase (GAPDH) to NADP, which consequently has the potential to produce additional NADPH in the glycolytic pathway. Specifically, the coenzyme specificity of GAPDH of Corynebacterium glutamicum is systematically manipulated by rational protein design and the effect of the manipulation for cellular metabolism and lysine production is evaluated. By a combinatorial modification of four key residues within the coenzyme binding sites, different GAPDH mutants with varied coenzyme specificity were constructed. While increasing the catalytic efficiency of GAPDH towards NADP enhanced lysine production in all of the tested mutants, the most significant improvement of lysine production (~60%) was achieved with the mutant showing similar preference towards both NAD and NADP. Metabolic flux analysis with (13)C isotope studies confirmed that there was no significant change of flux towards the pentose phosphate pathway and the increased lysine yield was mainly attributed to the NADPH generated by the mutated GAPDH. The present study highlights the importance of protein engineering as a key strategy in de novo pathway design and overproduction of desired products. PMID:24953302

  18. A systematic quantitative approach to rational drug design and discovery of novel human carbonic anhydrase IX inhibitors.

    PubMed

    Sethi, Kalyan K; Verma, Saurabh M

    2014-08-01

    Drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed for a series of carbonic anhydrase IX inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques with the help of SYBYL 7.1 software. The large set of 36 different aromatic/heterocyclic sulfamates carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, such as hCA IX, was chosen for this study. The conventional ligand-based 3D-QSAR studies were performed based on the low energy conformations employing database alignment rule. The ligand-based model gave q(2) values 0.802 and 0.829 and r(2) values 1.000 and 0.994 for CoMFA and CoMSIA, respectively, and the predictive ability of the model was validated. The predicted r(2) values are 0.999 and 0.502 for CoMFA and CoMSIA, respectively. SEA (steric, electrostatic, hydrogen bond acceptor) of CoMSIA has the significant contribution for the model development. The docking of inhibitors into hCA IX active site using Glide XP (Schrödinger) software revealed the vital interactions and binding conformation of the inhibitors. The CoMFA and CoMSIA field contour maps are well in agreement with the structural characteristics of the binding pocket of hCA IX active site, which suggests that the information rendered by 3D-QSAR models and the docking interactions can provide guidelines for the development of improved hCA IX inhibitors as leads for various types of metastatic cancers including those of cervical, renal, breast and head and neck origin. PMID:24090419

  19. Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses.

    PubMed

    Zervoudi, Efthalia; Saridakis, Emmanuel; Birtley, James R; Seregin, Sergey S; Reeves, Emma; Kokkala, Paraskevi; Aldhamen, Yasser A; Amalfitano, Andrea; Mavridis, Irene M; James, Edward; Georgiadis, Dimitris; Stratikos, Efstratios

    2013-12-01

    Intracellular aminopeptidases endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), and as well as insulin-regulated aminopeptidase (IRAP) process antigenic epitope precursors for loading onto MHC class I molecules and regulate the adaptive immune response. Their activity greatly affects the antigenic peptide repertoire presented to cytotoxic T lymphocytes and as a result can regulate cytotoxic cellular responses contributing to autoimmunity or immune evasion by viruses and cancer cells. Therefore, pharmacological regulation of their activity is a promising avenue for modulating the adaptive immune response with possible applications in controlling autoimmunity, in boosting immune responses to pathogens, and in cancer immunotherapy. In this study we exploited recent structural and biochemical analysis of ERAP1 and ERAP2 to design and develop phosphinic pseudopeptide transition state analogs that can inhibit this family of enzymes with nM affinity. X-ray crystallographic analysis of one such inhibitor in complex with ERAP2 validated our design, revealing a canonical mode of binding in the active site of the enzyme, and highlighted the importance of the S2' pocket for achieving inhibitor potency. Antigen processing and presentation assays in HeLa and murine colon carcinoma (CT26) cells showed that these inhibitors induce increased cell-surface antigen presentation of transfected and endogenous antigens and enhance cytotoxic T-cell responses, indicating that these enzymes primarily destroy epitopes in those systems. This class of inhibitors constitutes a promising tool for controlling the cellular adaptive immune response in humans by modulating the antigen processing and presentation pathway. PMID:24248368

  20. Functional and Mechanistic Analyses of Biomimetic Aminoacyl Transfer Reactions in de novo Designed Coiled Coil Peptides via Rational Active Site Engineering

    PubMed Central

    Leman, Luke J.; Weinberger, Dana A.; Huang, Zheng-Zheng; Wilcoxen, Keith M.; Ghadiri, M. Reza

    2008-01-01

    Ribosomes and nonribosomal peptide synthetases (NRPSs) carry out instructed peptide synthesis through a series of directed intermodular aminoacyl transfer reactions. We recently reported the design of coiled-coil assemblies that could functionally mimic the elementary aminoacyl loading and intermodular aminoacyl transfer steps of NRPSs. These peptides were designed initially to accelerate aminoacyl transfer mainly through catalysis by approximation by closely juxtaposing four active site moieties, two each from adjacent noncovalently-associated helical modules. In our designs peptide self-assembly positions a cysteine residue that is used to covalently capture substrates from solution via transthiolesterification (substrate loading step to generate the aminoacyl donor site) adjacent to an aminoacyl acceptor site provided by a covalently tethered amino acid or modeled by the ε-amine of an active site lysine. However, through systematic functional analyses of 48 rationally designed peptide sequences, we have now determined that the substrate loading and intermodular aminoacyl transfer steps can be significantly influenced (up to ~103-fold) by engineering changes in the active site microenvironment through amino acid substitutions and variations in the inter-residue distances and geometry. Mechanistic studies based on 15N-NMR and kinetic analysis further indicate that certain active site constellations furnish an unexpectedly large pKa depression (1.5 pH units) of the aminoacyl-acceptor moiety, helping to explain the observed high rates of aminoacyl transfer in those constructs. Taken together, our studies demonstrate the feasibility of engineering efficient de novo peptide sequences possessing active sites and functions reminiscent of those in natural enzymes. PMID:17302417

  1. Rational design of a fluorescent NADPH derivative imaging constitutive nitric-oxide synthases upon two-photon excitation

    PubMed Central

    Li, Yun; Wang, Huan; Tarus, Bogdan; Perez, Miguel Romero; Morellato, Laurence; Henry, Etienne; Berka, Vladimir; Tsai, Ah-Lim; Ramassamy, Booma; Dhimane, Hamid; Dessy, Chantal; Tauc, Patrick; Boucher, Jean-Luc; Deprez, Eric; Slama-Schwok, Anny

    2012-01-01

    We report the structure-based design and synthesis of a unique NOS inhibitor, called nanoshutter NS1, with two-photon absorption properties. NS1 targets the NADPH site of NOS by a nucleotide moiety mimicking NADPH linked to a conjugated push–pull chromophore with nonlinear absorption properties. Because NS1 could not provide reducing equivalents to the protein and competed with NADPH binding, it efficiently inhibited NOS catalysis. NS1 became fluorescent once bound to NOS with an excellent signal-to-noise ratio because of two-photon excitation avoiding interference from the flavin–autofluorescence and because free NS1 was not fluorescent in aqueous solutions. NS1 fluorescence enhancement was selective for constitutive NOS in vitro, in particular for endothelial NOS (eNOS). Molecular dynamics simulations suggested that two variable residues among NOS isoforms induced differences in binding of NS1 and in local solvation around NS1 nitro group, consistent with changes of NS1 fluorescence yield. NS1 colocalized with eNOS in living human umbilical vein endothelial cells. Thus, NS1 constitutes a unique class of eNOS probe with two-photon excitation in the 800–950-nm range, with great perspectives for eNOS imaging in living tissues. PMID:22802674

  2. Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability

    PubMed Central

    Camilloni, Carlo; Sala, Benedetta Maria; Sormanni, Pietro; Porcari, Riccardo; Corazza, Alessandra; De Rosa, Matteo; Zanini, Stefano; Barbiroli, Alberto; Esposito, Gennaro; Bolognesi, Martino; Bellotti, Vittorio; Vendruscolo, Michele; Ricagno, Stefano

    2016-01-01

    A wide range of human diseases is associated with mutations that, destabilizing proteins native state, promote their aggregation. However, the mechanisms leading from folded to aggregated states are still incompletely understood. To investigate these mechanisms, we used a combination of NMR spectroscopy and molecular dynamics simulations to compare the native state dynamics of Beta-2 microglobulin (β2m), whose aggregation is associated with dialysis-related amyloidosis, and its aggregation-resistant mutant W60G. Our results indicate that W60G low aggregation propensity can be explained, beyond its higher stability, by an increased average protection of the aggregation-prone residues at its surface. To validate these findings, we designed β2m variants that alter the aggregation-prone exposed surface of wild-type and W60G β2m modifying their aggregation propensity. These results allowed us to pinpoint the role of dynamics in β2m aggregation and to provide a new strategy to tune protein aggregation by modulating the exposure of aggregation-prone residues. PMID:27150430

  3. G4-DNA Formation in the HRAS Promoter and Rational Design of Decoy Oligonucleotides for Cancer Therapy

    PubMed Central

    Membrino, Alexandro; Cogoi, Susanna; Pedersen, Erik B.; Xodo, Luigi E.

    2011-01-01

    HRAS is a proto-oncogene involved in the tumorigenesis of urinary bladder cancer. In the HRAS promoter we identified two G-rich elements, hras-1 and hras-2, that fold, respectively, into an antiparallel and a parallel quadruplex (qhras-1, qhras-2). When we introduced in sequence hras-1 or hras-2 two point mutations that block quadruplex formation, transcription increased 5-fold, but when we stabilized the G-quadruplexes by guanidinium phthalocyanines, transcription decreased to 20% of control. By ChIP we found that sequence hras-1 is bound only by MAZ, while hras-2 is bound by MAZ and Sp1: two transcription factors recognizing guanine boxes. We also discovered by EMSA that recombinant MAZ-GST binds to both HRAS quadruplexes, while Sp1-GST only binds to qhras-1. The over-expression of MAZ and Sp1 synergistically activates HRAS transcription, while silencing each gene by RNAi results in a strong down-regulation of transcription. All these data indicate that the HRAS G-quadruplexes behave as transcription repressors. Finally, we designed decoy oligonucleotides mimicking the HRAS quadruplexes, bearing (R)-1-O-[4-(1-Pyrenylethynyl) phenylmethyl] glycerol and LNA modifications to increase their stability and nuclease resistance (G4-decoys). The G4-decoys repressed HRAS transcription and caused a strong antiproliferative effect, mediated by apoptosis, in T24 bladder cancer cells where HRAS is mutated. PMID:21931711

  4. Structural and Functional Analysis of G Protein–Coupled Receptor Kinase Inhibition by Paroxetine and a Rationally Designed Analog

    PubMed Central

    Homan, Kristoff T.; Wu, Emily; Wilson, Michael W.; Singh, Puja; Larsen, Scott D.

    2014-01-01

    Recently we identified the serotonin reuptake inhibitor paroxetine as an inhibitor of G protein–coupled receptor kinase 2 (GRK2) that improves cardiac performance in live animals. Paroxetine exhibits up to 50-fold selectivity for GRK2 versus other GRKs. A better understanding of the molecular basis of this selectivity is important for the development of even more selective and potent small molecule therapeutics and chemical genetic probes. We first sought to understand the molecular mechanisms underlying paroxetine selectivity among GRKs. We directly measured the KD for paroxetine and assessed its mechanism of inhibition for each of the GRK subfamilies and then determined the atomic structure of its complex with GRK1, the most weakly inhibited GRK tested. Our results suggest that the selectivity of paroxetine for GRK2 largely reflects its lower affinity for adenine nucleotides. Thus, stabilization of off-pathway conformational states unique to GRK2 will likely be key for the development of even more selective inhibitors. Next, we designed a benzolactam derivative of paroxetine that has optimized interactions with the hinge of the GRK2 kinase domain. The crystal structure of this compound in complex with GRK2 confirmed the predicted interactions. Although the benzolactam derivative did not significantly alter potency of inhibition among GRKs, it exhibited 20-fold lower inhibition of serotonin reuptake. However, there was an associated increase in the potency for inhibition of other AGC kinases, suggesting that the unconventional hydrogen bond formed by the benzodioxole ring of paroxetine is better accommodated by GRKs. PMID:24220010

  5. Rational design and synthesis of novel anti-prostate cancer agents bearing a 3,5-bis-trifluoromethylphenyl moiety.

    PubMed

    Ferla, Salvatore; Bassetto, Marcella; Pertusati, Fabrizio; Kandil, Sahar; Westwell, Andrew D; Brancale, Andrea; McGuigan, Christopher

    2016-08-01

    Prostate cancer is a major cause of male death worldwide and the identification of new and improved treatments is constantly required. Among the available options, different non-steroidal androgen receptor (AR) antagonists are approved also to treat castration-resistant forms. Most of these drugs show limited application due to the development of resistant mutants of their biological target. Following docking-based studies on a homology model for the AR open antagonist conformation, a series of novel 3,5-bis-trifluoromethylphenyl compounds was designed with the aim to improve the antiproliferative activity of anti-androgen drugs bicalutamide and enzalutamide. The new structural modifications might impede the receptor to adopt its closed agonist conformation also in the presence of adaptive mutations. Among the novel compounds synthesised, several displayed significantly improved in vitro activity in comparison with the parent structures, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145, 22Rv1). Selected hits demonstrated full AR antagonistic behaviour and promising candidates for further development were identified. PMID:27301368

  6. Solid-state supercapacitors with rationally designed heterogeneous electrodes fabricated by large area spray processing for wearable energy storage applications

    NASA Astrophysics Data System (ADS)

    Huang, Chun; Zhang, Jin; Young, Neil P.; Snaith, Henry J.; Grant, Patrick S.

    2016-05-01

    Supercapacitors are in demand for short-term electrical charge and discharge applications. Unlike conventional supercapacitors, solid-state versions have no liquid electrolyte and do not require robust, rigid packaging for containment. Consequently they can be thinner, lighter and more flexible. However, solid-state supercapacitors suffer from lower power density and where new materials have been developed to improve performance, there remains a gap between promising laboratory results that usually require nano-structured materials and fine-scale processing approaches, and current manufacturing technology that operates at large scale. We demonstrate a new, scalable capability to produce discrete, multi-layered electrodes with a different material and/or morphology in each layer, and where each layer plays a different, critical role in enhancing the dynamics of charge/discharge. This layered structure allows efficient utilisation of each material and enables conservative use of hard-to-obtain materials. The layered electrode shows amongst the highest combinations of energy and power densities for solid-state supercapacitors. Our functional design and spray manufacturing approach to heterogeneous electrodes provide a new way forward for improved energy storage devices.

  7. Solid-state supercapacitors with rationally designed heterogeneous electrodes fabricated by large area spray processing for wearable energy storage applications.

    PubMed

    Huang, Chun; Zhang, Jin; Young, Neil P; Snaith, Henry J; Grant, Patrick S

    2016-01-01

    Supercapacitors are in demand for short-term electrical charge and discharge applications. Unlike conventional supercapacitors, solid-state versions have no liquid electrolyte and do not require robust, rigid packaging for containment. Consequently they can be thinner, lighter and more flexible. However, solid-state supercapacitors suffer from lower power density and where new materials have been developed to improve performance, there remains a gap between promising laboratory results that usually require nano-structured materials and fine-scale processing approaches, and current manufacturing technology that operates at large scale. We demonstrate a new, scalable capability to produce discrete, multi-layered electrodes with a different material and/or morphology in each layer, and where each layer plays a different, critical role in enhancing the dynamics of charge/discharge. This layered structure allows efficient utilisation of each material and enables conservative use of hard-to-obtain materials. The layered electrode shows amongst the highest combinations of energy and power densities for solid-state supercapacitors. Our functional design and spray manufacturing approach to heterogeneous electrodes provide a new way forward for improved energy storage devices. PMID:27161379

  8. Rational plasmid design and bioprocess optimization to enhance recombinant adeno-associated virus (AAV) productivity in mammalian cells.

    PubMed

    Emmerling, Verena V; Pegel, Antje; Milian, Ernest G; Venereo-Sanchez, Alina; Kunz, Marion; Wegele, Jessica; Kamen, Amine A; Kochanek, Stefan; Hoerer, Markus

    2016-02-01

    Viral vectors used for gene and oncolytic therapy belong to the most promising biological products for future therapeutics. Clinical success of recombinant adeno-associated virus (rAAV) based therapies raises considerable demand for viral vectors, which cannot be met by current manufacturing strategies. Addressing existing bottlenecks, we improved a plasmid system termed rep/cap split packaging and designed a minimal plasmid encoding adenoviral helper function. Plasmid modifications led to a 12-fold increase in rAAV vector titers compared to the widely used pDG standard system. Evaluation of different production approaches revealed superiority of processes based on anchorage- and serum-dependent HEK293T cells, exhibiting about 15-fold higher specific and volumetric productivity compared to well-established suspension cells cultivated in serum-free medium. As for most other viral vectors, classical stirred-tank bioreactor production is thus still not capable of providing drug product of sufficient amount. We show that manufacturing strategies employing classical surface-providing culture systems can be successfully transferred to the new fully-controlled, single-use bioreactor system Integrity(TM) iCELLis(TM) . In summary, we demonstrate substantial bioprocess optimizations leading to more efficient and scalable production processes suggesting a promising way for flexible large-scale rAAV manufacturing. PMID:26284700

  9. From rational design of organometallic precursors to optimized synthesis of core/shell Ge/GeO2 nanoparticles.

    PubMed

    Matioszek, D; Ojo, W-S; Cornejo, A; Katir, N; El Ezzi, M; Le Troedec, M; Martinez, H; Gornitzka, H; Castel, A; Nayral, C; Delpech, F

    2015-04-28

    The synthesis of germanium nanoparticles has been carried out, thanks to the design of novel aminoiminate germanium(II) precursors: (ATI)GeZ (with Z = OMe, NPh2, and ATI = N,N'-diisopropyl-aminotroponiminate) and (Am)2Ge (Am = N,N'-bis(trimethylsilyl)phenyl amidinate). These complexes were fully characterized by spectroscopic techniques as well as single crystal X-ray diffraction. The thermolysis of both complexes yielded NPs which display similar features that are a Ge/GeO2 core/shell structure with a mean diameter close to 5 nm with a narrow size distribution (<15%). Whereas the high temperatures (>300 °C) classically reported in the literature for the preparation of germanium-based NPs were necessary for thermolysis of the complexes (ATI)GeZ, the use of amidinate-based precursors allows the preparation at an unprecedented low temperature (160 °C) for the thermolytic route. As suggested by a mechanistic study, the lower reactivity of (ATI)GeZ (for which the concomitant use of high temperature and acidic reagent is required) was explained in terms of lower ring strain compared to the case of (Am)2Ge. PMID:25790067

  10. Rational design of network properties in guest-host assembled and shear-thinning hyaluronic acid hydrogels.

    PubMed

    Rodell, Christopher B; Kaminski, Adam L; Burdick, Jason A

    2013-11-11

    Shear-thinning hydrogels afford direct injection or catheter delivery to tissues without potential premature gel formation and delivery failure or the use of triggers such as chemical initiators or heat. However, many shear-thinning hydrogels require long reassembly times or exhibit rapid erosion. We developed a shear-thinning hyaluronic acid (HA) hydrogel based on the guest-host interactions of adamantane modified HA (guest macromer, Ad-HA) and β-cyclodextrin modified HA (host macromer, CD-HA). The ability of the guest and host molecules to interact with their counterpart following conjugation to HA was confirmed by (1)H NMR spectroscopy and was similar to that of the native complex. Mixing of Ad-HA and CD-HA resulted in rapid formation of a hydrogel composed of guest-host bonds. The hydrogel physical properties, including mechanics and flow characteristics, were dependent on cross-link density and network structure, which were controlled through macromer concentration, the extent of guest macromer modification, and the molar ratio of guest and host functional groups. The guest-host assembly mechanism permitted both shear-thinning behavior for ease of injection and near-instantaneous reassembly for material retention at the target sight. The hydrogel erosion and release of a model biomolecule were also dependent on design parameters and were sustained for over 60 days. These hydrogels show potential as a minimally invasive injectable hydrogel for biomedical applications. PMID:24070551

  11. Rational Design of Highly Potent and Slow-Binding Cytochrome bc1 Inhibitor as Fungicide by Computational Substitution Optimization

    PubMed Central

    Hao, Ge-Fei; Yang, Sheng-Gang; Huang, Wei; Wang, Le; Shen, Yan-Qing; Tu, Wen-Long; Li, Hui; Huang, Li-Shar; Wu, Jia-Wei; Berry, Edward A.; Yang, Guang-Fu

    2015-01-01

    Hit to lead (H2L) optimization is a key step for drug and agrochemical discovery. A critical challenge for H2L optimization is the low efficiency due to the lack of predictive method with high accuracy. We described a new computational method called Computational Substitution Optimization (CSO) that has allowed us to rapidly identify compounds with cytochrome bc1 complex inhibitory activity in the nanomolar and subnanomolar range. The comprehensively optimized candidate has proved to be a slow binding inhibitor of bc1 complex, ~73-fold more potent (Ki = 4.1 nM) than the best commercial fungicide azoxystrobin (AZ; Ki = 297.6 nM) and shows excellent in vivo fungicidal activity against downy mildew and powdery mildew disease. The excellent correlation between experimental and calculated binding free-energy shifts together with further crystallographic analysis confirmed the prediction accuracy of CSO method. To the best of our knowledge, CSO is a new computational approach to substitution-scanning mutagenesis of ligand and could be used as a general strategy of H2L optimisation in drug and agrochemical design.

  12. Solid-state supercapacitors with rationally designed heterogeneous electrodes fabricated by large area spray processing for wearable energy storage applications

    PubMed Central

    Huang, Chun; Zhang, Jin; Young, Neil P.; Snaith, Henry J.; Grant, Patrick S.

    2016-01-01

    Supercapacitors are in demand for short-term electrical charge and discharge applications. Unlike conventional supercapacitors, solid-state versions have no liquid electrolyte and do not require robust, rigid packaging for containment. Consequently they can be thinner, lighter and more flexible. However, solid-state supercapacitors suffer from lower power density and where new materials have been developed to improve performance, there remains a gap between promising laboratory results that usually require nano-structured materials and fine-scale processing approaches, and current manufacturing technology that operates at large scale. We demonstrate a new, scalable capability to produce discrete, multi-layered electrodes with a different material and/or morphology in each layer, and where each layer plays a different, critical role in enhancing the dynamics of charge/discharge. This layered structure allows efficient utilisation of each material and enables conservative use of hard-to-obtain materials. The layered electrode shows amongst the highest combinations of energy and power densities for solid-state supercapacitors. Our functional design and spray manufacturing approach to heterogeneous electrodes provide a new way forward for improved energy storage devices. PMID:27161379

  13. Current experience in testing mitochondrial nutrients in disorders featuring oxidative stress and mitochondrial dysfunction: rational design of chemoprevention trials.

    PubMed

    Pagano, Giovanni; Aiello Talamanca, Annarita; Castello, Giuseppe; Cordero, Mario D; d'Ischia, Marco; Gadaleta, Maria Nicola; Pallardó, Federico V; Petrović, Sandra; Tiano, Luca; Zatterale, Adriana

    2014-01-01

    An extensive number of pathologies are associated with mitochondrial dysfunction (MDF) and oxidative stress (OS). Thus, mitochondrial cofactors termed "mitochondrial nutrients" (MN), such as α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and l-carnitine (CARN) (or its derivatives) have been tested in a number of clinical trials, and this review is focused on the use of MN-based clinical trials. The papers reporting on MN-based clinical trials were retrieved in MedLine up to July 2014, and evaluated for the following endpoints: (a) treated diseases; (b) dosages, number of enrolled patients and duration of treatment; (c) trial success for each MN or MN combinations as reported by authors. The reports satisfying the above endpoints included total numbers of trials and frequencies of randomized, controlled studies, i.e., 81 trials testing ALA, 107 reports testing CoQ10, and 74 reports testing CARN, while only 7 reports were retrieved testing double MN associations, while no report was found testing a triple MN combination. A total of 28 reports tested MN associations with "classical" antioxidants, such as antioxidant nutrients or drugs. Combinations of MN showed better outcomes than individual MN, suggesting forthcoming clinical studies. The criteria in study design and monitoring MN-based clinical trials are discussed. PMID:25380523

  14. Current Experience in Testing Mitochondrial Nutrients in Disorders Featuring Oxidative Stress and Mitochondrial Dysfunction: Rational Design of Chemoprevention Trials

    PubMed Central

    Pagano, Giovanni; Aiello Talamanca, Annarita; Castello, Giuseppe; Cordero, Mario D.; d’Ischia, Marco; Gadaleta, Maria Nicola; Pallardó, Federico V.; Petrović, Sandra; Tiano, Luca; Zatterale, Adriana

    2014-01-01

    An extensive number of pathologies are associated with mitochondrial dysfunction (MDF) and oxidative stress (OS). Thus, mitochondrial cofactors termed “mitochondrial nutrients” (MN), such as α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and l-carnitine (CARN) (or its derivatives) have been tested in a number of clinical trials, and this review is focused on the use of MN-based clinical trials. The papers reporting on MN-based clinical trials were retrieved in MedLine up to July 2014, and evaluated for the following endpoints: (a) treated diseases; (b) dosages, number of enrolled patients and duration of treatment; (c) trial success for each MN or MN combinations as reported by authors. The reports satisfying the above endpoints included total numbers of trials and frequencies of randomized, controlled studies, i.e., 81 trials testing ALA, 107 reports testing CoQ10, and 74 reports testing CARN, while only 7 reports were retrieved testing double MN associations, while no report was found testing a triple MN combination. A total of 28 reports tested MN associations with “classical” antioxidants, such as antioxidant nutrients or drugs. Combinations of MN showed better outcomes than individual MN, suggesting forthcoming clinical studies. The criteria in study design and monitoring MN-based clinical trials are discussed. PMID:25380523

  15. Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability.

    PubMed

    Camilloni, Carlo; Sala, Benedetta Maria; Sormanni, Pietro; Porcari, Riccardo; Corazza, Alessandra; De Rosa, Matteo; Zanini, Stefano; Barbiroli, Alberto; Esposito, Gennaro; Bolognesi, Martino; Bellotti, Vittorio; Vendruscolo, Michele; Ricagno, Stefano

    2016-01-01

    A wide range of human diseases is associated with mutations that, destabilizing proteins native state, promote their aggregation. However, the mechanisms leading from folded to aggregated states are still incompletely understood. To investigate these mechanisms, we used a combination of NMR spectroscopy and molecular dynamics simulations to compare the native state dynamics of Beta-2 microglobulin (β2m), whose aggregation is associated with dialysis-related amyloidosis, and its aggregation-resistant mutant W60G. Our results indicate that W60G low aggregation propensity can be explained, beyond its higher stability, by an increased average protection of the aggregation-prone residues at its surface. To validate these findings, we designed β2m variants that alter the aggregation-prone exposed surface of wild-type and W60G β2m modifying their aggregation propensity. These results allowed us to pinpoint the role of dynamics in β2m aggregation and to provide a new strategy to tune protein aggregation by modulating the exposure of aggregation-prone residues. PMID:27150430

  16. A Biophysical Model of CRISPR/Cas9 Activity for Rational Design of Genome Editing and Gene Regulation.

    PubMed

    Farasat, Iman; Salis, Howard M

    2016-01-01

    The ability to precisely modify genomes and regulate specific genes will greatly accelerate several medical and engineering applications. The CRISPR/Cas9 (Type II) system binds and cuts DNA using guide RNAs, though the variables that control its on-target and off-target activity remain poorly characterized. Here, we develop and parameterize a system-wide biophysical model of Cas9-based genome editing and gene regulation to predict how changing guide RNA sequences, DNA superhelical densities, Cas9 and crRNA expression levels, organisms and growth conditions, and experimental conditions collectively control the dynamics of dCas9-based binding and Cas9-based cleavage at all DNA sites with both canonical and non-canonical PAMs. We combine statistical thermodynamics and kinetics to model Cas9:crRNA complex formation, diffusion, site selection, reversible R-loop formation, and cleavage, using large amounts of structural, biochemical, expression, and next-generation sequencing data to determine kinetic parameters and develop free energy models. Our results identify DNA supercoiling as a novel mechanism controlling Cas9 binding. Using the model, we predict Cas9 off-target binding frequencies across the lambdaphage and human genomes, and explain why Cas9's off-target activity can be so high. With this improved understanding, we propose several rules for designing experiments for minimizing off-target activity. We also discuss the implications for engineering dCas9-based genetic circuits. PMID:26824432

  17. A Biophysical Model of CRISPR/Cas9 Activity for Rational Design of Genome Editing and Gene Regulation

    PubMed Central

    Farasat, Iman; Salis, Howard M.

    2016-01-01

    The ability to precisely modify genomes and regulate specific genes will greatly accelerate several medical and engineering applications. The CRISPR/Cas9 (Type II) system binds and cuts DNA using guide RNAs, though the variables that control its on-target and off-target activity remain poorly characterized. Here, we develop and parameterize a system-wide biophysical model of Cas9-based genome editing and gene regulation to predict how changing guide RNA sequences, DNA superhelical densities, Cas9 and crRNA expression levels, organisms and growth conditions, and experimental conditions collectively control the dynamics of dCas9-based binding and Cas9-based cleavage at all DNA sites with both canonical and non-canonical PAMs. We combine statistical thermodynamics and kinetics to model Cas9:crRNA complex formation, diffusion, site selection, reversible R-loop formation, and cleavage, using large amounts of structural, biochemical, expression, and next-generation sequencing data to determine kinetic parameters and develop free energy models. Our results identify DNA supercoiling as a novel mechanism controlling Cas9 binding. Using the model, we predict Cas9 off-target binding frequencies across the lambdaphage and human genomes, and explain why Cas9’s off-target activity can be so high. With this improved understanding, we propose several rules for designing experiments for minimizing off-target activity. We also discuss the implications for engineering dCas9-based genetic circuits. PMID:26824432

  18. Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability

    NASA Astrophysics Data System (ADS)

    Camilloni, Carlo; Sala, Benedetta Maria; Sormanni, Pietro; Porcari, Riccardo; Corazza, Alessandra; De Rosa, Matteo; Zanini, Stefano; Barbiroli, Alberto; Esposito, Gennaro; Bolognesi, Martino; Bellotti, Vittorio; Vendruscolo, Michele; Ricagno, Stefano

    2016-05-01

    A wide range of human diseases is associated with mutations that, destabilizing proteins native state, promote their aggregation. However, the mechanisms leading from folded to aggregated states are still incompletely understood. To investigate these mechanisms, we used a combination of NMR spectroscopy and molecular dynamics simulations to compare the native state dynamics of Beta-2 microglobulin (β2m), whose aggregation is associated with dialysis-related amyloidosis, and its aggregation-resistant mutant W60G. Our results indicate that W60G low aggregation propensity can be explained, beyond its higher stability, by an increased average protection of the aggregation-prone residues at its surface. To validate these findings, we designed β2m variants that alter the aggregation-prone exposed surface of wild-type and W60G β2m modifying their aggregation propensity. These results allowed us to pinpoint the role of dynamics in β2m aggregation and to provide a new strategy to tune protein aggregation by modulating the exposure of aggregation-prone residues.

  19. Near-IR BODIPY Dyes à la Carte-Programmed Orthogonal Functionalization of Rationally Designed Building Blocks.

    PubMed

    Gómez-Durán, Cesar F A; Esnal, Ixone; Valois-Escamilla, Ismael; Urías-Benavides, Arlette; Bañuelos, Jorge; López Arbeloa, Iñigo; García-Moreno, Inmaculada; Peña-Cabrera, Eduardo

    2016-01-18

    Herein, we report the synthesis of polyfunctional BODIPY building blocks suitable to be subjected to several reaction sequences with complete chemoselectivity, thereby allowing the preparation of complex BODIPY derivatives in a versatile and programmable manner. The reactions included the Liebeskind-Srogl cross-coupling reaction (LSCC), nucleophilic aromatic substitution (SN Ar), Suzuki, Sonogashira, and Stille couplings, and a desulfitative reduction of the MeS group. This novel synthetic protocol is a powerful route to design a library of compounds with tailored photophysical properties for advanced applications. In this context, it is noteworthy that it offers a straightforward and cost-effective strategy to shift the BODIPY emission deep into the near-infrared spectral region while retaining high fluorescence quantum yields as well as highly efficient and stable laser action. These new dyes outperform the lasing behaviour of dyes considered as benchmarks over the red spectral region, overcoming the important drawbacks associated with these commercial laser dyes, namely low absorption at the standard pump wavelengths (355 and 532 nm) and/or poor photostability. PMID:26608098

  20. Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery.

    PubMed

    Tykvart, Jan; Schimer, Jiří; Bařinková, Jitka; Pachl, Petr; Poštová-Slavětínská, Lenka; Majer, Pavel; Konvalinka, Jan; Šácha, Pavel

    2014-08-01

    Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA), is an established prostate cancer marker and is considered a promising target for specific anticancer drug delivery. Low-molecular-weight inhibitors of GCPII are advantageous specific ligands for this purpose. However, they must be modified with a linker to enable connection of the ligand with an imaging molecule, anticancer drug, and/or nanocarrier. Here, we describe a structure-activity relationship (SAR) study of GCPII inhibitors with linkers suitable for imaging and drug delivery. Structure-assisted inhibitor design and targeting of a specific GCPII exosite resulted in a 7-fold improvement in Ki value compared to the parent structure. X-ray structural analysis of the inhibitor series led to the identification of several inhibitor binding modes. We also optimized the length of the inhibitor linker for effective attachment to a biotin-binding molecule and showed that the optimized inhibitor could be used to target nanoparticles to cells expressing GCPII. PMID:24954515

  1. The Special Education Teacher as an Instructional Designer. Rational, Content, and Strategy for an Innovative Individualized Course on Instructional Design in Special Education. Working Paper 9.14.

    ERIC Educational Resources Information Center

    Thiagarajan, Sivasailam

    Provided are the rationale, content and strategy for an introductory course in instructional design for special education teachers. The teacher's need for varied competencies in instructional design, management and interaction are discussed. It is recommended that teacher training include development of such design skills as task analysis, learner…

  2. Rational design of viscosity reducing mutants of a monoclonal antibody: Hydrophobic versus electrostatic inter-molecular interactions

    PubMed Central

    Nichols, Pilarin; Li, Li; Kumar, Sandeep; Buck, Patrick M; Singh, Satish K; Goswami, Sumit; Balthazor, Bryan; Conley, Tami R; Sek, David; Allen, Martin J

    2015-01-01

    High viscosity of monoclonal antibody formulations at concentrations ≥100 mg/mL can impede their development as products suitable for subcutaneous delivery. The effects of hydrophobic and electrostatic intermolecular interactions on the solution behavior of MAB 1, which becomes unacceptably viscous at high concentrations, was studied by testing 5 single point mutants. The mutations were designed to reduce viscosity by disrupting either an aggregation prone region (APR), which also participates in 2 hydrophobic surface patches, or a negatively charged surface patch in the variable region. The disruption of an APR that lies at the interface of light and heavy chain variable domains, VH and VL, via L45K mutation destabilized MAB 1 and abolished antigen binding. However, mutation at the preceding residue (V44K), which also lies in the same APR, increased apparent solubility and reduced viscosity of MAB 1 without sacrificing antigen binding or thermal stability. Neutralizing the negatively charged surface patch (E59Y) also increased apparent solubility and reduced viscosity of MAB 1, but charge reversal at the same position (E59K/R) caused destabilization, decreased solubility and led to difficulties in sample manipulation that precluded their viscosity measurements at high concentrations. Both V44K and E59Y mutations showed similar increase in apparent solubility. However, the viscosity profile of E59Y was considerably better than that of the V44K, providing evidence that inter-molecular interactions in MAB 1 are electrostatically driven. In conclusion, neutralizing negatively charged surface patches may be more beneficial toward reducing viscosity of highly concentrated antibody solutions than charge reversal or aggregation prone motif disruption. PMID:25559441

  3. Experimental and Computational Mechanistic Studies Guiding the Rational Design of Molecular Electrocatalysts for Production and Oxidation of Hydrogen.

    PubMed

    Raugei, Simone; Helm, Monte L; Hammes-Schiffer, Sharon; Appel, Aaron M; O'Hagan, Molly; Wiedner, Eric S; Bullock, R Morris

    2016-01-19

    Understanding how to control the movement of protons and electrons is crucial to the design of fast, efficient electrocatalysts for H2 production and oxidation based on earth-abundant metals. Our work seeks to address fundamental questions about proton movement. We have demonstrated that incorporating a pendant amine functioning as a proton relay in the second coordination sphere of a metal complex helps proton mobility, resulting in faster and more energy-efficient catalysts. Proton-transfer reactions can be rate-limiting and are influenced by several factors, such as pKa values, steric effects, hydrogen bonding, and solvation/desolvation of the exogenous base and acid employed. The presence of multiple protonation sites introduces branching points along the catalytic cycle, making less productive pathways accessible or leading to the formation of stable off-cycle species. Using ligands with only one pendant amine mitigates this problem and results in catalysts with high rates for production of H2, although generally at higher overpotentials. For H2 oxidation catalysts, iron complexes with a high H2 binding affinity were developed. However, these iron complexes had a pKa mismatch between the protonated metal center and the protonated pendant amine, and consequently intramolecular proton movement was slow. Taken altogether, our results demonstrate the necessity of optimizing the entire catalytic cycle because optimization of a specific catalytic step can negatively influence another step and not necessarily lead to a better catalytic performance. We discuss a general procedure, based on thermodynamic arguments, which allows the simultaneous minimization of the free-energy change of each catalytic step, yielding a nearly flat free-energy surface, with no large barriers due to energy mismatches from either high- or low-energy intermediates. PMID:26653114

  4. Rational design, synthesis and evaluation of first generation inhibitors of the Giardia lamblia fructose-1,6-biphosphate aldolase.

    PubMed

    Li, Zhimin; Liu, Zhengang; Cho, Dae Won; Zou, Jiwen; Gong, Maozhen; Breece, Robert M; Galkin, Andrey; Li, Ling; Zhao, Hong; Maestas, Gabriel D; Tierney, David L; Herzberg, Osnat; Dunaway-Mariano, Debra; Mariano, Patrick S

    2011-04-01

    Inhibitors of the Giardia lamblia fructose 1,6-bisphosphate aldolase (GlFBPA), which transforms fructose 1,6-bisphosphate (FBP) to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, were designed based on 3-hydroxy-2-pyridone and 1,2-dihydroxypyridine scaffolds that position two negatively charged tetrahedral groups for interaction with substrate phosphate binding residues, a hydrogen bond donor to the catalytic Asp83, and a Zn(2+) binding group. The inhibition activities for the GlFBPA catalyzed reaction of FBP of the prepared alkyl phosphonate/phosphate substituted 3-hydroxy-2-pyridinones and a dihydroxypyridine were determined. The 3-hydroxy-2-pyridone inhibitor 8 was found to bind to GlFBPA with an affinity (K(i)=14μM) that is comparable to that of FBP (K(m)=2μM) or its inert analog TBP (K(i)=1μM). The X-ray structure of the GlFBPA-inhibitor 8 complex (2.3Å) shows that 8 binds to the active site in the manner predicted by in silico docking with the exception of coordination with Zn(2+). The observed distances and orientation of the pyridone ring O=C-C-OH relative to Zn(2+) are not consistent with a strong interaction. To determine if Zn(2+)coordination occurs in the GlFBPA-inhibitor 8 complex in solution, EXAFS spectra were measured. A four coordinate geometry comprised of the three enzyme histidine ligands and an oxygen atom from the pyridone ring O=C-C-OH was indicated. Analysis of the Zn(2+) coordination geometries in recently reported structures of class II FBPAs suggests that strong Zn(2+) coordination is reserved for the enediolate-like transition state, accounting for minimal contribution of Zn(2+) coordination to binding of 8 to GlFBPA. PMID:21333622

  5. Rational design of a transition state analogue with picomolar affinity for Pseudomonas aeruginosa PvdQ, a siderophore biosynthetic enzyme.

    PubMed

    Clevenger, Kenneth D; Wu, Rui; Er, Joyce A V; Liu, Dali; Fast, Walter

    2013-10-18

    The Pseudomonas aeruginosa enzyme PvdQ can process different substrates involved in quorum-sensing or in siderophore biosynthesis. Substrate selectivity was evaluated using steady-state kinetic constants for hydrolysis of N-acyl-homoserine lactones (HSLs) and p-nitrophenyl fatty acid esters. PvdQ prefers substrates with alkyl chains between 12 and 14 carbons long that do not bear a 3-oxo substitution and is revealed here to have a relatively high specificity constant for selected N-acyl-HSLs (kcat/KM = 10(5) to 10(6) M(-1) s(-1)). However, endogenous P. aeruginosa N-acyl-HSLs are ≥100-fold disfavored, supporting the conclusion that PvdQ was not primarily evolved to regulate endogenous quorum-sensing. PvdQ plays an essential biosynthetic role for the siderophore pyoverdine, on which P. aeruginosa depends for growth in iron-limited environments. A series of alkylboronate inhibitors was found to be reversible, competitive, and extremely potent (Ki ≥ 190 pM). A 1.8 Å X-ray structure shows that 1-tridecylboronic acid forms a monocovalent bond with the N-terminal β-chain Ser residue in the PvdQ heterodimer, mimicking a reaction transition state. This boronic acid inhibits growth of P. aeruginosa in iron-limited media, reproducing the phenotype of a genetic pvdQ disruption, although co-administration of an efflux pump inhibitor is required to maintain growth inhibition. These findings support the strategy of designing boron-based inhibitors of siderophore biosynthetic enzymes to control P. aeruginosa infections. PMID:23883096

  6. Rational Design, Synthesis and Evaluation of First Generation Inhibitors of the Giardia lamblia Fructose-1,6-biphosphate Aldolase

    PubMed Central

    Li, Zhimin; Liu, Zhengang; Cho, Dae Won; Zou, Jiwen; Gong, Maozhen; Breece, Robert M.; Galkin, Andrey; Li, Ling; Zhao, Hong; Maestas, Gabriel D.; Tierney, David L.; Herzberg, Osnat; Dunaway-Mariano, Debra; Mariano, Patrick S.

    2011-01-01

    Inhibitors of the Giardia lamblia fructose 1,6-bisphosphate aldolase (GlFBPA), which transforms fructose 1,6-bisphosphate (FBP) to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, were designed based on 3-hydroxy-2-pyridone and 1,2-dihydroxypyridine scaffolds that position two negatively charged tetrahedral groups for interaction with substrate phosphate binding residues, a hydrogen bond donor to the catalytic Asp83, and a Zn2+ binding group. The inhibition activities for the GlFBPA catalyzed reaction of FBP of the prepared alkyl phosphonate/phosphate substituted 3-hydroxy-2-pyridinones and a dihydroxypyridine were determined. The 3-hydroxy-2-pyridone inhibitor 8 was found to bind to GlFBPA with an affinity (Ki = 14 μM) that is comparable to that of FBP (Km = 2 μM) or its inert analog TBP (Ki = 1 μM). The X-ray structure of the GlFBPA-inhibitor 8 complex (2.3 Å) shows that 8 binds to the active site in the manner predicted by in silico docking with the exception of coordination with Zn2+. The observed distances and orientation of the pyridone ring O=C-C-OH relative to Zn2+ are not consistent with a strong interaction. To determine if Zn2+coordination occurs in the GlFBPA-inhibitor 8 complex in solution, EXAFS spectra were measured. A four coordinate geometry comprised of the three enzyme histidine ligands and an oxygen atom from the pyridone ring O=C-C-OH was indicated. Analysis of the Zn2+ coordination geometries in recently reported structures of class II FBPAs suggests that strong Zn2+ coordination is reserved for the enediolate-like transition state, accounting for minimal contribution of Zn2+ coordination to binding of 8 to GlFBPA. PMID:21333622

  7. Rational design of viscosity reducing mutants of a monoclonal antibody: hydrophobic versus electrostatic inter-molecular interactions.

    PubMed

    Nichols, Pilarin; Li, Li; Kumar, Sandeep; Buck, Patrick M; Singh, Satish K; Goswami, Sumit; Balthazor, Bryan; Conley, Tami R; Sek, David; Allen, Martin J

    2015-01-01

    High viscosity of monoclonal antibody formulations at concentrations ≥100 mg/mL can impede their development as products suitable for subcutaneous delivery. The effects of hydrophobic and electrostatic intermolecular interactions on the solution behavior of MAB 1, which becomes unacceptably viscous at high concentrations, was studied by testing 5 single point mutants. The mutations were designed to reduce viscosity by disrupting either an aggregation prone region (APR), which also participates in 2 hydrophobic surface patches, or a negatively charged surface patch in the variable region. The disruption of an APR that lies at the interface of light and heavy chain variable domains, VH and VL, via L45K mutation destabilized MAB 1 and abolished antigen binding. However, mutation at the preceding residue (V44K), which also lies in the same APR, increased apparent solubility and reduced viscosity of MAB 1 without sacrificing antigen binding or thermal stability. Neutralizing the negatively charged surface patch (E59Y) also increased apparent solubility and reduced viscosity of MAB 1, but charge reversal at the same position (E59K/R) caused destabilization, decreased solubility and led to difficulties in sample manipulation that precluded their viscosity measurements at high concentrations. Both V44K and E59Y mutations showed similar increase in apparent solubility. However, the viscosity profile of E59Y was considerably better than that of the V44K, providing evidence that inter-molecular interactions in MAB 1 are electrostatically driven. In conclusion, neutralizing negatively charged surface patches may be more beneficial toward reducing viscosity of highly concentrated antibody solutions than charge reversal or aggregation prone motif disruption. PMID:25559441

  8. Rational Design of Small-Molecule Stabilizers of Spermine Synthase Dimer by Virtual Screening and Free Energy-Based Approach

    PubMed Central

    Zhang, Zhe; Martiny, Virginie; Lagorce, David; Ikeguchi, Yoshihiko; Alexov, Emil; Miteva, Maria A.

    2014-01-01

    Snyder-Robinson Syndrome (SRS) is a rare mental retardation disorder which is caused by the malfunctioning of an enzyme, the spermine synthase (SMS), which functions as a homo-dimer. The malfunctioning of SMS in SRS patients is associated with several identified missense mutations that occur away from the active site. This investigation deals with a particular SRS-causing mutation, the G56S mutation, which was shown computationally and experimentally to destabilize the SMS homo-dimer and thus to abolish SMS enzymatic activity. As a proof-of-concept, we explore the possibility to restore the enzymatic activity of the malfunctioning SMS mutant G56S by stabilizing the dimer through small molecule binding at the mutant homo-dimer interface. For this purpose, we designed an in silico protocol that couples virtual screening and a free binding energy-based approach to identify potential small-molecule binders on the destabilized G56S dimer, with the goal to stabilize it and thus to increase SMS G56S mutant activity. The protocol resulted in extensive list of plausible stabilizers, among which we selected and tested 51 compounds experimentally for their capability to increase SMS G56S mutant enzymatic activity. In silico analysis of the experimentally identified stabilizers suggested five distinctive chemical scaffolds. This investigation suggests that druggable pockets exist in the vicinity of the mutation sites at protein-protein interfaces which can be used to alter the disease-causing effects by small molecule binding. The identified chemical scaffolds are drug-like and can serve as original starting points for development of lead molecules to further rescue the disease-causing effects of the Snyder-Robinson syndrome for which no efficient treatment exists up to now. PMID:25340632

  9. Rational Design Synthesis and Evaluation of First Generation Inhibitors of the Giardia Lamblia Fructose-1 6-biphosphate Aldolase

    SciTech Connect

    Z Li; Z Liu; D Cho; J Zou; M Gong; R Breece; A Galkin; L Li; H Zhao; et al.

    2011-12-31

    Inhibitors of the Giardia lamblia fructose 1,6-bisphosphate aldolase (GlFBPA), which transforms fructose 1,6-bisphosphate (FBP) to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, were designed based on 3-hydroxy-2-pyridone and 1,2-dihydroxypyridine scaffolds that position two negatively charged tetrahedral groups for interaction with substrate phosphate binding residues, a hydrogen bond donor to the catalytic Asp83, and a Zn{sup 2+} binding group. The inhibition activities for the GlFBPA catalyzed reaction of FBP of the prepared alkyl phosphonate/phosphate substituted 3-hydroxy-2-pyridinones and a dihydroxypyridine were determined. The 3-hydroxy-2-pyridone inhibitor 8 was found to bind to GlFBPA with an affinity (K{sub i} = 14 {micro}M) that is comparable to that of FBP (K{sub m} = 2 {micro}M) or its inert analog TBP (K{sub i} = 1 {micro}M). The X-ray structure of the GlFBPA-inhibitor 8 complex (2.3 {angstrom}) shows that 8 binds to the active site in the manner predicted by in silico docking with the exception of coordination with Zn{sup 2+}. The observed distances and orientation of the pyridone ring O=C-C-OH relative to Zn{sup 2+} are not consistent with a strong interaction. To determine if Zn{sup 2+} coordination occurs in the GlFBPA-inhibitor 8 complex in solution, EXAFS spectra were measured. A four coordinate geometry comprised of the three enzyme histidine ligands and an oxygen atom from the pyridone ring O=C-C-OH was indicated. Analysis of the Zn{sup 2+} coordination geometries in recently reported structures of class II FBPAs suggests that strong Zn{sup 2+} coordination is reserved for the enediolate-like transition state, accounting for minimal contribution of Zn{sup 2+} coordination to binding of 8 to GlFBPA.

  10. Rational design and synthesis of efficient Carbon and/or Silica functional nanomaterials for electrocatalysis and nanomedicine

    NASA Astrophysics Data System (ADS)

    Da Silva, Rafael

    In nanomaterials there is a strong correlation between structure and properties. Thus, the design and synthesis of nanomaterials with well-defined structures and morphology is essential in order to produce materials with not only unique but also tailorable properties. The unique properties of nanomaterials in turn can be taken advantage of to create materials and nanoscale devices that can help address important societal issues, such as meeting renewable energy sources and efficient therapeutic and diagnostic methods to cure a range of diseases. In this thesis, the different synthetic approaches I have developed to produce functional nanomaterials composed of earth-abundant elements (mainly carbon and silica) at low cost in a very sustainable manner are discussed. In Chapter 1, the fundamental properties of nanomaterials and their properties and potential applications in many areas are introduced. In chapter 2, a novel synthetic method that allows polymerization of polyaniline (PANI), a conducting polymer, inside cylindrical channel pores of nanoporous silica (SBA-15) is discussed. In addition, the properties of the III resulting conducting polymer in the confined nanochannel spaces of SBA-15, and more importantly, experimental demonstration of the use of the resulting hybrid material (PANI/SBA-15 material) as electocatalyst for electrooxidation reactions with good overpotential, close to zero, are detailed. In chapter 3, the synthetic approach discussed in Chapter 2 is further extended to afford nitrogen- and oxygen-doped mesoporous carbons. This is possible by pyrolysis of the PANI/SBA-15 composite materials under inert atmosphere, followed by etching away their silica framework. The high catalytic activity of resulting carbon-based materials towards oxygen reduction reaction despite they do not possess any metal dopants is also included. The potential uses of nanomaterials in areas such as nanomedicine need deep understanding of the biocompatibility/ toxicity of

  11. Structure-based rational design of peptide hydroxamic acid inhibitors to target tumor necrosis factor-α converting enzyme as potential therapeutics for hepatitis.

    PubMed

    Wu, Dan; Gu, Qiuhong; Zhao, Ning; Xia, Fei; Li, Zhiwei

    2015-12-01

    The human tumor necrosis factor-α converting enzyme (TACE) has recently been raised as a new and promising therapeutic target of hepatitis and other inflammatory diseases. Here, we reported a successful application of the solved crystal structure of TACE complex with a peptide-like ligand INN for rational design of novel peptide hydroxamic acid inhibitors with high potency and selectivity to target and inhibit TACE. First, the intermolecular interactions between TACE catalytic domain and INN were characterized through an integrated bioinformatics approach, with which the key substructures of INN that dominate ligand binding were identified. Subsequently, the INN molecular structure was simplified to a chemical sketch of peptide hydroxamic acid compound, which can be regarded as a linear tripeptide capped by a N-terminal carboxybenzyl group (chemically protective group) and a C-terminal hydroxamate moiety (coordinated to the Zn(2+) at TACE active site). Based on the sketch, a virtual combinatorial library containing 180 peptide hydroxamic acids was generated, from which seven samples were identified as promising candidates by using a knowledge-based protein-peptide affinity predictor and were then tested in vitro with a standard TACE activity assay protocol. Consequently, three designed peptide hydroxamic acids, i.e. Cbz-Pro-Ile-Gln-hydroxamic acid, Cbz-Leu-Ile-Val-hydroxamic acid and Cbz-Phe-Val-Met-hydroxamic acid, exhibited moderate or high inhibitory activity against TACE, with inhibition constants Ki of 36 ± 5, 510 ± 46 and 320 ± 26 nM, respectively. We also examined the structural basis and non-bonded profile of TACE interaction with a designed peptide hydroxamic acid inhibitor, and found that the inhibitor ligand is tightly buried in the active pocket of TACE, forming a number of hydrogen bonds, hydrophobic forces and van der Waals contacts at the interaction interface, conferring both stability and specificity for TACE-inhibitor complex

  12. 4. HEADGATE AND FLUME AT THE BEGINNING OF THE SNAKE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    4. HEADGATE AND FLUME AT THE BEGINNING OF THE SNAKE RIVER DITCH PASSING THROUGH BEAVER POND AREA, LOOKING EAST-SOUTHEAST. - Snake River Ditch, Headgate on north bank of Snake River, Dillon, Summit County, CO

  13. 5. GENERAL VIEW FROM SOUTH BANK OF SNAKE RIVER LYONS ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. GENERAL VIEW FROM SOUTH BANK OF SNAKE RIVER LYONS FERRY BRIDGE TO THE RIGHT, JOSO HIGH (UNION PACIFIC RAILROAD) BRIDGE TO THE LEFT - Snake River Bridge at Lyons' Ferry, State Route 261 spanning Snake River, Starbuck, Columbia County, WA

  14. 1. SNAKE RIVER VALLEY IRRIGATION DISTRICT DAM, VIEW OF NORTH ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. SNAKE RIVER VALLEY IRRIGATION DISTRICT DAM, VIEW OF NORTH ELEVATION OF INTAKE ON EAST SIDE OF DAM - Snake River Valley Irrigation District, East Side of Snake River (River Mile 796), Shelley, Bingham County, ID

  15. 3. NORTH SIDE OF DIVERSION DAM ON THE SNAKE RIVER ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. NORTH SIDE OF DIVERSION DAM ON THE SNAKE RIVER SHOWING HEADGATE ON THE NORTH BANK. VIEW IS TO THE NORTH-NORTHWEST. - Snake River Ditch, Headgate on north bank of Snake River, Dillon, Summit County, CO

  16. 2. UPSTREAM SIDE OF DIVERSION DAM ON THE SNAKE RIVER, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. UPSTREAM SIDE OF DIVERSION DAM ON THE SNAKE RIVER, LOOKING SOUTH-SOUTHWEST. NOTE BANK REINFORCEMENT ON LEFT AND SPILLWAY ON RIGHT. - Snake River Ditch, Headgate on north bank of Snake River, Dillon, Summit County, CO

  17. Rational design and synthesis of efficient Carbon and/or Silica functional nanomaterials for electrocatalysis and nanomedicine

    NASA Astrophysics Data System (ADS)

    Da Silva, Rafael

    In nanomaterials there is a strong correlation between structure and properties. Thus, the design and synthesis of nanomaterials with well-defined structures and morphology is essential in order to produce materials with not only unique but also tailorable properties. The unique properties of nanomaterials in turn can be taken advantage of to create materials and nanoscale devices that can help address important societal issues, such as meeting renewable energy sources and efficient therapeutic and diagnostic methods to cure a range of diseases. In this thesis, the different synthetic approaches I have developed to produce functional nanomaterials composed of earth-abundant elements (mainly carbon and silica) at low cost in a very sustainable manner are discussed. In Chapter 1, the fundamental properties of nanomaterials and their properties and potential applications in many areas are introduced. In chapter 2, a novel synthetic method that allows polymerization of polyaniline (PANI), a conducting polymer, inside cylindrical channel pores of nanoporous silica (SBA-15) is discussed. In addition, the properties of the III resulting conducting polymer in the confined nanochannel spaces of SBA-15, and more importantly, experimental demonstration of the use of the resulting hybrid material (PANI/SBA-15 material) as electocatalyst for electrooxidation reactions with good overpotential, close to zero, are detailed. In chapter 3, the synthetic approach discussed in Chapter 2 is further extended to afford nitrogen- and oxygen-doped mesoporous carbons. This is possible by pyrolysis of the PANI/SBA-15 composite materials under inert atmosphere, followed by etching away their silica framework. The high catalytic activity of resulting carbon-based materials towards oxygen reduction reaction despite they do not possess any metal dopants is also included. The potential uses of nanomaterials in areas such as nanomedicine need deep understanding of the biocompatibility/ toxicity of

  18. Highly stereoselective biosynthesis of (R)-α-hydroxy carboxylic acids through rationally re-designed mutation of d-lactate dehydrogenase

    PubMed Central

    Zheng, Zhaojuan; Sheng, Binbin; Gao, Chao; Zhang, Haiwei; Qin, Tong; Ma, Cuiqing; Xu, Ping

    2013-01-01

    An NAD-dependent d-lactate dehydrogenase (d-nLDH) of Lactobacillus bulgaricus ATCC 11842 was rationally re-designed for asymmetric reduction of a homologous series of α-keto carboxylic acids such as phenylpyruvic acid (PPA), α-ketobutyric acid, α-ketovaleric acid, β-hydroxypyruvate. Compared with wild-type d-nLDH, the Y52L mutant d-nLDH showed elevated activities toward unnatural substrates especially with large substitutes at C-3. By the biocatalysis combined with a formate dehydrogenase for in situ generation of NADH, the corresponding (R)-α-hydroxy carboxylic acids could be produced at high yields and highly optical purities. Taking the production of chiral (R)-phenyllactic acid (PLA) from PPA for example, 50 mM PPA was completely reduced to (R)-PLA in 90 min with a high yield of 99.0% and a highly optical purity (>99.9% e.e.) by the coupling system. The results presented in this work suggest a promising alternative for the production of chiral α-hydroxy carboxylic acids. PMID:24292439

  19. Rational Design of a Live Attenuated Dengue Vaccine: 2′-O-Methyltransferase Mutants Are Highly Attenuated and Immunogenic in Mice and Macaques

    PubMed Central

    Chang, David C.; Zhang, Bo; Balakrishnan, Thavamalar; Toh, Ying-Xiu; Jiang, Tao; Li, Shi-Hua; Deng, Yong-Qiang; Ellis, Brett R.; Ellis, Esther M.; Poidinger, Michael; Zolezzi, Francesca; Qin, Cheng-Feng; Shi, Pei-Yong; Fink, Katja

    2013-01-01

    Dengue virus is transmitted by Aedes mosquitoes and infects at least 100 million people every year. Progressive urbanization in Asia and South-Central America and the geographic expansion of Aedes mosquito habitats have accelerated the global spread of dengue, resulting in a continuously increasing number of cases. A cost-effective, safe vaccine conferring protection with ideally a single injection could stop dengue transmission. Current vaccine candidates require several booster injections or do not provide protection against all four serotypes. Here we demonstrate that dengue virus mutants lacking 2′-O-methyltransferase activity are highly sensitive to type I IFN inhibition. The mutant viruses are attenuated in mice and rhesus monkeys and elicit a strong adaptive immune response. Monkeys immunized with a single dose of 2′-O-methyltransferase mutant virus showed 100% sero-conversion even when a dose as low as 1,000 plaque forming units was administrated. Animals were fully protected against a homologous challenge. Furthermore, mosquitoes feeding on blood containing the mutant virus were not infected, whereas those feeding on blood containing wild-type virus were infected and thus able to transmit it. These results show the potential of 2′-O-methyltransferase mutant virus as a safe, rationally designed dengue vaccine that restrains itself due to the increased susceptibility to the host's innate immune response. PMID:23935499

  20. Rational design and synthesis of topoisomerase I and II inhibitors based on oleanolic acid moiety for new anti-cancer drugs.

    PubMed

    Ashour, Ahmed; El-Sharkawy, Saleh; Amer, Mohamed; Abdel Bar, Fatma; Katakura, Yoshinori; Miyamoto, Tomofumi; Toyota, Nozomi; Bang, Tran Hai; Kondo, Ryuichiro; Shimizu, Kuniyoshi

    2014-01-01

    Semisynthetic reactions were conducted on oleanolic acid, a common plant-derived oleanane-type triterpene. Ten rationally designed derivatives of oleanolic acid were synthesized based on docking studies and tested for their topoisomerase I and IIα inhibitory activity. Semisynthetic reactions targeted C-3, C-12, C-13, and C-17. Nine of the synthesized compounds were identified as new compounds. The structures of these compounds were confirmed by spectroscopic methods (1D, 2D NMR and MS). Five oleanolic acid analogues (S2, S3, S5, S7 and S9) showed higher activity than camptothecin (CPT) in the topoisomerase I DNA relaxation assay. Four oleanolic acid analogues (S2, S3, S5 and S6) showed higher activity than etoposide in a topoisomerase II assay. The results indicated that the C12-C13 double bond of the oleanolic acid skeleton is important for the inhibitory activity against both types of topoisomerases, while insertion of a longer chain at either position 3 or 17 increases the activity against topoisomerases by various degrees. Some of the synthesized compounds act as dual inhibitors for both topoisomerase I and IIα. PMID:24326278

  1. Carbon Dioxide Capture by a Metal-Organic Framework with Nitrogen-Rich Channels Based on Rationally Designed Triazole-Functionalized Tetraacid Organic Linker.

    PubMed

    Seth, Saona; Savitha, Govardhan; Moorthy, Jarugu Narasimha

    2015-07-20

    A semirigid tetraacid linker H4L functionalized with 1,2,3-triazole was rationally designed and synthesized to access nitrogen-rich MOFs for selective adsorption of CO2. The cadmium MOF, that is, Cd-L, obtained by the reaction of H4L with Cd(NO3)2, is found to be a 3D porous framework structure that is robust to desolvation. Crystal structure analysis reveals channels that are decorated by the triazole moieties of L. Gas adsorption studies show that Cd-L MOF permits remarkable CO2 uptake to the extent of 99 and 1000 cc/g at 1 and 30 bar, respectively, at 0 °C. While literature survey reveals that MIL-112, constructed from a 1,2,3-triazole functionalized linker, exhibits no porosity to gas adsorption due to structural flexibility, the results with Cd-L MOF described herein emphasize how rigidification of the organic linker improves gas uptake properties of the resultant MOF. PMID:26146942

  2. Preclinical Development of Novel Rac1-GEF Signaling Inhibitors using a Rational Design Approach in Highly Aggressive Breast Cancer Cell Lines

    PubMed Central

    Cardama, Georgina A; Comin, Maria J; Hornos, Leandro; Gonzalez, Nazareno; Defelipe, Lucas; Turjanski, Adrian G; Alonso, Daniel F; Gomez, Daniel E; Menna, Pablo Lorenzano

    2014-01-01

    Rho GTPases play a key role in the regulation of multiple essential cellular processes, including actin dynamics, gene transcription and cell cycle progression. Aberrant activation of Rac1, a member of Rho family of small GTPases, is associated with tumorigenesis, cancer progression, invasion and metastasis. Particularly, Rac1 is overexpressed and hyperactivated in highly aggressive breast cancer. Thus, Rac1 appears to be a promising and relevant target for the development of novel anticancer drugs. We identified the novel Rac1 inhibitor ZINC69391 through a docking-based virtual library screening targeting Rac1 activation by GEFs. This compound was able to block Rac1 interaction with its GEF Tiam1, prevented EGF-induced Rac1 activation and inhibited cell proliferation, cell migration and cell cycle progression in highly aggressive breast cancer cell lines. Moreover, ZINC69391 showed an in vivo antimetastatic effect in a syngeneic animal model. We further developed the novel analog 1A-116 by rational design and showed to be specific and more potent than the parental compound in vitro and interfered Rac1-P-Rex1 interaction. We also showed an enhanced in vivo potency of 1A-116 analog. These results show that we have developed novel Rac1 inhibitors that may be used as a novel anticancer therapy. PMID:24066799

  3. Rational design and synthesis of novel dibenzo[b,d]furan-1,2,3-triazole conjugates as potent inhibitors of Mycobacterium tuberculosis.

    PubMed

    Yempala, Thirumal; Sridevi, Jonnalagadda Padma; Yogeeswari, Perumal; Sriram, Dharmarajan; Kantevari, Srinivas

    2014-01-01

    A series of novel dibenzo[b,d]furan-1,2,3-triazole conjugates, rationally designed by reorientation of dibenzo[b,d]furan pharmacophore and alkyl/aryl groups appended on 1,2,3-triazole core, were synthesized using click chemistry. The required key intermediate, 2-ethynyl dibenzo[b,d]furan 3 was prepared from dibenzofuran-2-carboxaldehyde using Corey-Fuchs reaction. Further reaction of 3 with various alkyl/aryl azides in the presence of copper catalyst produced 1,2,3-triazole conjugates in excellent yields. Evaluation of all the new compounds for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294), resulted 5a (MIC: 1.56 μg/mL), 5d (MIC: 0.78 μg/mL) and 5f (MIC: 0.78 μg/mL) as promising lead analogues. Among these three compounds, 1-(4-bromobenzyl)-4-(dibenzo[b,d]furan-2-yl)-1H-1,2,3-triazole (5f) emerged as the most promising antitubercular agent with lowest cytotoxicity (selectivity index: ≫25) against the HEK-293T cell line. PMID:24292337

  4. Rational design of tetraphenylethylene-based luminescent down-shifting molecules: photophysical studies and photovoltaic applications in a CdTe solar cell from small to large units.

    PubMed

    Li, Yilin; Li, Zhipeng; Ablekim, Tursunjan; Ren, Tianhui; Dong, Wen-Ji

    2014-12-21

    A rational design strategy of novel fluorophores for luminescent down-shifting (LDS) application was proposed and tested in this paper. Three new fluorophores (1a-c) with specific intramolecular charge transfer (ICT) and aggregation-induced emission (AIE) characteristics were synthesized as LDS molecules for increasing the output short circuit current density (Jsc) of a CdTe solar cell. Photophysical studies of their solution and solid states, and photovoltaic measurements of their PMMA solid films applied on a CdTe solar cell suggested that the specific spectroscopic properties and Jsc enhancement effects of these molecules were highly related to their chemical structures. The Jsc enhancement effects of these fluorophores were measured on both a CdTe small cell and a large panel. An increase in the output Jsc by as high as 5.69% for a small cell and 8.88% for a large panel was observed. Compared to a traditional LDS molecule, Y083, these fluorophores exhibited more superior capabilities of LDS. PMID:25363326

  5. Rational Design of α-Fe2O3/Reduced Graphene Oxide Composites: Rapid Detection and Effective Removal of Organic Pollutants.

    PubMed

    Zhang, Lili; Bao, Zhiwei; Yu, Xinxin; Dai, Peng; Zhu, Jin; Wu, Mingzai; Li, Guang; Liu, Xiansong; Sun, Zhaoqi; Chen, Changle

    2016-03-01

    α-Fe2O3/reduced graphene oxide (α-Fe2O3/rGO) composites are rationally designed and prepared to integrate organic pollutants detection and their photocatalytic degradation. Specifically, the composites are used as the substrate for surface-enhanced Raman scattering (SERS) to detect rhodamine 6G (R6G). Repeatable strong SERS signals could be obtained with R6G concentration as low as 10(-5) M. In addition, the substrate exhibits self-cleaning properties under solar irradiation. Compared with pure α-Fe2O3 and α-Fe2O3/rGO mechanical mixtures, the α-Fe2O3/rGO composites show much higher photocatalytic activity and much greater Raman enhancement factor. After 10 cycling measurements, the photodegradation rate of R6G could be maintained at 90.5%, indicating high stability of the photocatalyst. This study suggests that the α-Fe2O3/rGO composites would serve both as recyclable SERS substrate and as excellent visible light photocatalyst. PMID:26907977

  6. Rational design of YAP WW1 domain-binding peptides to target TGFβ/BMP/Smad-YAP interaction in heterotopic ossification.

    PubMed

    Chen, Dong; Liu, Shenghe; Zhang, Wen; Sun, Luyuan

    2015-11-01

    The transforming growth factor-β/bone morphogenic protein/Smad signaling pathway has been raised as a new and promising therapeutic target of heterotopic ossification, which is mediated by recruitment of transcription coactivator Yes-associated protein (YAP) to Smad. Here, we described a successful integration of computational modeling and experimental assay to rationally design novel peptide aptamers to disrupt YAP-Smad interaction by targeting YAP WW1 domain. In the protocol, a computational genetic evolution strategy was used to improve a population of potential YAP WW1-binding peptides generated from the YAP-recognition site in Smad protein, from which several promising peptides were selected and their affinities toward YAP WW1 domain were determined using binding assay. In addition, a high-activity peptide was further optimized based on its complex structure with YAP WW1 domain to derive a number of derivative peptides with higher binding potency to the domain. We also found that a strong YAP WW1 binder should have a negatively charged N-terminus, a positively charged C-terminus and a nonpolar core to match the electrostatic distribution pattern in peptide-binding pocket of YAP WW1 domain, which may also form additional nonbonded interactions such as hydrogen bond, salt bridge and π-π stacking to confer stability and specificity for the domain-peptide recognition. PMID:26435515

  7. Achieving high performance electric field induced strain: a rational design of hyperbranched aromatic polyamide functionalized graphene-polyurethane dielectric elastomer composites.

    PubMed

    Chen, Tian; Qiu, Jinhao; Zhu, Kongjun; Li, Jinhuan; Wang, Jingwen; Li, Shuqin; Wang, Xiaoliang

    2015-03-26

    Dielectric elastomers have great potentials as flexible actuators in micro-electromechanical systems (MEMS) due to their large deformation, light weight, mechanical compliancy, and low cost. The low dielectric constant of these elastomers requires a rather high voltage electric field, which has greatly limited their applications. In this work, a diaphragm-type flexible microactuator comprising a hyperbranched aromatic polyamide functionalized graphene (HAPFG) filler embedded into the polyurethane (PU) dielectric elastomer matrix is described. The rational designed HAPFG sheets exhibits uniform dispersion in PU matrix and strong adhesion with the matrix by hydrogen-bond coupling. Consequently, the HAPFG-PU composites possess high dielectric performance and low loss modulus. The effect of hyperbranched aromatic polyamide functionalized graphene on high voltage electric field induced strain was experimentally investigated using the Fotonic sensor. The high electric field response of the composite was discussed by applying different kinds of alternating-current field. In addition, a comparison of the breakdown strength between the HAPFG-PU composite and the pure PU was carried out. PMID:25741878

  8. Rational Design in Catalysis: A Mechanistic Study of β-Hydride Eliminations in Gold(I) and Gold(III) Complexes Based on Features of the Reaction Valley.

    PubMed

    Castiñeira Reis, Marta; López, Carlos Silva; Kraka, Elfi; Cremer, Dieter; Faza, Olalla Nieto

    2016-09-01

    β-Hydride eliminations for ethylgold(III) dichloride complexes are identified as reactions with an unusually long prechemical stage corresponding to the conformational preparation of the reaction complex and spanning six phases. The prechemical process is characterized by a geared rotation of the L-Au-L group (L = Cl) driving methyl group rotation and causing a repositioning of the ligands. This requires more than 28 kcal/mol of the total barrier of 34.0 kcal/mol, according to the unified reaction valley approach, which also determines that the energy requirements of the actual chemical process leading to the β-elimination product are only about 5.5 kcal/mol. A detailed mechanistic analysis was used as a basis for a rational design of substrates (via substituents on the ethyl group) and/or ligands, which can significantly reduce the reaction barrier. This strategy takes advantage of either a higher trans activity of the ligands or a tuned electronic demand of the ethyl group. The β-hydride elimination of gold(I) was found to suffer from strong Coulomb and exchange repulsion when a positively charged hydrogen atom enforces a coordination position in a d(10)-configured gold atom, thus triggering an unassisted σ-π Au(I)-C conversion. PMID:27537214

  9. OBSERVATIONS OF SNAKE RESONANCE IN RHIC.

    SciTech Connect

    BAI, M.; HUANG, H.; MACKAY, W.W.; PITISYN, V.; ROSER, T.; TEPIKIAN, S.

    2005-05-16

    Siberian snakes now become essential in the polarized proton acceleration. With proper configuration of Siberian snakes, the spin precession tune of the beam becomes 1/2 which avoids all the spin depolarizing resonance. However, the enhancement of the perturbations on the spin motion can still occur when the spin precession tune is near some low order fractional numbers, called snake resonances, and. the beam can be depolarized when passing through the resonance. The snake resonances have been confirmed in the spin tracking calculations, and observed in RHIC with polarized proton beam. Equipped with two full Siberian snakes in each ring, RHIC provides us a perfect facility for snake resonance studies. This paper presents latest experimental results. New insights are also discussed.

  10. Selective targeting of MAPK family kinases JNK over p38 by rationally designed peptides as potential therapeutics for neurological disorders and epilepsy.

    PubMed

    Zhuo, Zhi-Hong; Sun, Yi-Zhen; Jin, Pei-Na; Li, Feng-Yan; Zhang, Yi-Le; Wang, Huai-Li

    2016-07-19

    Human mitogen-activated protein kinase (MAPK) family members JNK and p38 are two homologous protein-serine/threonine kinases but play distinct roles in the pathological process of neurological disorders. Selective targeting of JNK over p38 has been established as a potential therapeutic approach to epilepsy and other nervous system diseases. Herein, we describe an integrated in vitro-in silico protocol to rationally design kinase-peptide interaction specificity based on crystal structure data. In the procedure, a simulated annealing (SA) iteration optimization strategy is described to improve peptide selectivity between the two kinases. The optimization accepts moderate compromise in peptide affinity to JNK in order to maximize the affinity difference between peptide interactions with JNK and p38. The structural basis, energetic properties and dynamic behavior of SA-improved peptides bound with the peptide-docking sites of JNK and p38 kinase domains are investigated in detail using atomistic molecular dynamics (MD) simulations and post binding free energy analysis. The theoretical findings and computational designs are then confirmed by fluorescence polarization assays. Using the integrated protocol we successfully obtain three decapeptide ligands, namely RLHPSMTDFL, RAKLPTSVDY and KPSRPWNLEI, that exhibit both potent affinity to JNK (K = 8.0, 5.4 and 12.1 μM, respectively) and high selectivity for JNK over p38 (K/K = 9.2, 17.9 and 6.3 fold, respectively). We also demonstrate that a JNK-over-p38 selective peptide should have a positively charged N-terminus, a polar central region and a negatively charged C-terminus, in which a number of hydrophobic residues distribute randomly along the peptide sequence. In particular, the residue positions 1, 6 and 9 play a crucial role in shaping peptide selectivity; the presence of, respectively, Arg, Thr and Asp at the three positions confers high specificity to kinase-peptide interactions. PMID:27263470

  11. Rational design of a receptor-targeted photodynamic molecular beacon for the multilevel control of singlet oxygen production and PDT activity in cancer cells

    NASA Astrophysics Data System (ADS)

    Chen, Juan; Stefflova, Klara; Warren, Mike; Bu, Jiachuan; Wilson, Brian C.; Zheng, Gang

    2007-02-01

    Photodynamic therapy (PDT) involves the combined action of light, oxygen and a photosensitizer (PS). It offers unique control in the PS's action because the key cytotoxic agent, singlet oxygen (1O II), is only produced in situ upon irradiation. The 1O II production can be controlled in three levels. The first level involves the judicious use of fiber optics to selectively deliver light to disease tissues. The second level is to exert control over the PS's localization by selectively delivering PS to cancer cells. The third level is to exert control of the PS's ability to generate 1O II in responding to specific cancer biomarkers. Here, we present two PDT agents based on the latter two levels of 1O II control. The first PDT agent "PPF" contains a PS (Pyro) and a tumor homing molecule (folate) and a peptide linker. PPF was found to be selectively accumulated in cancer cells via folate receptor (FR) pathway. The second PDT agent "PP MMP7B" is a matrix metalloproteinase-7 (MMP7)-triggered photodynamic molecular beacon (PMB) containing a PS (Pyro), a 1O II quencher (BHQ3) and a MMP7-cleavable peptide linker. Thus, the 1O II production of PP MMP7B is highly sequence-specific and its photodynamic cytotoxicity is MMP7-dependent. Since these agents are designed to share functional modules (PS and peptide linker) and common cancer cell model (KB cells overexpress both FR and MMP7), it forms the basis for rational design of receptor-targeted PMB for achieving a multi-level control of 1O II production in cancer cells, which in term, could provide a much higher level of PDT selectivity.

  12. Recombinant snake venom prothrombin activators.

    PubMed

    Lövgren, Ann

    2013-01-01

    Three prothrombin activators; ecarin, which was originally isolated from the venom of the saw-scaled viper Echis carinatus, trocarin from the rough-scaled snake Tropidechis carinatus, and oscutarin from the Taipan snake Oxyuranus scutellatus, were expressed in mammalian cells with the purpose to obtain recombinant prothrombin activators that could be used to convert prothrombin to thrombin. We have previously reported that recombinant ecarin can efficiently generate thrombin without the need for additional cofactors, but does not discriminate non-carboxylated prothrombin from biologically active γ-carboxylated prothrombin. Here we report that recombinant trocarin and oscutarin could not efficiently generate thrombin without additional protein co-factors. We confirm that both trocarin and oscutarin are similar to human coagulation Factor X (FX), explaining the need for additional cofactors. Sequencing of a genomic fragment containing 7 out of the 8 exons coding for oscutarin further confirmed the similarity to human FX. PMID:23111318

  13. Rational design of nasal vaccines.

    PubMed

    Slütter, Bram; Hagenaars, Niels; Jiskoot, Wim

    2008-01-01

    Nasal vaccination is a promising alternative to classical parental vaccination, as it is non-invasive and, in principle, capable of eliciting strong systemic and local immune responses. However, the protective efficacy of nasally administered antigens is often impaired because of delivery problems: free antigens are readily cleared from the nasal cavity, poorly absorbed by nasal epithelial cells and generally have low intrinsic immunogenicity. In this review paper, we describe the main physiological hurdles to nasal vaccine delivery, survey the progress made in technological approaches to overcome these hurdles and discuss emerging opportunities for improving nasal vaccines. According to current insights, encapsulation of the antigen into bioadhesive (nano)particles is a promising approach towards successful nasal vaccine delivery. These antigen-loaded particles can be tailor made by supplying them with targeting ligands, adjuvants or endosomal escape mediators to form the desired vaccine that provides long-lasting protective immunity. PMID:18172815

  14. Homogeneous fluorescent specific PCR for the authentication of medicinal snakes using cationic conjugated polymers

    PubMed Central

    Jiang, Chao; Yuan, Yuan; Liu, Libing; Hou, Jingyi; Jin, Yan; Huang, Luqi

    2015-01-01

    A label-free, homogenous and sensitive one-step method for the molecular authentication of medicinal snakes has been developed by combining a rapid PCR technique with water-soluble cationic conjugated polyelectrolytes (CCPs). Three medicinal snake materials (Deinagkistrodon acutus, Zaocys dhumnades and Bungarus multicinctus; a total of 35 specimens) and 48 snake specimens with similar morphologies and textures were clearly distinguished by the naked eye by utilizing a CCP-based assay in a high-throughput manner. The identification of medicinal snakes in patented Chinese drugs was successfully performed using this detection system. In contrast to previous fluorescence-labeled oligonucleotide detection and direct DNA stain hybridization assays, this method does not require designing dye-labeled primers, and unfavorable dimer fluorescence is avoided in this homogenous method. PMID:26537289

  15. Rapid visuomotor processing of phobic images in spider- and snake-fearful participants.

    PubMed

    Haberkamp, Anke; Schmidt, Filipp; Schmidt, Thomas

    2013-10-01

    This study investigates enhanced visuomotor processing of phobic compared to fear-relevant and neutral stimuli. We used a response priming design to measure rapid, automatic motor activation by natural images (spiders, snakes, mushrooms, and flowers) in spider-fearful, snake-fearful, and control participants. We found strong priming effects in all tasks and conditions; however, results showed marked differences between groups. Most importantly, in the group of spider-fearful individuals, spider pictures had a strong and specific influence on even the fastest motor responses: Phobic primes entailed the largest priming effects, and phobic targets accelerated responses, both effects indicating speeded response activation by phobic images. In snake-fearful participants, this processing enhancement for phobic material was less pronounced and extended to both snake and spider images. We conclude that spider phobia leads to enhanced processing capacity for phobic images. We argue that this is enabled by long-term perceptual learning processes. PMID:23920405

  16. On the road to metallic nanoparticles by rational design: bridging the gap between atomic-level theoretical modeling and reality by total scattering experiments

    NASA Astrophysics Data System (ADS)

    Prasai, Binay; Wilson, A. R.; Wiley, B. J.; Ren, Y.; Petkov, Valeri

    2015-10-01

    The extent to which current theoretical modeling alone can reveal real-world metallic nanoparticles (NPs) at the atomic level was scrutinized and demonstrated to be insufficient and how it can be improved by using a pragmatic approach involving straightforward experiments is shown. In particular, 4 to 6 nm in size silica supported Au100-xPdx (x = 30, 46 and 58) explored for catalytic applications is characterized structurally by total scattering experiments including high-energy synchrotron X-ray diffraction (XRD) coupled to atomic pair distribution function (PDF) analysis. Atomic-level models for the NPs are built by molecular dynamics simulations based on the archetypal for current theoretical modeling Sutton-Chen (SC) method. Models are matched against independent experimental data and are demonstrated to be inaccurate unless their theoretical foundation, i.e. the SC method, is supplemented with basic yet crucial information on the length and strength of metal-to-metal bonds and, when necessary, structural disorder in the actual NPs studied. An atomic PDF-based approach for accessing such information and implementing it in theoretical modeling is put forward. For completeness, the approach is concisely demonstrated on 15 nm in size water-dispersed Au particles explored for bio-medical applications and 16 nm in size hexane-dispersed Fe48Pd52 particles explored for magnetic applications as well. It is argued that when ``tuned up'' against experiments relevant to metals and alloys confined to nanoscale dimensions, such as total scattering coupled to atomic PDF analysis, rather than by mere intuition and/or against data for the respective solids, atomic-level theoretical modeling can provide a sound understanding of the synthesis-structure-property relationships in real-world metallic NPs. Ultimately this can help advance nanoscience and technology a step closer to producing metallic NPs by rational design.The extent to which current theoretical modeling alone can

  17. Understanding MHC Class I Presentation of Viral Antigens by Human Dendritic Cells as a Basis for Rational Design of Therapeutic Vaccines

    PubMed Central

    van Montfoort, Nadine; van der Aa, Evelyn; Woltman, Andrea M.

    2014-01-01

    Effective viral clearance requires the induction of virus-specific CD8+ cytotoxic T lymphocytes (CTL). Since dendritic cells (DC) have a central role in initiating and shaping virus-specific CTL responses, it is important to understand how DC initiate virus-specific CTL responses. Some viruses can directly infect DC, which theoretically allow direct presentation of viral antigens to CTL, but many viruses target other cells than DC and thus the host depends on the cross-presentation of viral antigens by DC to activate virus-specific CTL. Research in mouse models has highly enhanced our understanding of the mechanisms underlying cross-presentation and the dendritic cells (DC) subsets involved, however, these results cannot be readily translated toward the role of human DC in MHC class I-antigen presentation of human viruses. Here, we summarize the insights gained in the past 20 years on MHC class I presentation of viral antigen by human DC and add to the current debate on the capacities of different human DC subsets herein. Furthermore, possible sources of viral antigens and essential DC characteristics for effective induction of virus-specific CTL are evaluated. We conclude that cross-presentation is not only an efficient mechanism exploited by DC to initiate immunity to viruses that do not infect DC but also to viruses that do infect DC, because cross-presentation has many conceptual advantages and bypasses direct immune modulatory effects of the virus on its infected target cells. Since knowledge on the mechanism of viral antigen presentation and the preferred DC subsets is crucial for rational vaccine design, the obtained insights are very instrumental for the development of effective anti-viral immunotherapy. PMID:24795724

  18. On the road to metallic nanoparticles by rational design: bridging the gap between atomic-level theoretical modeling and reality by total scattering experiments.

    PubMed

    Prasai, Binay; Wilson, A R; Wiley, B J; Ren, Y; Petkov, Valeri

    2015-11-14

    The extent to which current theoretical modeling alone can reveal real-world metallic nanoparticles (NPs) at the atomic level was scrutinized and demonstrated to be insufficient and how it can be improved by using a pragmatic approach involving straightforward experiments is shown. In particular, 4 to 6 nm in size silica supported Au(100-x)Pd(x) (x = 30, 46 and 58) explored for catalytic applications is characterized structurally by total scattering experiments including high-energy synchrotron X-ray diffraction (XRD) coupled to atomic pair distribution function (PDF) analysis. Atomic-level models for the NPs are built by molecular dynamics simulations based on the archetypal for current theoretical modeling Sutton-Chen (SC) method. Models are matched against independent experimental data and are demonstrated to be inaccurate unless their theoretical foundation, i.e. the SC method, is supplemented with basic yet crucial information on the length and strength of metal-to-metal bonds and, when necessary, structural disorder in the actual NPs studied. An atomic PDF-based approach for accessing such information and implementing it in theoretical modeling is put forward. For completeness, the approach is concisely demonstrated on 15 nm in size water-dispersed Au particles explored for bio-medical applications and 16 nm in size hexane-dispersed Fe48Pd52 particles explored for magnetic applications as well. It is argued that when "tuned up" against experiments relevant to metals and alloys confined to nanoscale dimensions, such as total scattering coupled to atomic PDF analysis, rather than by mere intuition and/or against data for the respective solids, atomic-level theoretical modeling can provide a sound understanding of the synthesis-structure-property relationships in real-world metallic NPs. Ultimately this can help advance nanoscience and technology a step closer to producing metallic NPs by rational design. PMID:26463562

  19. A Rational Expectations Experiment.

    ERIC Educational Resources Information Center

    Peterson, Norris A.

    1990-01-01

    Presents a simple classroom simulation of the Lucas supply curve mechanism with rational expectations. Concludes that the exercise has proved very useful as an introduction to the concepts of rational and adaptive expectations, the Lucas supply curve, the natural rate hypothesis, and random supply shocks. (DB)

  20. Enculturated Chimpanzees Imitate Rationally

    ERIC Educational Resources Information Center

    Buttelmann, David; Carpenter, Malinda; Call, Josep; Tomasello, Michael

    2007-01-01

    Human infants imitate others' actions "rationally": they copy a demonstrator's action when that action is freely chosen, but less when it is forced by some constraint (Gergely, Bekkering & Kiraly, 2002). We investigated whether enculturated chimpanzees (Pan troglodytes) also imitate rationally. Using Gergely and colleagues' (2002) basic procedure,…