WorldWideScience

Sample records for rationally designed scaffold-based

  1. Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.

    Directory of Open Access Journals (Sweden)

    Li-Song Zhang

    Full Text Available As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARα, PPARβ and PPARγ, all of which have been treated as attractive targets for developing drugs to treat type 2 diabetes. Due to the undesirable side-effects, many PPAR agonists including PPARα/γ and PPARβ/γ dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPARα, PPARβ and PPARγ. Under such an idea, in the current study we adopted the core hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608. It was observed by the docking procedures and molecular dynamics simulations that the compounds generated by the core hopping and glide docking not only possessed the similar functions as the original LY465608 compound to activate PPARα, PPARβ and PPARγ receptors, but also had more favorable conformation for binding to the PPAR receptors. The additional absorption, distribution, metabolism and excretion (ADME predictions showed that the 7 compounds (especially Cpd#1 hold high potential to be novel lead compounds for the PPAR pan-agonist. Our findings can provide a new strategy or useful insights for designing the effective pan-agonists against the type 2 diabetes.

  2. Introducing an attractive method for total biomimetic creation of a synthetic biodegradable bioactive bone scaffold based on statistical experimental design.

    Science.gov (United States)

    Shahbazi, Sara; Zamanian, Ali; Pazouki, Mohammad; Jafari, Yaser

    2018-05-01

    A new total biomimetic technique based on both the water uptake and degradation processes is introduced in this study to provide an interesting procedure to fabricate a bioactive and biodegradable synthetic scaffold, which has a good mechanical and structural properties. The optimization of effective parameters to scaffold fabrication was done by response surface methodology/central composite design (CCD). With this method, a synthetic scaffold was fabricated which has a uniform and open-interconnected porous structure with the largest pore size of 100-200μm. The obtained compressive ultimate strength of ~35MPa and compression modulus of 58MPa are similar to some of the trabecular bone. The pore morphology, size, and distribution of the scaffold were characterized using a scanning electron microscope and mercury porosimeter. Fourier transform infrared spectroscopy, EDAX and X-ray diffraction analyses were used to determine the chemical composition, Ca/P element ratio of mineralized microparticles, and the crystal structure of the scaffolds, respectively. The optimum biodegradable synthetic scaffold based on its raw materials of polypropylene fumarate, hydroxyethyl methacrylate and nano bioactive glass (PPF/HEMA/nanoBG) as 70/30wt/wt%, 20wt%, and 1.5wt/wt% (PHB.732/1.5) with desired porosity, pore size, and geometry were created by 4weeks immersion in SBF. This scaffold showed considerable biocompatibility in the ranging from 86 to 101% for the indirect and direct contact tests and good osteoblast cell attachment when studied with the bone-like cells. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Towards a formal logic of design rationalization

    DEFF Research Database (Denmark)

    Galle, Per

    1997-01-01

    Certain extensions to standard predicate logic are proposed and used as a framework for critical logical study of patterns of inference in design reasoning. It is shown that within this framework a modal logic of design rationalization (suggested by an empirical study reported earlier) can...... be formally defined in terms of quantification over a universe of discourse of ‘relevant points of view’. Five basic principles of the extended predicate logic are listed, on the basis of which the validity of ten modal patterns of inference encountered in design rationalization is tested. The basic idea...

  4. Rational Design of Improved Pharmabiotics

    Directory of Open Access Journals (Sweden)

    Roy D. Sleator

    2009-01-01

    Full Text Available 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.

  5. Rational design of improved pharmabiotics.

    LENUS (Irish Health Repository)

    Sleator, Roy D

    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.

  6. Design of 2-D rational digital filters

    International Nuclear Information System (INIS)

    Harris, D.B

    1981-01-01

    A novel 2-D rational filter design technique is presented which makes use of a reflection coefficient function (RCF) representation for the filter transfer function. The design problem is formulated in the frequency domain. A least-square error criterion is used though the usual error measure is augmented with barrier functions. These act to restrict the domain of approximation to the set of stable filters. Construction of suitable barrier functions is facilitated by the RCF characterization

  7. Rational design of nanomaterials for water treatment

    KAUST Repository

    Li, Renyuan

    2015-08-26

    The ever-increasing human demand for safe and clean water is gradually pushing conventional water treatment technologies to their limits and it is now a popular perception that the solutions to the existing and future water challenges will highly hinge upon the further development of nanomaterial sciences. The concept of rational design emphasizes ‘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 of the 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 on chemical concepts of the nanomaterial designs throughout the review.

  8. Geology and Design: Formal and Rational Connections

    Science.gov (United States)

    Eriksson, S. C.; Brewer, J.

    2016-12-01

    Geological forms and the manmade environment have always been inextricably linked. From the time that Upper Paleolithic man created drawings in the Lascaux Caves in the southwest of France, geology has provided a critical and dramatic spoil for human creativity. This inspiration has manifested itself in many different ways, and the history of architecture is rife with examples of geologically derived buildings. During the early 20th Century, German Expressionist art and architecture was heavily influenced by the natural and often translucent quality of minerals. Architects like Bruno Taut drew and built crystalline forms that would go on to inspire the more restrained Bauhaus movement. Even within the context of Contemporary architecture, geology has been a fertile source for inspiration. Architectural practices across the globe leverage the rationality and grounding found in geology to inform a process that is otherwise dominated by computer-driven parametric design. The connection between advanced design technology and the beautifully realized geo natural forms insures that geology will be a relevant source of architectural inspiration well into the 21st century. The sometimes hidden relationship of geology to the various sub-disciplines of Design such as Architecture, Interiors, Landscape Architecture, and Historic Preservation is explored in relation to curriculum and the practice of design. Topics such as materials, form, history, the cultural and physical landscape, natural hazards, and global design enrich and inform curriculum across the college. Commonly, these help define place-based education.

  9. Developing and Testing Rational Models of Message Design.

    Science.gov (United States)

    O'Keefe, Barbara J.

    1992-01-01

    Responds to an article in the same issue regarding research methods for conversational cognition. Argues for a noncognitive view of rational models in communication research. Sets out an analysis of the kinds of claims made by rational models of message design. Discusses the implications of this analysis for studies of the cognitive processes…

  10. Design rationalization and the logic of design: a case study

    DEFF Research Database (Denmark)

    Galle, Per

    1996-01-01

    various ‘sources of credibility’ of premises, items of general background knowledge, and several (abductive and deductive) patterns of inference which suggest a possible ‘logic of design’. Rationalization of decisions is defined, and many decisions are found not to be fully rationalized, despite...... the apparent rationality of the reasoning....

  11. Staurosporine scaffold-based rational discovery of the wild-type sparing reversible inhibitors of EGFR T790M gatekeeper mutant in lung cancer with analog-sensitive kinase technology.

    Science.gov (United States)

    Song, Xiaoyun; Liu, Xingcai; Ding, Xi

    2017-04-01

    The human epidermal growth factor receptor (EGFR) has been established as an attractive target for lung cancer therapy. However, an acquired EGFR T790M gatekeeper mutation is frequently observed in patients treated with first-line anticancer agents such as gefitinib and erlotinib to cause drug resistance, largely limiting the application of small-molecule kinase inhibitors in EGFR-targeted chemotherapy. Previously, the reversible pan-kinase inhibitor staurosporine and its several analogs such as Gö6976 and K252a have been reported to selectively inhibit the EGFR T790M mutant (EGFR T790M ) over wild-type kinase (EGFR WT ), suggesting that the staurosporine scaffold is potentially to develop the wild-type sparing reversible inhibitors of EGFR T790M . Here, we systematically evaluated the inhibitor response of 28 staurosporine scaffold-based compounds to EGFR T790M mutation at structural, energetic, and molecular levels by using an integrated in silico-in vitro analog-sensitive (AS) kinase technology. With the strategy, we were able to identify 4 novel wild-type sparing inhibitors UCN-01, UCN-02, AFN941, and SB-218078 with high or moderate selectivity of 30-, 45-, 5-, and 8-fold for EGFR T790M over EGFR WT , respectively, which are comparable with or even better than that of the parent compound staurosporine (24-fold). Molecular modeling and structural analysis revealed that van der Waals contacts and hydrophobic forces can form between the side chain of mutated residue Met790 and the pyrrolidinone moiety of inhibitor ligand UCN-02, which may simultaneously improve the favorable interaction energy between the kinase and inhibitor, and reduce the unfavorable desolvation penalty upon the kinase-inhibitor binding. A hydroxyl group of UCN-02 additional to staurosporine locates at the pyrrolidinone moiety, which can largely alter the electronic distribution of pyrrolidinone moiety and thus promote the intermolecular interaction with Met790 residue. This can well explain

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

    Science.gov (United States)

    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.

  13. Design thinking between rationalism and romanticism

    DEFF Research Database (Denmark)

    Engholm, Ida; Goldschmidt Salamon, Karen-Lisa

    2017-01-01

    This article presents a longue durée history of modern design thought, with particular focus on recurrent ideological frictions. Drawing on design history, design anthropology and cultural studies, the authors present an overview of more than 200 years of developments in European and North Americ...

  14. Designing institutions for climate change: Why rational design involves technology

    Energy Technology Data Exchange (ETDEWEB)

    Coninck, H. de [Energy Research Centre of the Netherlands, Petten (Netherlands)

    2008-09-30

    This paper aims to explore how to augment the institutional solutions offered by current political theory for addressing the unprecedented problem of climate change. Although steering directly at emission reductions in an international treaty has benefits in terms of cost-effectiveness, the paper arrives at the conclusion that considerations around technological development should be drawn into the treaty equation in order to generate sufficient reciprocity to have a politically feasible international regime. It then argues that the benefits of technology agreements for climate change mitigation may be larger than commonly assumed, as they - if properly designed - could lead to real emission reductions and provide more flexibility to reach agreement in post-2012 negotiations than proposals modelled exclusively on the Kyoto Protocol or other types of absolute emission targets. Based on rational design of international institutions for environmental governance, and attempting to take into account considerations of technological dynamics and the 'sociotechnical system', contours of a possible environmentally effective and politically feasible international climate change agreements are sketched.

  15. Evaluation of urban river landscape design rationality based on AHP

    Directory of Open Access Journals (Sweden)

    Qiao Lifang

    2008-12-01

    Full Text Available An evaluation model for the rationality of the landscape design of urban rivers was established with the analytic hierarchy process (AHP method so as to provide a foundation for updating the landscape design of urban rivers. The evaluation system was divided into four layers, including the target layer, the comprehensive layer, the element layer, and the index layer. Each layer was made of different indices. The evaluation standards for each index were also given in this paper. This evaluation model was proved tenable through its application to the landscape design rationality evaluation of the Weihe River in Xinxiang City of Henan Province. The results show that the water quality, space, activity, facility, community, width of vegetation, sense of beauty and water content are among the most influential factors and should be considered the main basis for evaluating the rationality of the landscape design of urban rivers.

  16. A RATIONAL APPROACH TO SEPTIC TANK DESIGN

    African Journals Online (AJOL)

    2012-03-01

    Mar 1, 2012 ... to obtain the volume of sludge accumulated in this time interval. Using a minimum ... Design charts and a Microsoft Excel based design programme were produced to ..... Jowett, E. C. and Lay, R. Comparative per- formance of ...

  17. Guest-responsive structural adaptation of a rationally-designed ...

    Indian Academy of Sciences (India)

    adaptability of the TB core to undergo subtle structural changes in response to the guest that is included. The structural ... we report the design, synthesis and inclusion behaviour of a novel ..... Based on a rational design, we have shown from ...

  18. Machine learning in the rational design of antimicrobial peptides.

    Science.gov (United States)

    Rondón-Villarreal, Paola; Sierra, Daniel A; Torres, Rodrigo

    2014-01-01

    One of the most important public health issues is the microbial and bacterial resistance to conventional antibiotics by pathogen microorganisms. In recent years, many researches have been focused on the development of new antibiotics. Among these, antimicrobial peptides (AMPs) have raised as a promising alternative to combat antibioticresistant microorganisms. For this reason, many theoretical efforts have been done in the development of new computational tools for the rational design of both better and effective AMPs. In this review, we present an overview of the rational design of AMPs using machine learning techniques and new research fields.

  19. A rational evaluation of structural design loads

    International Nuclear Information System (INIS)

    Tasaka, S.

    1993-01-01

    The reliability-based seismic design of structures is a design method ensuring that the structural seismic capacity is not less than the maximum seismic load or load effect for a prescribed value of the reliability index, wherein the design reference period, n, is used to specify the n-year maximum load. In the conventional Load and Resistance Factor Design (LRFD) method the design load is commonly determined on the basis of the n-year maximum the probability distribution of which may be given in some different ways. However, in contrast with the structural capacity the n-year maximum load usually involves much larger variabilities. The effort to decrease the variability would, hence, be effective for the purpose of avoiding nuclear power plant (NPP) structures having unnecessarily large capacities. A possible way to do this is to consider the joint probability distribution of the n-year 1st and 2nd maxima of the seismic load derived from the formula of extreme order statistics. Since the reliability index is conventionally associated with the n-year 1st maximum, the conditional probability distribution rather than the joint one of the n-year 1st maximum given a value of the n-year 2nd one will be considered. Three conditional extreme value distributions, which correspond to the usual extreme value distributions of Types I, II and III, and their statistical moments up to the second order are presented. Within the framework of the first-order second moment method, the conditional statistical moments are utilized to calculate the reliability index as well as the design value of the seismic load. The seismic load considered herein is represented by the peak ground acceleration (PGA) in n years. The present scheme is applied to evaluate the design PGA's at II sites in Japan where samples of the annual 1st and 2nd PGA's have been obtained by using historical seismic data. In this application the following two points are of our interest: (a) Define the reliability

  20. Rational design of reconfigurable prismatic architected materials

    Science.gov (United States)

    Overvelde, Johannes T. B.; Weaver, James C.; Hoberman, Chuck; Bertoldi, Katia

    2017-01-01

    Advances in fabrication technologies are enabling the production of architected materials with unprecedented properties. Most such materials are characterized by a fixed geometry, but in the design of some materials it is possible to incorporate internal mechanisms capable of reconfiguring their spatial architecture, and in this way to enable tunable functionality. Inspired by the structural diversity and foldability of the prismatic geometries that can be constructed using the snapology origami technique, here we introduce a robust design strategy based on space-filling tessellations of polyhedra to create three-dimensional reconfigurable materials comprising a periodic assembly of rigid plates and elastic hinges. Guided by numerical analysis and physical prototypes, we systematically explore the mobility of the designed structures and identify a wide range of qualitatively different deformations and internal rearrangements. Given that the underlying principles are scale-independent, our strategy can be applied to the design of the next generation of reconfigurable structures and materials, ranging from metre-scale transformable architectures to nanometre-scale tunable photonic systems.

  1. Rational Design of Zinc Phosphide Heterojunction Photovoltaics

    Science.gov (United States)

    Bosco, Jeffrey Paul

    The prospect of terawatt-scale electricity generation using a photovoltaic (PV) device places strict requirements on the active semiconductor optoelectronic properties and elemental abundance. After reviewing the constraints placed on an ``earth-abundant'' solar absorber, we find zinc phosphide (α-Zn 3P2) to be an ideal candidate. In addition to its near-optimal direct band gap of 1.5 eV, high visible-light absorption coefficient (>10. 4cm-1), and long minority-carrier diffusion length (>5 μm), Zn3P 2 is composed of abundant Zn and P elements and has excellent physical properties for scalable thin-film deposition. However, to date, a Zn 3P2 device of sufficient efficiency for commercial applications has not been demonstrated. Record efficiencies of 6.0% for multicrystalline and 4.3% for thin-film cells have been reported, respectively. Performance has been limited by the intrinsic p-type conductivity of Zn3P 2 which restricts us to Schottky and heterojunction device designs. Due to our poor understanding of Zn3P2 interfaces, an ideal heterojunction partner has not yet been found. The goal of this thesis is to explore the upper limit of solar conversion efficiency achievable with a Zn3P2 absorber through the design of an optimal heterojunction PV device. To do so, we investigate three key aspects of material growth, interface energetics, and device design. First, the growth of Zn3P2 on GaAs(001) is studied using compound-source molecular-beam epitaxy (MBE). We successfully demonstrate the pseudomorphic growth of Zn3P2 epilayers of controlled orientation and optoelectronic properties. Next, the energy-band alignments of epitaxial Zn3P2 and II-VI and III-V semiconductor interfaces are measured via high-resolution x-ray photoelectron spectroscopy in order to determine the most appropriate heterojunction partner. From this work, we identify ZnSe as a nearly ideal n-type emitter for a Zn3P 2 PV device. Finally, various II-VI/Zn3P2 heterojunction solar cells designs are

  2. Rational design of new electrodes for electrochemotherapy.

    Science.gov (United States)

    Spugnini, E P; Citro, G; Porrello, A

    2005-06-01

    Electrochemotherapy associates the local delivery of anticancer drugs with the administration of permeabilizing electric pulses that support the antiblastic action. The basic instrumentation for this therapy is constituted by a pulse generator and various specific electrodes. While many efforts have been profuse by researchers in this field to obtain the standardization of the pulse generating equipment over the past 15 years, the delivery apparatus still needs refinements in order to reach most of the body districts, to control the homogeneity and stability of the electric fields and to further reduce morbidity. With the aim to develop innovative electrodes able to satisfy, at least partially, these requirements, extensive studies on pet patients with spontaneous neoplasms have been conducted, leading to the manufacturing of several different prototypes. In this paper we discuss the rationale of 11 different electrodes, briefly summarize the results obtained and their experimental validation, also presenting five paradigmatic clinical cases. In particular, it is shown that the caliper electrodes are more suited for the treatment of cutaneous and subcutaneous lesions, while the needle arrays are more efficacious in intraoperative settings. Furthermore, relevant peculiarities of unipolar electrodes are examined with a particular focus on the irregular current paths that they produce and on the potentialities of this feature. Remarkably, the decrease of the steric encumbrance turned out to be a stronger factor in electrode design than the containment of the total number of electric fields covered in serial ECT sessions. In the conclusions, perspectives and new challenges of electrode design for electrochemotherapy are illustrated.

  3. A rational approach for ω-transaminase-catalyzed process design

    DEFF Research Database (Denmark)

    T. Gundersen, Maria; Lloyd, Richard; Tufvesson, Pär

    Herein we describe a novel rational approach to the design of a ω-transaminase process such that it will fulfill criteria necessary for industrial use. By first determining the fundamental properties of the reaction system, it is possible to suggest appropriate process strategies that may be used...

  4. RECENT ADVANCES TOWARDS THE RATIONAL DESIGN OF PEPTIDE DRUGS

    OpenAIRE

    YEŞİLADA, Akgül; ÖZKANLI, Fügen

    2004-01-01

    In this review, after a short introduction to definition and physiological roles of regulatory peptides, problems faced during the development of peptide drugs, studies directed to solve these problems and rational design of peptide drugs with special emphesis on peptidomimetics are mentioned

  5. Rational Design of an Ultrasensitive Quorum-Sensing Switch.

    Science.gov (United States)

    Zeng, Weiqian; Du, Pei; Lou, Qiuli; Wu, Lili; Zhang, Haoqian M; Lou, Chunbo; Wang, Hongli; Ouyang, Qi

    2017-08-18

    One of the purposes of synthetic biology is to develop rational methods that accelerate the design of genetic circuits, saving time and effort spent on experiments and providing reliably predictable circuit performance. We applied a reverse engineering approach to design an ultrasensitive transcriptional quorum-sensing switch. We want to explore how systems biology can guide synthetic biology in the choice of specific DNA sequences and their regulatory relations to achieve a targeted function. The workflow comprises network enumeration that achieves the target function robustly, experimental restriction of the obtained candidate networks, global parameter optimization via mathematical analysis, selection and engineering of parts based on these calculations, and finally, circuit construction based on the principles of standardization and modularization. The performance of realized quorum-sensing switches was in good qualitative agreement with the computational predictions. This study provides practical principles for the rational design of genetic circuits with targeted functions.

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

    Science.gov (United States)

    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.

  7. Fundamental understanding and rational design of high energy structural microbatteries

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yuxing; Li, Qiuyan; Cartmell, Samuel; Li, Huidong; Mendoza, Sarah; Zhang, Ji-Guang; Deng, Zhiqun Daniel; Xiao, Jie

    2018-01-01

    Microbatteries play a critical role in determining the lifetime of downsized sensors, wearable devices and medical applications, etc. More often, structural batteries are required from the perspective of aesthetics and space utilization, which is however rarely explored. Herein, we discuss the fundamental issues associated with the rational design of practically usable high energy microbatteries. The tubular shape of the cell further allows the flexible integration of microelectronics. A functioning acoustic micro-transmitter continuously powered by this tubular battery has been successfully demonstrated. Multiple design features adopted to accommodate large mechanical stress during the rolling process are discussed providing new insights in designing the structural microbatteries for emerging technologies.

  8. Rational assembly of nanoparticle superlattices with designed lattice symmetries

    Science.gov (United States)

    Gang, Oleg; Lu, Fang; Tagawa, Miho

    2017-09-05

    A method for lattice design via multivalent linkers (LDML) is disclosed that introduces a rationally designed symmetry of connections between particles in order to achieve control over the morphology of their assembly. The method affords the inclusion of different programmable interactions within one linker that allow an assembly of different types of particles. The designed symmetry of connections is preferably provided utilizing DNA encoding. The linkers may include fabricated "patchy" particles, DNA scaffold constructs and Y-shaped DNA linkers, anisotropic particles, which are preferably functionalized with DNA, multimeric protein-DNA complexes, and particles with finite numbers of DNA linkers.

  9. MIRATE: MIps RATional dEsign Science Gateway.

    Science.gov (United States)

    Busato, Mirko; Distefano, Rosario; Bates, Ferdia; Karim, Kal; Bossi, Alessandra Maria; López Vilariño, José Manuel; Piletsky, Sergey; Bombieri, Nicola; Giorgetti, Alejandro

    2018-06-13

    Molecularly imprinted polymers (MIPs) are high affinity robust synthetic receptors, which can be optimally synthesized and manufactured more economically than their biological equivalents (i.e. antibody). In MIPs production, rational design based on molecular modeling is a commonly employed technique. This mostly aids in (i) virtual screening of functional monomers (FMs), (ii) optimization of monomer-template ratio, and (iii) selectivity analysis. We present MIRATE, an integrated science gateway for the intelligent design of MIPs. By combining and adapting multiple state-of-the-art bioinformatics tools into automated and innovative pipelines, MIRATE guides the user through the entire process of MIPs' design. The platform allows the user to fully customize each stage involved in the MIPs' design, with the main goal to support the synthesis in the wet-laboratory. MIRATE is freely accessible with no login requirement at http://mirate.di.univr.it/. All major browsers are supported.

  10. Fundamental understanding and rational design of high energy structural microbatteries

    International Nuclear Information System (INIS)

    Wang, Yuxing; Li, Qiuyan; Cartmell, Samuel; Li, Huidong; Mendoza, Sarah

    2017-01-01

    We present that microbatteries play a critical role in determining the lifetime of downsized sensors, wearable devices, medical applications, and animal acoustic telemetry transmitters among others. More often, structural batteries are required from the perspective of aesthetics and space utilization, which is however rarely explored. Herein, we discuss the fundamental issues associated with the rational design of practically usable high energy microbatteries. The tubular shape of the cell further allows the flexible integration of microelectronics. A functioning acoustic micro-transmitter continuously powered by this tubular battery has been successfully demonstrated. Finally, multiple design features adopted to accommodate large mechanical stress during the rolling process are discussed providing new insights in designing the structural microbatteries for emerging technologies.

  11. Attenuation of Vibrio fischeri quorum sensing using rationally designed polymers.

    Science.gov (United States)

    Piletska, Elena V; Stavroulakis, Georgios; Karim, Kal; Whitcombe, Michael J; Chianella, Iva; Sharma, Anant; Eboigbodin, Kevin E; Robinson, Gary K; Piletsky, Sergey A

    2010-04-12

    A first attempt to attenuate the quorum sensing (QS) of a marine heterotroph microorganism, Vibrio fischeri , using signal molecule-sequestering polymers (SSPs) is presented. A set of rationally designed polymers with affinity toward a signal molecule of V. fischeri , N-(beta-ketocaproyl)-l-homoserine lactone (3-oxo-C6-AHL) was produced. It is reported that computationally designed polymers could sequester a signal molecule of V. fischeri and prevent QS-controlled phenotypes (in this case, bioluminescence) from being up-regulated. It was proven that the attenuation of bioluminescence of V. fischeri was due to sequestration of the signal molecule by specific polymers and not due to the toxicity of polymer or nonspecific depletion of nutrients. The ability to disrupt the bacterial communication using easy to synthesize and chemically inert polymers could provide a new concept for the development of pharmaceuticals and susceptible device coatings such as catheters.

  12. Nucleic acids for the rational design of reaction circuits.

    Science.gov (United States)

    Padirac, Adrien; Fujii, Teruo; Rondelez, Yannick

    2013-08-01

    Nucleic acid-based circuits are rationally designed in vitro assemblies that can perform complex preencoded programs. They can be used to mimic in silico computations. Recent works emphasized the modularity and robustness of these circuits, which allow their scaling-up. Another new development has led to dynamic, time-responsive systems that can display emergent behaviors like oscillations. These are closely related to biological architectures and provide an in vitro model of in vivo information processing. Nucleic acid circuits have already been used to handle various processes for technological or biotechnological purposes. Future applications of these chemical smart systems will benefit from the rapidly growing ability to design, construct, and model nucleic acid circuits of increasing size. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Rationally designed synthetic protein hydrogels with predictable mechanical properties.

    Science.gov (United States)

    Wu, Junhua; Li, Pengfei; Dong, Chenling; Jiang, Heting; Bin Xue; Gao, Xiang; Qin, Meng; Wang, Wei; Bin Chen; Cao, Yi

    2018-02-12

    Designing synthetic protein hydrogels with tailored mechanical properties similar to naturally occurring tissues is an eternal pursuit in tissue engineering and stem cell and cancer research. However, it remains challenging to correlate the mechanical properties of protein hydrogels with the nanomechanics of individual building blocks. Here we use single-molecule force spectroscopy, protein engineering and theoretical modeling to prove that the mechanical properties of protein hydrogels are predictable based on the mechanical hierarchy of the cross-linkers and the load-bearing modules at the molecular level. These findings provide a framework for rationally designing protein hydrogels with independently tunable elasticity, extensibility, toughness and self-healing. Using this principle, we demonstrate the engineering of self-healable muscle-mimicking hydrogels that can significantly dissipate energy through protein unfolding. We expect that this principle can be generalized for the construction of protein hydrogels with customized mechanical properties for biomedical applications.

  14. Rational Design of Semiconductor Nanostructures for Functional Subcellular Interfaces.

    Science.gov (United States)

    Parameswaran, Ramya; Tian, Bozhi

    2018-05-15

    One of the fundamental questions guiding research in the biological sciences is how cellular systems process complex physical and environmental cues and communicate with each other across multiple length scales. Importantly, aberrant signal processing in these systems can lead to diseases that can have devastating impacts on human lives. Biophysical studies in the past several decades have demonstrated that cells can respond to not only biochemical cues but also mechanical and electrical ones. Thus, the development of new materials that can both sense and modulate all of these pathways is necessary. Semiconducting nanostructures are an emerging class of discovery platforms and tools that can push the limits of our ability to modulate and sense biological behaviors for both fundamental research and clinical applications. These materials are of particular interest for interfacing with cellular systems due to their matched dimension with subcellular components (e.g., cytoskeletal filaments), and easily tunable properties in the electrical, optical and mechanical regimes. Rational design via traditional or new approaches, such as nanocasting and mesoscale chemical lithography, can allow us to control micro- and nanoscale features in nanowires to achieve new biointerfaces. Both processes endogenous to the target cell and properties of the material surface dictate the character of these interfaces. In this Account, we focus on (1) approaches for the rational design of semiconducting nanowires that exhibit unique structures for biointerfaces, (2) recent fundamental discoveries that yield robust biointerfaces at the subcellular level, (3) intracellular electrical and mechanical sensing, and (4) modulation of cellular behaviors through material topography and remote physical stimuli. In the first section, we discuss new approaches for the synthetic control of micro- and nanoscale features of these materials. In the second section, we focus on achieving biointerfaces with

  15. Principles underlying rational design of live attenuated influenza vaccines

    Science.gov (United States)

    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

  16. Structure-based, rational design of T cell receptors

    Directory of Open Access Journals (Sweden)

    Vincent eZoete

    2013-09-01

    Full Text Available Adoptive cell transfer using engineered T cells is emerging as a promising treatment for metastatic melanoma. Such an approach allows one to introduce TCR modifications that, while maintaining the specificity for the targeted antigen, can enhance the binding and kinetic parameters for the interaction pMHC. 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. 54% 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. Beyond the affinity threshold at KD < 1 μM we observed an attenuation in cellular function. We have also developed a homology modeling-based approach, TCRep 3D, to obtain accurate structural models of any TCR-pMHC complexes. We have complemented the approach with a simplified rigid method to predict the TCR orientation over pMHC. These methods potentially extend the use of our TCR engineering method to entire TCR repertoires for which no X-ray structure is available. We have also performed a steered molecular dynamics study of the unbinding of the TCR-pMHC complex to get a better understanding of how TCRs interact with pMHCs. This entire rational TCR design pipeline is now being used to produce rationally optimized TCRs for adoptive cell therapies of

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

    Science.gov (United States)

    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.

  18. Considerations for the rational design of a Chlamydia vaccine.

    Science.gov (United States)

    Liang, Steven; Bulir, David; Kaushic, Charu; Mahony, James

    2017-04-03

    Chlamydia trachomatis is the leading cause of preventable blindness and the most common bacterial sexually transmitted infection. Remarkable progress in vaccine research over the past six decades has led to the advancement of novel C. trachomatis vaccine candidates into clinical trials. However, many questions regarding the role of specific cellular populations and molecular mechanisms in protective immunity against human C. trachomatis genital tract infections remain unanswered. Biomarkers of vaccine induced protective immunity are elusive in humans, while a cautionary message on the translatability of data obtained from current animal models has emanated from vaccine research and development efforts against other important human pathogens. In this commentary, we highlight recent advances in Chlamydia vaccine development and discuss their implications in the context of a rational approach to the design of a human C. trachomatis vaccine.

  19. Rational design of the exchange-spring permanent magnet

    International Nuclear Information System (INIS)

    Jiang, J S; Bader, S D

    2014-01-01

    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. (paper)

  20. Rational Design of Coordination Polymers with Flexible Oxyethylene Side Chains

    International Nuclear Information System (INIS)

    Choi, Eun Young; Gao, Chunji; Lee, Suck Hyun; Kwon, O Pil

    2012-01-01

    We rationally designed and synthesized metallopolymers with organic 1,4-benzenedicarboxylic acid (BDC) linkers with different lengths of oxyethylene side chains in order to examine the influence of side chains on the coordination characteristics. While in a previous report the BDC linkers with alkyl side chains were found to form three-dimensional (3D) isoreticular metal-organic framework (IRMOF) structures or one-dimensional (1D) coordination polymeric structures with short -O(CH 2 ) 6 CH 3 or long -O(CH 2 ) 9 CH 3 side chains, respectively, new BDC linkers with oxyethylene side chains of the same lengths, -(OCH 2 CH 2 ) 2 CH 3 and -(OCH 2 CH 2 ) 3 CH 3 , form only 3D IRMOF structures. This result is attributed to the higher flexibility and smaller volume of oxyethylene side chains compared to alkyl side chains

  1. Rational design of functional and tunable oscillating enzymatic networks

    Science.gov (United States)

    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.

  2. Rational use of water in trickle irrigation design.

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

  4. Bioinformatics and multiepitope DNA immunization to design rational snake antivenom.

    Directory of Open Access Journals (Sweden)

    Simon C Wagstaff

    2006-06-01

    Full Text Available Snake venom is a potentially lethal and complex mixture of hundreds of functionally diverse proteins that are difficult to purify and hence difficult to characterize. These difficulties have inhibited the development of toxin-targeted therapy, and conventional antivenom is still generated from the sera of horses or sheep immunized with whole venom. Although life-saving, antivenoms contain an immunoglobulin pool of unknown antigen specificity and known redundancy, which necessitates the delivery of large volumes of heterologous immunoglobulin to the envenomed victim, thus increasing the risk of anaphylactoid and serum sickness adverse effects. Here we exploit recent molecular sequence analysis and DNA immunization tools to design more rational toxin-targeted antivenom.We developed a novel bioinformatic strategy that identified sequences encoding immunogenic and structurally significant epitopes from an expressed sequence tag database of a venom gland cDNA library of Echis ocellatus, the most medically important viper in Africa. Focusing upon snake venom metalloproteinases (SVMPs that are responsible for the severe and frequently lethal hemorrhage in envenomed victims, we identified seven epitopes that we predicted would be represented in all isomers of this multimeric toxin and that we engineered into a single synthetic multiepitope DNA immunogen (epitope string. We compared the specificity and toxin-neutralizing efficacy of antiserum raised against the string to antisera raised against a single SVMP toxin (or domains or antiserum raised by conventional (whole venom immunization protocols. The SVMP string antiserum, as predicted in silico, contained antibody specificities to numerous SVMPs in E. ocellatus venom and venoms of several other African vipers. More significantly, the antiserum cross-specifically neutralized hemorrhage induced by E. ocellatus and Cerastes cerastes cerastes venoms.These data provide valuable sequence and structure

  5. Harvesting bioenergy with rationally designed complex functional materials

    Science.gov (United States)

    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

  6. Rational design of protamine nanocapsules as antigen delivery carriers.

    Science.gov (United States)

    González-Aramundiz, José Vicente; Presas, Elena; Dalmau-Mena, Inmaculada; Martínez-Pulgarín, Susana; Alonso, Covadonga; Escribano, José M; Alonso, María J; Csaba, Noemi Stefánia

    2017-01-10

    Current challenges in global immunization indicate the demand for new delivery strategies, which could be applied to the development of new vaccines against emerging diseases, as well as to improve safety and efficacy of currently existing vaccine formulations. Here, we report a novel antigen nanocarrier consisting of an oily core and a protamine shell, further stabilized with pegylated surfactants. These nanocarriers, named protamine nanocapsules, were rationally designed to promote the intracellular delivery of antigens to immunocompetent cells and to trigger an efficient and long-lasting immune response. Protamine nanocapsules have nanometric size, positive zeta potential and high association capacity for H1N1 influenza hemagglutinin, a protein that was used here as a model antigen. The new formulation shows an attractive stability profile both, as an aqueous suspension or a freeze-dried powder formulation. In vitro studies showed that protamine nanocapsules were efficiently internalized by macrophages without eliciting significant toxicity. In vivo studies indicate that antigen-loaded nanocapsules trigger immune responses comparable to those achieved with alum, even when using significantly lower antigen doses, thus indicating their adjuvant properties. These promising in vivo data, alongside with their versatility for the loading of different antigens and oily immunomodulators and their excellent stability profile, make these nanocapsules a promising platform for the delivery of antigens. Protamine sulphate (PubChem SID: 7849283), Sodium Cholate (PubChem CID: 23668194), Miglyol (PubChem CID: 53471835), α tocopherol (PubChem CID: 14985), Tween® 20(PubChem CID: 443314), Tween® 80(PubChem CID: 5281955), TPGS (PubChem CID: 71406). Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Rationally Designed TLR4 Ligands for Vaccine Adjuvant Discovery

    Directory of Open Access Journals (Sweden)

    Kelsey A. Gregg

    2017-05-01

    Full Text Available Adjuvant properties of bacterial cell wall components like MPLA (monophosphoryl lipid A are well described and have gained FDA approval for use in vaccines such as Cervarix. MPLA is the product of chemically modified lipooligosaccharide (LOS, altered to diminish toxic proinflammatory effects while retaining adequate immunogenicity. Despite the virtually unlimited number of potential sources among bacterial strains, the number of useable compounds within this promising class of adjuvants are few. We have developed bacterial enzymatic combinatorial chemistry (BECC as a method to generate rationally designed, functionally diverse lipid A. BECC removes endogenous or introduces exogenous lipid A-modifying enzymes to bacteria, effectively reprogramming the lipid A biosynthetic pathway. In this study, BECC is applied within an avirulent strain of Yersinia pestis to develop structurally distinct LOS molecules that elicit differential Toll-like receptor 4 (TLR4 activation. Using reporter cell lines that measure NF-κB activation, BECC-derived molecules were screened for the ability to induce a lower proinflammatory response than Escherichia coli LOS. Their structures exhibit varied, dose-dependent, TLR4-driven NF-κB activation with both human and mouse TLR4 complexes. Additional cytokine secretion screening identified molecules that induce levels of tumor necrosis factor alpha (TNF-α and interleukin-8 (IL-8 comparable to the levels induced by phosphorylated hexa-acyl disaccharide (PHAD. The lead candidates demonstrated potent immunostimulation in mouse splenocytes, human primary blood mononuclear cells (PBMCs, and human monocyte-derived dendritic cells (DCs. This newly described system allows directed programming of lipid A synthesis and has the potential to generate a diverse array of TLR4 agonist candidates.

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

    Science.gov (United States)

    Glaser, Thorsten

    2011-01-07

    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

  9. Structured morphological modeling as a framework for rational strain design of Streptomyces species

    NARCIS (Netherlands)

    Celler, K.; Picioreanu, C.; Van Loosdrecht, M.C.M.; Van Wezel, G.P.

    2012-01-01

    Successful application of a computational model for rational design of industrial Streptomyces exploitation requires a better understanding of the relationship between morphology—dictated by microbial growth, branching, fragmentation and adhesion—and product formation. Here we review the

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

    Science.gov (United States)

    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. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Does decision documentation help junior designers rationalize their decisions? A comparative multiple-case study

    NARCIS (Netherlands)

    Heesch, U. van; Avgeriou, P.; Tang, A.

    Software architecture design is challenging, especially for junior software designers. Lacking practice and experience, junior designers need process support in order to make rational architecture decisions. In this paper, we present the results of a comparative multiple-case study conducted to find

  12. Rational design of soft mechanical metamaterials : Independent tailoring of elastic properties with randomness

    NARCIS (Netherlands)

    Mirzaali Mazandarani, M.J.; Hedayati, R.; Vena, P; Vergani, L.; Strano, M.; Zadpoor, A.A.

    2017-01-01

    The elastic properties of mechanical metamaterials are direct functions of their topological designs. Rational design approaches based on computational models could, therefore, be used to devise topological designs that result in the desired properties. It is of particular importance to

  13. Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm.

    Science.gov (United States)

    Kesisoglou, Filippos; Mitra, Amitava

    2015-09-01

    Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling—(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

  14. Rational design of a cyclin A fluorescent peptide sensor.

    Science.gov (United States)

    Pazos, Elena; Pérez, Miguel; Gutiérrez-de-Terán, Hugo; Orzáez, Mar; Guevara, Tatiana; Mascareñas, José L; Vázquez, M Eugenio

    2011-10-26

    We report the design and development of a fluorescent sensor specifically designed to target cyclin A, a protein that plays a key role in the regulation of the cell cycle. Computational studies provide a molecular picture that explains the observed emission increase, suggesting that the 4-DMAP fluorophore in the peptide is protected from the bulk solvent when inserted into the hydrophobic binding groove of cyclin A.

  15. Guest-responsive structural adaptation of a rationally-designed ...

    Indian Academy of Sciences (India)

    From molecules and crystals to materials NATO ASI. Series (The Netherlands: Kluwer). 3. Desiraju G R 2007 Angew. Chem. Int. Ed. 46 8342. 4. MacNicol D D 1994 In Inclusion compounds (London: Academic Press). 5. Weber E 1996 In Shape and symmetry in the design of new hosts, in Comprehensive Supramolecular ...

  16. Coleman's problem with institutional design : neglect of social rationality

    NARCIS (Netherlands)

    Lindenberg, S

    2003-01-01

    This paper tries to answer the question how it is possible that such a giant of sociology as James Coleman produced so little of what he considered the most important work for sociologists : good institutional design. I argue that the answer lies in the fact that the most serious problem for which

  17. On Rational Design of Double Hull Tanker Structures against Collision

    DEFF Research Database (Denmark)

    Paik, Jeom Kee; Chung, Jang Young; Choe, Ich Hung

    1999-01-01

    This paper is a summary of recent research and development in areas related to the design technology for double hull tanker structures against low energy collision, jointly undertaken by the Hyundai Heavy Industries, the American Bureau of Shipping, the Technical University of Denmark and the Pusan...... in the present study were (i) developing a framework for the collision design procedure for double hull tanker structures, (ii) experimental investigation of the structural crashworthiness of the collided vessels in collision or stranding, using double skinned structural models, (iii) validation of the special...... investigation of the energy absorption capability characteristics of a collided double hull VLCC side structure in collision, and (vi) development of a new modified Minorsky method for double hull tanker side structures. The tools developed and the results and insights obtained by the present study should...

  18. Rationally designed porous silicon as platform for optical biosensors

    International Nuclear Information System (INIS)

    Priano, G.; Acquaroli, L.N.; Lasave, L.C.; Battaglini, F.; Arce, R.D.; Koropecki, R.R.

    2012-01-01

    Optical porous silicon multilayer structures are able to work as sensitive chemical sensors or biosensors based in their optical response. An algorithm to simulate the optical response of these multilayers was developed, considering the optical properties of the individual layers. The algorithm allows designing and customizing the porous silicon structures according to a given application. The results obtained by the simulation were experimentally verified; for this purpose different photonic structures were prepared, such as Bragg reflectors and microcavities. Some of these structures have been derivatized by the introduction of aminosilane groups on the porous silicon surface. The algorithm also permits to simulate the effects produced by a non uniform derivatization of the multilayer. - Highlights: ► Mesoporous silicon structure ► Functionalization of mesoporous silicon as sensors ► Design of the one-dimensional photonic crystal ► Simulation of non-uniformity in covering the sensor structure

  19. Rationally designed porous silicon as platform for optical biosensors

    Energy Technology Data Exchange (ETDEWEB)

    Priano, G. [INQUIMAE, DQIAyQF, FCEN, Universidad de Buenos Aires, Ciudad Universitaria, Pabellon 2 (C1428EHA) Buenos Aires (Argentina); Acquaroli, L.N.; Lasave, L.C. [Instituto De Desarrollo Tecnologico Para La Industria Quimica, UNL, CONICET, Gueemes 3450 (S3000GLN) Santa Fe (Argentina); Battaglini, F. [INQUIMAE, DQIAyQF, FCEN, Universidad de Buenos Aires, Ciudad Universitaria, Pabellon 2 (C1428EHA) Buenos Aires (Argentina); Arce, R.D., E-mail: rarce@intec.unl.edu.ar [Instituto De Desarrollo Tecnologico Para La Industria Quimica, UNL, CONICET, Gueemes 3450 (S3000GLN) Santa Fe (Argentina); Departamento De Materiales, Facultad De Ingenieria Quimica, UNL, Santiago del Estero 2829 (S3000) Santa Fe (Argentina); Koropecki, R.R. [Instituto De Desarrollo Tecnologico Para La Industria Quimica, UNL, CONICET, Gueemes 3450 (S3000GLN) Santa Fe (Argentina); Departamento De Materiales, Facultad De Ingenieria Quimica, UNL, Santiago del Estero 2829 (S3000) Santa Fe (Argentina)

    2012-08-01

    Optical porous silicon multilayer structures are able to work as sensitive chemical sensors or biosensors based in their optical response. An algorithm to simulate the optical response of these multilayers was developed, considering the optical properties of the individual layers. The algorithm allows designing and customizing the porous silicon structures according to a given application. The results obtained by the simulation were experimentally verified; for this purpose different photonic structures were prepared, such as Bragg reflectors and microcavities. Some of these structures have been derivatized by the introduction of aminosilane groups on the porous silicon surface. The algorithm also permits to simulate the effects produced by a non uniform derivatization of the multilayer. - Highlights: Black-Right-Pointing-Pointer Mesoporous silicon structure Black-Right-Pointing-Pointer Functionalization of mesoporous silicon as sensors Black-Right-Pointing-Pointer Design of the one-dimensional photonic crystal Black-Right-Pointing-Pointer Simulation of non-uniformity in covering the sensor structure.

  20. Lumican Peptides: Rational Design Targeting ALK5/TGFBRI

    Science.gov (United States)

    Gesteira, Tarsis Ferreira; Coulson-Thomas, Vivien J.; Yuan, Yong; Zhang, Jianhua; Nader, Helena B.; Kao, Winston W.-Y.

    2017-02-01

    Lumican, a small leucine rich proteoglycan (SLRP), is a component of extracellular matrix which also functions as a matrikine regulating multiple cell activities. In the cornea, lumican maintains corneal transparency by regulating collagen fibrillogenesis, promoting corneal epithelial wound healing, regulating gene expression and maintaining corneal homeostasis. We have recently shown that a peptide designed from the 13 C-terminal amino acids of lumican (LumC13) binds to ALK5/TGFBR1 (type1 receptor of TGFβ) to promote wound healing. Herein we evaluate the mechanism by which this synthetic C-terminal amphiphilic peptide (LumC13), binds to ALK5. These studies clearly reveal that LumC13-ALK5 form a stable complex. In order to determine the minimal amino acids required for the formation of a stable lumican/ALK5 complex derivatives of LumC13 were designed and their binding to ALK5 investigated in silico. These LumC13 derivatives were tested both in vitro and in vivo to evaluate their ability to promote corneal epithelial cell migration and corneal wound healing, respectively. These validations add to the therapeutic value of LumC13 (Lumikine) and aid its clinical relevance of promoting the healing of corneal epithelium debridement. Moreover, our data validates the efficacy of our computational approach to design active peptides based on interactions of receptor and chemokine/ligand.

  1. Rational Design of Glucose-Responsive Insulin Using Pharmacokinetic Modeling.

    Science.gov (United States)

    Bakh, Naveed A; Bisker, Gili; Lee, Michael A; Gong, Xun; Strano, Michael S

    2017-11-01

    A glucose responsive insulin (GRI) is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. In this work, an approach to mathematically model the relevant parameter space for effective GRIs is induced, and design rules for linking GRI performance to therapeutic benefit are developed. Well-developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI are used to determine the desired kinetic parameters and dosing for optimal glycemic control. The model examines a subcutaneous dose of GRI with kinetic parameters in an optimal range that results in successful glycemic control within prescribed constraints over a 24 h period. Additionally, it is demonstrated that the modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. The results provide a framework for exploring the parameter space of GRIs, potentially without extensive, iterative in vivo animal testing. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Rational design of diagnostic and vaccination strategies for tuberculosis

    Directory of Open Access Journals (Sweden)

    Sibele Borsuk

    Full Text Available The development of diagnostic tests which can readily differentiate between vaccinated and tuberculosis-infected individuals is crucial for the wider utilization of bacillus Calmette-Guérin (BCG as vaccine in humans and animals. BCG_0092 is an antigen that elicits specific delayed type hypersensitivity reactions similar in size and morphological aspects to that elicited by purified protein derivative, in both animals and humans infected with the tubercle bacilli. We carried out bioinformatics analyses of the BCG_0092 and designed a diagnostic test by using the predicted MHC class I epitopes. In addition, we performed a knockout of this gene by homologous recombination in the BCG vaccine strain to allow differentiation of vaccinated from infected individuals. For that, the flanking sequences of the target gene (BCG_0092were cloned into a suicide vector. Spontaneous double crossovers, which result in wild type revertants or knockouts were selected using SacB. BCG_0092 is present only in members of the Mycobacterium tuberculosis complex. Eight predicted MHC class I epitopes with potential for immunological diagnosis were defined, allowing the design of a specific diagnostic test. The strategy used to delete the (BCG_0092 gene from BCG was successful. The knockout genotype was confirmed by PCR and by Southern blot. The mutant BCG strain has the potential of inducing protection against tuberculosis without interfering with the diagnostic test based on the use of selected epitopes from BCG_0092.

  3. Does decision documentation help junior designers rationalize their decisions? A comparative multiple-case study

    OpenAIRE

    Heesch, U. van; Avgeriou, P.; Tang, A.

    2013-01-01

    Software architecture design is challenging, especially for junior software designers. Lacking practice and experience, junior designers need process support in order to make rational architecture decisions. In this paper, we present the results of a comparative multiple-case study conducted to find out if decision viewpoints from van Heesch et al. (2012, in press) can provide such a support. The case study was conducted with four teams of software engineering students working in industrial s...

  4. Heuristic lipophilicity potential for computer-aided rational drug design

    Science.gov (United States)

    Du, Qishi; Arteca, Gustavo A.; Mezey, Paul G.

    1997-09-01

    In this contribution we suggest a heuristic molecular lipophilicitypotential (HMLP), which is a structure-based technique requiring noempirical indices of atomic lipophilicity. The input data used in thisapproach are molecular geometries and molecular surfaces. The HMLP is amodified electrostatic potential, combined with the averaged influences fromthe molecular environment. Quantum mechanics is used to calculate theelectron density function ρ(r) and the electrostatic potential V(r), andfrom this information a lipophilicity potential L(r) is generated. The HMLPis a unified lipophilicity and hydrophilicity potential. The interactions ofdipole and multipole moments, hydrogen bonds, and charged atoms in amolecule are included in the hydrophilic interactions in this model. TheHMLP is used to study hydrogen bonds and water-octanol partitioncoefficients in several examples. The calculated results show that the HMLPgives qualitatively and quantitatively correct, as well as chemicallyreasonable, results in cases where comparisons are available. Thesecomparisons indicate that the HMLP has advantages over the empiricallipophilicity potential in many aspects. The HMLP is a three-dimensional andeasily visualizable representation of molecular lipophilicity, suggested asa potential tool in computer-aided three-dimensional drug design.

  5. Plasmonic Solar Cells: From Rational Design to Mechanism Overview.

    Science.gov (United States)

    Jang, Yoon Hee; Jang, Yu Jin; Kim, Seokhyoung; Quan, Li Na; Chung, Kyungwha; Kim, Dong Ha

    2016-12-28

    Plasmonic effects have been proposed as a solution to overcome the limited light absorption in thin-film photovoltaic devices, and various types of plasmonic solar cells have been developed. This review provides a comprehensive overview of the state-of-the-art progress on the design and fabrication of plasmonic solar cells and their enhancement mechanism. The working principle is first addressed in terms of the combined effects of plasmon decay, scattering, near-field enhancement, and plasmonic energy transfer, including direct hot electron transfer and resonant energy transfer. Then, we summarize recent developments for various types of plasmonic solar cells based on silicon, dye-sensitized, organic photovoltaic, and other types of solar cells, including quantum dot and perovskite variants. We also address several issues regarding the limitations of plasmonic nanostructures, including their electrical, chemical, and physical stability, charge recombination, narrowband absorption, and high cost. Next, we propose a few potentially useful approaches that can improve the performance of plasmonic cells, such as the inclusion of graphene plasmonics, plasmon-upconversion coupling, and coupling between fluorescence resonance energy transfer and plasmon resonance energy transfer. This review is concluded with remarks on future prospects for plasmonic solar cell use.

  6. Phytosterol Recognition via Rationally Designed Molecularly Imprinted Polymers

    Directory of Open Access Journals (Sweden)

    Lachlan J. Schwarz

    2018-02-01

    Full Text Available Molecularly imprinted polymers (MIPs prepared via a semi-covalent imprinting strategy using stigmasteryl methacrylate as a polymerisable template have been evaluated by static binding methods for their ability to selectively capture other valuable phytosterol targets, including campesterol and brassicasterol. Design criteria based on molecular modelling procedures and interaction energy calculations were employed to aid the selection of the co-monomer type, as well as the choice of co-monomer:template ratios for the formation of the pre-polymerisation complex. These novel hybrid semi-covalently imprinted polymers employed N,N′-dimethylacryl-amide (N,N′-DMAAM as the functional co-monomer and displayed specific binding capacities in the range 5.2–5.9 mg sterol/g MIP resin. Their binding attributes and selectivities towards phytosterol compounds were significantly different to the corresponding MIPs prepared via non-covalent procedures or when compared to non-imprinted polymers. Cross-reactivity studies using stigmasterol, ergosterol, cholesterol, campesterol, and brassicasterol as single analytes revealed the importance of the A-ring C-3-β-hydroxyl group and the orientational preferences of the D-ring alkyl chain structures in their interaction in the templated cavity with the N,N′-dimethylamide functional groups of the MIP. Finally, to obtain useful quantities of both campersterol and brassicasterol for these investigations, improved synthetic routes have been developed to permit the conversion of the more abundant, lower cost stigmasterol via a reactive aldehyde intermediate to these other sterols.

  7. Modulation of prion polymerization and toxicity by rationally designed peptidomimetics.

    Science.gov (United States)

    Srivastava, Ankit; Sharma, Sakshi; Sadanandan, Sandhya; Gupta, Sakshi; Singh, Jasdeep; Gupta, Sarika; Haridas, V; Kundu, Bishwajit

    2017-01-01

    Misfolding and aggregation of cellular prion protein is associated with a large array of neurological disorders commonly called the transmissible spongiform encephalopathies. Designing inhibitors against prions has remained a daunting task owing to limited information about mechanism(s) of their pathogenic self-assembly. Here, we explore the anti-prion properties of a combinatorial library of bispidine-based peptidomimetics (BPMs) that conjugate amino acids with hydrophobic and aromatic side chains. Keeping the bispidine unit unaltered, a series of structurally diverse BPMs were synthesized and tested for their prion-modulating properties. Administration of Leu- and Trp-BPMs delayed and completely inhibited the amyloidogenic conversion of human prion protein (HuPrP), respectively. We found that each BPM induced the HuPrP to form unique oligomeric nanostructures differing in their biophysical properties, cellular toxicities and response to conformation-specific antibodies. While Leu-BPMs were found to stabilize the oligomers, Trp-BPMs effected transient oligomerization, resulting in the formation of non-toxic, non-fibrillar aggregates. Yet another aromatic residue, Phe, however, accelerated the aggregation process in HuPrP. Molecular insights obtained through MD (molecular dynamics) simulations suggested that each BPM differently engages a conserved Tyr 169 residue at the α2-β2 loop of HuPrP and affects the stability of α2 and α3 helices. Our results demonstrate that this new class of molecules having chemical scaffolds conjugating hydrophobic/aromatic residues could effectively modulate prion aggregation and toxicity. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  8. Rationalization of design and construction of buildings for nuclear power plants

    Energy Technology Data Exchange (ETDEWEB)

    Satoh, Shunsaku; Mitsumatsu, Kazuo

    1987-02-01

    This article presents various rationalization methods introduced in the past few years for design and construction of BWR nuclear power plant buildings. When the site for a nuclear power plant has been decided, investigation is made on various aspects of possible earthquakes, based on which anti-earthquake design for the plant site is established. The next step is to examine the displacements and stresses that may occur to various parts of the bulding from a postulated earthquake. This is normally called the earthquake response analysis and consists of calculating the behaviors of the buildings using large computers. A seismic controlled structure system has recently proposed, aiming to reduce the displacements and stresses of the building itself by controlling the flexibility of the installed seismic apparatus against the input of external loads. Lately, high strength concrete and high strength reinforcing steel bars (rebars) are being considered for practical application. If advanced computers and related accessories are utilized to the maximum, it will lead not only to efficiency in the design work but to the possibility of optimized design. For rational construction, a combined scaffolding and temporary support has been devised to reduce the time and volume of required temporary work. What have been developed for rationalization of construction work also include robots for heavy weight rebar fabrication, horizontal reed blind type rebars, portable concrete distributor, all weather environment facilities, and construction materials conveyance system. (Nogami, K.).

  9. Rationalization of design and construction of buildings for nuclear power plants

    International Nuclear Information System (INIS)

    Satoh, Shunsaku; Mitsumatsu, Kazuo

    1987-01-01

    This article presents various rationalization methods introduced in the past few years for design and construction of BWR nuclear power plant buildings. When the site for a nuclear power plant has been decided, investigation is made on various aspects of possible earthquakes, based on which anti-earthquake design for the plant site is established. The next step is to examine the displacements and stresses that may occur to various parts of the bulding from a postulated earthquake. This is normally called the earthquake response analysis and consists of calculating the behaviors of the buildings using large computers. A seismic controlled structure system has recently proposed, aiming to reduce the displacements and stresses of the building itself by controlling the flexibility of the installed seismic apparatus against the input of external loads. Lately, high strength concrete and high strength reinforcing steel bars (rebars) are being considered for practical application. If advanced computers and related accessories are utilized to the maximum, it will lead not only to efficiency in the design work but to the possibility of optimized design. For rational construction, a combined scaffolding and temporary support has been devised to reduce the time and volume of required temporary work. What have been developed for rationalization of construction work also include robots for heavy weight rebar fabrication, horizontal reed blind type rebars, portable concrete distributor, all weather environment facilities, and construction materials conveyance system. (Nogami, K.)

  10. From bricolage to BioBricks™: Synthetic biology and rational design.

    Science.gov (United States)

    Lewens, Tim

    2013-12-01

    Synthetic biology is often described as a project that applies rational design methods to the organic world. Although humans have influenced organic lineages in many ways, it is nonetheless reasonable to place synthetic biology towards one end of a continuum between purely 'blind' processes of organic modification at one extreme, and wholly rational, design-led processes at the other. An example from evolutionary electronics illustrates some of the constraints imposed by the rational design methodology itself. These constraints reinforce the limitations of the synthetic biology ideal, limitations that are often freely acknowledged by synthetic biology's own practitioners. The synthetic biology methodology reflects a series of constraints imposed on finite human designers who wish, as far as is practicable, to communicate with each other and to intervene in nature in reasonably targeted and well-understood ways. This is better understood as indicative of an underlying awareness of human limitations, rather than as expressive of an objectionable impulse to mastery over nature. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Residualization Rates of Near Infrared Dyes for the Rational Design of Molecular Imaging Agents

    Science.gov (United States)

    Cilliers, Cornelius; Liao, Jianshan; Atangcho, Lydia; Thurber, Greg M.

    2016-01-01

    Purpose Near infrared (NIR) fluorescence imaging is widely used for tracking antibodies and biomolecules in vivo. Clinical and preclinical applications include intraoperative imaging, tracking therapeutics, and fluorescent labeling as a surrogate for subsequent radiolabeling. Despite their extensive use, one of the fundamental properties of NIR dyes, the residualization rate within cells following internalization, has not been systematically studied. This rate is required for the rational design of probes and proper interpretation of in vivo results. Procedures In this brief report, we measure the cellular residualization rate of eight commonly used dyes encompassing three core structures (cyanine, BODIPY, and oxazine/thiazine/carbopyronin). Results We identify residualizing (half-life > 24 hrs) and non-residualizing dyes (half-life < 24 hrs) in both the far red (~650-680 nm) and near infrared (~740-800 nm) regions. Conclusions This data will allow researchers to independently and rationally select the wavelength and residualizing nature of dyes for molecular imaging agent design. PMID:25869081

  12. Development of rational design technique for frame steel structure combining seismic resistance and economic performance

    International Nuclear Information System (INIS)

    Kato, Motoki; Morishita, Kunihiro; Shimono, Masaki; Chuman, Yasuharu; Okafuji, Takashi; Monaka, Toshiaki

    2015-01-01

    Anti-seismic designs have been applied to plant support steel frames for years. Today, a rational structure that further improves seismic resistance and ensures economic performance is required in response to an increase of seismic load on the assumption of predicted future massive earthquakes. For satisfying this requirement, a steel frame design method that combines a steel frame weight minimizing method, which enables economic design through simultaneous minimization of multiple steel frame materials, and a seismic response control design technology that improves seismic resistance has been established. Its application in the design of real structures has been promoted. This paper gives an overview of this design technology and presents design examples to which this design technology is applied. (author)

  13. Testing the rationality assumption using a design difference in the TV game show 'Jeopardy'

    OpenAIRE

    Sjögren Lindquist, Gabriella; Säve-Söderbergh, Jenny

    2006-01-01

    Abstract This paper empirically investigates the rationality assumption commonly applied in economic modeling by exploiting a design difference in the game-show Jeopardy between the US and Sweden. In particular we address the assumption of individuals’ capabilities to process complex mathematical problems to find optimal strategies. The vital difference is that US contestants are given explicit information before they act, while Swedish contestants individually need to calculate the same info...

  14. Design of a Discrete Tracking Controller for a Magnetic Levitation System: A Nonlinear Rational Model Approach

    Directory of Open Access Journals (Sweden)

    Fernando Gómez-Salas

    2015-01-01

    Full Text Available This work proposes a discrete-time nonlinear rational approximate model for the unstable magnetic levitation system. Based on this model and as an application of the input-output linearization technique, a discrete-time tracking control design will be derived using the corresponding classical state space representation of the model. A simulation example illustrates the efficiency of the proposed methodology.

  15.   A rationally designed tyrosine hydroxylase DNA vaccine induces specific antineuroblastoma immunity

    DEFF Research Database (Denmark)

    Huebener, Nicole; Fest, Stefan; Strandsby, Anne Bystrup

    2008-01-01

    Therapeutic vaccination against tumor antigens without induction of autoimmunity remains a major challenge in cancer immunotherapy. Here, we show for the first time effective therapeutic vaccination followed by suppression of established spontaneous neuroblastoma metastases using a tyrosine...... show effective therapeutic vaccination against neuroblastoma with a novel rationally designed TH minigene vaccine without induction of autoimmunity providing an important baseline for future clinical application of this strategy....

  16. Rational Design of Cancer-Targeted Benzoselenadiazole by RGD Peptide Functionalization for Cancer Theranostics.

    Science.gov (United States)

    Yang, Liye; Li, Wenying; Huang, Yanyu; Zhou, Yangliang; Chen, Tianfeng

    2015-09-01

    A cancer-targeted conjugate of the selenadiazole derivative BSeC (benzo[1,2,5] selenadiazole-5-carboxylic acid) with RGD peptide as targeting molecule and PEI (polyethylenimine) as a linker is rationally designed and synthesized in the present study. The results show that RGD-PEI-BSeC forms nanoparticles in aqueous solution with a core-shell nanostructure and high stability under physiological conditions. This rational design effectively enhances the selective cellular uptake and cellular retention of BSeC in human glioma cells, and increases its selectivity between cancer and normal cells. The nanoparticles enter the cells through receptor-mediated endocytosis via clathrin-mediated and nystatin-dependent lipid raft-mediated pathways. Internalized nanoparticles trigger glioma cell apoptosis by activation of ROS-mediated p53 phosphorylation. Therefore, this study provides a strategy for the rational design of selenium-containing cancer-targeted theranostics. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Chemical engineering in the electronics industry: progress towards the rational design of organic semiconductor heterojunctions

    KAUST Repository

    Clancy, Paulette

    2012-01-01

    We review the current status of heterojunction design for combinations of organic semiconductor materials, given its central role in affecting the device performance for electronic devices and solar cell applications. We provide an emphasis on recent progress towards the rational design of heterojunctions that may lead to higher performance of charge separation and mobility. We also play particular attention to the role played by computational approaches and its potential to help define the best choice of materials for solar cell development in the future. We report the current status of the field with respect to such goals. © 2012 Elsevier Ltd.

  18. Chemical engineering in the electronics industry: progress towards the rational design of organic semiconductor heterojunctions

    KAUST Repository

    Clancy, Paulette

    2012-05-01

    We review the current status of heterojunction design for combinations of organic semiconductor materials, given its central role in affecting the device performance for electronic devices and solar cell applications. We provide an emphasis on recent progress towards the rational design of heterojunctions that may lead to higher performance of charge separation and mobility. We also play particular attention to the role played by computational approaches and its potential to help define the best choice of materials for solar cell development in the future. We report the current status of the field with respect to such goals. © 2012 Elsevier Ltd.

  19. Rational design of new materials using recombinant structural proteins: Current state and future challenges.

    Science.gov (United States)

    Sutherland, Tara D; Huson, Mickey G; Rapson, Trevor D

    2018-01-01

    Sequence-definable polymers are seen as a prerequisite for design of future materials, with many polymer scientists regarding such polymers as the holy grail of polymer science. Recombinant proteins are sequence-defined polymers. Proteins are dictated by DNA templates and therefore the sequence of amino acids in a protein is defined, and molecular biology provides tools that allow redesign of the DNA as required. Despite this advantage, proteins are underrepresented in materials science. In this publication we investigate the advantages and limitations of using proteins as templates for rational design of new materials. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  20. Cofactor specificity switch in Shikimate dehydrogenase by rational design and consensus engineering.

    Science.gov (United States)

    García-Guevara, Fernando; Bravo, Iris; Martínez-Anaya, Claudia; Segovia, Lorenzo

    2017-08-01

    Consensus engineering has been used to design more stable variants using the most frequent amino acid at each site of a multiple sequence alignment; sometimes consensus engineering modifies function, but efforts have mainly been focused on studying stability. Here we constructed a consensus Rossmann domain for the Shikimate dehydrogenase enzyme; separately we decided to switch the cofactor specificity through rational design in the Escherichia coli Shikimate dehydrogenase enzyme and then analyzed the effect of consensus mutations on top of our design. We found that consensus mutations closest to the 2' adenine moiety increased the activity in our design. Consensus engineering has been shown to result in more stable proteins and our findings suggest it could also be used as a complementary tool for increasing or modifying enzyme activity during design. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Multi-Step Usage of in Vivo Models During Rational Drug Design and Discovery

    Directory of Open Access Journals (Sweden)

    Charles H. Williams

    2011-04-01

    Full Text Available In this article we propose a systematic development method for rational drug design while reviewing paradigms in industry, emerging techniques and technologies in the field. Although the process of drug development today has been accelerated by emergence of computational methodologies, it is a herculean challenge requiring exorbitant resources; and often fails to yield clinically viable results. The current paradigm of target based drug design is often misguided and tends to yield compounds that have poor absorption, distribution, metabolism, and excretion, toxicology (ADMET properties. Therefore, an in vivo organism based approach allowing for a multidisciplinary inquiry into potent and selective molecules is an excellent place to begin rational drug design. We will review how organisms like the zebrafish and Caenorhabditis elegans can not only be starting points, but can be used at various steps of the drug development process from target identification to pre-clinical trial models. This systems biology based approach paired with the power of computational biology; genetics and developmental biology provide a methodological framework to avoid the pitfalls of traditional target based drug design.

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

    Science.gov (United States)

    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

  3. Rationalization and Design of the Complementarity Determining Region Sequences in an Antibody-Antigen Recognition Interface

    Science.gov (United States)

    Chen, Ing-Chien; Lee, Yu-Ching; Chen, Jun-Bo; Tsai, Keng-Chang; Chen, Ching-Tai; Chang, Jeng-Yih; Yang, Ei-Wen; Hsu, Po-Chiang; Jian, Jhih-Wei; Hsu, Hung-Ju; Chang, Hung-Ju; Hsu, Wen-Lian; Huang, Kai-Fa; Ma, Alex Che; Yang, An-Suei

    2012-01-01

    Protein-protein interactions are critical determinants in biological systems. Engineered proteins binding to specific areas on protein surfaces could lead to therapeutics or diagnostics for treating diseases in humans. But designing epitope-specific protein-protein interactions with computational atomistic interaction free energy remains a difficult challenge. Here we show that, with the antibody-VEGF (vascular endothelial growth factor) interaction as a model system, the experimentally observed amino acid preferences in the antibody-antigen interface can be rationalized with 3-dimensional distributions of interacting atoms derived from the database of protein structures. Machine learning models established on the rationalization can be generalized to design amino acid preferences in antibody-antigen interfaces, for which the experimental validations are tractable with current high throughput synthetic antibody display technologies. Leave-one-out cross validation on the benchmark system yielded the accuracy, precision, recall (sensitivity) and specificity of the overall binary predictions to be 0.69, 0.45, 0.63, and 0.71 respectively, and the overall Matthews correlation coefficient of the 20 amino acid types in the 24 interface CDR positions was 0.312. The structure-based computational antibody design methodology was further tested with other antibodies binding to VEGF. The results indicate that the methodology could provide alternatives to the current antibody technologies based on animal immune systems in engineering therapeutic and diagnostic antibodies against predetermined antigen epitopes. PMID:22457753

  4. Rational design of hierarchical ZnO@Carbon nanoflower for high performance lithium ion battery anodes

    Science.gov (United States)

    liu, Huichao; Shi, Ludi; Li, Dongzhi; Yu, Jiali; Zhang, Han-Ming; Ullah, Shahid; Yang, Bo; Li, Cuihua; Zhu, Caizhen; Xu, Jian

    2018-05-01

    The rational structure design and strong interfacial bonding are crucially desired for high performance zinc oxide (ZnO)/carbon composite electrodes. In this context, micro-nano secondary structure design and strong dopamine coating strategies are adopted for the fabrication of flower-like ZnO/carbon (ZnO@C nanoflowers) composite electrodes. The results show the ZnO@C nanoflowers (2-6 μm) are assembled by hierarchical ZnO nanosheets (∼27 nm) and continuous carbon framework. The micro-nano secondary architecture can facilitate the penetration of electrolyte, shorten lithium ions diffusion length, and hinder the aggregation of the nanosheets. Moreover, the strong chemical interaction between ZnO and coating carbon layer via C-Zn bond improves structure stability as well as the electronic conductivity. As a synergistic result, when evaluated as lithium ion batteries (LIBs) anode, the ZnO@C nanoflower electrodes show high reversible capacity of ca. 1200 mA h g-1 at 0.1 A g-1 after 80 cycles. As well as good long-cycling stability (638 and 420 mA h g-1 at 1 and 5 A g-1 after 500 cycles, respectively) and excellent rate capability. Therefore, this rational design of ZnO@C nanoflowers electrode is a promising anode for high-performance LIBs.

  5. Rational Design of a Green-Light-Mediated Unimolecular Platform for Fast Switchable Acidic Sensing.

    Science.gov (United States)

    Zhou, Yunyun; Zou, Qi; Qiu, Jing; Wang, Linjun; Zhu, Liangliang

    2018-02-01

    A controllable sensing ability strongly connects to complex and precise events in diagnosis and treatment. However, imposing visible light into the molecular-scale mediation of sensing processes is restricted by the lack of structural relevance. To address this critical challenge, we present the rational design, synthesis, and in vitro studies of a novel cyanostyryl-modified azulene system for green-light-mediated fast switchable acidic sensing. The advantageous features of the design include a highly efficient green-light-driven Z/E-isomerization (a quantum yield up to 61.3%) for fast erasing chromatic and luminescent expressions and a superior compatibility with control of ratiometric protonation. Significantly, these merits of the design enable the development of a microfluidic system to perform a green-light-mediated reusable sensing function toward a gastric acid analyte in a miniaturized platform. The results may provide new insights for building future integrated green materials.

  6. Residualization Rates of Near-Infrared Dyes for the Rational Design of Molecular Imaging Agents.

    Science.gov (United States)

    Cilliers, Cornelius; Liao, Jianshan; Atangcho, Lydia; Thurber, Greg M

    2015-12-01

    Near-infrared (NIR) fluorescence imaging is widely used for tracking antibodies and biomolecules in vivo. Clinical and preclinical applications include intraoperative imaging, tracking therapeutics, and fluorescent labeling as a surrogate for subsequent radiolabeling. Despite their extensive use, one of the fundamental properties of NIR dyes, the residualization rate within cells following internalization, has not been systematically studied. This rate is required for the rational design of probes and proper interpretation of in vivo results. In this brief report, we measure the cellular residualization rate of eight commonly used dyes encompassing three core structures (cyanine, boron-dipyrromethene (BODIPY), and oxazine/thiazine/carbopyronin). We identify residualizing (half-life >24 h) and non-residualizing (half-life <24 h) dyes in both the far-red (~650-680 nm) and near-infrared (~740-800 nm) regions. This data will allow researchers to independently and rationally select the wavelength and residualizing nature of dyes for molecular imaging agent design.

  7. Rational modular design of metabolic network for efficient production of plant polyphenol pinosylvin.

    Science.gov (United States)

    Wu, Junjun; Zhang, Xia; Zhu, Yingjie; Tan, Qinyu; He, Jiacheng; Dong, Mingsheng

    2017-05-03

    Efficient biosynthesis of the plant polyphenol pinosylvin, which has numerous applications in nutraceuticals and pharmaceuticals, is necessary to make biological production economically viable. To this end, an efficient Escherichia coli platform for pinosylvin production was developed via a rational modular design approach. Initially, different candidate pathway enzymes were screened to construct de novo pinosylvin pathway directly from D-glucose. A comparative analysis of pathway intermediate pools identified that this initial construct led to the intermediate cinnamic acid accumulation. The pinosylvin synthetic pathway was then divided into two new modules separated at cinnamic acid. Combinatorial optimization of transcriptional and translational levels of these two modules resulted in a 16-fold increase in pinosylvin titer. To further improve the concentration of the limiting precursor malonyl-CoA, the malonyl-CoA synthesis module based on clustered regularly interspaced short palindromic repeats interference was assembled and optimized with other two modules. The final pinosylvin titer was improved to 281 mg/L, which was the highest pinosylvin titer even directly from D-glucose without any additional precursor supplementation. The rational modular design approach described here could bolster our capabilities in synthetic biology for value-added chemical production.

  8. Improving specific activity and thermostability of Escherichia coli phytase by structure-based rational design.

    Science.gov (United States)

    Wu, Tzu-Hui; Chen, Chun-Chi; Cheng, Ya-Shan; Ko, Tzu-Ping; Lin, Cheng-Yen; Lai, Hui-Lin; Huang, Ting-Yung; Liu, Je-Ruei; Guo, Rey-Ting

    2014-04-10

    Escherichia coli phytase (EcAppA) which hydrolyzes phytate has been widely applied in the feed industry, but the need to improve the enzyme activity and thermostability remains. Here, we conduct rational design with two strategies to enhance the EcAppA performance. First, residues near the substrate binding pocket of EcAppA were modified according to the consensus sequence of two highly active Citrobacter phytases. One out of the eleven mutants, V89T, exhibited 17.5% increase in catalytic activity, which might be a result of stabilized protein folding. Second, the EcAppA glycosylation pattern was modified in accordance with the Citrobacter phytases. An N-glycosylation motif near the substrate binding site was disrupted to remove spatial hindrance for phytate entry and product departure. The de-glycosylated mutants showed 9.6% increase in specific activity. On the other hand, the EcAppA mutants that adopt N-glycosylation motifs from CbAppA showed improved thermostability that three mutants carrying single N-glycosylation motif exhibited 5.6-9.5% residual activity after treatment at 80°C (1.8% for wild type). Furthermore, the mutant carrying all three glycosylation motifs exhibited 27% residual activity. In conclusion, a successful rational design was performed to obtain several useful EcAppA mutants with better properties for further applications. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Simultaneous inhibition of aberrant cancer kinome using rationally designed polymer-protein core-shell nanomedicine.

    Science.gov (United States)

    Chandran, Parwathy; Gupta, Neha; Retnakumari, Archana Payickattu; Malarvizhi, Giridharan Loghanathan; Keechilat, Pavithran; Nair, Shantikumar; Koyakutty, Manzoor

    2013-11-01

    Simultaneous inhibition of deregulated cancer kinome using rationally designed nanomedicine is an advanced therapeutic approach. Herein, we have developed a polymer-protein core-shell nanomedicine to inhibit critically aberrant pro-survival kinases (mTOR, MAPK and STAT5) in primitive (CD34(+)/CD38(-)) Acute Myeloid Leukemia (AML) cells. The nanomedicine consists of poly-lactide-co-glycolide core (~250 nm) loaded with mTOR inhibitor, everolimus, and albumin shell (~25 nm thick) loaded with MAPK/STAT5 inhibitor, sorafenib and the whole construct was surface conjugated with monoclonal antibody against CD33 receptor overexpressed in AML. Electron microscopy confirmed formation of core-shell nanostructure (~290 nm) and flow cytometry and confocal studies showed enhanced cellular uptake of targeted nanomedicine. Simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells, was demonstrated using immunoblotting, cytotoxicity and apoptosis assays. This cell receptor plus multi-kinase targeted core-shell nanomedicine was found better specific and tolerable compared to current clinical regime of cytarabine and daunorubicin. These authors demonstrate simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells by using rationally designed polymer-protein core-shell nanomedicine, provoding an advanced method to eliminate cancer cells, with the hope of future therapeutic use. Copyright © 2013 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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

  11. Rational design of competitive electrocatalysts for the oxygen reduction reaction in hydrogen fuel cells

    Science.gov (United States)

    Stolbov, Sergey; Alcántara Ortigoza, Marisol

    2012-02-01

    The large-scale application of one of the most promising clean and renewable sources of energy, hydrogen fuel cells, still awaits efficient and cost-effective electrocatalysts for the oxygen reduction reaction (ORR) occurring on the cathode. We demonstrate that truly rational design renders electrocatalysts possessing both qualities. By unifying the knowledge on surface morphology, composition, electronic structure and reactivity, we solve that sandwich-like structures are an excellent choice for optimization. Their constituting species couple synergistically yielding reaction-environment stability, cost-effectiveness and tunable reactivity. This cooperative-action concept enabled us to predict two advantageous ORR electrocatalysts. Density functional theory calculations of the reaction free-energy diagrams confirm that these materials are more active toward ORR than the so far best Pt-based catalysts. Our designing concept advances also a general approach for engineering materials in heterogeneous catalysis.

  12. Rational design of highly potent HIV-1 fusion inhibitory proteins: Implication for developing antiviral therapeutics

    International Nuclear Information System (INIS)

    Ni Ling; Gao, George F.; Tien Po

    2005-01-01

    Recombinant protein containing one heptad-repeat 1 (HR1) segment and one HR2 segment of the HIV-1 gp41 (HR1-HR2) has been shown to fold into thermally stable six-helix bundle, representing the fusogenic core of gp41. In this study, we have used the fusogenic core as a scaffold to design HIV-1 fusion inhibitory proteins by linking another HR1 to the C terminus of HR1-HR2 (HR121) or additional HR2 to the N terminus of HR1-HR2 (HR212). Both recombinant proteins could be abundantly and solubly expressed and easily purified, exhibiting high stability and potent inhibitory activity on HIV-1 fusion with IC 50 values of 16.2 ± 2.8 and 2.8 ± 0.63 nM, respectively. These suggest that these rationally designed proteins can be further developed as novel anti-HIV-1 therapeutics

  13. Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid

    DEFF Research Database (Denmark)

    Bunch, Lennart; Liljefors, Tommy; Greenwood, Jeremy R

    2003-01-01

    conformationally restricted (S)-glutamic acid (Glu) analogue intended as a mimic of the folded Glu conformation. The synthesis of 1 was completed in its racemic form in eight steps from commercially available starting materials. As a key step, the first facially selective hydroboration of a 5-methylidene[2......The design and synthesis of conformationally restricted analogues of alpha-amino acids is an often used strategy in medicinal chemistry research. Here we present the rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid (1), a novel...... studies on native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) (IC(50) > 300 microM, [(3)H]AMPA) or kainic acid (IC(50) > 160 microM, [(3)H]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC(50) > 300 microM, [(3)H]kainic acid)....

  14. Rational Design and Synthesis of Efficient Sunscreens To Boost the Solar Protection Factor.

    Science.gov (United States)

    Losantos, Raúl; Funes-Ardoiz, Ignacio; Aguilera, José; Herrera-Ceballos, Enrique; García-Iriepa, Cristina; Campos, Pedro J; Sampedro, Diego

    2017-03-01

    Skin cancer incidence has been increasing in the last decades, but most of the commercial formulations used as sunscreens are designed to protect only against solar erythema. Many of the active components present in sunscreens show critical weaknesses, such as low stability and toxicity. Thus, the development of more efficient components is an urgent health necessity and an attractive industrial target. We have rationally designed core moieties with increased photoprotective capacities and a new energy dissipation mechanism. Using these scaffolds, we have synthesized a series of compounds with tunable properties suitable for their use in sunscreens, and enhanced properties in terms of stability, light energy dissipation, and toxicity. Moreover, some representative compounds were included in final sunscreen formulations and a relevant solar protection factor boost was measured. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Rational In Silico Design of an Organic Semiconductor with Improved Electron Mobility.

    Science.gov (United States)

    Friederich, Pascal; Gómez, Verónica; Sprau, Christian; Meded, Velimir; Strunk, Timo; Jenne, Michael; Magri, Andrea; Symalla, Franz; Colsmann, Alexander; Ruben, Mario; Wenzel, Wolfgang

    2017-11-01

    Organic semiconductors find a wide range of applications, such as in organic light emitting diodes, organic solar cells, and organic field effect transistors. One of their most striking disadvantages in comparison to crystalline inorganic semiconductors is their low charge-carrier mobility, which manifests itself in major device constraints such as limited photoactive layer thicknesses. Trial-and-error attempts to increase charge-carrier mobility are impeded by the complex interplay of the molecular and electronic structure of the material with its morphology. Here, the viability of a multiscale simulation approach to rationally design materials with improved electron mobility is demonstrated. Starting from one of the most widely used electron conducting materials (Alq 3 ), novel organic semiconductors with tailored electronic properties are designed for which an improvement of the electron mobility by three orders of magnitude is predicted and experimentally confirmed. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Rational design of capillary-driven flows for paper-based microfluidics.

    Science.gov (United States)

    Elizalde, Emanuel; Urteaga, Raúl; Berli, Claudio L A

    2015-05-21

    The design of paper-based assays that integrate passive pumping requires a precise programming of the fluid transport, which has to be encoded in the geometrical shape of the substrate. This requirement becomes critical in multiple-step processes, where fluid handling must be accurate and reproducible for each operation. The present work theoretically investigates the capillary imbibition in paper-like substrates to better understand fluid transport in terms of the macroscopic geometry of the flow domain. A fluid dynamic model was derived for homogeneous porous substrates with arbitrary cross-sectional shapes, which allows one to determine the cross-sectional profile required for a prescribed fluid velocity or mass transport rate. An extension of the model to slit microchannels is also demonstrated. Calculations were validated by experiments with prototypes fabricated in our lab. The proposed method constitutes a valuable tool for the rational design of paper-based assays.

  17. Molecular and macro-scale analysis of enzyme-crosslinked silk hydrogels for rational biomaterial design.

    Science.gov (United States)

    McGill, Meghan; Coburn, Jeannine M; Partlow, Benjamin P; Mu, Xuan; Kaplan, David L

    2017-11-01

    Silk fibroin-based hydrogels have exciting applications in tissue engineering and therapeutic molecule delivery; however, their utility is dependent on their diffusive properties. The present study describes a molecular and macro-scale investigation of enzymatically-crosslinked silk fibroin hydrogels, and demonstrates that these systems have tunable crosslink density and diffusivity. We developed a liquid chromatography tandem mass spectroscopy (LC-MS/MS) method to assess the quantity and order of covalent tyrosine crosslinks in the hydrogels. This analysis revealed between 28 and 56% conversion of tyrosine to dityrosine, which was dependent on the silk concentration and reactant concentration. The crosslink density was then correlated with storage modulus, revealing that both crosslinking and protein concentration influenced the mechanical properties of the hydrogels. The diffusive properties of the bulk material were studied by fluorescence recovery after photobleaching (FRAP), which revealed a non-linear relationship between silk concentration and diffusivity. As a result of this work, a model for synthesizing hydrogels with known crosslink densities and diffusive properties has been established, enabling the rational design of silk hydrogels for biomedical applications. Hydrogels from naturally-derived silk polymers offer versitile opportunities in the biomedical field, however, their design has largely been an empirical process. We present a fundamental study of the crosslink density, storage modulus, and diffusion behavior of enzymatically-crosslinked silk hydrogels to better inform scaffold design. These studies revealed unexpected non-linear trends in the crosslink density and diffusivity of silk hydrogels with respect to protein concentration and crosslink reagent concentration. This work demonstrates the tunable diffusivity and crosslinking in silk fibroin hydrogels, and enables the rational design of biomaterials. Further, the characterization methods

  18. Rational design and optimization of downstream processes of virus particles for biopharmaceutical applications: current advances.

    Science.gov (United States)

    Vicente, Tiago; Mota, José P B; Peixoto, Cristina; Alves, Paula M; Carrondo, Manuel J T

    2011-01-01

    The advent of advanced therapies in the pharmaceutical industry has moved the spotlight into virus-like particles and viral vectors produced in cell culture holding great promise in a myriad of clinical targets, including cancer prophylaxis and treatment. Even though a couple of cases have reached the clinic, these products have yet to overcome a number of biological and technological challenges before broad utilization. Concerning the manufacturing processes, there is significant research focusing on the optimization of current cell culture systems and, more recently, on developing scalable downstream processes to generate material for pre-clinical and clinical trials. We review the current options for downstream processing of these complex biopharmaceuticals and underline current advances on knowledge-based toolboxes proposed for rational optimization of their processing. Rational tools developed to increase the yet scarce knowledge on the purification processes of complex biologicals are discussed as alternative to empirical, "black-boxed" based strategies classically used for process development. Innovative methodologies based on surface plasmon resonance, dynamic light scattering, scale-down high-throughput screening and mathematical modeling for supporting ion-exchange chromatography show great potential for a more efficient and cost-effective process design, optimization and equipment prototyping. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Application of 3D-QSAR in the rational design of receptor ligands and enzyme inhibitors.

    Science.gov (United States)

    Mor, Marco; Rivara, Silvia; Lodola, Alessio; Lorenzi, Simone; Bordi, Fabrizio; Plazzi, Pier Vincenzo; Spadoni, Gilberto; Bedini, Annalida; Duranti, Andrea; Tontini, Andrea; Tarzia, Giorgio

    2005-11-01

    Quantitative structure-activity relationships (QSARs) are frequently employed in medicinal chemistry projects, both to rationalize structure-activity relationships (SAR) for known series of compounds and to help in the design of innovative structures endowed with desired pharmacological actions. As a difference from the so-called structure-based drug design tools, they do not require the knowledge of the biological target structure, but are based on the comparison of drug structural features, thus being defined ligand-based drug design tools. In the 3D-QSAR approach, structural descriptors are calculated from molecular models of the ligands, as interaction fields within a three-dimensional (3D) lattice of points surrounding the ligand structure. These descriptors are collected in a large X matrix, which is submitted to multivariate analysis to look for correlations with biological activity. Like for other QSARs, the reliability and usefulness of the correlation models depends on the validity of the assumptions and on the quality of the data. A careful selection of compounds and pharmacological data can improve the application of 3D-QSAR analysis in drug design. Some examples of the application of CoMFA and CoMSIA approaches to the SAR study and design of receptor or enzyme ligands is described, pointing the attention to the fields of melatonin receptor ligands and FAAH inhibitors.

  20. One-pot synthesis of water soluble iron nanoparticles using rationally-designed peptides and ligand release.

    Science.gov (United States)

    Papst, Stefanie; Cheong, Soshan; Banholzer, Moritz J; Brimble, Margaret A; Williams, David E; Tilley, Richard D

    2013-05-18

    Herein we report the rational design of new phosphopeptides for control of nucleation, growth and aggregation of water-soluble, superparamagnetic iron-iron oxide core-shell nanoparticles. The use of the designed peptides enables a one-pot synthesis that avoids utilizing unstable or toxic iron precursors, organic solvents, and the need for exchange of capping agent after synthesis of the NPs.

  1. Design for Additive Bio-Manufacturing: From Patient-Specific Medical Devices to Rationally Designed Meta-Biomaterials.

    Science.gov (United States)

    Zadpoor, Amir A

    2017-07-25

    Recent advances in additive manufacturing (AM) techniques in terms of accuracy, reliability, the range of processable materials, and commercial availability have made them promising candidates for production of functional parts including those used in the biomedical industry. The complexity-for-free feature offered by AM means that very complex designs become feasible to manufacture, while batch-size-indifference enables fabrication of fully patient-specific medical devices. Design for AM (DfAM) approaches aim to fully utilize those features for development of medical devices with substantially enhanced performance and biomaterials with unprecedented combinations of favorable properties that originate from complex geometrical designs at the micro-scale. This paper reviews the most important approaches in DfAM particularly those applicable to additive bio-manufacturing including image-based design pipelines, parametric and non-parametric designs, metamaterials, rational and computationally enabled design, topology optimization, and bio-inspired design. Areas with limited research have been identified and suggestions have been made for future research. The paper concludes with a brief discussion on the practical aspects of DfAM and the potential of combining AM with subtractive and formative manufacturing processes in so-called hybrid manufacturing processes.

  2. Design for Additive Bio-Manufacturing: From Patient-Specific Medical Devices to Rationally Designed Meta-Biomaterials

    Directory of Open Access Journals (Sweden)

    Amir A. Zadpoor

    2017-07-01

    Full Text Available Recent advances in additive manufacturing (AM techniques in terms of accuracy, reliability, the range of processable materials, and commercial availability have made them promising candidates for production of functional parts including those used in the biomedical industry. The complexity-for-free feature offered by AM means that very complex designs become feasible to manufacture, while batch-size-indifference enables fabrication of fully patient-specific medical devices. Design for AM (DfAM approaches aim to fully utilize those features for development of medical devices with substantially enhanced performance and biomaterials with unprecedented combinations of favorable properties that originate from complex geometrical designs at the micro-scale. This paper reviews the most important approaches in DfAM particularly those applicable to additive bio-manufacturing including image-based design pipelines, parametric and non-parametric designs, metamaterials, rational and computationally enabled design, topology optimization, and bio-inspired design. Areas with limited research have been identified and suggestions have been made for future research. The paper concludes with a brief discussion on the practical aspects of DfAM and the potential of combining AM with subtractive and formative manufacturing processes in so-called hybrid manufacturing processes.

  3. Rational design of DNA sequences for nanotechnology, microarrays and molecular computers using Eulerian graphs.

    Science.gov (United States)

    Pancoska, Petr; Moravek, Zdenek; Moll, Ute M

    2004-01-01

    Nucleic acids are molecules of choice for both established and emerging nanoscale technologies. These technologies benefit from large functional densities of 'DNA processing elements' that can be readily manufactured. To achieve the desired functionality, polynucleotide sequences are currently designed by a process that involves tedious and laborious filtering of potential candidates against a series of requirements and parameters. Here, we present a complete novel methodology for the rapid rational design of large sets of DNA sequences. This method allows for the direct implementation of very complex and detailed requirements for the generated sequences, thus avoiding 'brute force' filtering. At the same time, these sequences have narrow distributions of melting temperatures. The molecular part of the design process can be done without computer assistance, using an efficient 'human engineering' approach by drawing a single blueprint graph that represents all generated sequences. Moreover, the method eliminates the necessity for extensive thermodynamic calculations. Melting temperature can be calculated only once (or not at all). In addition, the isostability of the sequences is independent of the selection of a particular set of thermodynamic parameters. Applications are presented for DNA sequence designs for microarrays, universal microarray zip sequences and electron transfer experiments.

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

    Science.gov (United States)

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

    2016-03-07

    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.

  5. Rational design of peptide affinity ligands for the purification of therapeutic enzymes.

    Science.gov (United States)

    Trasatti, John P; Woo, James; Ladiwala, Asif; Cramer, Steven; Karande, Pankaj

    2018-04-25

    Non-mAb biologics represent a growing class of therapeutics under clinical development. Although affinity chromatography is a potentially attractive approach for purification, the development of platform technologies, such as Protein A for mAbs, has been challenging due to the inherent chemical and structural diversity of these molecules. Here, we present our studies on the rapid development of peptide affinity ligands for the purification of biologics using a prototypical enzyme therapeutic in clinical use. Employing a suite of de novo rational and combinatorial design strategies we designed and screened a library of peptides on microarray platforms for their ability to bind to the target with high affinity and selectivity in cell culture fluid. Lead peptides were evaluated on resin in batch conditions and compared with a commercially available resin to evaluate their efficacy. Two lead candidates identified from microarray studies provided high binding capacity to the target while demonstrating high selectivity against culture contaminants and product variants compared to a commercial resin system. These findings provide a proof-of-concept for developing affinity peptide-based bioseparations processes for a target biologic. Peptide affinity ligand design and screening approaches presented in this work can also be easily translated to other biologics of interest. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. © 2018 American Institute of Chemical Engineers.

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

    Directory of Open Access Journals (Sweden)

    Giordano Emanuele

    2010-11-01

    Full Text Available Abstract 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.

  7. Rational design of hypoallergens applied to the major cat allergen Fel d 1.

    Science.gov (United States)

    Saarne, T; Kaiser, L; Grönlund, H; Rasool, O; Gafvelin, G; van Hage-Hamsten, M

    2005-05-01

    Allergen-specific immunotherapy is the only treatment for allergic disease providing long-lasting symptom relief. Currently, it is mainly based on the use of crude allergen extracts. The treatment may be improved by the use of genetically engineered allergens, hypoallergens, aiming at a more effective and safer therapy. The aim of this study was to provide a rational design of hypoallergen candidates for immunotherapy by using structural information and knowledge of B and T cell epitopes of an allergen. The three-dimensional structure of the major cat allergen Fel d 1 was systematically altered by duplication of selected T cell epitopes and disruption of disulphide bonds. Seven Fel d 1 derivatives were generated and screened for allergenic reactivity in comparison with recombinant Fel d 1 in competition-ELISA. The allergenicity was further evaluated in basophil activation experiments and T cell reactivity was assessed in a lymphoproliferation assay. Three out of seven Fel d 1 derivatives, with two duplicated T cell epitopes and one or two disulphide bonds disrupted, were carefully evaluated. The three derivatives displayed a strong reduction in allergenicity with 400-900 times lower IgE-binding capacity than recombinant Fel d 1. In addition, they induced a lower degree of basophil activation and similar or stronger T cell proliferation than recombinant Fel d 1. By a rational approach, we have constructed three Fel d 1 hypoallergens with reduced IgE-binding capacities and retained T cell reactivities. This strategy may be applied to any well-characterized allergen to improve immunotherapy for allergic patients.

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

    Science.gov (United States)

    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

  9. Core/shell PLGA microspheres with controllable in vivo release profile via rational core phase design.

    Science.gov (United States)

    Yu, Meiling; Yao, Qing; Zhang, Yan; Chen, Huilin; He, Haibing; Zhang, Yu; Yin, Tian; Tang, Xing; Xu, Hui

    2018-02-27

    the microspheres prepared by various methods were mainly controlled by either the porosity inside the microspheres or the degradation of materials, which could, therefore, lead to different release behaviours. This results indicated great potential of the PLGA microsphere formulation as an injectable depot for controllable in vivo release profile via rational core phase design. Core/shell microspheres fabricated by modified double emulsification-solvent evaporation methods, with various inner phases, to obtain high loading drugs system, as well as appropriate release behaviours. Accordingly, control in vivo release profile via rational core phase design.

  10. Elaborating and Making Rational Decisions in Designing Process Operations of a Group of Holes

    Directory of Open Access Journals (Sweden)

    A. I. Solov'ev

    2015-01-01

    Full Text Available To manufacture engineering products are used expensive multi-purpose CNC machines with five operated coordinates, allowing a single setup of the work-piece to process a group of holes in the housing part from all sides.Because of the haphazard arrangement of a large number of holes available in the space it is difficult to ensure the effective use of these machines.Onsite operational research, conducted on six CNC GS-500 models, involved actual observations and time measurements during 15 working shifts, processing of observation results, and calculations of equipment performance parameters such as machine utilization rate, arrangement and changeover time loss, and real output. Time loss (downtime because of arrangement amounted 44.52%, while that of due to changeover was 20.1% of the total downtime value. These downtimes hide irrational design solutions concerning the engineering process and a large number of changeovers for a new operation to process a group of the specified work-pieces.It is found that to reduce the changeover downtimes it is necessary to increase, first of all, the average number of single tool travels per one setup in generalized characteristics of a group of the work-pieces. That means to increase a changeover concentration of processing within a single operation, as well as to choose rational values for machining a batch of the work-pieces. Under study conditions, it is, at least. 20-50 pieces.To implement a development of the principle of increasing concentration of the processing changeovers it is advised to apply the developed mathematical models, algorithms, and programs that can be used, as modules or their parts, in computer-aided design (CAD systems. This allows a 3-5 times reduction in time to find the rational option of the work-piece position on the machine work surface when developing a process technology, a review and an analysis of more than the usual number of such possible options. It also improves the

  11. The Boundedly Rational User Equilibrium : A parametric analysis with application to the Network Design Problem

    NARCIS (Netherlands)

    Eikenbroek, Oskar Adriaan Louis; Still, Georg J.; van Berkum, E.C.; Kern, Walter

    In this paper, we study a static traffic assignment that accounts for the boundedly rational route choice behavior of travelers. This assignment induces uncertainties to the ex-ante evaluation of a policy measure: the boundedly rational assignment is non-unique and the indifference band is an

  12. A rational and economical seismic design of beam columns in steel frames

    International Nuclear Information System (INIS)

    Gupta, A.K.; Fang, S.-J.; Chu, S.-L.

    1977-01-01

    In the present study, a new rational procedure is used in which simultaneous variation in various response quantities is predicted. For designing the beam column section according to the AISC Manual of Steel Construction, one has to know the values of the axial force, the moment about x and y axes at the two ends, and the maximum moments about x, y axes near the center of the beam column, which altogether constitutes seven response quantities of interest for each beam column element. Normally, seven equivalent modes will be required to represent the response. However, by designing the two end sections and the intermediate section independently one can consider three equivalent modes for each section, thus simplifying the problem a great deal. An existing computer program is used for the implementation of the proposed method. Results for typical example problems have been presented. It is shown that savings up to 42% in the steel cross-sectional area can be obtained depending upon combination of various forces and moments. The propposed method is 'exact' within the existing assumptions of the SRSS (square root of the sum of the squares) or the double sum method

  13. GREEN: A program package for docking studies in rational drug design

    Science.gov (United States)

    Tomioka, Nobuo; Itai, Akiko

    1994-08-01

    A program package, GREEN, has been developed that enables docking studies between ligand molecules and a protein molecule. Based on the structure of the protein molecule, the physical and chemical environment of the ligand-binding site is expressed as three-dimensional grid-point data. The grid-point data are used for the real-time evaluation of the protein-ligand interaction energy, as well as for the graphical representation of the binding-site environment. The interactive docking operation is facilitated by various built-in functions, such as energy minimization, energy contribution analysis and logging of the manipulation trajectory. Interactive modeling functions are incorporated for designing new ligand molecules while considering the binding-site environment and the protein-ligand interaction. As an example of the application of GREEN, a docking study is presented on the complex between trypsin and a synthetic trypsin inhibitor. The program package will be useful for rational drug design, based on the 3D structure of the target protein.

  14. Rational design of botulinum neurotoxin A1 mutants with improved oxidative stability.

    Science.gov (United States)

    López de la Paz, Manuela; Scheps, Daniel; Jurk, Marcel; Hofmann, Fred; Frevert, Jürgen

    2018-06-01

    Botulinum neurotoxins (BoNTs) are the most potent toxic proteins to mankind known but applied in low doses trigger a localized muscle paralysis that is beneficial for the therapy of several neurological disorders and aesthetic treatment. The paralytic effect is generated by the enzymatic activity of the light chain (LC) that cleaves specifically one of the SNARE proteins responsible for neurotransmitter exocytosis. The activity of the LC in a BoNT-containing therapeutic can be compromised by denaturing agents present during manufacturing and/or in the cell. Stabilization of the LC by reducing vulnerability towards denaturants would thus be advantageous for the development of BoNT-based therapeutics. In this work, we focused on increasing the stability of LC of BoNT/A1 (LC/A1) towards oxidative stress. We tackled this task by rational design of mutations at cysteine and methionine LC/A1 sites. Designed mutants showed improved oxidative stability in vitro and equipotency to wildtype toxin in vivo. Our results suggest that suitable modification of the catalytic domain can lead to more stable BoNTs without impairing their therapeutic efficacy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Virus-Like Particle Engineering: From Rational Design to Versatile Applications.

    Science.gov (United States)

    Ding, Xuanwei; Liu, Dong; Booth, George; Gao, Wei; Lu, Yuan

    2018-05-01

    As mimicking natural virus structures, virus-like particles (VLPs) have evolved to become a widely accepted technology used for humans which are safe, highly efficacious, and profitable. Several remarkable advantages have been achieved to revolutionize the molecule delivery for diverse applications in nanotechnology, biotechnology, and medicine. Here, the rational structure design, manufacturing process, functionalization strategy, and emerging applications of VLPs is reviewed. The situation and challenges in the VLP engineering, the key development orientation, and future applications have been discussed. To develop a good VLP design concept, the virus/VLP-host interactions need to be examined and the screening methods of the VLP stabilization factors need to be established. The functionalization toolbox can be expanded to fabricate smart, robust, and multifunctional VLPs. Novel robust VLP manufacturing platforms are required to deliver vaccines in resource-poor regions with a significant reduction in the production time and cost. The future applications of VLPs are always driven by the development of emerging technologies and new requirements of modern life. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Rational design of stealthy hyperuniform two-phase media with tunable order

    Science.gov (United States)

    DiStasio, Robert A.; Zhang, Ge; Stillinger, Frank H.; Torquato, Salvatore

    2018-02-01

    Disordered stealthy hyperuniform materials are exotic amorphous states of matter that have attracted recent attention because of their novel structural characteristics (hidden order at large length scales) and physical properties, including desirable photonic and transport properties. It is therefore useful to devise algorithms that enable one to design a wide class of such amorphous configurations at will. In this paper, we present several algorithms enabling the systematic identification and generation of discrete (digitized) stealthy hyperuniform patterns with a tunable degree of order, paving the way towards the rational design of disordered materials endowed with novel thermodynamic and physical properties. To quantify the degree of order or disorder of the stealthy systems, we utilize the discrete version of the τ order metric, which accounts for the underlying spatial correlations that exist across all relevant length scales in a given digitized two-phase (or, equivalently, a two-spin state) system of interest. Our results impinge on a myriad of fields, ranging from physics, materials science and engineering, visual perception, and information theory to modern data science.

  17. On rationally supported surfaces

    DEFF Research Database (Denmark)

    Gravesen, Jens; Juttler, B.; Sir, Z.

    2008-01-01

    We analyze the class of surfaces which are equipped with rational support functions. Any rational support function can be decomposed into a symmetric (even) and an antisymmetric (odd) part. We analyze certain geometric properties of surfaces with odd and even rational support functions....... In particular it is shown that odd rational support functions correspond to those rational surfaces which can be equipped with a linear field of normal vectors, which were discussed by Sampoli et al. (Sampoli, M.L., Peternell, M., Juttler, B., 2006. Rational surfaces with linear normals and their convolutions...... with rational surfaces. Comput. Aided Geom. Design 23, 179-192). As shown recently, this class of surfaces includes non-developable quadratic triangular Bezier surface patches (Lavicka, M., Bastl, B., 2007. Rational hypersurfaces with rational convolutions. Comput. Aided Geom. Design 24, 410426; Peternell, M...

  18. METHODOLOGICAL ASPECTS OF RATIONAL DESIGN FORMATION OF INFRASTRUCTURE OF AGRARIAN SECTOR OF UKRAINE

    Directory of Open Access Journals (Sweden)

    Ivan Korchynskyy

    2016-11-01

    Full Text Available Methodological aspects of formation of rational design of infrastructure of agrarian sector of Ukraine on the basis of the institutional approach and laws of architectonics are examined. It is shown that the agrarian sector of Ukraine is a complex socio-economic system, the formation and development of which is in the process of market transformation what is caused by institutional influences. In general the process of relations institutionalization imply their formalization and standardization, in other case the subject of public life could not predict the actions of other entities associated with him and ensure their cooperation. One of the specific characteristic of human society is formed institutional system that regulates behaviour. In the article the factors of influence on the conduct of being in charge subjects are considered in the conditions of development of market economy. The special attention is spared the institutional factors of the economy growing. Methodology. The meaning of “agricultural field” and “infrastructure” and their mutual consistency is classified. As the scientific method, the institutional approach of principles of architectonics has been used, which allowed to justify the creation of a rational approach to the design of infrastructure in agrarian sector as a whole on the basis, relation and interdependence of its elements, based on the fundamental laws of architectonics (law of equilibrium, law of the golden mean structuring. The article demonstrates a necessary of the choice of a theory of institutionalism as the main methodological basis for the study of the process of innovation development of economic system of Ukraine. It is determined that the inefficient activities of institutions in Ukraine are the main cause of the low level of innovation, which has a negative impact on the development of the economy as a whole. Results. Research points on new aspects of infrastructure as a part of the entire

  19. Rational design of carbon and TiO2 assembly materials: covered or strewn, which is better for photocatalysis?

    Science.gov (United States)

    Cui, Guan-wei; Wang, Wei-liang; Ma, Ming-yue; Zhang, Ming; Xia, Xin-yuan; Han, Feng-yun; Shi, Xi-feng; Zhao, Ying-qiang; Dong, Yu-bin; Tang, Bo

    2013-07-21

    The rational design of carbonaceous hybrid nanostructures is very important for obtaining high photoactivity. TiO2 particles strewn with an optimal quantity of carbon nanodots have a much higher photoactivity than that of TiO2 covered with a carbon layer, showing the importance of carbon morphology in the photocatalysis of carbonaceous hybrid nanostructures.

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

    Science.gov (United States)

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

    2014-01-01

    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. PMID:25189418

  1. Rationalization and Design of Enhanced Photoinduced Cycloreversion in Photochromic Dimethyldihydropyrenes by Theoretical Calculations.

    Science.gov (United States)

    Boggio-Pasqua, Martial; Garavelli, Marco

    2015-06-11

    This study presents a computational investigation of the initial step of the dimethyldihydropyrene (DHP) to cyclophanediene (CPD) photoinduced ring-opening reaction using time-dependent density functional theory (TD-DFT). In particular, the photochemical path corresponding to the formation of the CPD precursor (CPD*) on the zwitterionic state is scrutinized. The TD-DFT approach was first validated on the parent compound against accurate ab initio calculations. It confirms that CPD* formation is efficiently quenched in this system by an easily accessible S2/S1 conical intersection located in the vicinity of the CPD* minimum and leading to a locally excited state minimum responsible for DHP luminescence. Increased ring-opening quantum yields were observed in benzo[e]-fused-DHP (DHP-1), isobutenyl-DHP (DHP-2), and naphthoyl-DHP (DHP-3). The calculations show that CPD* formation is much more favorable in these systems, either due to an inversion of electronic states in DHP-1, suppressing the formation of the locally excited state, or due to efficient stabilization of CPD* on the S1 potential energy surface in DHP-2 and DHP-3. Both effects can be combined in a rationally designed benzo[e]-fused-naphthoyl-DHP (DHP-4) for which we anticipate an unprecedented efficiency.

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

    Energy Technology Data Exchange (ETDEWEB)

    Guliants, Vadim [Univ. of Cincinnati, OH (United States)

    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.

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

    Science.gov (United States)

    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

  4. Appendix to rationally designing of machine tools for example of universal lathe

    Directory of Open Access Journals (Sweden)

    Pejović Branko B.

    2015-01-01

    Full Text Available In this paper, for the universal machine tool for turning and function of the thrust of the cutting speed for blasting area efficiency and stability of the tool and sectional filings. These dependencies were used to determine the main characteristics of the optimal and maximum operating power equipment. Based on this, an analysis of the increase in operating power equipment typical cases in order to adapt to the new needs of exploitation properties and improve productivity. Using the previous analysis, it was determined the best solution in terms of the rational design of machines, by ensuring the simultaneous use of the main features on the basis of increase in speed with the use of tools and higher stability. In order to better display problems, an analysis of the appropriate diagrams P-V and V-D. On a typical example of the manufacturing practice at the end of the work, we demonstrate improvement of exploitation characteristics of a universal machine through appropriate calculations in terms of new needs adjustment feature, where it is expected that the reconstruction of the smallest machines.

  5. A density functional theory insight towards the rational design of ionic liquids for SO2 capture.

    Science.gov (United States)

    García, Gregorio; Atilhan, Mert; Aparicio, Santiago

    2015-05-28

    A systematic density functional theory (DFT) analysis has been carried out to obtain information at the molecular level on the key parameters related to efficient SO2 capture by ionic liquids (ILs). A set of 55 ILs, for which high gas solubility is expected, has been selected. SO2 solubility of ILs was firstly predicted based on the COSMO-RS (Conductor-like Screening Model for Real Solvents) method, which provides a good prediction of gas solubility data in ILs without prior experimental knowledge of the compounds' features. Then, interactions between SO2 and ILs were deeply analyzed through DFT simulations. This work provides valuable information about required factors at the molecular level to provide high SO2 solubility in ILs, which is crucial for further implementation of these materials in the future. In our opinion, systematic research on ILs for SO2 capture increases our knowledge about those factors which could be controlled at the molecular level, providing an approach for the rational design of task-specific ILs.

  6. Rational design of single-ion magnets and spin qubits based on mononuclear lanthanoid complexes.

    Science.gov (United States)

    Baldoví, José J; Cardona-Serra, Salvador; Clemente-Juan, Juan M; Coronado, Eugenio; Gaita-Ariño, Alejandro; Palii, Andrew

    2012-11-19

    Here we develop a general approach to calculating the energy spectrum and the wave functions of the low-lying magnetic levels of a lanthanoid ion submitted to the crystal field created by the surrounding ligands. This model allows us to propose general criteria for the rational design of new mononuclear lanthanoid complexes behaving as single-molecule magnets (SMMs) or acting as robust spin qubits. Three typical environments exhibited by these metal complexes are considered, namely, (a) square antiprism, (b) triangular dodecahedron, and (c) trigonal prism. The developed model is used to explain the properties of some representative examples showing these geometries. Key questions in this area, such as the chemical tailoring of the superparamagnetic energy barrier, tunneling gap, or spin relaxation time, are discussed. Finally, in order to take into account delocalization and/or covalent effects of the ligands, this point-charge model is complemented with ab initio calculations, which provide accurate information on the charge distribution around the metal, allowing for an explanation of the SMM behavior displayed by some sandwich-type organometallic compounds.

  7. Rational design of multifunctional devices based on molybdenum disulfide and graphene hybrid nanostructures

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Yi Rang; Lee, Young Bum; Kim, Seong Ku; Kim, Seong Jun [Thin Film Materials Research Center, Korea Research Institute of Chemical Technology, Yuseong, Post Office Box 107, Daejeon 305-600 (Korea, Republic of); Kim, Yooseok; Jeon, Cheolho [Nano-Surface Research Group, Korea Basic Science Institute, Daejeon, 302-333 (Korea, Republic of); Song, Wooseok, E-mail: wssong@krict.re.kr [Thin Film Materials Research Center, Korea Research Institute of Chemical Technology, Yuseong, Post Office Box 107, Daejeon 305-600 (Korea, Republic of); Myung, Sung; Lee, Sun Sook; An, Ki-Seok [Thin Film Materials Research Center, Korea Research Institute of Chemical Technology, Yuseong, Post Office Box 107, Daejeon 305-600 (Korea, Republic of); Lim, Jongsun, E-mail: jslim@krict.re.kr [Thin Film Materials Research Center, Korea Research Institute of Chemical Technology, Yuseong, Post Office Box 107, Daejeon 305-600 (Korea, Republic of)

    2017-01-15

    Highlights: • We fabricated MoS{sub 2}-graphene hybrid thin films for multifunctional applications. • Large-area, uniform multilayer MoS{sub 2} was synthesized on TCVD-grown graphene. • The mobility and photocurrent of the hybrid devices were improved significantly. - Abstract: We rationally designed a new type of hybrid materials, molybdenum disulfide (MoS{sub 2}) synthesized by Mo pre-deposition followed by subsequent sulfurization process directly on thermal chemical vapor deposition (TCVD)-grown graphene, for applications in a multifunctional device. The synthesis of stoichiometric and uniform multilayer MoS{sub 2} and high-crystalline monolayer graphene was evaluated by X-ray photoelectron spectroscopy and Raman spectroscopy. To examine the electrical transport and photoelectrical properties of MoS{sub 2}-graphene hybrid films, field effect transistors (FETs) and visible-light photodetectors based on MoS{sub 2}-graphene were both fabricated. As a result, the extracted mobility for MoS{sub 2}-graphene hybrid FETs was two times higher than that of MoS{sub 2} FETs. In addition, the MoS{sub 2}-graphene photodetectors revealed a significant photocurrent with abrupt switching behavior under periodic illumination.

  8. Drug Partitioning in Micellar Media and Its Implications in Rational Drug Design: Insights with Streptomycin.

    Science.gov (United States)

    Judy, Eva; Pagariya, Darshna; Kishore, Nand

    2018-03-20

    Oral bioavailability of a drug molecule requires its effective delivery to the target site. In general, majority of synthetically developed molecular entities have high hydrophobic nature as well as low bioavailability, therefore the need for suitable delivery vehicles arises. Self-assembled structures such as micelles, niosomes, and liposomes have been used as effective delivery vehicles and studied extensively. However, the information available in literature is mostly qualitative in nature. We have quantitatively investigated the partitioning of antibiotic drug streptomycin into cationic, nonionic, and a mixture of cationic and nonionic surfactant micelles and its interaction with the transport protein serum albumin upon subsequent delivery. A combination of calorimetry and spectroscopy has been used to obtain the thermodynamic signatures associated with partitioning and interaction with the protein and the resulting conformational changes in the latter. The results have been correlated with other class of drugs of different nature to understand the role of molecular features in the partitioning process. These studies are oriented toward understanding the physical chemistry of partitioning of a variety of drug molecules into suitable delivery vehicles and hence establishing structure-property-energetics relationships. Such studies provide general guidelines toward a broader goal of rational drug design.

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

    Science.gov (United States)

    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.

  10. Rational design of an EGF-IL18 fusion protein: Implication for developing tumor therapeutics

    International Nuclear Information System (INIS)

    Lu Jianxin; Peng Ying; Meng Zhefeng; Jin Liqin; Lu Yongsui; Guan Minxin

    2005-01-01

    Interleukin-18 (IL-18) is a proinflammatory cytokine. This protein has a role in regulating immune responses and exhibits significant anti-tumor activities. Epidermal growth factor (EGF) is an important growth factor that plays a central role in the regulation of cell cycle and differentiation. It was proposed that a targeted delivery of IL-18 by generation of IL-18-EGF fusion protein might decrease adverse effects and result in enhancing cytotoxic and antitumor activities. In the present study, a fusion protein, consisting of EGFR binding domain fused to human IL-18 mature peptide via a linker peptide of (Gly 4 Ser) 3, was constructed and expressed in the insect cell line Sf9 using Bac-to-Bac baculovirus expression system. We showed that the purified recombinant fusion protein induced similar levels of IFN-γ to that of native IL-18 protein in human PBMC in the presence of ConA. Furthermore, EGF receptor competitive test in human epithelial cancer A431 cell line showed that EGF-IL18 fusion protein can specifically bind with EGFR by competing with native EGF protein. These suggest that this rationally designed protein can be further developed as novel tumor therapeutics

  11. A Rationally Designed Agonist Defines Subfamily IIIA Abscisic Acid Receptors As Critical Targets for Manipulating Transpiration.

    Science.gov (United States)

    Vaidya, Aditya S; Peterson, Francis C; Yarmolinsky, Dmitry; Merilo, Ebe; Verstraeten, Inge; Park, Sang-Youl; Elzinga, Dezi; Kaundal, Amita; Helander, Jonathan; Lozano-Juste, Jorge; Otani, Masato; Wu, Kevin; Jensen, Davin R; Kollist, Hannes; Volkman, Brian F; Cutler, Sean R

    2017-11-17

    Increasing drought and diminishing freshwater supplies have stimulated interest in developing small molecules that can be used to control transpiration. Receptors for the plant hormone abscisic acid (ABA) have emerged as key targets for this application, because ABA controls the apertures of stomata, which in turn regulate transpiration. Here, we describe the rational design of cyanabactin, an ABA receptor agonist that preferentially activates Pyrabactin Resistance 1 (PYR1) with low nanomolar potency. A 1.63 Å X-ray crystallographic structure of cyanabactin in complex with PYR1 illustrates that cyanabactin's arylnitrile mimics ABA's cyclohexenone oxygen and engages the tryptophan lock, a key component required to stabilize activated receptors. Further, its sulfonamide and 4-methylbenzyl substructures mimic ABA's carboxylate and C6 methyl groups, respectively. Isothermal titration calorimetry measurements show that cyanabactin's compact structure provides ready access to high ligand efficiency on a relatively simple scaffold. Cyanabactin treatments reduce Arabidopsis whole-plant stomatal conductance and activate multiple ABA responses, demonstrating that its in vitro potency translates to ABA-like activity in vivo. Genetic analyses show that the effects of cyanabactin, and the previously identified agonist quinabactin, can be abolished by the genetic removal of PYR1 and PYL1, which form subclade A within the dimeric subfamily III receptors. Thus, cyanabactin is a potent and selective agonist with a wide spectrum of ABA-like activities that defines subfamily IIIA receptors as key target sites for manipulating transpiration.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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

  14. Structural Basis for Escape of Human Astrovirus from Antibody Neutralization: Broad Implications for Rational Vaccine Design

    Energy Technology Data Exchange (ETDEWEB)

    Bogdanoff, Walter A.; Perez, Edmundo I.; López, Tomás; Arias, Carlos F.; DuBois, Rebecca M. (UNAM-Mexico); (UCSC)

    2017-10-25

    a single amino acid mutation induces a structural change in a loop that is responsible for antibody binding. Our findings reveal how viruses can escape antibody neutralization and provide insight for the rational design of vaccines to elicit diverse antibodies that provide broader protection from infection.

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

    Directory of Open Access Journals (Sweden)

    Brian Healy

    Full Text Available 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.

  16. Adsorption of rationally designed "surf-tides" to a liquid-crystal interface.

    Science.gov (United States)

    Badami, Joseph V; Bernstein, Chaim; Maldarelli, Charles; Tu, Raymond S

    2015-09-07

    The interfacial adsorption of proteins in surfactant laden systems occurs both in nature and industrial processing, yet much of the fundamental behavior behind these systems is still not well understood. We report the development of a system that monitors optical transitions of a liquid-crystalline/aqueous interface to examine the dynamics of adsorption of two rationally designed model peptide molecules. The two molecules synthesized in this study were both designed to become surface-active upon folding and contain the same net charge of +3, but one of the peptides, K-2.5, has its three charges separated by 2.5 amino acids as compared to K-6.0, which has its three charges separated by 6 amino acids. Our study examines the roles that surfactant adsorption, peptide charge distribution and secondary structure have on the relative adsorption dynamics of these two models peptides onto a fluid/fluid interface. Using the optical detection of molecular adsorption and image analysis of these events, we obtain quantitative information about the dynamics as a function of the charge spacing and initial peptide concentration. We show that both peptides initially follow a diffusion-limited adsorption model onto the interface. Additionally, our results suggest that the K-6.0 peptides demonstrate enhanced adsorption kinetics, where the enhanced rates are a consequence of the well-folded adsorbed state and spatial distribution on the surface. These findings provide further insights into the role that charge spacing has on secondary structure and subsequently the dynamics of adsorption, while developing a versatile system capable of extracting quantitative information from a simple inexpensive optical system.

  17. Rational design of molecularly imprinted polymer: the choice of cross-linker.

    Science.gov (United States)

    Muhammad, Turghun; Nur, Zohre; Piletska, Elena V; Yimit, Osmanjan; Piletsky, Sergey A

    2012-06-07

    The paper describes a rational approach for the selection of cross-linkers during the development of molecularly imprinted polymers (MIPs). As a model system for this research MIPs specific for the drug zidovudine (AZT) were designed and tested. Three cross-linkers trimethylolpropane trimethacrylate (TRIM), ethylene glycol dimethacrylate (EGDMA) and divinylbenzene (DVB) were studied. The analogue of zidovudine (AZT) ester (AZT-ES) was used as a dummy template. The imprinting factors for all of the polymers in the static adsorption experiments were calculated. The data on the AZT adsorption by control polymers (CP), which were prepared with different cross-linkers without a functional monomer, was also analyzed. DVB was found to be more inert towards zidovudine than EGDMA and TRIM, which was confirmed by both molecular modelling and adsorption experiments. It was demonstrated that DVB-based polymers had a higher imprinting factor (I = 1.85) compared with other tested cross-linked polymers. It was suggested that the selection of the cross-linker should be based on the strength of the interaction with the template: the cross-linker which displays lower binding of the template should be preferential because it generates MIPs with lower non-specific binding and a higher imprinting factor, and therefore specificity. Which cross-linker to use for the preparation of any particular MIP can be determined by analysis of the interactions between the cross-linker and template. This could be done either virtually using computational modelling or by template adsorption using a small library of polymers prepared using different cross-linkers.

  18. Rational Design and Tuning of Functional RNA Switch to Control an Allosteric Intermolecular Interaction.

    Science.gov (United States)

    Endoh, Tamaki; Sugimoto, Naoki

    2015-08-04

    Conformational transitions of biomolecules in response to specific stimuli control many biological processes. In natural functional RNA switches, often called riboswitches, a particular RNA structure that has a suppressive or facilitative effect on gene expression transitions to an alternative structure with the opposite effect upon binding of a specific metabolite to the aptamer region. Stability of RNA secondary structure (-ΔG°) can be predicted based on thermodynamic parameters and is easily tuned by changes in nucleobases. We envisioned that tuning of a functional RNA switch that causes an allosteric interaction between an RNA and a peptide would be possible based on a predicted switching energy (ΔΔG°) that corresponds to the energy difference between the RNA secondary structure before (-ΔG°before) and after (-ΔG°after) the RNA conformational transition. We first selected functional RNA switches responsive to neomycin with predicted ΔΔG° values ranging from 5.6 to 12.2 kcal mol(-1). We then demonstrated a simple strategy to rationally convert the functional RNA switch to switches responsive to natural metabolites thiamine pyrophosphate, S-adenosyl methionine, and adenine based on the predicted ΔΔG° values. The ΔΔG° values of the designed RNA switches proportionally correlated with interaction energy (ΔG°interaction) between the RNA and peptide, and we were able to tune the sensitivity of the RNA switches for the trigger molecule. The strategy demonstrated here will be generally applicable for construction of functional RNA switches and biosensors in which mechanisms are based on conformational transition of nucleic acids.

  19. Fundamental Investigations and Rational Design of Durable High-Performance SOFC Cathodes

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yu [Georgia Inst. of Technology, Atlanta, GA (United States); Ding, Dong [Georgia Inst. of Technology, Atlanta, GA (United States); Wei, Tao [Georgia Inst. of Technology, Atlanta, GA (United States); Liu, Meilin [Georgia Inst. of Technology, Atlanta, GA (United States)

    2016-03-31

    The main objective of this project is to unravel the degradation mechanism of LSCF cathodes under realistic operating conditions with different types of contaminants, aiming towards the rational design of cathodes with high-performance and enhanced durability by combining a porous backbone (such as LSCF) with a thin catalyst coating. The mechanistic understanding will help us to optimize the composition and morphology of the catalyst layer and microstructure of the LSCF backbone for better performance and durability. More specifically, the technical objectives include: (1) to unravel the degradation mechanism of LSCF cathodes under realistic operating conditions with different types of contaminants using in situ and ex situ measurements performed on specially-designed cathodes; (2) to examine the microstructural and compositional evolution of LSCF cathodes as well as the cathode/electrolyte interfaces under realistic operating conditions; (3) to correlate the fuel cell performance instability and degradation with the microstructural and morphological evolution and surface chemistry change of the cathode under realistic operating conditions; (4) to explore new catalyst materials and electrode structures to enhance the stability of the LSCF cathode under realistic operating conditions; and (5) to validate the long term stability of the modified LSCF cathode in commercially available cells under realistic operating conditions. We have systematically evaluated LSCF cathodes in symmetrical cells and anode supported cells under realistic conditions with different types of contaminants such as humidity, CO2, and Cr. Electrochemical models for the design of test cells and understanding of mechanisms have been developed for the exploration of fundamental properties of electrode materials. It is demonstrated that the activity and stability of LSCF cathodes can be degraded by the introduction of contaminants. The microstructural and compositional evolution of LSCF

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

    International Nuclear Information System (INIS)

    Szigethy, Geza

    2009-01-01

    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, UO 2 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 saturation, these

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

    Energy Technology Data Exchange (ETDEWEB)

    Szigethy, Geza [Univ. of California, Berkeley, CA (United States)

    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

  2. Rational Design of a New Trypanosoma rangeli Trans-Sialidase for Efficient Sialylation of Glycans

    DEFF Research Database (Denmark)

    Jers, Carsten; Michalak, Malwina; Larsen, Dorte Møller

    2014-01-01

    This paper reports rational engineering of Trypanosoma rangeli sialidase to develop an effective enzyme for a potentially important type of reactivity: production of sialylated prebiotic glycans. The Trypanosoma cruzi trans-sialidase and the homologous T. rangeli sialidase has previously been use...

  3. P-glycoprotein recognition of substrates and circumvention through rational drug design.

    Science.gov (United States)

    Raub, Thomas J

    2006-01-01

    It is now well recognized that membrane efflux transporters, especially P-glycoprotein (P-gp; ABCB1), play a role in determining the absorption, distribution, metabolism, excretion, and toxicology behaviors of some drugs and molecules in development. An investment in screening structure-activity relationship (SAR) is warranted in early discovery when exposure and/or target activity in an in vivo efficacy model is not achieved and P-gp efflux is identified as a rate-limiting factor. However, the amount of investment in SAR must be placed into perspective by assessing the risks associated with the intended therapeutic target, the potency and margin of safety of the compound, the intended patient population(s), and the market competition. The task of rationally designing a chemistry strategy for circumventing a limiting P-gp interaction can be daunting. The necessity of retaining biological potency and metabolic stability places restrictions on what can be done, and the factors for P-gp recognition of substrates are complicated and poorly understood. The parameters within the assays that affect overall pump efficiency or net efflux, such as passive diffusion, membrane partitioning, and molecular interaction between pump and substrate, should be understood when interpreting data sets associated with chemistry around a scaffold. No single, functional group alone is often the cause, but one group can accentuate the recognition points existing within a scaffold. This can be likened to a rheostat, rather than an on/off switch, where addition or removal of a key group can increase or decrease the pumping efficiency. The most practical approach to de-emphasize the limiting effects of P-gp on a particular scaffold is to increase passive diffusion. Efflux pumping efficiency may be overcome when passive diffusion is fast enough. Eliminating, or substituting with fewer, groups that solvate in water, or decreasing their hydrogen bonding capacity, and adding halogen groups can

  4. Rational design of nanoparticles towards targeting antigen-presenting cells and improved T cell priming.

    Science.gov (United States)

    Zupančič, Eva; Curato, Caterina; Paisana, Maria; Rodrigues, Catarina; Porat, Ziv; Viana, Ana S; Afonso, Carlos A M; Pinto, João; Gaspar, Rogério; Moreira, João N; Satchi-Fainaro, Ronit; Jung, Steffen; Florindo, Helena F

    2017-07-28

    Vaccination is a promising strategy to trigger and boost immune responses against cancer or infectious disease. We have designed, synthesized and characterized aliphatic-polyester (poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) to investigate how the nature of protein association (adsorbed versus entrapped) and polymer/surfactant concentrations impact on the generation and modulation of antigen-specific immune responses. The ability of the NP formulations to target dendritic cells (DC), be internalized and activate the T cells was characterized and optimized in vitro and in vivo using markers of DC activation and co-stimulatory molecules. Ovalbumin (OVA) was used as a model antigen in combination with the engraftment of CD4 + and CD8 + T cells, carrying a transgenic OVA-responding T cell receptor (TCR), to trace and characterize the activation of antigen-specific CD4 + and CD8 + lymph node T cells upon NP vaccination. Accordingly, the phenotype and frequency of immune cell stimulation induced by the NP loaded with OVA, isolated or in combination with synthetic unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotide (ODN) motifs, were characterized. DC-NP interactions increased with incubation time, presenting internalization values between 50 and 60% and 30-40%, in vitro and in vivo, respectively. Interestingly, animal immunization with antigen-adsorbed NP up-regulated major histocompatibility complex (MHC) class II (MHCII), while NP entrapping the antigen up-regulated MHCI, suggesting a more efficient cross-presentation. On the other hand, rather surprisingly, the surfactant used in the NP formulation had a major impact on the activation of antigen presenting cells (APC). In fact, DC collected from lymph nodes of animals immunized with NP prepared using poly(vinil alcohol) (PVA), as a surfactant, expressed significantly higher levels of CD86, MHCI and MHCII. In addition, those NP prepared with PVA and co-entrapping OVA and the toll

  5. Rational design of a bi-layered reduced graphene oxide film on polystyrene foam for solar-driven interfacial water evaporation

    KAUST Repository

    Shi, Le; Wang, Yuchao; Zhang, Lianbin; Wang, Peng

    2016-01-01

    Solar-driven water evaporation has been emerging as a highly efficient way for utilizing solar energy for clean water production and wastewater treatment. Here we rationally designed and fabricated a bi-layered photothermal membrane with a porous

  6. Development of a Preventive HIV Vaccine Requires Solving Inverse Problems Which Is Unattainable by Rational Vaccine Design

    Directory of Open Access Journals (Sweden)

    Marc H. V. Van Regenmortel

    2018-01-01

    Full Text Available Hypotheses and theories are essential constituents of the scientific method. Many vaccinologists are unaware that the problems they try to solve are mostly inverse problems that consist in imagining what could bring about a desired outcome. An inverse problem starts with the result and tries to guess what are the multiple causes that could have produced it. Compared to the usual direct scientific problems that start with the causes and derive or calculate the results using deductive reasoning and known mechanisms, solving an inverse problem uses a less reliable inductive approach and requires the development of a theoretical model that may have different solutions or none at all. Unsuccessful attempts to solve inverse problems in HIV vaccinology by reductionist methods, systems biology and structure-based reverse vaccinology are described. The popular strategy known as rational vaccine design is unable to solve the multiple inverse problems faced by HIV vaccine developers. The term “rational” is derived from “rational drug design” which uses the 3D structure of a biological target for designing molecules that will selectively bind to it and inhibit its biological activity. In vaccine design, however, the word “rational” simply means that the investigator is concentrating on parts of the system for which molecular information is available. The economist and Nobel laureate Herbert Simon introduced the concept of “bounded rationality” to explain why the complexity of the world economic system makes it impossible, for instance, to predict an event like the financial crash of 2007–2008. Humans always operate under unavoidable constraints such as insufficient information, a limited capacity to process huge amounts of data and a limited amount of time available to reach a decision. Such limitations always prevent us from achieving the complete understanding and optimization of a complex system that would be needed to achieve a truly

  7. Rational Design Approach for Enhancing Higher-Mode Response of a Microcantilever in Vibro-Impacting Mode

    Directory of Open Access Journals (Sweden)

    Ieva Migliniene

    2017-12-01

    Full Text Available This paper proposes an approach for designing an efficient vibration energy harvester based on a vibro-impacting piezoelectric microcantilever with a geometric shape that has been rationally modified in accordance with results of dynamic optimization. The design goal is to increase the amplitudes of higher-order vibration modes induced during the vibro-impact response of the piezoelectric transducer, thereby providing a means to improve the energy conversion efficiency and power output. A rational configuration of the energy harvester is proposed and it is demonstrated that the new design retains essential modal characteristics of the optimal microcantilever structures, further providing the added benefit of less costly fabrication. The effects of structural dynamics associated with advantageous exploitation of higher vibration modes are analyzed experimentally by means of laser vibrometry as well as numerically via transient simulations of microcantilever response to random excitation. Electrical characterization results indicate that the proposed harvester outperforms its conventional counterpart (based on the microcantilever of the constant cross-section in terms of generated electrical output. Reported results may serve for the development of impact-type micropower generators with harvesting performance that is enhanced by virtue of self-excitation of large intensity higher-order mode responses when the piezoelectric transducer is subjected to relatively low-frequency excitation with strongly variable vibration magnitudes.

  8. Indirect three-dimensional printing of synthetic polymer scaffold based on thermal molding process

    International Nuclear Information System (INIS)

    Park, Jeong Hun; Jung, Jin Woo; Cho, Dong-Woo; Kang, Hyun-Wook

    2014-01-01

    One of the major issues in tissue engineering has been the development of three-dimensional (3D) scaffolds, which serve as a structural template for cell growth and extracellular matrix formation. In scaffold-based tissue engineering, 3D printing (3DP) technology has been successfully applied for the fabrication of complex 3D scaffolds by using both direct and indirect techniques. In principle, direct 3DP techniques rely on the straightforward utilization of the final scaffold materials during the actual scaffold fabrication process. In contrast, indirect 3DP techniques use a negative mold based on a scaffold design, to which the desired biomaterial is cast and then sacrificed to obtain the final scaffold. Such indirect 3DP techniques generally impose a solvent-based process for scaffold fabrication, resulting in a considerable increase in the fabrication time and poor mechanical properties. In addition, the internal architecture of the resulting scaffold is affected by the properties of the biomaterial solution. In this study, we propose an advanced indirect 3DP technique using projection-based micro-stereolithography and an injection molding system (IMS) in order to address these challenges. The scaffold was fabricated by a thermal molding process using IMS to overcome the limitation of the solvent-based molding process in indirect 3DP techniques. The results indicate that the thermal molding process using an IMS has achieved a substantial reduction in scaffold fabrication time and has also provided the scaffold with higher mechanical modulus and strength. In addition, cell adhesion and proliferation studies have indicated no significant difference in cell activity between the scaffolds prepared by solvent-based and thermal molding processes. (paper)

  9. Rational Multiparty Computation

    OpenAIRE

    Wallrabenstein, John Ross

    2014-01-01

    The field of rational cryptography considers the design of cryptographic protocols in the presence of rational agents seeking to maximize local utility functions. This departs from the standard secure multiparty computation setting, where players are assumed to be either honest or malicious. ^ We detail the construction of both a two-party and a multiparty game theoretic framework for constructing rational cryptographic protocols. Our framework specifies the utility function assumptions neces...

  10. Standby Gasoline Rationing Plan. Contingency gasoline rationing regulations

    Energy Technology Data Exchange (ETDEWEB)

    1979-02-01

    The Economic Regulatory Administration issues final rules with respect to standby gasoline rationing. The plan is designed for and would be used only in the event of a severe gasoline shortage. The plan provides that eligibility for ration allotments will be primarily on the basis of motor vehicle registrations. DOE will mail government ration checks to the parties named in a national vehicle registration file to be maintained by DOE. Ration recipients may cash these checks for ration coupons at various designated coupon issuance points. Retail outlets and other suppliers will be required to redeem the ration coupons received in exchange for gasoline sold. Supplemental gas will be given to high-priority activities. A ration banking system will be established with two separate and distinct of ration accounts: retail outlets and other suppliers will open redemption accounts for the deposit of redeemed ration rights; and individuals or firms may open ration rights accounts, which will operate in much the same manner as monetary checking accounts. A white market will be permitted for the sale of transfer of ration rights. A percentage of the total ration rights to be issued will be reserved for distribution to the states as a State Ration Reserve, to be used by the states primarily for the relief of hardship. A National Ration Reserave will also be established. All sections of the Standby Gasoline Rationing Regulations are analyzed. (MCW)

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

    Science.gov (United States)

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

    2016-03-04

    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.

  12. Rational design and evolutional fine tuning of Saccharomyces cerevisiae for biomass breakdown.

    Science.gov (United States)

    Hasunuma, Tomohisa; Ishii, Jun; Kondo, Akihiko

    2015-12-01

    Conferring biomass hydrolysis activity on yeast through genetic engineering has paved the way for the development of groundbreaking processes for producing liquid fuels and commodity chemicals from lignocellulosic biomass. However, the overproduction and misfolding of heterologous and endogenous proteins can trigger cellular stress, increasing the metabolic burden and retarding growth. Improving the efficiency of lignocellulosic breakdown requires engineering of yeast secretory pathway based on system-wide metabolic analysis as well as DNA constructs for enhanced cellulase gene expression with advanced molecular biology tools. Also, yeast is subjected to severe stress due to toxic compounds generated during lignocellulose pretreatment in consolidated saccharification and fermentation processes. The prospect for development of robust yeast strains makes combining evolutionary and rational engineering strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies

    Science.gov (United States)

    Hudson, Lauren E.; Anderson, Sarah E.; Corbett, Anita H.

    2016-01-01

    SUMMARY Beneficial microorganisms hold promise for the treatment of numerous gastrointestinal diseases. The transfer of whole microbiota via fecal transplantation has already been shown to ameliorate the severity of diseases such as Clostridium difficile infection, inflammatory bowel disease, and others. However, the exact mechanisms of fecal microbiota transplant efficacy and the particular strains conferring this benefit are still unclear. Rationally designed combinations of microbial preparations may enable more efficient and effective treatment approaches tailored to particular diseases. Here we use an infectious disease, C. difficile infection, and an inflammatory disorder, the inflammatory bowel disease ulcerative colitis, as examples to facilitate the discussion of how microbial therapy might be rationally designed for specific gastrointestinal diseases. Fecal microbiota transplantation has already shown some efficacy in the treatment of both these disorders; detailed comparisons of studies evaluating commensal and probiotic organisms in the context of these disparate gastrointestinal diseases may shed light on potential protective mechanisms and elucidate how future microbial therapies can be tailored to particular diseases. PMID:27856521

  15. Evolutionary and Comparative Genomics to Drive Rational Drug Design, with Particular Focus on Neuropeptide Seven-Transmembrane Receptors.

    Science.gov (United States)

    Furlong, Michael; Seong, Jae Young

    2017-01-01

    Seven transmembrane receptors (7TMRs), also known as G protein-coupled receptors, are popular targets of drug development, particularly 7TMR systems that are activated by peptide ligands. Although many pharmaceutical drugs have been discovered via conventional bulk analysis techniques the increasing availability of structural and evolutionary data are facilitating change to rational, targeted drug design. This article discusses the appeal of neuropeptide-7TMR systems as drug targets and provides an overview of concepts in the evolution of vertebrate genomes and gene families. Subsequently, methods that use evolutionary concepts and comparative analysis techniques to aid in gene discovery, gene function identification, and novel drug design are provided along with case study examples.

  16. Balancing intuition and rationality for improving innovation decision-making : The role of design consultancies

    NARCIS (Netherlands)

    Calabretta, G.; Gemser, G.; Wijnberg, N.M.; Hekkert, P.P.M.

    2013-01-01

    To contain risks and increase the profitability of innovation efforts, firms frequently engage in joint innovation activities with external sources of knowledge, like design consultancies. Innovation literature has given limited consideration to the strategic role that design consultancies can play

  17. Identification of novel Mycobacterium tuberculosis dihydrofolate reductase inhibitors through rational drug design

    Directory of Open Access Journals (Sweden)

    Mymoona Akhter

    2016-01-01

    Conclusion: Structure based drug design can be used as an effective tool for the design of new cheiocal entity. Number of novel agents have been identified as antitubercular agents whose mechanism of action needs to be ascertained.

  18. Rational design of reduced graphene oxide for superior performance of supercapacitor electrodes

    KAUST Repository

    Rasul, Shahid

    2016-10-24

    Strategies to synthesize reduced graphene oxide (rGO) abound but, in most studies, research teams select one particular oxidation-reduction method without providing a methodic reasoning for doing so. Herein, it is analyzed how diverse oxidation-reduction strategies commonly used can result in considerable performance differences of rGO for supercapacitor applications. Depending on the graphite oxidation method followed, the surface chemistry analysis of the products confirms that there is a marked disparity in the degree of oxidation and the nature of the oxygen functional groups present. Subsequent reduction of the oxidized graphite (using three different methods) showed that the maximum specific capacitance of rGOs produced from the classical Hummers\\' method was 128 F g−1 whereas an analogous material obtained from an improved Hummers\\' method reached ∼274 F g−1 (both via an hydrothermal reduction route). Besides showing that the improved oxidation method results in superior capacitance performance, explained by the higher number of structural defects allied to a surface chemistry where residual hydroxyl and epoxy functional groups predominate, this study highlights the need to rationalize the oxidation-reduction strategies followed when investigating applications of rGO materials.

  19. Rational design of temperature swing adsorption cycles for post-combustion CO2 capture

    NARCIS (Netherlands)

    Joss, Lisa; Gazzani, Matteo; Mazzotti, Marco

    2017-01-01

    The design of temperature swing adsorption (TSA) cycles aimed at recovering the heavy product at high purity is investigated by model-based design and applied to the capture of CO2 from flue gases. This model based design strategy and an extensive parametric analysis enables gaining an understanding

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

    Science.gov (United States)

    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

    2016-02-25

    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.

  1. Pre-Rationalized Parametric Designing of Roof Shells Formed by Repetitive Modules of Catalan Surfaces

    Directory of Open Access Journals (Sweden)

    Jolanta Dzwierzynska

    2018-04-01

    Full Text Available The aim of the study is to develop an original, methodical, and practical approach to the early stages of parametric design of roof shells formed by repetitive modules of Catalan surfaces. It is presented on the example of designing the roof shells compound of four concrete elements. The designing process proposed by us consists in linking geometric shaping of roofs’ models with their structural analysis and optimization. Contrary to other methods, which use optimization process in order to find free roof forms, we apply it in order to explore and improve design alternatives. It is realized with the application of designing tools working in Rhinoceros 3D software. The flexible scripts elaborated by us, in order to achieve roofs’ models of regular and symmetrical shapes, are converted into simulation models to perform structural analysis. It is mainly focused on how the roof shells perform dependently on their geometric characteristics. The simulation enables one to evaluate various roof shells’ shapes, as well as to select an optimal design solution. The proposed approach to the conceptual design process may drive the designing to achieve geometric and structural forms which not only follow the design intentions but also target better results.

  2. Rationalization of safety factors for breakwater design in hurricane-prone areas

    NARCIS (Netherlands)

    Tsimopoulou, V.; Kanning, W.; Verhagen, H.J.; Vrijling, J.K.

    2011-01-01

    This paper presents the development of a semi-probabilistic method for armour layer design of rubble mound breakwaters, which is based on the use of safety factors. The objective is to introduce an approach that is both attractive to designers and sufficiently reliable when a high degree of

  3. A Novel Rational Design Method for Laminated Composite Structures Exhibiting Complex Geometrically Nonlinear Buckling Behaviour

    DEFF Research Database (Denmark)

    Lindgaard, Esben; Lund, Erik

    2012-01-01

    This paper presents a novel FEM-based approach for fiber angle optimal design of laminated composite structures exhibiting complicated nonlinear buckling behavior, thus enabling design of lighter and more cost-effective structures. The approach accounts for the geometrically nonlinear behavior of...

  4. Final Report: Rational Design of Wide Band Gap Buffer Layers for High-Efficiency Thin-Film Photovoltaics

    Energy Technology Data Exchange (ETDEWEB)

    Lordi, Vincenzo [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2016-09-30

    The main objective of this project is to enable rational design of wide band gap buffer layer materials for CIGS thin-film PV by building understanding of the correlation of atomic-scale defects in the buffer layer and at the buffer/absorber interface with device electrical properties. Optimized wide band gap buffers are needed to reduce efficiency loss from parasitic absorption in the buffer. The approach uses first-principles materials simulations coupled with nanoscale analytical electron microscopy as well as device electrical characterization. Materials and devices are produced by an industrial partner in a manufacturing line to maximize relevance, with the goal of enabling R&D of new buffer layer compositions or deposition processes to push device efficiencies above 21%. Cadmium sulfide (CdS) is the reference material for analysis, as the prototypical high-performing buffer material.

  5. Rationally Designed Peptides and Peptidomimetics as Inhibitors of Amyloid-β (Aβ) Aggregation: Potential Therapeutics of Alzheimer's Disease.

    Science.gov (United States)

    Goyal, Deepti; Shuaib, Suniba; Mann, Sukhmani; Goyal, Bhupesh

    2017-02-13

    Alzheimer's disease (AD) is a progressive neurodegenerative disease with no clinically accepted treatment to cure or halt its progression. The worldwide effort to develop peptide-based inhibitors of amyloid-β (Aβ) aggregation can be considered an unplanned combinatorial experiment. An understanding of what has been done and achieved may advance our understanding of AD pathology and the discovery of effective therapeutic agents. We review here the history of such peptide-based inhibitors, including those based on the Aβ sequence and those not derived from that sequence, containing both natural and unnatural amino acid building blocks. Peptide-based aggregation inhibitors hold significant promise for future AD therapy owing to their high selectivity, effectiveness, low toxicity, good tolerance, low accumulation in tissues, high chemical and biological diversity, possibility of rational design, and highly developed methods for analyzing their mode of action, proteolytic stability (modified peptides), and blood-brain barrier (BBB) permeability.

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

    Science.gov (United States)

    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.

  7. Rationalization design on large equipment dismantling facility. The cell fire-extinguishing examination (3)

    International Nuclear Information System (INIS)

    Donomae, Yasushi; Matsumoto, Yoshihiro; Takita, Koji; Kikuchi, Yutaka; Katoh, Noriyoshi; Miyazaki, Hitoshi; Tanimoto, Ken-ichi

    2002-07-01

    In order to rationalize for Large Equipment Dismantling Facility (LEDF), the plan of removing vaporizer belong to Cell-fire-extinguishing-system was investigated. When a vaporizer is cut down, it is necessary to grasp a fire-extinguishing performance. The fire-extinguishing performance check examination by liquefaction carbon dioxide in the cell fire-extinguishing examination (I) was carried out in 1999 fiscal year. As the result, the good performance was obtained to polyethylene. But there was the deep-seated fire about a piece of wood. Then, the check items were carbon dioxide (CO2) concentration and CO2 concentration holding time for the deep-seated fire in the cell fire-extinguishing examination (III). The results were as follows; (1) By use of the combustion model in which a piece of wood and cotton were put is lit, temperature inside model, mass reduction, and combustion situation were examined. The model burned remarkably in 30∼60 min. The peak temperature rise to 680 degC (MAX), and attained smoldering after (ignition) 70 min. Moreover, in order to determine the generating conditions of a deep-seated fire, the situation of CO2 extinguishing after ignition by the time lag of 50∼90 min were examined. The model around ignition 50 minutes was the most difficult to extinguish, and it turned out that they are the conditions which were most suitable for the deep-seated fire examination model of an exam. (2) In order to decide on CO2 concentration and concentration holding time required for fire extinguishing of the deep-seated fire in LEDF, the fire-extinguishing performance was investigated by 40 ∼ 65% of CO2 concentration. Consequently, CO2 concentration required for deep-seated fire extinguishing was understood that 60% or more was required when safety was taken into consideration at 50% or more. Moreover, when it was 50% or more of CO2 concentration and the holding time of CO2 concentration was 180 minutes or more and 60% or more of CO2 concentration, it

  8. Reflections on architectural design education: The return of rationalism in the studio

    Directory of Open Access Journals (Sweden)

    Fathi Bashier

    2014-12-01

    The Department of Architecture and Urban Planning at the Ethiopian Institute of Technology EiT of Mekelle University (MU is currently developing a research program in which the development of and reflection on design methods is a key research area. Within this framework, the present study is intends to be an introductory effort to guide future empirical research. The present study aims to describe the design process of architects, and introduces theoretical and technical frameworks. The integrated design paradigm as a system of inquiry within the spatial relationship strategy is framed.

  9. Pragmatics & rationality.

    OpenAIRE

    Allott, N. E.

    2007-01-01

    This thesis is about the reconciliation of realistic views of rationality with inferential-intentional theories of communication. Grice (1957 1975) argued that working out what a speaker meant by an utterance is a matter of inferring the speaker's intentions on the presumption that she is acting rationally. This is abductive inference: inference to the best explanation for the utterance. Thus an utterance both rationalises and causes the interpretation the hearer constructs. Human rationality...

  10. THE CHOICE OF A RATIONAL STRUCTURAL DESIGN OF ELECTRODYNAMIC TRANSPORT SYSTEMS

    Directory of Open Access Journals (Sweden)

    M. O. Radchenko

    2009-03-01

    Full Text Available The design schemes of electrodynamic maglev systems with a plane track structure are developed and the results of investigation of levitating motion of such systems along rectilinear or curvilinear tracks are presented.

  11. Rational Design of Regulators of Programmed Cell Death in Human Breast Cancer

    National Research Council Canada - National Science Library

    Cowburn, David

    2000-01-01

    The purpose of this research is to develop a better understanding of the intricate pathways of cell death and their contributions to breast cancers, with the goal of designing potential therapeutic...

  12. Rational and Safe Design of Concrete Transportation Structures for Size Effect and Multi-Decade Sustainability

    Science.gov (United States)

    2012-10-01

    The overall goal of this project was to improve the safety and sustainability in the design of large : prestressed concrete bridges and other transportation structures. The safety of large concrete : structures, including bridges, has been insufficie...

  13. Targeting a heterologous protein to multiple plant organelles via rationally designed 5? mRNA tags

    NARCIS (Netherlands)

    Voges, M.J.; Silver, P.A.; Way, J.C.; Mattozzi, M.D.

    2013-01-01

    Background Plant bioengineers require simple genetic devices for predictable localization of heterologous proteins to multiple subcellular compartments. Results We designed novel hybrid signal sequences for multiple-compartment localization and characterize their function when fused to GFP in

  14. Rational designing of the internal water supply system in reconstructed residential buildings of mass standard series

    OpenAIRE

    Orlov Evgeny

    2018-01-01

    The issues of water supply system reconstruction in mass series buildings are reviewed with consideration of water- and resource saving. Principal points for location of plumbing cells in apartments, arrangement of water devices and wastewater receivers, selection of pipelines for reconstructed water line are described. Comparative analysis of design variants of inner water line before and following reconstruction are given. It was found that applying the developed system design approaches th...

  15. Biophysically inspired rational design of structured chimeric substrates for DNAzyme cascade engineering.

    Directory of Open Access Journals (Sweden)

    Matthew R Lakin

    Full Text Available The development of large-scale molecular computational networks is a promising approach to implementing logical decision making at the nanoscale, analogous to cellular signaling and regulatory cascades. DNA strands with catalytic activity (DNAzymes are one means of systematically constructing molecular computation networks with inherent signal amplification. Linking multiple DNAzymes into a computational circuit requires the design of substrate molecules that allow a signal to be passed from one DNAzyme to another through programmed biochemical interactions. In this paper, we chronicle an iterative design process guided by biophysical and kinetic constraints on the desired reaction pathways and use the resulting substrate design to implement heterogeneous DNAzyme signaling cascades. A key aspect of our design process is the use of secondary structure in the substrate molecule to sequester a downstream effector sequence prior to cleavage by an upstream DNAzyme. Our goal was to develop a concrete substrate molecule design to achieve efficient signal propagation with maximal activation and minimal leakage. We have previously employed the resulting design to develop high-performance DNAzyme-based signaling systems with applications in pathogen detection and autonomous theranostics.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  17. Advanced Energy Storage Devices: Basic Principles, Analytical Methods, and Rational Materials Design

    Science.gov (United States)

    Liu, Jilei; Wang, Jin; Xu, Chaohe; Li, Chunzhong; Lin, Jianyi

    2017-01-01

    Abstract Tremendous efforts have been dedicated into the development of high‐performance energy storage devices with nanoscale design and hybrid approaches. The boundary between the electrochemical capacitors and batteries becomes less distinctive. The same material may display capacitive or battery‐like behavior depending on the electrode design and the charge storage guest ions. Therefore, the underlying mechanisms and the electrochemical processes occurring upon charge storage may be confusing for researchers who are new to the field as well as some of the chemists and material scientists already in the field. This review provides fundamentals of the similarities and differences between electrochemical capacitors and batteries from kinetic and material point of view. Basic techniques and analysis methods to distinguish the capacitive and battery‐like behavior are discussed. Furthermore, guidelines for material selection, the state‐of‐the‐art materials, and the electrode design rules to advanced electrode are proposed. PMID:29375964

  18. Selection of rational technical solutions in designing a robotized assembly complex

    International Nuclear Information System (INIS)

    Petrov, B.M.; Rasulbekov, R.I.

    1984-01-01

    One of the methods permitting a more objective approach to decision making in design is the method of ordered search which, in combination with the methods of expert estimate was used in designing the robotized assembly-finishing complex for automobile tires. The assembly-finishing complex consists of a number of functionally independent parts, i.e., modules provided with manipulators and mutually connected by a transport system with intermediate storage. The modified method of ordered search, examined in the present work, was therefore used for each module separately, and not for the complex as a whole. We will examine the main principles of our approach to the selection of design solutions for the example of a module for laying on the bottom-cushion cords

  19. Two is better than one; toward a rational design of combinatorial therapy.

    Science.gov (United States)

    Chen, Sheng-Hong; Lahav, Galit

    2016-12-01

    Drug combination is an appealing strategy for combating the heterogeneity of tumors and evolution of drug resistance. However, the rationale underlying combinatorial therapy is often not well established due to lack of understandings of the specific pathways responding to the drugs, and their temporal dynamics following each treatment. Here we present several emerging trends in harnessing properties of biological systems for the optimal design of drug combinations, including the type of drugs, specific concentration, sequence of addition and the temporal schedule of treatments. We highlight recent studies showing different approaches for efficient design of drug combinations including single-cell signaling dynamics, adaption and pathway crosstalk. Finally, we discuss novel and feasible approaches that can facilitate the optimal design of combinatorial therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Theoretical Study on the Rational Design of Cyano-Substituted P3HT Materials for OSCs

    DEFF Research Database (Denmark)

    Qiu, Meng; Brandt, Rasmus Guldbæk; Niu, Yingli

    2015-01-01

    Calculations have been made regarding the strong electron-withdrawing cyano (-CN) group, which was introduced onto the backbone of poly(3-hexylthiophene) (P3HT), as an effective way to improve the parameters essential for the photovoltaic performance of organic solar cells (OSCs). The substitution...... useful information for better design strategy for OSCs....

  1. Rational design and dynamics of self-propelled colloidal bead chains: from rotators to flagella

    NARCIS (Netherlands)

    Vutukuri, Hanumantha Rao|info:eu-repo/dai/nl/304838926; Bet, Bram|info:eu-repo/dai/nl/370530667; van Roij, Rene|info:eu-repo/dai/nl/152978984; Dijkstra, Marjolein|info:eu-repo/dai/nl/123538807; Huck, Wilhelm T S

    2017-01-01

    The quest for designing new self-propelled colloids is fuelled by the demand for simple experimental models to study the collective behaviour of their more complex natural counterparts. Most synthetic self-propelled particles move by converting the input energy into translational motion. In this

  2. The rational design of a Au(I) precursor for focused electron beam induced deposition

    NARCIS (Netherlands)

    Marashdeh, Ali; Tiesma, Thiadrik; van Velzen, Niels J. C.; Harder, Sjoerd; Havenith, Remco W. A.; De Hosson, Jeff T. M.; van Dorp, Willem F.

    2017-01-01

    Au(I) complexes are studied as precursors for focused electron beam induced processing (FEBIP). FEBIP is an advanced direct-write technique for nanometer-scale chemical synthesis. The stability and volatility of the complexes are characterized to design an improved precursor for pure Au deposition.

  3. Evaluation and rational design of guide RNAs for efficient CRISPR/Cas9-mediated mutagenesis in Ciona.

    Science.gov (United States)

    Gandhi, Shashank; Haeussler, Maximilian; Razy-Krajka, Florian; Christiaen, Lionel; Stolfi, Alberto

    2017-05-01

    The CRISPR/Cas9 system has emerged as an important tool for various genome engineering applications. A current obstacle to high throughput applications of CRISPR/Cas9 is the imprecise prediction of highly active single guide RNAs (sgRNAs). We previously implemented the CRISPR/Cas9 system to induce tissue-specific mutations in the tunicate Ciona. In the present study, we designed and tested 83 single guide RNA (sgRNA) vectors targeting 23 genes expressed in the cardiopharyngeal progenitors and surrounding tissues of Ciona embryo. Using high-throughput sequencing of mutagenized alleles, we identified guide sequences that correlate with sgRNA mutagenesis activity and used this information for the rational design of all possible sgRNAs targeting the Ciona transcriptome. We also describe a one-step cloning-free protocol for the assembly of sgRNA expression cassettes. These cassettes can be directly electroporated as unpurified PCR products into Ciona embryos for sgRNA expression in vivo, resulting in high frequency of CRISPR/Cas9-mediated mutagenesis in somatic cells of electroporated embryos. We found a strong correlation between the frequency of an Ebf loss-of-function phenotype and the mutagenesis efficacies of individual Ebf-targeting sgRNAs tested using this method. We anticipate that our approach can be scaled up to systematically design and deliver highly efficient sgRNAs for the tissue-specific investigation of gene functions in Ciona. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Rational Design of in Vivo Tau Tangle-Selective Near-Infrared Fluorophores: Expanding the BODIPY Universe.

    Science.gov (United States)

    Verwilst, Peter; Kim, Hye-Ri; Seo, Jinho; Sohn, Nak-Won; Cha, Seung-Yun; Kim, Yeongmin; Maeng, Sungho; Shin, Jung-Won; Kwak, Jong Hwan; Kang, Chulhun; Kim, Jong Seung

    2017-09-27

    The elucidation of the cause of Alzheimer's disease remains one of the greatest questions in neurodegenerative research. The lack of highly reliable low-cost sensors to study the structural changes in key proteins during the progression of the disease is a contributing factor to this lack of insight. In the current work, we describe the rational design and synthesis of two fluorescent BODIPY-based probes, named Tau 1 and Tau 2. The probes were evaluated on the molecular surface formed by a fibril of the PHF6 ( 306 VQIVYK 311 ) tau fragment using molecular docking studies to provide a potential molecular model to rationalize the selectivity of the new probes as compared to a homologous Aβ-selective probe. The probes were synthesized in a few steps from commercially available starting products and could thus prove to be highly cost-effective. We demonstrated the excellent photophysical properties of the dyes, such as a large Stokes shift and emission in the near-infrared window of the electromagnetic spectrum. The probes demonstrated a high selectivity for self-assembled microtubule-associated protein tau (Tau protein), in both solution and cell-based experiments. Moreover, the administration to an acute murine model of tauopathy clearly revealed the staining of self-assembled hyperphosphorylated tau protein in pathologically relevant hippocampal brain regions. Tau 1 demonstrated efficient blood-brain barrier penetrability and demonstrated a clear selectivity for tau tangles over Aβ plaques, as well as the capacity for in vivo imaging in a transgenic mouse model. The current work could open up avenues for the cost-effective monitoring of the tau protein aggregation state in animal models as well as tissue staining. Furthermore, these fluorophores could serve as the basis for the development of clinically relevant sensors, for example based on PET imaging.

  5. Rational Design of Mixed-Metal Oxides for Chemical Looping Combustion of Coal via Coupled Computational-Experimental Studies

    Energy Technology Data Exchange (ETDEWEB)

    Mishra, Amit [North Carolina State Univ., Raleigh, NC (United States); Li, Fanxing [North Carolina State Univ., Raleigh, NC (United States); Santiso, Erik [North Carolina State Univ., Raleigh, NC (United States)

    2017-09-18

    Energy and global climate change are two grand challenges to the modern society. An urgent need exists for development of clean and efficient energy conversion processes. The chemical looping strategy, which utilizes regenerable oxygen carriers (OCs) to indirectly convert carbonaceous fuels via redox reactions, is considered to be one of the more promising approaches for CO2 capture by the U.S. Department of Energy (USDOE). To date, most long-term chemical looping operations were conducted using gaseous fuels, even though direct conversion of coal is more desirable from both economics and CO2 capture viewpoints. The main challenges for direct coal conversion reside in the stringent requirements on oxygen carrier performances. In addition, coal char and volatile compounds are more challenging to convert than gaseous fuels. A promising approach for direct conversion of coal is the so called chemical looping with oxygen uncoupling (CLOU) technique. In the CLOU process, a metal oxide that decomposes at the looping temperature, and releases oxygen to the gas phase is used as the OC. The overarching objective of this project was to discover the fundamental principles for rational design and optimization of oxygen carriers (OC) in coal chemical looping combustion (CLC) processes. It directly addresses Topic Area B of the funding opportunity announcement (FOA) in terms of “predictive description of the phase behavior and mechanical properties” of “mixed metal oxide” based OCs and rational development of new OC materials with superior functionality. This was achieved through studies exploring i) iron-containing mixed-oxide composites as oxygen carriers for CLOU, ii) Ca1-xAxMnO3-δ (A = Sr and Ba) as oxygen carriers for CLOU, iii) CaMn1-xBxO3-δ (B=Al, V, Fe, Co, and Ni) as oxygen carrier for CLOU and iv) vacancy creation energy in Mn-containing perovskites as an indicator chemical looping with oxygen uncoupling.

  6. Standby Gasoline Rationing Plan

    Energy Technology Data Exchange (ETDEWEB)

    None

    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)

  7. One consideration about rational design of the multi tunnels in geological disposal facility

    International Nuclear Information System (INIS)

    Mizutani, Kazuhiko; Hiramoto, Masayuki; Morita, Atsushi

    2008-01-01

    In the geological disposal facility of the high-level radioactive waste, a group of galleries is designed in parallel at the depth of more than 300 m below surface. This is an unprecedented structure in the field of conventional engineering, and it is necessary to take this characteristic into consideration in the design of the galleries. In the geological disposal facility, as well as ensuring the dynamic stability of the gallery during construction and operational periods, it is necessary to dynamic characteristic of rock mass for long-term stability after the closure. In this study, analysis of the 'multi tunnels model' which represents the whole gallery group was performed and the results about load to act on a pillar. (author)

  8. Rational Design and Enhanced Biocompatibility of a Dry Adhesive Medical Skin Patch

    KAUST Repository

    Kwak, Moon Kyu

    2011-07-28

    A new type of medical skin patch is developed that contains high-density, mushroom-like micropillars. Such dry-adhesive micropillars are highly biocompatible, have minimized side effects, and provide reasonable normal adhesion strength. To arrive at optimal conditions for the dry adhesive skin patch, the proper design of various structural and material parameters of micropillars is investigated. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Fluorescence detection of natural RNA using rationally designed "clickable" oligonucleotide probes

    DEFF Research Database (Denmark)

    Okholm, Anders; Kjems, Jørgen; Astakhova, Kira

    2014-01-01

    Herein a reliable approach to the design of effective fluorescent probes for RNA detection is described. The fluorescence signalling of hybridization by internally positioned polyaromatic hydrocarbons and rhodamine dyes was achieved with a low fluorescence background signal, high fluorescence qua...... quantum yields at ambient and elevated temperature, high selectivity and signal specificity of the probes when binding to miR-7 and circRNA targets....

  10. Activation of Hsp90 Enzymatic Activity and Conformational Dynamics through Rationally Designed Allosteric Ligands.

    Science.gov (United States)

    Sattin, Sara; Tao, Jiahui; Vettoretti, Gerolamo; Moroni, Elisabetta; Pennati, Marzia; Lopergolo, Alessia; Morelli, Laura; Bugatti, Antonella; Zuehlke, Abbey; Moses, Mike; Prince, Thomas; Kijima, Toshiki; Beebe, Kristin; Rusnati, Marco; Neckers, Len; Zaffaroni, Nadia; Agard, David A; Bernardi, Anna; Colombo, Giorgio

    2015-09-21

    Hsp90 is a molecular chaperone of pivotal importance for multiple cell pathways. ATP-regulated internal dynamics are critical for its function and current pharmacological approaches block the chaperone with ATP-competitive inhibitors. Herein, a general approach to perturb Hsp90 through design of new allosteric ligands aimed at modulating its functional dynamics is proposed. Based on the characterization of a first set of 2-phenylbenzofurans showing stimulatory effects on Hsp90 ATPase and conformational dynamics, new ligands were developed that activate Hsp90 by targeting an allosteric site, located 65 Å from the active site. Specifically, analysis of protein responses to first-generation activators was exploited to guide the design of novel derivatives with improved ability to stimulate ATP hydrolysis. The molecules' effects on Hsp90 enzymatic, conformational, co-chaperone and client-binding properties were characterized through biochemical, biophysical and cellular approaches. These designed probes act as allosteric activators of the chaperone and affect the viability of cancer cell lines for which proper functioning of Hsp90 is necessary. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients

    Science.gov (United States)

    Wang, Conan K.; Northfield, Susan E.; Colless, Barbara; Chaousis, Stephanie; Hamernig, Ingrid; Lohman, Rink-Jan; Nielsen, Daniel S.; Schroeder, Christina I.; Liras, Spiros; Price, David A.; Fairlie, David P.; Craik, David J.

    2014-01-01

    Enhancing the oral bioavailability of peptide drug leads is a major challenge in drug design. As such, methods to address this challenge are highly sought after by the pharmaceutical industry. Here, we propose a strategy to identify appropriate amides for N-methylation using temperature coefficients measured by NMR to identify exposed amides in cyclic peptides. N-methylation effectively caps these amides, modifying the overall solvation properties of the peptides and making them more membrane permeable. The approach for identifying sites for N-methylation is a rapid alternative to the elucidation of 3D structures of peptide drug leads, which has been a commonly used structure-guided approach in the past. Five leucine-rich peptide scaffolds are reported with selectively designed N-methylated derivatives. In vitro membrane permeability was assessed by parallel artificial membrane permeability assay and Caco-2 assay. The most promising N-methylated peptide was then tested in vivo. Here we report a novel peptide (15), which displayed an oral bioavailability of 33% in a rat model, thus validating the design approach. We show that this approach can also be used to explain the notable increase in oral bioavailability of a somatostatin analog. PMID:25416591

  12. Assessing barriers to a rational chemoprevention trial design in young patients with familial adenomatous polyposis.

    Science.gov (United States)

    Wood, Joanna P; Howells, Lynne M; Brown, Karen; Thomas, Anne L

    2017-07-01

    Familial adenomatous polyposis coli (FAP) is an autosomal dominant condition caused by a germline mutation in the adenomatous polyposis coli gene. Colonic adenomas form and almost all patients will develop colorectal cancer if they are not managed at an early stage. The safest preventive strategy is surgical resection of the colon, most commonly performed in late teenage years. There is a paucity of trials investigating the use of primary chemoprevention to delay polyp formation in paediatric FAP. There are extensive preclinical and early clinical data demonstrating that curcumin may be a safe and effective chemotherapeutic agent in reducing the polyp burden in this disease. We ultimately proposed to design and conduct a clinical study to assess whether curcumin treatment delays the need for surgery and/or prevents cancer in young patients with FAP. Research into clinical trial protocols has demonstrated that assessing patients' perceptions at the initial stage leads to better outcomes. We therefore conducted a questionnaire study of patients and parents of children affected by FAP to gain information to aid the protocol design. Results demonstrated that there are some FAP patients for whom this study is relevant and desirable. Those with a personal history of curcumin use reported that it was well tolerated. However, the response rate was poor (25%), indicating that there are potential difficulties ensuring adequate recruitment to the proposed trial. This report draws on lessons learnt from prior trials and the findings from the questionnaire to outline the challenges faced in designing such a study.

  13. Advancements in rationally designed PGM-free fuel cell catalysts derived from metal–organic frameworks

    International Nuclear Information System (INIS)

    Barkholtz, Heather M.; Liu, Di-Jia

    2016-01-01

    Over the past several years, metal-organic framework (MOF)-derived platinum group metal free (PGM-free) electrocatalysts have gained considerable attention due to their high efficiency and low cost as potential replacement for platinum in catalyzing oxygen reduction reaction (ORR). In this review, we summarize the recent advancements in design, synthesis and characterization of MOF-derived ORR catalysts and their performances in acidic and alkaline media. As a result, we also discuss the key challenges such as durability and activity enhancement critical in moving forward this emerging electrocatalyst science.

  14. Rational Design of Alpha-Helical Antimicrobial Peptides: Do's and Don'ts

    DEFF Research Database (Denmark)

    Uggerhøj, Lars Erik; Poulsen, Tanja Juul; Munk, Jens Kristian

    2015-01-01

    Antimicrobial peptides (AMPs) are promising candidates for battling multiresistant bacteria. Despite extensive research, structure–activity relationships of AMPs are not fully understood, and there is a lack of structural data relating to AMPs in lipids. Here we present the NMR structure of anoplin...... (GLLKRIKTLL-NH2) in a micellar environment. A vast library of substitutions was designed and tested for antimicrobial and hemolytic activity, as well as for changes in structure and lipid interactions. This showed that improvement of antimicrobial activity without concomitant introduction of strong hemolytic...

  15. Towards Rational Design Method for Strengthening of Concrete Structures by External Bonding

    Directory of Open Access Journals (Sweden)

    Furuuchi H.

    2012-01-01

    Full Text Available Many infrastructures need to be repaired or strengthened due to various reasons, such as unexpected deterioration and changes in performance requirement. This paper presents the following recent achievements by the authors’ group on design method for flexural strengthening of concrete structures by external bonding; (i fracture characteristics of interface between substrate concrete and cementitious overlay, (ii crack spacing of flexural strengthened beams, which affects debonding strength, (iii strengths of intermediate crack (IC debonding and end peeling, (iv strength of concrete cover separation, and (v effectiveness of strengthening by external bonding. A unified approach for flexural strengthening by steel plate, fiber reinforced polymer lami¬nate and cementitious overlay, for both intermediate crack (IC debonding, including end peeling, and concrete cover separation is pre¬sented with consideration of crack spacing in the streng¬thened members. Appropriate interfacial rough¬¬¬ness to achieve efficient interface bond property is clari¬fied and the concept of effectiveness of strengthen¬ing is proposed for better strengthening design.

  16. Rational design and dynamics of self-propelled colloidal bead chains: from rotators to flagella.

    Science.gov (United States)

    Vutukuri, Hanumantha Rao; Bet, Bram; van Roij, René; Dijkstra, Marjolein; Huck, Wilhelm T S

    2017-12-01

    The quest for designing new self-propelled colloids is fuelled by the demand for simple experimental models to study the collective behaviour of their more complex natural counterparts. Most synthetic self-propelled particles move by converting the input energy into translational motion. In this work we address the question if simple self-propelled spheres can assemble into more complex structures that exhibit rotational motion, possibly coupled with translational motion as in flagella. We exploit a combination of induced dipolar interactions and a bonding step to create permanent linear bead chains, composed of self-propelled Janus spheres, with a well-controlled internal structure. Next, we study how flexibility between individual swimmers in a chain can affect its swimming behaviour. Permanent rigid chains showed only active rotational or spinning motion, whereas longer semi-flexible chains showed both translational and rotational motion resembling flagella like-motion, in the presence of the fuel. Moreover, we are able to reproduce our experimental results using numerical calculations with a minimal model, which includes full hydrodynamic interactions with the fluid. Our method is general and opens a new way to design novel self-propelled colloids with complex swimming behaviours, using different complex starting building blocks in combination with the flexibility between them.

  17. Rational computational design for the development of andrographolide molecularly imprinted polymer

    Science.gov (United States)

    Krishnan, Hemavathi; Islam, K. M. Shafiqul; Hamzah, Zainab; Ahmad, Mohd Noor

    2017-10-01

    Andrographolide is a popular medicinal compound derived from Andrographis Paniculata (AP). Molecularly Imprint Polymer (MIP) is a "Lock and Key" approach, where MIP is the lock and Andrographolide is the key which fits to the MIP lock by both physically and chemically. MIP will be used as selective extraction tool to enrich Andrographolide bioactive compound. Pre-polymerization step is crucial to design MIP. This work investigates molecular interactions and the Gibbs free binding energies on the development of MIP. The structure of Andrographolide (template) and functional monomers were drawn in HyperChem 8.0.10. A hybrid quantum chemical model was used with a few functional monomers. Possible conformations of template and functional monomer as 1:n (n < 4) were designed and simulated to geometrically optimize the complex to the lowest energy in gas phase. The Gibbs free binding energies of each conformation were calculated using semi-empirical PM3 simulation method. Results proved that functional monomers that contain carboxylic group shows higher binding energy compared to those with amine functional group. Itaconic acid (IA) chosen as the best functional monomer at optimum ratio (1:3) of template: monomer to prepare andrographolide MIP. This study demonstrates the importance of studying intermolecular interaction among template, functional monomer and template-monomer ratio in developing MIP.

  18. Band engineering and rational design of high-performance thermoelectric materials by first-principles

    Directory of Open Access Journals (Sweden)

    Lili Xi

    2016-06-01

    Full Text Available Understanding and manipulation of the band structure are important in designing high-performance thermoelectric (TE materials. Our recent work has involved the utilization of band structure in various topics of TE research, i.e., the band convergence, the conductive network, dimensionality reduction by quantum effects, and high throughput material screening. In non-cubic chalcopyrite compounds, we revealed the relations between structural factors and band degeneracy, and a simple unity-η rule was proposed for selecting high performance diamond-like TE materials. Based on the deep understanding of the electrical and thermal transport, we identified the conductive network in filled skutterudites with the “phonon glass-electron crystal” (PGEC paradigm, and extended this concept to caged-free Cu-based diamond-like compounds. By combining the band structure calculations and the Boltzmann transport theory, we conducted a high-throughput material screening in half-Heusler (HH systems, and several promising compositions with high power factors were proposed out of a large composition collection. At last, we introduced the Rashba spin-splitting effect into thermoelectrics, and its influence on the electrical transport properties was discussed. This review demonstrated the importance of the microscopic perspectives for the optimization and design of novel TE materials.

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

    Directory of Open Access Journals (Sweden)

    Schmidt-Pokrzywniak Andrea

    2004-08-01

    Full Text Available Abstract 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.

  20. Rational Design of a Hierarchical Tin Dendrite Electrode for Efficient Electrochemical Reduction of CO2.

    Science.gov (United States)

    Won, Da Hye; Choi, Chang Hyuck; Chung, Jaehoon; Chung, Min Wook; Kim, Eun-Hee; Woo, Seong Ihl

    2015-09-21

    Catalysis is a key technology for the synthesis of renewable fuels through electrochemical reduction of CO2 . However, successful CO2 reduction still suffers from the lack of affordable catalyst design and understanding the factors governing catalysis. Herein, we demonstrate that the CO2 conversion selectivity on Sn (or SnOx /Sn) electrodes is correlated to the native oxygen content at the subsurface. Electrochemical analyses show that the reduced Sn electrode with abundant oxygen species effectively stabilizes a CO2 (.-) intermediate rather than the clean Sn surface, and consequently results in enhanced formate production in the CO2 reduction. Based on this design strategy, a hierarchical Sn dendrite electrode with high oxygen content, consisting of a multi-branched conifer-like structure with an enlarged surface area, was synthesized. The electrode exhibits a superior formate production rate (228.6 μmol h(-1)  cm(-2) ) at -1.36 VRHE without any considerable catalytic degradation over 18 h of operation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Organic fluorescent dye-based nanomaterials: Advances in the rational design for imaging and sensing applications.

    Science.gov (United States)

    Svechkarev, Denis; Mohs, Aaron M

    2018-02-25

    Self-assembled fluorescent nanomaterials based on small-molecule organic dyes are gaining increasing popularity in imaging and sensing applications over the past decade. This is primarily due to their ability to combine spectral property tunability and biocompatibility of small molecule organic fluorophores with brightness, chemical, and colloidal stability of inorganic materials. Such a unique combination of features comes with rich versatility of dye-based nanomaterials: from aggregates of small molecules to sophisticated core-shell nanoarchitectures involving hyperbranched polymers. Along with the ongoing discovery of new materials and better ways of their synthesis, it is very important to continue systematic studies of fundamental factors that regulate the key properties of fluorescent nanomaterials: their size, polydispersity, colloidal stability, chemical stability, absorption and emission maxima, biocompatibility, and interactions with biological interfaces. In this review, we focus on the systematic description of various types of organic fluorescent nanomaterials, approaches to their synthesis, and ways to optimize and control their characteristics. The discussion is built on examples from reports on recent advances in design and applications of such materials. Conclusions made from this analysis allow a perspective on future development of fluorescent nanomaterials design for biomedical and related applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. Rational design and evaluation of HBsAg polymeric nanoparticles as antigen delivery carriers.

    Science.gov (United States)

    Dewangan, Hitesh Kumar; Pandey, Tarun; Maurya, Lakshmi; Singh, Sanjay

    2018-05-01

    The present work is focused on the development and evaluation of single dose sustained-release Hepatitis B surface antigen (HBsAg) loaded nanovaccine for Hepatitis B. The conventional treatment suffers from repeated administration and hence requires a booster dose. Therefore, polymeric nanovaccine of HBsAg was developed by double emulsion solvent evaporation technique, utilizing central composite design for formulation optimization. The effects of independent variables (like polymer amount, stabilizer concentration, aqueous/organic phase ratio and homogenizer speed) were also studied on critical quality attributes like particle size and entrapment efficiency. Nanovaccine was characterized in terms of physicochemical parameters, release, internalization and in vivo immunological evaluation in BALB/c mice after administration by different routes such as oral, sub-cutaneous, nasal and intramuscular. The designed nanovaccine demonstrated nanometric size with smooth surface, negative zeta potential, maximum entrapment, sustained release and better internalization in macrophage and MRC-5 cell line. The immune-stimulating activity of nanovaccine administered by different routes was evaluated by measuring anti-HBsAg titre like specific immunoglobulin IgG and IgA response and cytokine level (interleukin-2, interferon-Y) measurement. The results indicated that the nanovaccine administered by intramuscular route produced better humoral as well as cellular responses and potential carriers for antigen delivery at single dose administration via intramuscular route. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Rational Design of Cyclic Antimicrobial Peptides Based on BPC194 and BPC198

    Directory of Open Access Journals (Sweden)

    Anna D. Cirac

    2017-06-01

    Full Text Available A strategy for the design of antimicrobial cyclic peptides derived from the lead compounds c(KKLKKFKKLQ (BPC194 and c(KLKKKFKKLQ (BPC198 is reported. First, the secondary β-structure of BPC194 and BPC198 was analyzed by carrying out molecular dynamics (MD simulations. Then, based on the sequence pattern and the β-structure of BPC194 or BPC198, fifteen analogues were designed and synthesized on solid-phase. The best peptides (BPC490, BPC918, and BPC924 showed minimum inhibitory concentration (MIC values <6.2 μM against Pseudomonas syringae pv. syringae and Xanthomonas axonopodis pv. vesicatoria, and an MIC value of 12.5 to 25 μM against Erwinia amylovora, being as active as BPC194 and BPC198. Interestingly, these three analogues followed the structural pattern defined from the MD simulations of the parent peptides. Thus, BPC490 maintained the parallel alignment of the hydrophilic pairs K1–K8, K2–K7, and K4–K5, whereas BPC918 and BPC924 included the two hydrophilic interactions K3–Q10 and K5–K8. In short, MD simulations have proved to be very useful for ascertaining the structural features of cyclic peptides that are crucial for their biological activity. Such approaches could be further employed for the development of new antibacterial cyclic peptides.

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

    Science.gov (United States)

    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 (ΔGbind, 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 ΔGbind, expt (calculated from the Kd value) are consistent with the predicted value of ΔGbind, pred calculated based on LIE-SGB. Based on these results, one of the derivative 5e of this series was used for further toxicological

  5. The rational design of a peptide-based hydrogel responsive to H2S.

    Science.gov (United States)

    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.

  6. Rational Design of Glycomimetic Compounds Targeting the Saccharomyces cerevisiae Transglycosylase Gas2.

    Science.gov (United States)

    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. © 2015 John Wiley & Sons A/S.

  7. Multilevel Molecular Modeling Approach for a Rational Design of Ionic Current Sensors for Nanofluidics.

    Science.gov (United States)

    Kirch, Alexsandro; de Almeida, James M; Miranda, Caetano R

    2018-05-10

    The complexity displayed by nanofluidic-based systems involves electronic and dynamic aspects occurring across different size and time scales. To properly model such kind of system, we introduced a top-down multilevel approach, combining molecular dynamics simulations (MD) with first-principles electronic transport calculations. The potential of this technique was demonstrated by investigating how the water and ionic flow through a (6,6) carbon nanotube (CNT) influences its electronic transport properties. We showed that the confinement on the CNT favors the partially hydrated Na, Cl, and Li ions to exchange charge with the nanotube. This leads to a change in the electronic transmittance, allowing for the distinguishing of cations from anions. Such an ionic trace may handle an indirect measurement of the ionic current that is recorded as a sensing output. With this case study, we are able to show the potential of this top-down multilevel approach, to be applied on the design of novel nanofluidic devices.

  8. Glutamic acid and its derivatives: candidates for rational design of anticancer drugs.

    Science.gov (United States)

    Ali, Imran; Wani, Waseem A; Haque, Ashanul; Saleem, Kishwar

    2013-05-01

    Throughout the history of human civilizations, cancer has been a major health problem. Its treatment has been interesting but challenging to scientists. Glutamic acid and its derivative glutamine are known to play interesting roles in cancer genesis, hence, it was realized that structurally variant glutamic acid derivatives may be designed and developed and, might be having antagonistic effects on cancer. The present article describes the state-of-art of glutamic acid and its derivatives as anticancer agents. Attempts have been made to explore the effectivity of drug-delivery systems based on glutamic acid for the delivery of anticancer drugs. Moreover, efforts have also been made to discuss the mechanism of action of glutamic acid derivatives as anticancer agents, clinical applications of glutamic acid derivatives, as well as recent developments and future perspectives of glutamic acid drug development have also been discussed.

  9. Towards Rational Design of Functional Fluoride and Oxyfluoride Materials from First Principles

    Science.gov (United States)

    Charles, Nenian

    Complex transition metal compounds (TMCs) research has produced functional materials with a range of properties, including ferroelectricity, colossal magnetoresistance, nonlinear optical activity and high-temperature superconductivity. Conventional routes to tune properties in transition metal oxides, for example, have relied primarily on cation chemical substitution and interfacial effects in thin film heterostructures. In heteroanionic TMCs, exhibiting two chemically distinct anions coordinating the same or different cations, engineering of the anion sub-lattice for property control is a promising alternative approach. The presence of multiple anions provides additional design variables, such as anion order, that are absent in homoanionic counterparts. The more complex structural and chemical phase space of heteroanionic materials provides a unique opportunity to realize enhanced or unanticipated electronic, optical, and magnetic responses. Although there is growing interest in heteroanionic materials, and synthetic and characterization advances are occurring for these materials, the crystal-chemistry principles for realizing structural and property control are only slowing emerging. This dissertation employs anion engineering to investigate phenomena in transition metal fluorides and oxyfluorides compounds using first principles density functional theory calculations. Oxyfluorides are particularly intriguing owing their tendency to stabilize highly ordered anion sublattices as well as the potential to combine the advantageous properties of transition metal oxides and fluorides. This work 1) addresses the challenges of studying fluorides and oxyfluorides using first principles calculations; 2) evaluates the feasibility of using external stimuli, such as epitaxial strain and hydrostatic pressure, to control properties of fluorides and oxyfluorides; and 3) formulates a computational workflow based on multiple levels of theory and computation to elucidate structure

  10. Rational design of a fibroblast growth factor 21-based clinical candidate, LY2405319.

    Directory of Open Access Journals (Sweden)

    Alexei Kharitonenkov

    Full Text Available Fibroblast growth factor 21 is a novel hormonal regulator with the potential to treat a broad variety of metabolic abnormalities, such as type 2 diabetes, obesity, hepatic steatosis, and cardiovascular disease. Human recombinant wild type FGF21 (FGF21 has been shown to ameliorate metabolic disorders in rodents and non-human primates. However, development of FGF21 as a drug is challenging and requires re-engineering of its amino acid sequence to improve protein expression and formulation stability. Here we report the design and characterization of a novel FGF21 variant, LY2405319. To enable the development of a potential drug product with a once-daily dosing profile, in a preserved, multi-use formulation, an additional disulfide bond was introduced in FGF21 through Leu118Cys and Ala134Cys mutations. FGF21 was further optimized by deleting the four N-terminal amino acids, His-Pro-Ile-Pro (HPIP, which was subject to proteolytic cleavage. In addition, to eliminate an O-linked glycosylation site in yeast a Ser167Ala mutation was introduced, thus allowing large-scale, homogenous protein production in Pichia pastoris. Altogether re-engineering of FGF21 led to significant improvements in its biopharmaceutical properties. The impact of these changes was assessed in a panel of in vitro and in vivo assays, which confirmed that biological properties of LY2405319 were essentially identical to FGF21. Specifically, subcutaneous administration of LY2405319 in ob/ob and diet-induced obese (DIO mice over 7-14 days resulted in a 25-50% lowering of plasma glucose coupled with a 10-30% reduction in body weight. Thus, LY2405319 exhibited all the biopharmaceutical and biological properties required for initiation of a clinical program designed to test the hypothesis that administration of exogenous FGF21 would result in effects on disease-related metabolic parameters in humans.

  11. Rational Catalyst Design of Titanium-Silica Materials Aided by Site-Specific Titration Tools

    Science.gov (United States)

    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.

  12. High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance.

    Directory of Open Access Journals (Sweden)

    Morgan A Wambaugh

    2017-06-01

    Full Text Available Antibiotic-resistant infections kill approximately 23,000 people and cost $20,000,000,000 each year in the United States alone despite the widespread use of small-molecule antimicrobial combination therapy. Antibiotic combinations typically have an additive effect: the efficacy of the combination matches the sum of the efficacies of each antibiotic when used alone. Small molecules can also act synergistically when the efficacy of the combination is greater than the additive efficacy. However, synergistic combinations are rare and have been historically difficult to identify. High-throughput identification of synergistic pairs is limited by the scale of potential combinations: a modest collection of 1,000 small molecules involves 1 million pairwise combinations. Here, we describe a high-throughput method for rapid identification of synergistic small-molecule pairs, the overlap2 method (O2M. O2M extracts patterns from chemical-genetic datasets, which are created when a collection of mutants is grown in the presence of hundreds of different small molecules, producing a precise set of phenotypes induced by each small molecule across the mutant set. The identification of mutants that show the same phenotype when treated with known synergistic molecules allows us to pinpoint additional molecule combinations that also act synergistically. As a proof of concept, we focus on combinations with the antibiotics trimethoprim and sulfamethizole, which had been standard treatment against urinary tract infections until widespread resistance decreased efficacy. Using O2M, we screened a library of 2,000 small molecules and identified several that synergize with the antibiotic trimethoprim and/or sulfamethizole. The most potent of these synergistic interactions is with the antiviral drug azidothymidine (AZT. We then demonstrate that understanding the molecular mechanism underlying small-molecule synergistic interactions allows the rational design of additional

  13. High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance.

    Science.gov (United States)

    Wambaugh, Morgan A; Shakya, Viplendra P S; Lewis, Adam J; Mulvey, Matthew A; Brown, Jessica C S

    2017-06-01

    Antibiotic-resistant infections kill approximately 23,000 people and cost $20,000,000,000 each year in the United States alone despite the widespread use of small-molecule antimicrobial combination therapy. Antibiotic combinations typically have an additive effect: the efficacy of the combination matches the sum of the efficacies of each antibiotic when used alone. Small molecules can also act synergistically when the efficacy of the combination is greater than the additive efficacy. However, synergistic combinations are rare and have been historically difficult to identify. High-throughput identification of synergistic pairs is limited by the scale of potential combinations: a modest collection of 1,000 small molecules involves 1 million pairwise combinations. Here, we describe a high-throughput method for rapid identification of synergistic small-molecule pairs, the overlap2 method (O2M). O2M extracts patterns from chemical-genetic datasets, which are created when a collection of mutants is grown in the presence of hundreds of different small molecules, producing a precise set of phenotypes induced by each small molecule across the mutant set. The identification of mutants that show the same phenotype when treated with known synergistic molecules allows us to pinpoint additional molecule combinations that also act synergistically. As a proof of concept, we focus on combinations with the antibiotics trimethoprim and sulfamethizole, which had been standard treatment against urinary tract infections until widespread resistance decreased efficacy. Using O2M, we screened a library of 2,000 small molecules and identified several that synergize with the antibiotic trimethoprim and/or sulfamethizole. The most potent of these synergistic interactions is with the antiviral drug azidothymidine (AZT). We then demonstrate that understanding the molecular mechanism underlying small-molecule synergistic interactions allows the rational design of additional combinations that

  14. A Rational Electrode-Electrolyte Design for Efficient Ammonia Electrosynthesis under Ambient Conditions

    KAUST Repository

    Suryanto, Bryan Harry Rahmat

    2018-04-25

    Renewable energy driven ammonia electrosynthesis by N2 reduction reaction (NRR) at ambient conditions is vital for the sustainability of the global population and energy demand. However, NRR under ambient conditions to date has been plagued with low yield rate and selectivity (<10%) due to the more favourable hydrogen evolution reaction (HER) in aqueous media. Herein, surface area enhanced α-Fe nanorods grown on carbon fibre paper was used as a NRR cathode in an aprotic fluorinated solvent – ionic liquid mixture. Through this design, a significantly enhanced NRR activity with NH3 yield rate of ~2.35 × 10-11 mol s-1 cmGSA-2, (3.71 × 10-13 mol s-1 cmECSA-2) and selectivity of ~32% has been achieved under ambient conditions. This study reveals that the use of hydrophobic fluorinated aprotic electrolyte effectively limits the availability of protons and thus suppresses the competing HER. Therefore, electrode-electrolyte engineering is essential in advancing the NH3 electrosynthesis technology.

  15. Rational design of dendrimer/lipid nanoassemblies in drug delivery for cancer chemotherapy

    Science.gov (United States)

    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.

  16. Rational Design and Nanoscale Integration of Multi-Heterostructures as Highly Efficient Photocatalysts

    Energy Technology Data Exchange (ETDEWEB)

    Duan, Xiangfeng [Univ. of California, Los Angeles, CA (United States)

    2017-11-03

    The central goal of this project is to design and synthesize complex multi-hetero-nanostructures and fundamental investigation of their potential as efficient and robust photocatalysts. Specifically, the project aims to develop a nanoscale light-harvesting antenna that can efficiently convert solar photon energy into excited electrons and holes, and integrate such antenna with efficient redox nanocatalysts that can harness the photo-generated carriers for productive electrochemical processes. Focusing on this central goal, we have investigated several potential light-harvesting antennas including: silicon nanowires, nitrogen-doped TiO2 nanowires and the emerging perovskite materials. We also devoted considerable effort in developing electrocatalysts including: hydrogen evolution reaction (HER) catalysts, oxygen evolution reaction (OER) catalysts and oxygen reduction reaction catalysts (ORR). In previous annual reports, we have described our effort in the synthesis and photoelectrochemical properties of silicon, TiO2, perovskite-based materials and heterostructures. Here, we focus our discussion on the recent effort in investigating charge transport dynamics in organolead halide perovskites, as well as carbon nanostructure and platinum nanostructure-based electrocatalysts for energy conversion and storage.

  17. A rational design approach to nanostructured catalysts for the oxidation of carbon monoxide

    Science.gov (United States)

    Karwacki, Christopher

    . 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 and surface chemistries, can enhance or stabilize the catalytic activity of neighboring Au NP. Gold dispersed on active carbon and hybrid structures consisting of Au/ZrO 2/C shows interesting properties, which lend themselves to catalytic particle stabilization and to the advancement of multifunctional

  18. A Rational Engineering Strategy for Designing Protein A-Binding Camelid Single-Domain Antibodies

    Science.gov (United States)

    Henry, Kevin A.; Sulea, Traian; van Faassen, Henk; Hussack, Greg; Purisima, Enrico O.; MacKenzie, C. Roger; Arbabi-Ghahroudi, Mehdi

    2016-01-01

    Staphylococcal protein A (SpA) and streptococcal protein G (SpG) affinity chromatography are the gold standards for purifying monoclonal antibodies (mAbs) in therapeutic applications. However, camelid VHH single-domain Abs (sdAbs or VHHs) are not bound by SpG and only sporadically bound by SpA. Currently, VHHs require affinity tag-based purification, which limits their therapeutic potential and adds considerable complexity and cost to their production. Here we describe a simple and rapid mutagenesis-based approach designed to confer SpA binding upon a priori non-SpA-binding VHHs. We show that SpA binding of VHHs is determined primarily by the same set of residues as in human mAbs, albeit with an unexpected degree of tolerance to substitutions at certain core and non-core positions and some limited dependence on at least one residue outside the SpA interface, and that SpA binding could be successfully introduced into five VHHs against three different targets with no adverse effects on expression yield or antigen binding. Next-generation sequencing of llama, alpaca and dromedary VHH repertoires suggested that species differences in SpA binding may result from frequency variation in specific deleterious polymorphisms, especially Ile57. Thus, the SpA binding phenotype of camelid VHHs can be easily modulated to take advantage of tag-less purification techniques, although the frequency with which this is required may depend on the source species. PMID:27631624

  19. Rationally designed turn promoting mutation in the amyloid-β peptide sequence stabilizes oligomers in solution.

    Directory of Open Access Journals (Sweden)

    Jayakumar Rajadas

    Full Text Available Enhanced production of a 42-residue beta amyloid peptide (Aβ(42 in affected parts of the brain has been suggested to be the main causative factor for the development of Alzheimer's Disease (AD. The severity of the disease depends not only on the amount of the peptide but also its conformational transition leading to the formation of oligomeric amyloid-derived diffusible ligands (ADDLs in the brain of AD patients. Despite being significant to the understanding of AD mechanism, no atomic-resolution structures are available for these species due to the evanescent nature of ADDLs that hinders most structural biophysical investigations. Based on our molecular modeling and computational studies, we have designed Met35Nle and G37p mutations in the Aβ(42 peptide (Aβ(42Nle35p37 that appear to organize Aβ(42 into stable oligomers. 2D NMR on the Aβ(42Nle35p37 peptide revealed the occurrence of two β-turns in the V24-N27 and V36-V39 stretches that could be the possible cause for the oligomer stability. We did not observe corresponding NOEs for the V24-N27 turn in the Aβ(21-43Nle35p37 fragment suggesting the need for the longer length amyloid peptide to form the stable oligomer promoting conformation. Because of the presence of two turns in the mutant peptide which were absent in solid state NMR structures for the fibrils, we propose, fibril formation might be hindered. The biophysical information obtained in this work could aid in the development of structural models for toxic oligomer formation that could facilitate the development of therapeutic approaches to AD.

  20. Rational design of organic semiconductors for texture control and self-patterning on halogenated surfaces

    KAUST Repository

    Ward, Jeremy W.

    2014-05-15

    Understanding the interactions at interfaces between the materials constituting consecutive layers within organic thin-film transistors (OTFTs) is vital for optimizing charge injection and transport, tuning thin-film microstructure, and designing new materials. Here, the influence of the interactions at the interface between a halogenated organic semiconductor (OSC) thin film and a halogenated self-assembled monolayer on the formation of the crystalline texture directly affecting the performance of OTFTs is explored. By correlating the results from microbeam grazing incidence wide angle X-ray scattering (μGIWAXS) measurements of structure and texture with OTFT characteristics, two or more interaction paths between the terminating atoms of the semiconductor and the halogenated surface are found to be vital to templating a highly ordered morphology in the first layer. These interactions are effective when the separating distance is lower than 2.5 dw, where dw represents the van der Waals distance. The ability to modulate charge carrier transport by several orders of magnitude by promoting "edge-on" versus "face-on" molecular orientation and crystallographic textures in OSCs is demonstrated. It is found that the "edge-on" self-assembly of molecules forms uniform, (001) lamellar-textured crystallites which promote high charge carrier mobility, and that charge transport suffers as the fraction of the "face-on" oriented crystallites increases. The role of interfacial halogenation in mediating texture formation and the self-patterning of organic semiconductor films, as well as the resulting effects on charge transport in organic thin-film transistors, are explored. The presence of two or more anchoring sites between a halogenated semiconductor and a halogenated self-assembled monolayer, closer than about twice the corresponding van der Waals distance, alter the microstructure and improve electrical properties. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Rational Design of Iron Oxide Nanoparticles as Targeted Nanomedicines for Cancer Therapy

    Science.gov (United States)

    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. Baseline rationing

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Moreno-Ternero, Juan D.; Østerdal, Lars Peter Raahave

    The standard problem of adjudicating conflicting claims describes a situation in which a given amount of a divisible good has to be allocated among agents who hold claims against it exceeding the available amount. This paper considers more general rationing problems in which, in addition to claims...... to international protocols for the reduction of greenhouse emissions, or water distribution in drought periods. We define a family of allocation methods for such general rationing problems - called baseline rationing rules - and provide an axiomatic characterization for it. Any baseline rationing rule within...... the family is associated with a standard rule and we show that if the latter obeys some properties reflecting principles of impartiality, priority and solidarity, the former obeys them too....

  3. Adolescent rationality.

    Science.gov (United States)

    Moshman, David

    2013-01-01

    Adolescents are commonly seen as irrational, a position supported to varying degrees by many developmentalists, who often appeal to recent research on adolescent brains. Careful review of relevant evidence, however, shows that (1) adults are less rational than is generally assumed, (2) adolescents (and adults) are categorically different from children with respect to the attainment of advanced levels of rationality and psychological functioning, and (3) adolescents and adults do not differ categorically from each other with respect to any rational competencies, irrational tendencies, brain structures, or neurological functioning. Development often continues in adolescence and beyond but categorical claims about adolescents as distinct from adults cannot be justified. A review of U.S. Supreme Court decisions concerning intellectual freedom, reproductive freedom, and criminal responsibility shows ongoing ambivalence and confusion about the rationality of adolescents. Developmental theory and research suggest that adolescents should be conceptualized as young adults, not immature brains, with important implications for their roles, rights, and responsibilities.

  4. The dementia and disability project in Thai elderly: rational, design, methodology and early results

    Directory of Open Access Journals (Sweden)

    Senanarong Vorapun

    2013-01-01

    .5% of 1964 subjects were free of chronic diseases. Treatment gap (indicating those who have untreated or inadequate treatment of diabetes mellitus and hypertension in Thai elders in this study was 37% and 55.5% respectively. 62.6% of Thai elders have ApoE3E3 allele. Prevalence of positive ApoE4 gene in this study is 22.85%. 38.6% of Thai elders who had MRI brain study have moderate to severe white matter lesions. Conclusion The large and comprehensive set of measurements in DDP allows a wide-ranging explanation of the functional and clinical features to be investigated in relation to white matter lesions or cortical atrophy of the brain in Thai elderly population. An almost 2 year follow up was made available to those with MCI and dementia and some of the cognitively normal elderly. The longitudinal design will provide great understanding of the possible contributors to disability in the elderly and to the progression of cognitive decline in Thai elders.

  5. The Dementia and Disability Project in Thai Elderly: rational, design, methodology and early results.

    Science.gov (United States)

    Senanarong, Vorapun; Harnphadungkit, Kamolthip; Poungvarin, Niphon; Vannasaeng, Sathit; Chongwisal, Samut; Chakorn, Tipa; Jamjumrus, Piyanuch; Raksthaput, Atthapon; Chaichanettee, Sinisa; Aoonkaew, Nattapol; Udompunthurak, Suthipol; Doody, Rachelle S; Cummings, Jeffrey L

    2013-01-10

    . Treatment gap (indicating those who have untreated or inadequate treatment) of diabetes mellitus and hypertension in Thai elders in this study was 37% and 55.5% respectively. 62.6% of Thai elders have ApoE3E3 allele. Prevalence of positive ApoE4 gene in this study is 22.85%. 38.6% of Thai elders who had MRI brain study have moderate to severe white matter lesions. The large and comprehensive set of measurements in DDP allows a wide-ranging explanation of the functional and clinical features to be investigated in relation to white matter lesions or cortical atrophy of the brain in Thai elderly population. An almost 2 year follow up was made available to those with MCI and dementia and some of the cognitively normal elderly. The longitudinal design will provide great understanding of the possible contributors to disability in the elderly and to the progression of cognitive decline in Thai elders.

  6. Embodying rationality

    OpenAIRE

    Mastrogiorgio, Antonio; Petracca, Enrico

    2016-01-01

    The current notions of bounded rationality in economics share distinctive features with Simon’s original notion, which still influences the theoretical and experimental research in the fields of choice, judgment, decision making, problem solving, and social cognition. All these notions of bounded rationality are in fact equally rooted in the information-processing approach to human cognition, expressing the view that reasoning is disembodied and that it can be reduced to the processing of abs...

  7. Ni And Co Segregations On Selective Surface Facets And Rational Design Of Layered Lithium Transition-metal Oxide Cathodes

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Pengfei; Zheng, Jianming; Zheng, Jiaxin; Wang, Zhiguo; Teng, Gaofeng; Kuppan, Saravanan; Xiao, Jie; Chen, Guoying; Zhang, Jiguang; Wang, Chong M.; Pan, Feng

    2016-05-05

    The chemical processes occurring on the surface of cathode materials during battery cycling play a crucial role in determining battery’s performance. However, our understanding on such surface chemistry is far from clear due to the complexity of redox chemistry during battery charge/discharge. In this work, through intensive aberration corrected STEM investigation on eight layered oxide cathode materials, we report two important findings on the pristine oxides. First, Ni and Co show strong plane selectivity when building up their respective surface segregation layers (SSL). Specifically, Ni-SSL is exclusively developed on (200)m facet in Li-Mn-rich oxides (monoclinic C2/m symmetry) and (012)h facet in Mn-Ni equally rich oxides (hexagonal R-3m symmetry), while Co-SSL has a strong preference to (20-2)m plane with minimal Co-SSL also developed on some other planes in LMR cathodes. Structurally, Ni-SSLs tend to form spinel-like lattice while Co-SSLs are in a rock-salt-like structure. Secondly, by increasing Ni concentration in these layered oxides, Ni and Co SSLs can be suppressed and even eliminated. Our findings indicate that Ni and Co SSLs are tunable through controlling particle morphology and oxide composition, which opens up a new way for future rational design and synthesis of cathode materials.

  8. Rational Design of Molecular Hole-Transporting Materials for Perovskite Solar Cells: Direct versus Inverted Device Configurations.

    Science.gov (United States)

    Grisorio, Roberto; Iacobellis, Rosabianca; Listorti, Andrea; De Marco, Luisa; Cipolla, Maria Pia; Manca, Michele; Rizzo, Aurora; Abate, Antonio; Gigli, Giuseppe; Suranna, Gian Paolo

    2017-07-26

    Due to a still limited understanding of the reasons making 2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (Spiro-OMeTAD) the state-of-the-art hole-transporting material (HTM) for emerging photovoltaic applications, the molecular tailoring of organic components for perovskite solar cells (PSCs) lacks in solid design criteria. Charge delocalization in radical cationic states can undoubtedly be considered as one of the essential prerequisites for an HTM, but this aspect has been investigated to a relatively minor extent. In marked contrast with the 3-D structure of Spiro-OMeTAD, truxene-based HTMs Trux1 and Trux2 have been employed for the first time in PSCs fabricated with a direct (n-i-p) or inverted (p-i-n) architecture, exhibiting a peculiar behavior with respect to the referential HTM. Notwithstanding the efficient hole extraction from the perovskite layer exhibited by Trux1 and Trux2 in direct configuration devices, their photovoltaic performances were detrimentally affected by their poor hole transport. Conversely, an outstanding improvement of the photovoltaic performances in dopant-free inverted configuration devices compared to Spiro-OMeTAD was recorded, ascribable to the use of thinner HTM layers. The rationalization of the photovoltaic performances exhibited by different configuration devices discussed in this paper can provide new and unexpected prospects for engineering the interface between the active layer of perovskite-based solar cells and the hole transporters.

  9. Rational Design of Zirconium-doped Titania Photocatalysts with Synergistic Brønsted Acidity and Photoactivity.

    Science.gov (United States)

    Ma, Runyuan; Wang, Liang; Zhang, Bingsen; Yi, Xianfeng; Zheng, Anmin; Deng, Feng; Yan, Xuhua; Pan, Shuxiang; Wei, Xiao; Wang, Kai-Xue; Su, Dang Sheng; Xiao, Feng-Shou

    2016-10-06

    The preparation of photocatalysts with high activities under visible-light illumination is challenging. We report the rational design and construction of a zirconium-doped anatase catalyst (S-Zr-TiO 2 ) with Brønsted acidity and photoactivity as an efficient catalyst for the degradation of phenol under visible light. Electron microscopy images demonstrate that the zirconium sites are uniformly distributed on the sub-10 nm anatase crystals. UV-visible spectrometry indicates that the S-Zr-TiO 2 is a visible-light-responsive catalyst with narrower band gap than conventional anatase. Pyridine-adsorption infrared and acetone-adsorption 13 C NMR spectra confirm the presence of Brønsted acidic sites on the S-Zr-TiO 2 sample. Interestingly, the S-Zr-TiO 2 catalyst exhibits high catalytic activity in the degradation of phenol under visible-light illumination, owing to a synergistic effect of the Brønsted acidity and photoactivity. Importantly, the S-Zr-TiO 2 shows good recyclability. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Towards Sustainable H2 Production: Rational Design of Hydrophobic Triphenylamine-based Dyes for Sensitized Ethanol Photoreforming.

    Science.gov (United States)

    Dessì, Alessio; Monai, Matteo; Bessi, Matteo; Montini, Tiziano; Calamante, Massimo; Mordini, Alessandro; Reginato, Gianna; Trono, Cosimo; Fornasiero, Paolo; Zani, Lorenzo

    2018-02-22

    Donor-acceptor dyes are a well-established class of photosensitizers, used to enhance visible-light harvesting in solar cells and in direct photocatalytic reactions, such as H 2 production by photoreforming of sacrificial electron donors (SEDs). Amines-typically triethanolamine (TEOA)-are commonly employed as SEDs in such reactions. Dye-sensitized photoreforming of more sustainable, biomass-derived alcohols, on the other hand, was only recently reported by using methanol as the electron donor. In this work, several rationally designed donor-acceptor dyes were used as sensitizers in H 2 photocatalytic production, comparing the efficiency of TEOA and EtOH as SEDs. In particular, the effect of hydrophobic chains in the spacer and/or the donor unit of the dyes was systematically studied. The H 2 production rates were higher when TEOA was used as SED, whereas the activity trends depended on the SED used. The best performance was obtained with TEOA by using a sensitizer with just one bulky hydrophobic moiety, propylenedioxythiophene, placed on the spacer unit. In the case of EtOH, the best-performing sensitizers were the ones featuring a thiazolo[5,4-d]thiazole internal unit, needed for enhancing light harvesting, and carrying alkyl chains on both the donor part and the spacer unit. The results are discussed in terms of reaction mechanism, interaction with the SED, and structural/electrochemical properties of the sensitizers. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Exploring G Protein-Coupled Receptors (GPCRs) Ligand Space via Cheminformatics Approaches: Impact on Rational Drug Design

    Science.gov (United States)

    Basith, Shaherin; Cui, Minghua; Macalino, Stephani J. Y.; Park, Jongmi; Clavio, Nina A. B.; Kang, Soosung; Choi, Sun

    2018-01-01

    The primary goal of rational drug discovery is the identification of selective ligands which act on single or multiple drug targets to achieve the desired clinical outcome through the exploration of total chemical space. To identify such desired compounds, computational approaches are necessary in predicting their drug-like properties. G Protein-Coupled Receptors (GPCRs) represent one of the largest and most important integral membrane protein families. These receptors serve as increasingly attractive drug targets due to their relevance in the treatment of various diseases, such as inflammatory disorders, metabolic imbalances, cardiac disorders, cancer, monogenic disorders, etc. In the last decade, multitudes of three-dimensional (3D) structures were solved for diverse GPCRs, thus referring to this period as the “golden age for GPCR structural biology.” Moreover, accumulation of data about the chemical properties of GPCR ligands has garnered much interest toward the exploration of GPCR chemical space. Due to the steady increase in the structural, ligand, and functional data of GPCRs, several cheminformatics approaches have been implemented in its drug discovery pipeline. In this review, we mainly focus on the cheminformatics-based paradigms in GPCR drug discovery. We provide a comprehensive view on the ligand– and structure-based cheminformatics approaches which are best illustrated via GPCR case studies. Furthermore, an appropriate combination of ligand-based knowledge with structure-based ones, i.e., integrated approach, which is emerging as a promising strategy for cheminformatics-based GPCR drug design is also discussed. PMID:29593527

  12. Rationally Designed, Multifunctional Self-Assembled Nanoparticles for Covalently Networked, Flexible and Self-Healable Superhydrophobic Composite Films.

    Science.gov (United States)

    Lee, Yujin; You, Eun-Ah; Ha, Young-Geun

    2018-03-21

    For constructing bioinspired functional films with various superhydrophobic functions, including self-cleaning, anticorrosion, antibioadhesion, and oil-water separation, hydrophobic nanomaterials have been widely used as crucial structural components. In general, hydrophobic nanomaterials, however, cannot form strong chemical bond networks in organic-inorganic hybrid composite films because of the absence of chemically compatible binding components. Herein, we report the rationally designed, multifunctional self-assembled nanoparticles with tunable functionalities of covalent cross-linking and hydrophobicity for constructing three-dimensionally interconnected superhydrophobic composite films via a facile solution-based fabrication at room temperature. The multifunctional self-assembled nanoparticles allow the systematic control of functionalities of composite films, as well as the stable formation of covalently linked superhydrophobic composite films with excellent flexibility (bending radii of 6.5 and 3.0 mm, 1000 cycles) and self-healing ability (water contact angle > 150°, ≥10 cycles). The presented strategy can be a versatile and effective route to generating other advanced functional films with covalently interconnected composite networks.

  13. Combined data preprocessing and multivariate statistical analysis characterizes fed-batch culture of mouse hybridoma cells for rational medium design.

    Science.gov (United States)

    Selvarasu, Suresh; Kim, Do Yun; Karimi, Iftekhar A; Lee, Dong-Yup

    2010-10-01

    We present an integrated framework for characterizing fed-batch cultures of mouse hybridoma cells producing monoclonal antibody (mAb). This framework systematically combines data preprocessing, elemental balancing and statistical analysis technique. Initially, specific rates of cell growth, glucose/amino acid consumptions and mAb/metabolite productions were calculated via curve fitting using logistic equations, with subsequent elemental balancing of the preprocessed data indicating the presence of experimental measurement errors. Multivariate statistical analysis was then employed to understand physiological characteristics of the cellular system. The results from principal component analysis (PCA) revealed three major clusters of amino acids with similar trends in their consumption profiles: (i) arginine, threonine and serine, (ii) glycine, tyrosine, phenylalanine, methionine, histidine and asparagine, and (iii) lysine, valine and isoleucine. Further analysis using partial least square (PLS) regression identified key amino acids which were positively or negatively correlated with the cell growth, mAb production and the generation of lactate and ammonia. Based on these results, the optimal concentrations of key amino acids in the feed medium can be inferred, potentially leading to an increase in cell viability and productivity, as well as a decrease in toxic waste production. The study demonstrated how the current methodological framework using multivariate statistical analysis techniques can serve as a potential tool for deriving rational medium design strategies. Copyright © 2010 Elsevier B.V. All rights reserved.

  14. Hydrogen initiative: An integrated approach toward rational nanocatalyst design for hydrogen production. Technical Report-Year 1

    Energy Technology Data Exchange (ETDEWEB)

    Vlachos, Dionisios G. [Univ. of Delaware, Newark, DE (United States); Buttrey, Douglas J. [Univ. of Delaware, Newark, DE (United States); Lauterbach, Jochen A. [Univ. of Delaware, Newark, DE (United States)

    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

  15. Rational design of anode materials based on Group IVA elements (Si, Ge, and Sn) for lithium-ion batteries.

    Science.gov (United States)

    Wu, Xing-Long; Guo, Yu-Guo; Wan, Li-Jun

    2013-09-01

    Lithium-ion batteries (LIBs) represent the state-of-the-art technology in rechargeable energy-storage devices and they currently occupy the prime position in the marketplace for powering an increasingly diverse range of applications. However, the fast development of these applications has led to increasing demands being placed on advanced LIBs in terms of higher energy/power densities and longer life cycles. For LIBs to meet these requirements, researchers have focused on active electrode materials, owing to their crucial roles in the electrochemical performance of batteries. For anode materials, compounds based on Group IVA (Si, Ge, and Sn) elements represent one of the directions in the development of high-capacity anodes. Although these compounds have many significant advantages when used as anode materials for LIBs, there are still some critical problems to be solved before they can meet the high requirements for practical applications. In this Focus Review, we summarize a series of rational designs for Group IVA-based anode materials, in terms of their chemical compositions and structures, that could address these problems, that is, huge volume variations during cycling, unstable surfaces/interfaces, and invalidation of transport pathways for electrons upon cycling. These designs should at least include one of the following structural benefits: 1) Contain a sufficient number of voids to accommodate the volume variations during cycling; 2) adopt a "plum-pudding"-like structure to limit the volume variations during cycling; 3) facilitate an efficient and permanent transport pathway for electrons and lithium ions; or 4) show stable surfaces/interfaces to stabilize the in situ formed SEI layers. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Rational design of Sn/SnO{sub 2}/porous carbon nanocomposites as anode materials for sodium-ion batteries

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaojia [Tianjin International Joint Research Centre of Surface Technology for Energy Storage Materials, College of Physics and Materials Science, Tianjin Normal University, Tianjin 300387 (China); Li, Xifei, E-mail: xfli2011@hotmail.com [Tianjin International Joint Research Centre of Surface Technology for Energy Storage Materials, College of Physics and Materials Science, Tianjin Normal University, Tianjin 300387 (China); Center for Advanced Energy Materials and Devices, Xi’an University of Technology, Xi’an 710048 (China); Key Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), Collaborative Innovation Center of Chemical Science and Engineering, College of Chemistry, Nankai University, Tianjin 300071 (China); Fan, Linlin; Yu, Zhuxin; Yan, Bo; Xiong, Dongbin; Song, Xiaosheng; Li, Shiyu [Tianjin International Joint Research Centre of Surface Technology for Energy Storage Materials, College of Physics and Materials Science, Tianjin Normal University, Tianjin 300387 (China); Adair, Keegan R. [Nanomaterials and Energy Lab., Department of Mechanical and Materials Engineering, Western University, London, Ontario N6A 5B9 (Canada); Li, Dejun, E-mail: dejunli@mail.tjnu.edu.cn [Tianjin International Joint Research Centre of Surface Technology for Energy Storage Materials, College of Physics and Materials Science, Tianjin Normal University, Tianjin 300387 (China); Sun, Xueliang, E-mail: xsun9@uwo.ca [Nanomaterials and Energy Lab., Department of Mechanical and Materials Engineering, Western University, London, Ontario N6A 5B9 (Canada); Tianjin International Joint Research Centre of Surface Technology for Energy Storage Materials, College of Physics and Materials Science, Tianjin Normal University, Tianjin 300387 (China)

    2017-08-01

    Highlights: • Sn/SnO{sub 2}/porous carbon nanocomposites are rationally designed via a facile strategy. • The porous carbon mitigates the volume change and poor conductivity of Sn/SnO{sub 2}. • The nanocomposites exhibit the enhanced sodium storage performance. - Abstract: Sodium-ion batteries (SIBs) have successfully attracted considerable attention for application in energy storage, and have been proposed as an alternative to lithium ion batteries (LIBs) due to the abundance of sodium resources and low price. Sn has been deemed as a promising anode material in SIBs which holds high theoretical specific capacity of 845 mAh g{sup −1}. In this work we design nanocomposite materials consisting of porous carbon (PC) with SnO{sub 2} and Sn (Sn/SnO{sub 2}/PC) via a facile reflux method. Served as an anode material for SIBs, the Sn/SnO{sub 2}/PC nanocomposite delivers the primary discharge and charge capacities of 1148.1 and 303.0 mAh g{sup −1}, respectively. Meanwhile, it can preserve the discharge capacity approximately of 265.4 mAh g{sup −1} after 50 cycles, which is much higher than those of SnO{sub 2}/PC (138.5 mAh g{sup −1}) and PC (92.2 mAh g{sup −1}). Furthermore, the Sn/SnO{sub 2}/PC nanocomposite possesses better cycling stability with 77.8% capacity retention compared to that of SnO{sub 2}/PC (61.88%) over 50 cycles. Obviously, the Sn/SnO{sub 2}/PC composite with excellent electrochemical performance shows the great possibility of application in SIBs.

  17. Rational Design, Synthesis and Pharmacological Evaluation of the (2R)- and (2S)-Stereoisomers of 3-(2-Carboxypyrrolidinyl)-2-methyl Acetic Acid as Ligands for the Ionotropic Glutamate Receptors

    DEFF Research Database (Denmark)

    Rasmussen, Julie; Storgaard, Morten; Pickering, Darryl S

    2011-01-01

    In this paper we describe the rational design, synthesis and pharmacological evaluation of two new stereoisomeric (S)-glutamate (Glu) analogues. The rational design was based on hybrid structures of the natural product kainic acid, a synthetic analogue CPAA and the high-affinity Glu analogue SYM...

  18. Supramolecular Architectures and Mimics of Complex Natural Folds Derived from Rationally Designed alpha-Helical Protein Structures

    Science.gov (United States)

    Tavenor, Nathan Albert

    Protein-based supramolecular polymers (SMPs) are a class of biomaterials which draw inspiration from and expand upon the many examples of complex protein quaternary structures observed in nature: collagen, microtubules, viral capsids, etc. Designing synthetic supramolecular protein scaffolds both increases our understanding of natural superstructures and allows for the creation of novel materials. Similar to small-molecule SMPs, protein-based SMPs form due to self-assembly driven by intermolecular interactions between monomers, and monomer structure determines the properties of the overall material. Using protein-based monomers takes advantage of the self-assembly and highly specific molecular recognition properties encodable in polypeptide sequences to rationally design SMP architectures. The central hypothesis underlying our work is that alpha-helical coiled coils, a well-studied protein quaternary folding motif, are well-suited to SMP design through the addition of synthetic linkers at solvent-exposed sites. Through small changes in the structures of the cross-links and/or peptide sequence, we have been able to control both the nanoscale organization and the macroscopic properties of the SMPs. Changes to the linker and hydrophobic core of the peptide can be used to control polymer rigidity, stability, and dimensionality. The gaps in knowledge that this thesis sought to fill on this project were 1) the relationship between the molecular structure of the cross-linked polypeptides and the macroscopic properties of the SMPs and 2) a means of creating materials exhibiting multi-dimensional net or framework topologies. Separate from the above efforts on supramolecular architectures was work on improving backbone modification strategies for an alpha-helix in the context of a complex protein tertiary fold. Earlier work in our lab had successfully incorporated unnatural building blocks into every major secondary structure (beta-sheet, alpha-helix, loops and beta

  19. Rational Emotive Education

    Science.gov (United States)

    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)

  20. Rational BRDF.

    Science.gov (United States)

    Pacanowski, Romain; Salazar Celis, Oliver; Schlick, Christophe; Granier, Xavier; Poulin, Pierre; Cuyt, Annie

    2012-11-01

    Over the last two decades, much effort has been devoted to accurately measuring Bidirectional Reflectance Distribution Functions (BRDFs) of real-world materials and to use efficiently the resulting data for rendering. Because of their large size, it is difficult to use directly measured BRDFs for real-time applications, and fitting the most sophisticated analytical BRDF models is still a complex task. In this paper, we introduce Rational BRDF, a general-purpose and efficient representation for arbitrary BRDFs, based on Rational Functions (RFs). Using an adapted parametrization, we demonstrate how Rational BRDFs offer 1) a more compact and efficient representation using low-degree RFs, 2) an accurate fitting of measured materials with guaranteed control of the residual error, and 3) efficient importance sampling by applying the same fitting process to determine the inverse of the Cumulative Distribution Function (CDF) generated from the BRDF for use in Monte-Carlo rendering.

  1. Rational emotions.

    Science.gov (United States)

    Meshulam, Meir; Winter, Eyal; Ben-Shakhar, Gershon; Aharon, Itzhak

    2012-01-01

    We present here the concept of rational emotions: Emotions may be directly controlled and utilized in a conscious, analytic fashion, enabling an individual to size up a situation, to determine that a certain "mental state" is strategically advantageous and adjust accordingly. Building on the growing body of literature recognizing the vital role of emotions in determining decisions, we explore the complementary role of rational choice in choosing emotional states. Participants played the role of "recipient" in the dictator game, in which an anonymous "dictator" decides how to split an amount of money between himself and the recipient. A subset of recipients was given a monetary incentive to be angry at low-split offers. That subset demonstrated increased physiological arousal at low offers relative to high offers as well as more anger than other participants. These results provide a fresh outlook on human decision-making and contribute to the continuing effort to build more complete models of rational behavior.

  2. Computational molecular modeling and structural rationalization for the design of a drug-loaded PLLA/PVA biopolymeric membrane

    International Nuclear Information System (INIS)

    Sibeko, B; Pillay, V; Choonara, Y E; Khan, R A; Danckwerts, M P; Modi, G; Iyuke, S E; Naidoo, D

    2009-01-01

    The purpose of this study was to design, characterize and assess the influence of triethanolamine (TEA) on the physicomechanical properties and release of methotrexate (MTX) from a composite biopolymeric membrane. Conjugated poly(L-lactic acid) (PLLA) and poly(vinyl alcohol) (PVA) membranes were prepared by immersion precipitation with and without the addition of TEA. Drug entrapment efficiency (DEE) and release studies were performed in phosphate buffered saline (pH 7.4, 37 deg. C). Scanning electron microscopy elucidated the membrane surface morphology. Computational and structural molecular modeling rationalized the potential mechanisms of membrane formation and MTX release. Bi-axial force-distance (F-D) extensibility profiles were generated to determine the membrane toughness, elasticity and fracturability. Membranes were significantly toughened by the addition of TEA as a discrete rubbery phase within the co-polymer matrix. MTX-TEA-PLLA-PVA membranes were tougher (F = 89 N) and more extensible (D = 8.79 mm) compared to MTX-PLLA-PVA (F = 35 N, D = 3.7 mm) membranes as a greater force of extension and fracture distance were required (N = 10). DEE values were relatively high (>80%, N = 5) for both formulations. Photomicrographs revealed distinct crystalline layered morphologies with macro-pores. MTX was released by tri-phasic kinetics with a lower fractional release of MTX from MTX-TEA-PLLA-PVA membranes compared to MTX-PLLA-PVA. TEA provided a synergistic approach to improving the membrane physicomechanical properties and modulation of MTX release. The composite biopolymeric membrane may therefore be suitable for the novel delivery of MTX in the treatment of chronic primary central nervous system lymphoma.

  3. Rationally designed graphene-nanotube 3D architectures with a seamless nodal junction for efficient energy conversion and storage.

    Science.gov (United States)

    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.

  4. Rational Design of Adjuvant for Skin Delivery: Conjugation of Synthetic β-Glucan Dectin-1 Agonist to Protein Antigen.

    Science.gov (United States)

    Donadei, Agnese; Gallorini, Simona; Berti, Francesco; O'Hagan, Derek T; Adamo, Roberto; Baudner, Barbara C

    2015-05-04

    The potential benefits of skin delivery of vaccines derive from the presence of a densely connected network of antigen presenting cells in the skin layer, most significantly represented by Langerhans cells and dermal dendritic cells. Targeting these cells by adjuvant conjugated to an antigen should result in enhanced immunogenicity of a vaccine. Since one of the most widely used adjuvants is an insoluble salt of aluminum (aluminum hydroxide) that cannot be used for skin delivery due to reactogenicity, we focused our attention on agonists of receptors present on skin dendritic cells, including the Dectin-1 receptor. β-(1-3)-glucans, which are the most abundant components of the fungal surface, are known to activate the innate immune response by interaction with the C-type lectin-like Dectin-1 receptor. In this work we identified by rational design a well-defined synthetic β-(1-3)-glucan hexasaccharide as a Dectin-1 agonist and chemically conjugated it to the genetically detoxified diphtheria toxin (CRM197) protein antigen, as a means to increase the binding to Dectin-1 receptor and to target to skin dendritic cells. We demonstrated that the in vitro activation of the receptor was significantly impacted by the presentation of the glucan on the protein carrier. In vivo results in mice showed that the conjugation of the synthetic β-(1-3)-glucan when delivered intradermally resulted in higher antibody titers in comparison to intramuscular (i.m.) immunization and was not different from subcutaneous (s.c.) delivery. These findings suggest that weak receptor binders can be turned into more potent agonists by the multivalent presentation of many ligands covalently conjugated to the protein core. Moreover, this approach is particularly valuable to increase the immunogenicity of antigens administered via skin delivery.

  5. Site-Directed Mutagenesis of a Hyperthermophilic Endoglucanase Cel12B from Thermotoga maritima Based on Rational Design.

    Directory of Open Access Journals (Sweden)

    Jinfeng Zhang

    Full Text Available 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.

  6. Confucian Rationalism

    Science.gov (United States)

    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,…

  7. Design and Applications of Biodegradable Polyester Tissue Scaffolds Based on Endogenous Monomers Found in Human Metabolism

    Directory of Open Access Journals (Sweden)

    Devin G. Barrett

    2009-10-01

    Full Text Available Synthetic polyesters have deeply impacted various biomedical and engineering fields, such as tissue scaffolding and therapeutic delivery. Currently, many applications involving polyesters are being explored with polymers derived from monomers that are endogenous to the human metabolism. Examples of these monomers include glycerol, xylitol, sorbitol, and lactic, sebacic, citric, succinic, α-ketoglutaric, and fumaric acids. In terms of mechanical versatility, crystallinity, hydrophobicity, and biocompatibility, polyesters synthesized partially or completely from these monomers can display a wide range of properties. The flexibility in these macromolecular properties allows for materials to be tailored according to the needs of a particular application. Along with the presence of natural monomers that allows for a high probability of biocompatibility, there is also an added benefit that this class of polyesters is more environmentally friendly than many other materials used in biomedical engineering. While the selection of monomers may be limited by nature, these polymers have produced or have the potential to produce an enormous number of successes in vitro and in vivo.

  8. Rational valuations

    Directory of Open Access Journals (Sweden)

    Georg Spielthenner

    2007-01-01

    Full Text Available Valuations are ubiquitous. We may be for or against genetically modified food; we find some politicians irresponsible; we prefer Beethoven to rock ‘n’ roll or vice versa; some enjoy bird-watching while others find it boring; and we may think that we have to tighten up on green-house gas emissions. Valuing is pervasive and often we are not even aware that we are valuing. However, many of ourvaluations are ill grounded and rationally defective. They are frequently based on misinformation, sloppy thinking, prejudice, and are biased in many ways as psychological research shows. For this reason there is widespread agreement among phi-losophers that we need an account of substantive valuational rationality, both for the theory of practical reasoning and for ethics as well. My main objectin this paper is to outline such an account and to present a principle that allows a non-technical rational criticism of valuations

  9. Rational decisions

    CERN Document Server

    Binmore, Ken

    2008-01-01

    It is widely held that Bayesian decision theory is the final word on how a rational person should make decisions. However, Leonard Savage--the inventor of Bayesian decision theory--argued that it would be ridiculous to use his theory outside the kind of small world in which it is always possible to ""look before you leap."" If taken seriously, this view makes Bayesian decision theory inappropriate for the large worlds of scientific discovery and macroeconomic enterprise. When is it correct to use Bayesian decision theory--and when does it need to be modified? Using a minimum of mathematics,

  10. Rational design of human metapneumovirus live attenuated vaccine candidates by inhibiting viral mRNA cap methyltransferase.

    Science.gov (United States)

    Zhang, Yu; Wei, Yongwei; Zhang, Xiaodong; Cai, Hui; Niewiesk, Stefan; Li, Jianrong

    2014-10-01

    The paramyxoviruses human respiratory syncytial virus (hRSV), human metapneumovirus (hMPV), and human parainfluenza virus type 3 (hPIV3) are responsible for the majority of pediatric respiratory diseases and inflict significant economic loss, health care costs, and emotional burdens. Despite major efforts, there are no vaccines available for these viruses. The conserved region VI (CR VI) of the large (L) polymerase proteins of paramyxoviruses catalyzes methyltransferase (MTase) activities that typically methylate viral mRNAs at positions guanine N-7 (G-N-7) and ribose 2'-O. In this study, we generated a panel of recombinant hMPVs carrying mutations in the S-adenosylmethionine (SAM) binding site in CR VI of L protein. These recombinant viruses were specifically defective in ribose 2'-O methylation but not G-N-7 methylation and were genetically stable and highly attenuated in cell culture and viral replication in the upper and lower respiratory tracts of cotton rats. Importantly, vaccination of cotton rats with these recombinant hMPVs (rhMPVs) with defective MTases triggered a high level of neutralizing antibody, and the rats were completely protected from challenge with wild-type rhMPV. Collectively, our results indicate that (i) amino acid residues in the SAM binding site in the hMPV L protein are essential for 2'-O methylation and (ii) inhibition of mRNA cap MTase can serve as a novel target to rationally design live attenuated vaccines for hMPV and perhaps other paramyxoviruses, such as hRSV and hPIV3. Human paramyxoviruses, including hRSV, hMPV, and hPIV3, cause the majority of acute upper and lower respiratory tract infections in humans, particularly in infants, children, the elderly, and immunocompromised individuals. Currently, there is no licensed vaccine available. A formalin-inactivated vaccine is not suitable for these viruses because it causes enhanced lung damage upon reinfection with the same virus. A live attenuated vaccine is the most promising

  11. Rationalization: A Bibliography.

    Science.gov (United States)

    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…

  12. Rational inattention or rational overreaction?

    DEFF Research Database (Denmark)

    Browning, Martin; Hansen, Lars Gårn; Smed, Sinne

    We investigate differences in how consumers of fish react to health information in the mass media. We specify a dynamic empirical model that allows for heterogeneity in all basic parameters of consumer behavior as well as in how consumers react to information. We estimate the model using a unique...... houshold panel tracking consumption, prices, news stories and media habits over 24 quarters. We fi nd that the consumers most likely to be ’rationally ignorant’ of health effects react more dramatically to health news than the consumers who most likely are well informed....

  13. Rationality of limited rationality : some aggregate implications

    OpenAIRE

    Uri M. Possen; Mikko Puhakka

    1994-01-01

    In this paper we let economic agents choose whether to become fully rational or stay boundedly rational. Boundedly rational agents are less sophisticated in their information processing abilities. It is costly to acquire information needed to become fully rational, and thus not all agents are willing to incur those costs. We then explore the aggregate effects of endogenizing the decision whether the agent should or should not become fully rational in handling information. Since fully and boun...

  14. Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

    DEFF Research Database (Denmark)

    Larsen, Ann Møller; Venskutonyte, Raminta; Valadés, Elena Antón

    2011-01-01

    The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/ or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1......-5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic...

  15. Theoretical Studies in Heterogenous Catalysis: Towards a Rational Design of Novel Catalysts for Hydrodesulfurization and Hydrogen Production

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez,J.A.; Liu, P.

    2008-10-01

    potential to become the next generation of industrial HDS catalysts. Then, systematic studies concerned with the hydrogen-evolution reaction (HER) on extended surfaces, organometallic complexes and enzymes are presented. Finally, the reasons for the high catalytic activity of Au-CeO{sub 2} and Cu-CeO{sub 2} in the production of hydrogen through the water-gas shift reaction (CO + H{sub 2}O {yields} H{sub 2} + CO{sub 2}) are analyzed. It is shown that theoretical methods are very valuable tools for helping in the rational design of heterogeneous catalysts.

  16. Preparation, characterization and biological test of 3D-scaffolds based on chitosan, fibroin and hydroxyapatite for bone tissue engineering

    International Nuclear Information System (INIS)

    Lima, Paulo Autran Leite; Resende, Cristiane Xavier; Dulce de Almeida Soares, Glória; Anselme, Karine; Almeida, Luís Eduardo

    2013-01-01

    This work describes the preparation and characterization of porous 3D-scaffolds based on chitosan (CHI), chitosan/silk fibroin (CHI/SF) and chitosan/silk fibroin/hydroxyapatite (CHI/SF/HA) by freeze drying. The biomaterials were characterized by X-ray diffraction, attenuated total reflection Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy and energy dispersive spectroscopy. In addition, studies of porosity, pore size, contact angle and biological response of SaOs-2osteoblastic cells were performed. The CHI scaffolds have a porosity of 94.2 ± 0.9%, which is statistically higher than the one presented by CHI/SF/HA scaffolds, 89.7 ± 2.6%. Although all scaffolds were able to promote adhesion, growth and maintenance of osteogenic differentiation of SaOs-2 cells, the new 3D-scaffold based on CHI/SF/HA showed a significantly higher cell growth at 7 days and 21 days and the level of alkaline phosphatase at 14 and 21 days was statistically superior compared to other tested materials. - Highlights: • Preparation of 3D-scaffolds based on CHI, with or without addition of SF and HA. • Scaffolds exhibited interconnected porous structure (pore size superior to 50 μm). • The tripolyphosphate did not induce any significant cytotoxic response. • The CHI/SF/HA composite showed a higher cell growth and ALP activity

  17. Thermodynamic dissection of the binding energetics of proline-rich peptides to the Abl-SH3 domain: implications for rational ligand design.

    Science.gov (United States)

    Palencia, Andrés; Cobos, Eva S; Mateo, Pedro L; Martínez, Jose C; Luque, Irene

    2004-02-13

    The inhibition of the interactions between SH3 domains and their targets is emerging as a promising therapeutic strategy. To date, rational design of potent ligands for these domains has been hindered by the lack of understanding of the origins of the binding energy. We present here a complete thermodynamic analysis of the binding energetics of the p41 proline-rich decapeptide (APSYSPPPPP) to the SH3 domain of the c-Abl oncogene. Isothermal titration calorimetry experiments have revealed a thermodynamic signature for this interaction (very favourable enthalpic contributions opposed by an unfavourable binding entropy) inconsistent with the highly hydrophobic nature of the p41 ligand and the Abl-SH3 binding site. Our structural and thermodynamic analyses have led us to the conclusion, having once ruled out any possible ionization events or conformational changes coupled to the association, that the establishment of a complex hydrogen-bond network mediated by water molecules buried at the binding interface is responsible for the observed thermodynamic behaviour. The origin of the binding energetics for proline-rich ligands to the Abl-SH3 domain is further investigated by a comparative calorimetric analysis of a set of p41-related ligands. The striking effects upon the enthalpic and entropic contributions provoked by conservative substitutions at solvent-exposed positions in the ligand confirm the complexity of the interaction. The implications of these results for rational ligand design are discussed.

  18. Rational design of anatase TiO2 architecture with hierarchical nanotubes and hollow microspheres for high-performance dye-sensitized solar cells

    Science.gov (United States)

    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.

  19. Ferroelectric polymer scaffolds based on a copolymer of tetrafluoroethylene with vinylidene fluoride: Fabrication and properties

    Energy Technology Data Exchange (ETDEWEB)

    Bolbasov, E.N., E-mail: ebolbasov@gmail.com [Tomsk Polytechnic University, 634050, 30, Lenin Avenue, Tomsk (Russian Federation); Anissimov, Y.G., E-mail: Y.Anissimov@Griffith.edu.au [Griffith University, School of Biomolecular and Physical Sciences, Brisbane, QLD (Australia); Pustovoytov, A.V., E-mail: andrius_222@mail.ru [Tomsk Polytechnic University, 634050, 30, Lenin Avenue, Tomsk (Russian Federation); Khlusov, I.A., E-mail: khlusov63@mail.ru [Tomsk Polytechnic University, 634050, 30, Lenin Avenue, Tomsk (Russian Federation); Tomsk Scientific Research Institute of Balneology and Physiotherapy, Tomsk (Russian Federation); Zaitsev, A.A., E-mail: prim@niikf.tomsk.ru [Tomsk Scientific Research Institute of Balneology and Physiotherapy, Tomsk (Russian Federation); Zaitsev, K.V., E-mail: zaitsev-kv@mail.ru [Tomsk Scientific Research Institute of Balneology and Physiotherapy, Tomsk (Russian Federation); Lapin, I.N., E-mail: 201kiop@mail.ru [Tomsk State University, 634050, 36, Lenin Avenue, Tomsk (Russian Federation); Tverdokhlebov, S.I., E-mail: tverd@tpu.ru [Tomsk Polytechnic University, 634050, 30, Lenin Avenue, Tomsk (Russian Federation)

    2014-07-01

    A solution blow spinning technique is a method developed recently for making nonwoven webs of micro- and nanofibres. The principal advantage of this method compared to a more traditional electrospinning process is its significantly higher production rate. In this work, the solution blow spinning method was further developed to produce nonwoven polymeric scaffolds based on a copolymer of tetrafluoroethylene with vinylidene fluoride solution in acetone. A crucial feature of the proposed method is that high-voltage equipment is not required, which further improves the method's economics. Scanning electron microscopy analysis of the samples demonstrated that the surface morphology of the nonwoven materials is dependent on the polymer concentration in the spinning solution. It was concluded that an optimum morphology of the nonwoven scaffolds for medical applications is achieved by using a 5% solution of the copolymer. It was established that the scaffolds produced from the 5% solution have a fractal structure and anisotropic mechanical properties. X-ray diffraction, infrared spectroscopy, Raman spectroscopy and differential scanning calorimetry demonstrated that the fabricated nonwoven materials have crystal structures that exhibit ferroelectric properties. Gas chromatography has shown that the amount of acetone in the nonwoven material does not exceed the maximum allowable concentration of 0.5%. In vitro analysis, using the culture of motile cells, confirmed that the nonwoven material is non-toxic and does not alter the morpho-functional status of stem cells for short-term cultivation, and therefore can potentially be used in medical applications. - Highlights: • Solution blow spinning was used to fabricate nonwoven material based on VDF-TeFE. • The nonwoven material has complex spatial organization and high porosity. • It was established that the nonwoven material exhibits ferroelectric properties. • In vitro testing demonstrated that the material is non

  20. Ferroelectric polymer scaffolds based on a copolymer of tetrafluoroethylene with vinylidene fluoride: Fabrication and properties

    International Nuclear Information System (INIS)

    Bolbasov, E.N.; Anissimov, Y.G.; Pustovoytov, A.V.; Khlusov, I.A.; Zaitsev, A.A.; Zaitsev, K.V.; Lapin, I.N.; Tverdokhlebov, S.I.

    2014-01-01

    A solution blow spinning technique is a method developed recently for making nonwoven webs of micro- and nanofibres. The principal advantage of this method compared to a more traditional electrospinning process is its significantly higher production rate. In this work, the solution blow spinning method was further developed to produce nonwoven polymeric scaffolds based on a copolymer of tetrafluoroethylene with vinylidene fluoride solution in acetone. A crucial feature of the proposed method is that high-voltage equipment is not required, which further improves the method's economics. Scanning electron microscopy analysis of the samples demonstrated that the surface morphology of the nonwoven materials is dependent on the polymer concentration in the spinning solution. It was concluded that an optimum morphology of the nonwoven scaffolds for medical applications is achieved by using a 5% solution of the copolymer. It was established that the scaffolds produced from the 5% solution have a fractal structure and anisotropic mechanical properties. X-ray diffraction, infrared spectroscopy, Raman spectroscopy and differential scanning calorimetry demonstrated that the fabricated nonwoven materials have crystal structures that exhibit ferroelectric properties. Gas chromatography has shown that the amount of acetone in the nonwoven material does not exceed the maximum allowable concentration of 0.5%. In vitro analysis, using the culture of motile cells, confirmed that the nonwoven material is non-toxic and does not alter the morpho-functional status of stem cells for short-term cultivation, and therefore can potentially be used in medical applications. - Highlights: • Solution blow spinning was used to fabricate nonwoven material based on VDF-TeFE. • The nonwoven material has complex spatial organization and high porosity. • It was established that the nonwoven material exhibits ferroelectric properties. • In vitro testing demonstrated that the material is non

  1. Rational kinematics

    CERN Document Server

    Angeles, Jorge

    1988-01-01

    A rational study of kinematics is a treatment of the subject based on invariants, i.e., quantities that remain essentially unchanged under a change of observer. An observer is understood to be a reference frame supplied with a clock (Truesdell 1966). This study will therefore include an introduction to invariants. The language of these is tensor analysis and multilinear algebra, both of which share many isomorphic relations, These subjects are treated in full detail in Ericksen (1960) and Bowen and Wang (1976), and hence will not be included here. Only a short account of notation and definitions will be presented. Moreover, definitions and basic concepts pertaining to the kinematics of rigid bodies will be also included. Although the kinematics of rigid bodies can be regarded as a particular case of the kinematics of continua, the former deserves attention on its own merits for several reasons. One of these is that it describes locally the motions undergone by continua. Another reason is that a whole area of ...

  2. Rational interface design of epoxy-organoclay nanocomposites: role of structure-property relationship for silane modifiers.

    Science.gov (United States)

    Bruce, Alex N; Lieber, Danielle; Hua, Inez; Howarter, John A

    2014-04-01

    Montmorillonite was modified by three silane surfactants with different functionalities to investigate the role of surfactant structure on the properties of a final epoxy-organoclay nanocomposite. N-aminopropyldimethylethoxysilane (APDMES), an aminated monofunctional silane, was chosen as a promising surfactant for several reasons: (1) it will bond to silica in montmorillonite, (2) it will bond to epoxide groups, and (3) to overcome difficulties found with trifunctional aminosilane bonding clay layers together and preventing exfoliation. A trifunctional and non-aminated version of APDMES, 3-aminopropyltriethoxysilane (APTES) and n-propyldimethylmethoxysilane (PDMMS), respectively, was also studied to provide comparison to this rationally chosen surfactant. APDMES and APTES were grafted onto montmorillonite in the same amount, while PDMMS was barely grafted (nanocomposite gallery spacing was not dependent on the surfactant used. Different concentrations of APDMES modified montmorillonite yielded different properties, as concentration decreased glass transition temperature increased, thermal stability increased, and the storage modulus decreased. Storage modulus, glass transition temperature, and thermal stability were more similar for epoxy-organoclay composites modified with the same concentration of silane surfactant, neat epoxy, and epoxy-montmorillonite nanocomposite. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Rational Design of Disulfide Bonds Increases Thermostability of a Mesophilic 1,3-1,4-β-Glucanase from Bacillus terquilensis.

    Directory of Open Access Journals (Sweden)

    Chengtuo Niu

    Full Text Available 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.

  4. Rational design of carboxyl groups perpendicularly attached to a graphene sheet: a platform for enhanced biosensing applications.

    Science.gov (United States)

    Bonanni, Alessandra; Chua, Chun Kiang; Pumera, Martin

    2014-01-03

    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

  5. Rationality in Society

    NARCIS (Netherlands)

    Flache, Andreas; Dijkstra, Jacob; Wright, James D.

    2015-01-01

    Contemporary theories of rational behavior in human society augment the orthodox model of rationality both by adding various forms of bounded rationality and relaxing the assumptions of self-interest and materialistic preferences. This entry discusses how these extensions of the theory of rational

  6. Rational design of micro-RNA-like bifunctional siRNAs targeting HIV and the HIV coreceptor CCR5.

    Science.gov (United States)

    Ehsani, Ali; Saetrom, Pål; Zhang, Jane; Alluin, Jessica; Li, Haitang; Snøve, Ola; Aagaard, Lars; Rossi, John J

    2010-04-01

    Small-interfering RNAs (siRNAs) and micro-RNAs (miRNAs) are distinguished by their modes of action. SiRNAs serve as guides for sequence-specific cleavage of complementary mRNAs and the targets can be in coding or noncoding regions of the target transcripts. MiRNAs inhibit translation via partially complementary base-pairing to 3' untranslated regions (UTRs) and are generally ineffective when targeting coding regions of a transcript. In this study, we deliberately designed siRNAs that simultaneously direct cleavage and translational suppression of HIV RNAs, or cleavage of the mRNA encoding the HIV coreceptor CCR5 and suppression of translation of HIV. These bifunctional siRNAs trigger inhibition of HIV infection and replication in cell culture. The design principles have wide applications throughout the genome, as about 90% of genes harbor sites that make the design of bifunctional siRNAs possible.

  7. Rational Design of Si@SiO2/C Composites Using Sustainable Cellulose as a Carbon Resource for Anodes in Lithium-Ion Batteries.

    Science.gov (United States)

    Shen, Dazhi; Huang, Chaofan; Gan, Lihui; Liu, Jian; Gong, Zhengliang; Long, Minnan

    2018-03-07

    In this work, we propose a novel and facile route for the rational design of Si@SiO 2 /C anode materials by using sustainable and environment-friendly cellulose as a carbon resource. To simultaneously obtain a SiO 2 layer and a carbon scaffold, a specially designed homogeneous cellulose solution and commercial Si nanopowder are used as the starting materials, and the cellulose/Si composite is directly assembled by an in situ regenerating method. Subsequently, Si@SiO 2 /C composite is obtained after carbonization. As expected, Si@SiO 2 is homogeneously encapsulated in the cellulose-derived carbon network. The obtained Si@SiO 2 /C composite shows a high reversible capacity of 1071 mA h g -1 at a current density of 420 mA g -1 and 70% capacity retention after 200 cycles. This novel, sustainable, and effective design is a promising approach to obtain high-performance and cost-effective composite anodes for practical applications.

  8. Rational Design of High-Number dsDNA Fragments Based on Thermodynamics for the Construction of Full-Length Genes in a Single Reaction.

    Science.gov (United States)

    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.

  9. Rational Design of High-Number dsDNA Fragments Based on Thermodynamics for the Construction of Full-Length Genes in a Single Reaction.

    Directory of Open Access Journals (Sweden)

    Bhagyashree S Birla

    Full Text Available 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.

  10. Toward Rational Design of Cu/SSZ-13 Selective Catalytic Reduction Catalysts: Implications from Atomic-Level Understanding of Hydrothermal Stability

    Energy Technology Data Exchange (ETDEWEB)

    Song, James [Institute; The; amp, Linda Voiland School of Chemical Engineering and Bioengineering, Washington State University, P.O. Box 646515, Pullman, Washington 99164, United States; Wang, Yilin [Institute; Walter, Eric D. [Environmental; Washton, Nancy M. [Environmental; Mei, Donghai [Institute; Kovarik, Libor [Environmental; Engelhard, Mark H. [Environmental; Prodinger, Sebastian [Institute; Wang, Yong [Institute; The; amp, Linda Voiland School of Chemical Engineering and Bioengineering, Washington State University, P.O. Box 646515, Pullman, Washington 99164, United States; Peden, Charles H. F. [Institute; Gao, Feng [Institute

    2017-11-03

    The hydrothermal stability of Cu/SSZ-13 SCR catalysts has been extensively studied, yet atomic level understanding of changes to the zeolite support and the Cu active sites during hydrothermal aging are still lacking. In this work, via the utilization of spectroscopic methods including solid-state 27Al and 29Si NMR, EPR, DRIFTS, and XPS, together with imaging and elemental mapping using STEM, detailed kinetic analyses, and theoretical calculations with DFT, various Cu species, including two types of isolated active sites and CuOx clusters, were precisely quantified for samples hydrothermally aged under varying conditions. This quantification convincingly confirms the exceptional hydrothermal stability of isolated Cu2+-2Z sites, and the gradual conversion of [Cu(OH)]+-Z to CuOx clusters with increasing aging severity. This stability difference is rationalized from the hydrolysis activation barrier difference between the two isolated sites via DFT. Discussions are provided on the nature of the CuOx clusters, and their possible detrimental roles on catalyst stability. Finally, a few rational design principles for Cu/SSZ-13 are derived rigorously from the atomic-level understanding of this catalyst obtained here. The authors gratefully acknowledge the US Department of Energy (DOE), Energy Efficiency and Renewable Energy, Vehicle Technologies Office for the support of this work. Computing time was granted by a user proposal at the William R. Wiley Environmental Molecular Sciences Laboratory (EMSL) and by the National Energy Research Scientific Computing Center (NERSC). The experimental studies described in this paper were performed in the EMSL, a national scientific user facility sponsored by the DOE’s Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory (PNNL). PNNL is operated for the US DOE by Battelle.

  11. Mapping Determinants of Virus Neutralization and Viral Escape for Rational Design of a Hepatitis C Virus Vaccine

    Directory of Open Access Journals (Sweden)

    Mei-Le Keck

    2018-05-01

    Full Text Available Hepatitis C virus (HCV continues to spread worldwide with an annual increase of 1.75 million new infections. The number of HCV cases in the U.S. is now greater than the number of HIV cases and is increasing in young adults because of the opioid epidemic sweeping the country. HCV-related liver disease is the leading indication of liver transplantation. An effective vaccine is of paramount importance to control and prevent HCV infection. While this vaccine will need to induce both cellular and humoral immunity, this review is focused on the required antibody responses. For highly variable viruses, such as HCV, isolation and characterization of monoclonal antibodies mediating broad virus neutralization are an important guide for vaccine design. The viral envelope glycoproteins, E1 and E2, are the main targets of these antibodies. Epitopes on the E2 protein have been studied more extensively than epitopes on E1, due to higher antibody targeting that reflects these epitopes having higher degrees of immunogenicity. E2 epitopes are overall organized in discrete clusters of overlapping epitopes that ranged from high conservation to high variability. Other epitopes on E1 and E1E2 also are targets of neutralizing antibodies. Taken together, these regions are important for vaccine design. Another element in vaccine design is based on information on how the virus escapes from broadly neutralizing antibodies. Escape mutations can occur within the epitopes that are involved in antibody binding and in regions that are not involved in their epitopes, but nonetheless reduce the efficiency of neutralizing antibodies. An understanding on the specificities of a protective B cell response, the molecular locations of these epitopes on E1, E2, and E1E2, and the mechanisms, which enable the virus to negatively modulate neutralizing antibody responses to these regions will provide the necessary guidance for vaccine design.

  12. Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery

    Czech Academy of Sciences Publication Activity Database

    Tykvart, Jan; Schimer, Jiří; Bařinková, Jitka; Pachl, Petr; Poštová Slavětínská, Lenka; Majer, Pavel; Konvalinka, Jan; Šácha, Pavel

    2014-01-01

    Roč. 22, č. 15 (2014), s. 4099-4108 ISSN 0968-0896 R&D Projects: GA ČR GBP208/12/G016 Grant - others:OPPK(CZ) CZ.2.16/3.1.00/24016 Institutional support: RVO:61388963 Keywords : GCPII * PSMA * structure-aided drug design * specific drug targeting Subject RIV: CE - Biochemistry Impact factor: 2.793, year: 2014

  13. A comparison of scaffold-free and scaffold-based reconstructed human skin models as alternatives to animal use.

    Science.gov (United States)

    Kinikoglu, Beste

    2017-12-01

    Tissue engineered full-thickness human skin substitutes have various applications in the clinic and in the laboratory, such as in the treatment of burns or deep skin defects, and as reconstructed human skin models in the safety testing of drugs and cosmetics and in the fundamental study of skin biology and pathology. So far, different approaches have been proposed for the generation of reconstructed skin, each with its own advantages and disadvantages. Here, the classic tissue engineering approach, based on cell-seeded polymeric scaffolds, is compared with the less-studied cell self-assembly approach, where the cells are coaxed to synthesise their own extracellular matrix (ECM). The resulting full-thickness human skin substitutes were analysed by means of histological and immunohistochemical analyses. It was found that both the scaffold-free and the scaffold-based skin equivalents successfully mimicked the functionality and morphology of native skin, with complete epidermal differentiation (as determined by the expression of filaggrin), the presence of a continuous basement membrane expressing collagen VII, and new ECM deposition by dermal fibroblasts. On the other hand, the scaffold-free model had a thicker epidermis and a significantly higher number of Ki67-positive proliferative cells, indicating a higher capacity for self-renewal, as compared to the scaffold-based model. 2017 FRAME.

  14. Preparation and characterization of a three-dimensional printed scaffold based on a functionalized polyester for bone tissue engineering applications.

    Science.gov (United States)

    Seyednejad, Hajar; Gawlitta, Debby; Dhert, Wouter J A; van Nostrum, Cornelus F; Vermonden, Tina; Hennink, Wim E

    2011-05-01

    At present there is a strong need for suitable scaffolds that meet the requirements for bone tissue engineering applications. The objective of this study was to investigate the suitability of porous scaffolds based on a hydroxyl functionalized polymer, poly(hydroxymethylglycolide-co-ε-caprolactone) (pHMGCL), for tissue engineering. In a recent study this polymer was shown to be a promising material for bone regeneration. The scaffolds consisting of pHMGCL or poly(ε-caprolactone) (PCL) were produced by means of a rapid prototyping technique (three-dimensional plotting) and were shown to have a high porosity and an interconnected pore structure. The thermal and mechanical properties of both scaffolds were investigated and human mesenchymal stem cells were seeded onto the scaffolds to evaluate the cell attachment properties, as well as cell viability and differentiation. It was shown that the cells filled the pores of the pHMGCL scaffold within 7 days and displayed increased metabolic activity when compared with cells cultured in PCL scaffolds. Importantly, pHMGCL scaffolds supported osteogenic differentiation. Therefore, scaffolds based on pHMGCL are promising templates for bone tissue engineering applications. Copyright © 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  15. Preparation, characterization and biological test of 3D-scaffolds based on chitosan, fibroin and hydroxyapatite for bone tissue engineering.

    Science.gov (United States)

    Lima, Paulo Autran Leite; Resende, Cristiane Xavier; Soares, Glória Dulce de Almeida; Anselme, Karine; Almeida, Luís Eduardo

    2013-08-01

    This work describes the preparation and characterization of porous 3D-scaffolds based on chitosan (CHI), chitosan/silk fibroin (CHI/SF) and chitosan/silk fibroin/hydroxyapatite (CHI/SF/HA) by freeze drying. The biomaterials were characterized by X-ray diffraction, attenuated total reflection Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy and energy dispersive spectroscopy. In addition, studies of porosity, pore size, contact angle and biological response of SaOs-2osteoblastic cells were performed. The CHI scaffolds have a porosity of 94.2±0.9%, which is statistically higher than the one presented by CHI/SF/HA scaffolds, 89.7±2.6%. Although all scaffolds were able to promote adhesion, growth and maintenance of osteogenic differentiation of SaOs-2 cells, the new 3D-scaffold based on CHI/SF/HA showed a significantly higher cell growth at 7 days and 21 days and the level of alkaline phosphatase at 14 and 21 days was statistically superior compared to other tested materials. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Rational design, synthesis, biologic evaluation, and structure-activity relationship studies of novel 1-indanone alpha(1)-adrenoceptor antagonists.

    Science.gov (United States)

    Li, Minyong; Xia, Lin

    2007-11-01

    In the present report, a novel series of 1-indanone alpha(1)-adrenoceptor antagonists were designed and synthesized based on 3D-pharmacophore model. Their in vitro alpha(1)-adrenoceptor antagonistic assay showed that three compounds (2a, 2m, and 2o) had similar or improved alpha(1)-adrenoceptor antagonistic activities relative to the positive control prazosin. Based on these results, a three-dimensional quantitative structure-activity relationship study was performed using a Self-Organizing Molecular Field Analysis method to provide insight for the future development of alpha(1)-adrenoceptor antagonists.

  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.

    Science.gov (United States)

    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. Copyright © 2014 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

  18. A rationally designed photo-chemo core-shell nanomedicine for inhibiting the migration of metastatic breast cancer cells followed by photodynamic killing.

    Science.gov (United States)

    Malarvizhi, Giridharan Loghanathan; Chandran, Parwathy; Retnakumari, Archana Payickattu; Ramachandran, Ranjith; Gupta, Neha; Nair, Shantikumar; Koyakutty, Manzoor

    2014-04-01

    A multifunctional core-shell nanomedicine capable of inhibiting the migratory capacity of metastatic cancer cells followed by imparting cytotoxic stress by photodynamic action is reported. Based on in silico design, we have developed a core-shell nanomedicine comprising of ~80nm size poly(lactic-co-glycolic acid) (PLGA) nano-core encapsulating photosensitizer, m-tetra(hydroxyphenyl)chlorin (mTHPC), and ~20nm size albumin nano-shell encapsulating tyrosine kinase inhibitor, Dasatinib, which impair cancer migration. This system was prepared by a sequential process involving electrospray of polymer core and coacervation of protein shell. Cell studies using metastatic breast cancer cells demonstrated disruption of Src kinase involved in the cancer migration by albumin-dasatinib nano-shell and generation of photoactivated oxidative stress by mTHPC-PLGA nano-core. This unique combinatorial photo-chemo nanotherapy resulted synergistic cytotoxicity in ~99% of the motility-impaired metastatic cells. This approach of blocking cancer migration followed by photodynamic killing using rationally designed nanomedicine is a promising new strategy against cancer metastasis. A multifunctional core-shell nanomedicine capable of inhibiting metastatic cancer cell migration, in addition to inducing photodynamic effects, is described in this paper. The authors document cytotoxicity in approximately 99% of the studied metastatic breast cancer cells. Similar approaches would be a very welcome addition to the treatment protocols of advanced metastatic breast cancer and other types of neoplasms. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. A Rational Approach to Rational Suicide.

    Science.gov (United States)

    Richman, Joseph

    1992-01-01

    Describes suicide as reaction to internal and external sources of stress and the impact of life events. Notes that, in the elderly, these situations are prevalent in many who are not suicidal. Contends that much more is written about rational suicide than its alternative (rational nonsuicide). Reviews reasons for this and suggests rational…

  20. Rational design, synthesis and biological screening of triazine-triazolopyrimidine hybrids as multitarget anti-Alzheimer agents.

    Science.gov (United States)

    Jameel, Ehtesham; Meena, Poonam; Maqbool, Mudasir; Kumar, Jitendra; Ahmed, Waqar; Mumtazuddin, Syed; Tiwari, Manisha; Hoda, Nasimul; Jayaram, B

    2017-08-18

    In our endeavor towards the development of potent multitarget ligands for the treatment of Alzheimer's disease, a series of triazine-triazolopyrimidine hybrids were designed, synthesized and characterized by various spectral techniques. Docking and scoring techniques were used to design the inhibitors and to display their interaction with key residues of active site. Organic synthesis relied upon convergent synthetic routes were mono and di-substituted triazines were connected with triazolopyrimidine using piperazine as a linker. In total, seventeen compounds were synthesized in which the di-substituted triazine-triazolopyrimidine derivatives 9a-d showed better acetylcholinesterase (AChE) inhibitory activity than the corresponding tri-substituted triazine-triazolopyrimidine derivatives 10a-f. Out of the disubstituted triazine-triazolopyrimidine based compounds, 9a and 9b showed encouraging inhibitory activity on AChE with IC 50 values 0.065 and 0.092 μM, respectively. Interestingly, 9a and 9b also demonstrated good inhibition selectivity towards AChE over BuChE by ∼28 folds. Furthermore, kinetic analysis and molecular modeling studies showed that 9a and 9b target both catalytic active site as well as peripheral anionic site of AChE. In addition, these derivatives effectively modulated Aβ self-aggregation as investigated through CD spectroscopy, ThT fluorescence assay and electron microscopy. Besides, these compounds exhibited potential antioxidants (2.15 and 2.91 trolox equivalent by ORAC assay) and metal chelating properties. In silico ADMET profiling highlighted that, these novel triazine derivatives have appropriate drug like properties and possess very low toxic effects in the primarily pharmacokinetic study. Overall, the multitarget profile exerted by these novel triazine molecules qualified them as potential anti-Alzheimer drug candidates in AD therapy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  1. Tunable, Chemo- and Site-Selective Nitrene Transfer Reactions through the Rational Design of Silver(I) Catalysts.

    Science.gov (United States)

    Alderson, Juliet M; Corbin, Joshua R; Schomaker, Jennifer M

    2017-09-19

    Carbon-nitrogen (C-N) bonds are ubiquitous in pharmaceuticals, agrochemicals, diverse bioactive natural products, and ligands for transition metal catalysts. An effective strategy for introducing a new C-N bond into a molecule is through transition metal-catalyzed nitrene transfer chemistry. In these reactions, a metal-supported nitrene can either add across a C═C bond to form an aziridine or insert into a C-H bond to furnish the corresponding amine. Typical catalysts for nitrene transfer include Rh 2 L n and Ru 2 L n complexes supported by bridging carboxylate and related ligands, as well as complexes based on Cu, Co, Ir, Fe, and Mn supported by porphyrins and related ligands. A limitation of metal-catalyzed nitrene transfer is the ability to predictably select which specific site will undergo amination in the presence of multiple reactive groups; thus, many reactions rely primarily on substrate control. Achieving true catalyst-control over nitrene transfer would open up exciting possibilities for flexible installation of new C-N bonds into hydrocarbons, natural product-inspired scaffolds, existing pharmaceuticals or biorenewable building blocks. Silver-catalyzed nitrene transfer enables flexible control over the position at which a new C-N bond is introduced. Ag(I) supported by simple N-donor ligands accommodates a diverse range of coordination geometries, from linear to tetrahedral to seesaw, enabling the electronic and steric parameters of the catalyst to be tuned independently. In addition, the ligand, Ag salt counteranion, Ag/ligand ratio and the solvent all influence the fluxional and dynamic behavior of Ag(I) complexes in solution. Understanding the interplay of these parameters to manipulate the behavior of Ag-nitrenes in a predictable manner is a key design feature of our work. In this Account, we describe successful applications of a variety of design principles to tunable, Ag-catalyzed aminations, including (1) changing Ag/ligand ratios to influence

  2. Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties

    Directory of Open Access Journals (Sweden)

    Martinho N

    2017-09-01

    Full Text Available Nuno Martinho,1–3 Liana C Silva,1,4 Helena F Florindo,1 Steve Brocchini,2 Mire Zloh,3 Teresa S Barata2 1Research Institute for Medicines (iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; 2Department of Pharmaceutics, UCL School of Pharmacy, London, 3School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK; 4Centro de Química-Física Molecular and IN – Institute of Nanoscience and Nanotechnology, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal Abstract: Dendrimers are hyperbranched polymers with a multifunctional architecture that can be tailored for the use in various biomedical applications. Peptide dendrimers are particularly relevant for drug delivery applications due to their versatility and safety profile. The overall lack of knowledge of their three-dimensional structure, conformational behavior and structure–activity relationship has slowed down their development. Fluorophores are often conjugated to dendrimers to study their interaction with biomolecules and provide information about their mechanism of action at the molecular level. However, these probes can change dendrimer surface properties and have a direct impact on their interactions with biomolecules and with lipid membranes. In this study, we have used computer-aided molecular design and molecular dynamics simulations to identify optimal topology of a poly(L-glutamic acid (PG backbone dendrimer that allows incorporation of fluorophores in the core with minimal availability for undesired interactions. Extensive all-atom molecular dynamic simulations with the CHARMM force field were carried out for different generations of PG dendrimers with the core modified with a fluorophore (nitrobenzoxadiazole and Oregon Green 488 and various surface groups (glutamic acid, lysine and tryptophan. Analysis of structural and topological features of all designed dendrimers provided information about their size, shape

  3. Rational design of small molecules that modulate the transcriptional function of the response regulator PhoP.

    Science.gov (United States)

    Qing, Xiaoyu; De Weerdt, Ami; De Maeyer, Marc; Steenackers, Hans; Voet, Arnout

    2018-01-01

    The response regulator PhoP, which is part of the PhoP/PhoQ two-component system, regulates the expression of multiple genes involved in controlling virulence in Salmonella enterica serovar Typhimurium and other species of Gram-negative bacteria. Modulating the phosphorylation-mediated dimerization in the receiver domain may interfere with the transcriptional function of PhoP. In this study, we analyzed the therapeutic potential of the PhoP receiver domain by exploring it as a potential target for drug design. The structural information was then applied to identify the first hit compounds from commercial chemical libraries by combining pharmacophore modelling and docking methods with a GFP (Green Fluorescent Protein)-based promoter-fusion bioassay. In total, one hundred and forty compounds were selected, purchased, and tested for biological activity. Several novel scaffolds showed acceptable potency to modulate the transcriptional function of PhoP, either by enhancing or inhibiting the expression of PhoP-dependent genes. These compounds may be used as the starting point for developing modulators that target the protein-protein interface of the PhoP protein as an alternative strategy against antibiotic resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. A Biophysical Model of CRISPR/Cas9 Activity for Rational Design of Genome Editing and Gene Regulation

    Science.gov (United States)

    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

  5. Solid-state supercapacitors with rationally designed heterogeneous electrodes fabricated by large area spray processing for wearable energy storage applications

    Science.gov (United States)

    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

  6. Current Experience in Testing Mitochondrial Nutrients in Disorders Featuring Oxidative Stress and Mitochondrial Dysfunction: Rational Design of Chemoprevention Trials

    Directory of Open Access Journals (Sweden)

    Giovanni Pagano

    2014-11-01

    Full Text Available 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.

  7. Rational design of intrinsically ultramicroporous polyimides containing bridgehead-substituted triptycene for highly selective and permeable gas separation membranes

    KAUST Repository

    Swaidan, Raja

    2014-08-12

    Highly ultramicroporous, solution-processable polyimides bearing 9,10-bridgehead-substituted triptycene demonstrated the highest BET surface area reported for polyimides (840 m2 g-1) and several new highs in gas selectivity and permeability for hydrogen (1630-3980 barrers, H2/CH4 ∼ 38) and air (230-630 barrers, O 2/N2 = 5.5-5.9) separations. Two new dianhydrides bearing 9,10-diethyl- and 9,10-dipropyltriptycenes indicate that the ultramicroporosity is optimized for fast polymeric sieving with the use of short, bulky isopropyl bridgeheads and methyl-substituted diamines (TrMPD, TMPD, and TMBZ) that increase intrachain rigidity. Mechanically, the triptycene-based analogue of a spirobisindane-based polyimide exhibited 50% increases in both tensile strength at break (94 MPa) and elastic modulus (2460 MPa) with corresponding 90% lower elongations at break (6%) likely due to the ability of highly entangled spiro-based chains to unwind. To guide future polyimide design, structure/property relationships are suggested between the geometry of the contortion center, the diamine and bridgehead substituent, and the mechanical, microstructural, and gas transport properties. © 2014 American Chemical Society.

  8. Rational Design of Two-Dimensional Metallic and Semiconducting Spintronic Materials Based on Ordered Double-Transition-Metal MXenes

    KAUST Repository

    Dong, Liang

    2016-12-30

    Two-dimensional (2D) materials that display robust ferromagnetism have been pursued intensively for nanoscale spintronic applications, but suitable candidates have not been identified. Here we present theoretical predictions on the design of ordered double-transition-metal MXene structures to achieve such a goal. On the basis of the analysis of electron filling in transition-metal cations and first-principles simulations, we demonstrate robust ferromagnetism in Ti2MnC2Tx monolayers regardless of the surface terminations (T = O, OH, and F), as well as in Hf2MnC2O2 and Hf2VC2O2 monolayers. The high magnetic moments (3–4 μB/unit cell) and high Curie temperatures (495–1133 K) of these MXenes are superior to those of existing 2D ferromagnetic materials. Furthermore, semimetal-to-semiconductor and ferromagnetic-to-antiferromagnetic phase transitions are predicted to occur in these materials in the presence of small or moderate tensile in-plane strains (0–3%), which can be externally applied mechanically or internally induced by the choice of transition metals.

  9. Solid-state supercapacitors with rationally designed heterogeneous electrodes fabricated by large area spray processing for wearable energy storage applications.

    Science.gov (United States)

    Huang, Chun; Zhang, Jin; Young, Neil P; Snaith, Henry J; Grant, Patrick S

    2016-05-10

    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.

  10. A Photo-triggered and photo-calibrated nitric oxide donor: Rational design, spectral characterizations, and biological applications.

    Science.gov (United States)

    He, Haihong; Liu, Yuxin; Zhou, Zhongneng; Guo, Chunlei; Wang, Hong-Yin; Wang, Zhuang; Wang, Xueli; Zhang, Ziqian; Wu, Fu-Gen; Wang, Haolu; Chen, Daijie; Yang, Dahai; Liang, Xiaowen; Chen, Jinquan; Zhou, Shengmin; Liang, Xin; Qian, Xuhong; Yang, Youjun

    2018-04-27

    Nitric oxide (NO) donors are valuable tools to probe the profound implications of NO in health and disease. The elusive nature of NO bio-relevance has largely limited the use of spontaneous NO donors and promoted the development of next generation NO donors, whose NO release is not only stimulated by a trigger, but also readily monitored via a judiciously built-in self-calibration mechanism. Light is without a doubt the most sensitive, versatile and biocompatible method of choice for both triggering and monitoring, for applications in complex biological matrices. Herein, we designed and synthesized an N-nitroso rhodamine derivative (NOD560) as a photo-triggered and photo-calibrated NO donor to address this need. NOD560 is essentially non-fluorescent. Upon irradiation by green light (532 nm), it efficiently release NO and a rhodamine dye, the dramatic fluorescence turn-on from which could be harnessed to conveniently monitor the localization, flux, and dose of NO release. The potentials of NOD560 for in vitro biological applications were also exemplified in in vitro biological models, i.e. mesenchymal stem cell (MSC) migration suppression. NOD560 is expected to complement the existing NO donors and find widespread applications in chemical biological studies. Copyright © 2018 Elsevier Inc. All rights reserved.

  11. G4-DNA formation in the HRAS promoter and rational design of decoy oligonucleotides for cancer therapy.

    Directory of Open Access Journals (Sweden)

    Alexandro Membrino

    Full Text Available 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.

  12. New method developments and rationalization of tools for LMFBR design in the frame of the European collaboration

    International Nuclear Information System (INIS)

    Palmiotti, G.; Burstall, R.F.; Kiefhaber, E.; Gebhardt, W.; Rieunier, J.M.

    1991-01-01

    The collaboration in Western Europe on fast reactor works has been active for more than two decades. The present collaboration on the research and development was initiated by the inter-government memorandum of understanding in January, 1984, and the research and development agreement was formally signed in January, 1989. The agreement originally involved the governments of France, the FRG, the U.K., Italy, Belgium and the Netherlands, though the latter three have since withdrawn. The works of the research and development collaboration is controlled by the steering committee with a permanent secretariat, and the technical works are overseen by 11 committees, the AGTs, each related to a specific topic. AGT3 is related to plant performance. The objective of the works is to provide for those performing design calculation with the calculating method and the data, and to recommend bias factors where necessary. It was agreed to use only one scheme for future works by all the partners. ERANOS functionalities, software and quality assurance aspects and so on are described. (K.I.)

  13. Rational design of reversible fluorescent probes for live-cell imaging and quantification of fast glutathione dynamics

    Science.gov (United States)

    Umezawa, Keitaro; Yoshida, Masafumi; Kamiya, Mako; Yamasoba, Tatsuya; Urano, Yasuteru

    2017-03-01

    Alterations in glutathione (GSH) homeostasis are associated with a variety of diseases and cellular functions, and therefore, real-time live-cell imaging and quantification of GSH dynamics are important for understanding pathophysiological processes. However, existing fluorescent probes are unsuitable for these purposes due to their irreversible fluorogenic mechanisms or slow reaction rates. In this work, we have successfully overcome these problems by establishing a design strategy inspired by Mayr's work on nucleophilic reaction kinetics. The synthesized probes exhibit concentration-dependent, reversible and rapid absorption/fluorescence changes (t1/2 = 620 ms at [GSH] = 1 mM), as well as appropriate Kd values (1-10 mM: within the range of intracellular GSH concentrations). We also developed FRET-based ratiometric probes, and demonstrated that they are useful for quantifying GSH concentration in various cell types and also for real-time live-cell imaging of GSH dynamics with temporal resolution of seconds.

  14. Rational design of methicillin resistance staphylococcus aureus inhibitors through 3D-QSAR, molecular docking and molecular dynamics simulations.

    Science.gov (United States)

    Ballu, Srilata; Itteboina, Ramesh; Sivan, Sree Kanth; Manga, Vijjulatha

    2018-04-01

    Staphylococcus aureus is a gram positive bacterium. It is the leading cause of skin and respiratory infections, osteomyelitis, Ritter's disease, endocarditis, and bacteraemia in the developed world. We employed combined studies of 3D QSAR, molecular docking which are validated by molecular dynamics simulations and in silico ADME prediction have been performed on Isothiazoloquinolones inhibitors against methicillin resistance Staphylococcus aureus. Three-dimensional quantitative structure-activity relationship (3D-QSAR) study was applied using comparative molecular field analysis (CoMFA) with Q 2 of 0.578, R 2 of 0.988, and comparative molecular similarity indices analysis (CoMSIA) with Q 2 of 0.554, R 2 of 0.975. The predictive ability of these model was determined using a test set of molecules that gave acceptable predictive correlation (r 2 Pred) values 0.55 and 0.57 of CoMFA and CoMSIA respectively. Docking, simulations were employed to position the inhibitors into protein active site to find out the most probable binding mode and most reliable conformations. Developed models and Docking methods provide guidance to design molecules with enhanced activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Rational Design of Single Molybdenum Atoms Anchored on N-Doped Carbon for Effective Hydrogen Evolution Reaction.

    Science.gov (United States)

    Chen, Wenxing; Pei, Jiajing; He, Chun-Ting; Wan, Jiawei; Ren, Hanlin; Zhu, Youqi; Wang, Yu; Dong, Juncai; Tian, Shubo; Cheong, Weng-Chon; Lu, Siqi; Zheng, Lirong; Zheng, Xusheng; Yan, Wensheng; Zhuang, Zhongbin; Chen, Chen; Peng, Qing; Wang, Dingsheng; Li, Yadong

    2017-12-11

    The highly efficient electrochemical hydrogen evolution reaction (HER) provides a promising pathway to resolve energy and environment problems. An electrocatalyst was designed with single Mo atoms (Mo-SAs) supported on N-doped carbon having outstanding HER performance. The structure of the catalyst was probed by aberration-corrected scanning transmission electron microscopy (AC-STEM) and X-ray absorption fine structure (XAFS) spectroscopy, indicating the formation of Mo-SAs anchored with one nitrogen atom and two carbon atoms (Mo 1 N 1 C 2 ). Importantly, the Mo 1 N 1 C 2 catalyst displayed much more excellent activity compared with Mo 2 C and MoN, and better stability than commercial Pt/C. Density functional theory (DFT) calculation revealed that the unique structure of Mo 1 N 1 C 2 moiety played a crucial effect to improve the HER performance. This work opens up new opportunities for the preparation and application of highly active and stable Mo-based HER catalysts. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. The cancer-immunity cycle as rational design for synthetic cancer drugs: Novel DC vaccines and CAR T-cells.

    Science.gov (United States)

    Ramachandran, Mohanraj; Dimberg, Anna; Essand, Magnus

    2017-08-01

    Cell therapy is an advanced form of cancer immunotherapy that has had remarkable clinical progress in the past decade in the search for cure of cancer. Most success has been achieved for chimeric antigen receptor (CAR) T-cells where CAR T-cells targeting CD19 show very high complete response rates for patients with refractory acute B-cell acute lymphoblastic leukemia (ALL) and are close to approval for this indication. CD19 CAR T-cells are also effective against B-cell chronic lymphoblastic leukemia (CLL) and B-cell lymphomas. Although encouraging, CAR T-cells have not yet proven clinically effective for solid tumors. This is mainly due to the lack of specific and homogenously expressed targets to direct the T-cells against and a hostile immunosuppressive tumor microenvironment in solid tumors. Cancer vaccines based on dendritic cells (DC) are also making progress although clinical efficacy is still lacking. The likelihood of success is however increasing now when individual tumors can be sequences and patient-specific neoepitopes identified. Neoepitopes and/or neoantigens can then be included in patient-based DC vaccines. This review discusses recent advancements of DC vaccines and CAR T-cells with emphasis on the cancer-immunity cycle, and current efforts to design novel cell therapies. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  17. Rational design of syn-safencin, a novel linear antimicrobial peptide derived from the circular bacteriocin safencin AS-48.

    Science.gov (United States)

    Fields, Francisco R; Carothers, Katelyn E; Balsara, Rashna D; Ploplis, Victoria A; Castellino, Francis J; Lee, Shaun W

    2018-06-01

    Bacteriocins hold unprecedented promise as a largely untapped source of antibiotic alternatives in the age of multidrug resistance. Here, we describe the first approach to systematically design variants of a novel AS-48 bacteriocin homologue, which we have termed safencin AS-48, from Bacillus safensis, to gain insights into engineering improved activity of bacteriocins. A library of synthetic peptides in which systematic amino acid substitutions to vary the periodicity and abundance of polar, acidic, aliphatic, and hydrophobic residues were generated for a total of 96 novel peptide variants of a single bacteriocin candidate. Using this method, we identified nine synthetic safencin (syn-safencin) variants with broad and potent antimicrobial activities with minimal inhibitory concentrations (MIC) as low as 250 nM against E. coli, P. aeruginosa, X. axonopodis, and S. pyogenes with minimal cytotoxicity to mammalian cells. It is anticipated that the strategies we have developed will serve as general guides for tuning the specificity of a given natural bacteriocin compound for therapeutic specificity.

  18. Current Experience in Testing Mitochondrial Nutrients in Disorders Featuring Oxidative Stress and Mitochondrial Dysfunction: Rational Design of Chemoprevention Trials

    Science.gov (United States)

    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

  19. α-Amino acid containing degradable polymers as functional biomaterials: rational design, synthetic pathway, and biomedical applications.

    Science.gov (United States)

    Sun, Huanli; Meng, Fenghua; Dias, Aylvin A; Hendriks, Marc; Feijen, Jan; Zhong, Zhiyuan

    2011-06-13

    Currently, biomedical engineering is rapidly expanding, especially in the areas of drug delivery, gene transfer, tissue engineering, and regenerative medicine. A prerequisite for further development is the design and synthesis of novel multifunctional biomaterials that are biocompatible and biologically active, are biodegradable with a controlled degradation rate, and have tunable mechanical properties. In the past decades, different types of α-amino acid-containing degradable polymers have been actively developed with the aim to obtain biomimicking functional biomaterials. The use of α-amino acids as building units for degradable polymers may offer several advantages: (i) imparting chemical functionality, such as hydroxyl, amine, carboxyl, and thiol groups, which not only results in improved hydrophilicity and possible interactions with proteins and genes, but also facilitates further modification with bioactive molecules (e.g., drugs or biological cues); (ii) possibly improving materials biological properties, including cell-materials interactions (e.g., cell adhesion, migration) and degradability; (iii) enhancing thermal and mechanical properties; and (iv) providing metabolizable building units/blocks. In this paper, recent developments in the field of α-amino acid-containing degradable polymers are reviewed. First, synthetic approaches to prepare α-amino acid-containing degradable polymers will be discussed. Subsequently, the biomedical applications of these polymers in areas such as drug delivery, gene delivery and tissue engineering will be reviewed. Finally, the future perspectives of α-amino acid-containing degradable polymers will be evaluated.

  20. Rational design of intrinsically ultramicroporous polyimides containing bridgehead-substituted triptycene for highly selective and permeable gas separation membranes

    KAUST Repository

    Swaidan, Raja; Al-Saeedi, Majed; Ghanem, Bader; Litwiller, Eric; Pinnau, Ingo

    2014-01-01

    Highly ultramicroporous, solution-processable polyimides bearing 9,10-bridgehead-substituted triptycene demonstrated the highest BET surface area reported for polyimides (840 m2 g-1) and several new highs in gas selectivity and permeability for hydrogen (1630-3980 barrers, H2/CH4 ∼ 38) and air (230-630 barrers, O 2/N2 = 5.5-5.9) separations. Two new dianhydrides bearing 9,10-diethyl- and 9,10-dipropyltriptycenes indicate that the ultramicroporosity is optimized for fast polymeric sieving with the use of short, bulky isopropyl bridgeheads and methyl-substituted diamines (TrMPD, TMPD, and TMBZ) that increase intrachain rigidity. Mechanically, the triptycene-based analogue of a spirobisindane-based polyimide exhibited 50% increases in both tensile strength at break (94 MPa) and elastic modulus (2460 MPa) with corresponding 90% lower elongations at break (6%) likely due to the ability of highly entangled spiro-based chains to unwind. To guide future polyimide design, structure/property relationships are suggested between the geometry of the contortion center, the diamine and bridgehead substituent, and the mechanical, microstructural, and gas transport properties. © 2014 American Chemical Society.

  1. Rational design and synthesis of water-compatible molecularly imprinted polymers for selective solid phase extraction of amiodarone.

    Science.gov (United States)

    Muhammad, Turghun; Cui, Liu; Jide, Wang; Piletska, Elena V; Guerreiro, Antonio R; Piletsky, Sergey A

    2012-01-04

    Novel water-compatible molecularly imprinted polymers (MIPs) selective for amiodarone (AD) were designed via a new methodology which relies on screening library of non-imprinted polymers (NIPs). The NIP library consisted of eighteen cross-linked co-polymers synthesized from monomers commonly used in molecular imprinting. The binding capacity of each polymer in the library was analyzed in two different solvents. Binding in water was used to assess non-specific (hydrophobic) interactions and binding in an appropriate organic solvent was used to assess specific interactions. A good correlation was found between the screening tests and modeling of monomer-template interactions performed using computational approach. Additionally, analysis of template-monomer interactions was performed using UV-vis spectroscopy. As the result, 4-vinylpyridine (4-VP) was selected as the best monomer for developing MIP for AD. The 4-VP-based polymers demonstrated imprinting factor equal 3.9. The polymers performance in SPE was evaluated using AD and its structural analogues. The recovery of AD was as high as 96% when extracted from spiked phosphate buffer (pH 4.5) solution and 82.1% from spiked serum samples. The developed MIP shown as a material with specific binding to AD, comparing to its structural analogues, 1-(2-diethylaminoethoxy)-2,6-diiodo-4-nitrobenzene and lidocaine, which shown 9.9% and 25.4% of recovery from the buffer solution, correspondingly. We believe that the screening of NIP library could be proposed as an alternative to commonly used computational and combinatorial approaches. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Experimental and Computational Mechanistic Studies Guiding the Rational Design of Molecular Electrocatalysts for Production and Oxidation of Hydrogen

    Energy Technology Data Exchange (ETDEWEB)

    Raugei, Simone [Center for Molecular Electrocatalysis,; Helm, Monte L. [Center for Molecular Electrocatalysis,; Hammes-Schiffer, Sharon [Department of Chemistry, University of Illinois at Urbana—Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United States; Appel, Aaron M. [Center for Molecular Electrocatalysis,; O’Hagan, Molly [Center for Molecular Electrocatalysis,; Wiedner, Eric S. [Center for Molecular Electrocatalysis,; Bullock, R. Morris [Center for Molecular Electrocatalysis,

    2015-11-25

    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.

  3. Experimental and Computational Mechanistic Studies Guiding the Rational Design of Molecular Electrocatalysts for Production and Oxidation of Hydrogen

    Energy Technology Data Exchange (ETDEWEB)

    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.

  4. Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants.

    Science.gov (United States)

    Srinivasan, Bharath; Rodrigues, João V; Tonddast-Navaei, Sam; Shakhnovich, Eugene; Skolnick, Jeffrey

    2017-07-21

    In drug discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug resistance. On the other hand, conventional drug discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein's surface to overcome the above problems. Dihydrofolate reductase, DHFR, is a critical enzyme involved in thymidine and purine nucleotide biosynthesis. Several classes of compounds that are structural analogues of the substrate dihydrofolate have been explored for their antifolate activity. Here, we describe 10 novel small-molecule inhibitors of Escherichia coli DHFR, EcDHFR, belonging to the stilbenoid, deoxybenzoin, and chalcone family of compounds discovered by a combination of pocket-based virtual ligand screening and systematic scaffold hopping. These inhibitors show a unique uncompetitive or noncompetitive inhibition mechanism, distinct from those reported for all known inhibitors of DHFR, indicative of binding to a unique pocket distinct from either substrate or cofactor-binding pockets. Furthermore, we demonstrate that rescue mutants of EcDHFR, with reduced affinity to all known classes of DHFR inhibitors, are inhibited at the same concentration as the wild-type. These compounds also exhibit antibacterial activity against E. coli harboring the drug-resistant variant of DHFR. This discovery is the first report on a novel class of inhibitors targeting a unique pocket on EcDHFR.

  5. Rational design of viscosity reducing mutants of a monoclonal antibody: hydrophobic versus electrostatic inter-molecular interactions.

    Science.gov (United States)

    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.

  6. The rational designed graphene oxide-Fe{sub 2}O{sub 3} composites with low cytotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Dong; Zhao, Haiyan, E-mail: hyzhao@tsinghua.edu.cn; Pei, Jiayun; Wu, Xin; Liu, Yue

    2017-03-01

    Novel two-dimensional materials with a layered structure are of special interest for a variety of promising applications. In current research, the nanostructured graphene oxide-Fe{sub 2}O{sub 3} composite (GO-Fe{sub 2}O{sub 3}) was firstly obtained via a carefully elaborated approach of vacuum freeze-drying. The scanning electron microscopy (SEM) and transmission electron microscope (TEM) images revealed that α-Fe{sub 2}O{sub 3} nanoparticles loaded well on the surfaces of graphene. A series of characterization were performed to further elucidate the as-obtained nanomaterial's physicochemical properties. These results suggested the current route could be further extended to obtain the other kinds of two-dimensional materials based composites. For the sake of extending the potential application of herein achieved graphene composites, its cytotoxicity assessment on HeLa cells was systematically investigated. CCK-8 assay in HeLa cells treated by GO-Fe{sub 2}O{sub 3} showed dose- (1–100 μg/ml) and time- (24–48 h) dependent cytotoxicity, which was comparable to that of GO. The excess generation of intracellular reactive oxygen species (ROS) induced by these nanomaterials was responsible for the cytotoxicity. TEM analysis vividly illustrated GO-Fe{sub 2}O{sub 3} internalized by HeLa cells in endomembrane compartments such as lysosomes, and degraded through autophagic pathway. The detrimental biological consequence accompanied by cell internalization was limited. Based on the above results, it expected to render useful information for the development of new and popular strategies to design graphene-based composites, as well as deep insights into the mechanism of graphene-based composites cytotoxicity for further potential application.

  7. Rationing medical education.

    African Journals Online (AJOL)

    This paper discussed the pros and cons of the application of rationing to medical education and the different ... Different types of rationing exist in healthcare professional education. ... state-of-the-art resources, technology and tutors con-.

  8. Toward the design of new DNA G-quadruplex ligands through rational analysis of polymorphism and binding data.

    Science.gov (United States)

    Artese, Anna; Costa, Giosuè; Distinto, Simona; Moraca, Federica; Ortuso, Francesco; Parrotta, Lucia; Alcaro, Stefano

    2013-10-01

    Human telomeres play a key role in protecting chromosomal ends from fusion events; they are composed of d(TTAGGG) repeats, ranging in size from 3 to 15 kb. They form G-quadruplex DNA structures, stabilized by G-quartets in the presence of cations, and are involved in several biological processes. In particular, a telomere maintenance mechanism is provided by a specialized enzyme called telomerase, a reverse transcriptase able to add multiple copies of the 5'-GGTTAG-3' motif to the end of the G-strand of the telomere and which is over-expressed in the majority of cancer cells. The central cation has a crucial role in maintaining the stability of the structure. Based on its nature, it can be associated with different topological telomeric quadruplexes, which depend also on the orientation of the DNA strands and the syn/anti conformation of the guanines. Such a polymorphism, confirmed by the different structures deposited in the Protein Data Bank (PDB), prompted us to apply a computational protocol in order to investigate the conformational properties of a set of known G-quadruplex ligands and their molecular recognition against six different experimental models of the human telomeric sequence d[AG3(T2AG3)3]. The average AutoDock correlation between theoretical and experimental data yielded an r2 value equal to 0.882 among all the studied models. Such a result was always improved with respect to those of the single folds, with the exception of the parallel structure (r2 equal to 0.886), thus suggesting a key role of this G4 conformation in the stacking interaction network. Among the studied binders, a trisubstituted acridine and a dibenzophenanthroline derivative were well recognized by the parallel and the mixed G-quadruplex structures, allowing the identification of specific key contacts with DNA and the further design of more potent or target specific G-quadruplex ligands. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  9. Towards Cost-Effective Crystalline Silicon Based Flexible Solar Cells: Integration Strategy by Rational Design of Materials, Process, and Devices

    KAUST Repository

    Bahabry, Rabab R.

    2017-11-30

    The solar cells market has an annual growth of more than 30 percent over the past 15 years. At the same time, the cost of the solar modules diminished to meet both of the rapid global demand and the technological improvements. In particular for the crystalline silicon solar cells, the workhorse of this technology. The objective of this doctoral thesis is enhancing the efficiency of c-Si solar cells while exploring the cost reduction via innovative techniques. Contact metallization and ultra-flexible wafer based c-Si solar cells are the main areas under investigation. First, Silicon-based solar cells typically utilize screen printed Silver (Ag) metal contacts which affect the optimal electrical performance. To date, metal silicide-based ohmic contacts are occasionally used for the front contact grid lines. In this work, investigation of the microstructure and the electrical characteristics of nickel monosilicide (NiSi) ohmic contacts on the rear side of c-Si solar cells has been carried out. Significant enhancement in the fill factor leading to increasing the total power conversion efficiency is observed. Second, advanced classes of modern application require a new generation of versatile solar cells showcasing extreme mechanical resilience. However, silicon is a brittle material with a fracture strains <1%. Highly flexible Si-based solar cells are available in the form thin films which seem to be disadvantageous over thick Si solar cells due to the reduction of the optical absorption with less active Si material. Here, a complementary metal oxide semiconductor (CMOS) technology based integration strategy is designed where corrugation architecture to enable an ultra-flexible solar cell module from bulk mono-crystalline silicon solar wafer with 17% efficiency. This periodic corrugated array benefits from an interchangeable solar cell segmentation scheme which preserves the active silicon thickness and achieves flexibility via interdigitated back contacts. These cells

  10. Rationing with baselines

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Moreno-Ternero, Juan D.; Østerdal, Lars Peter Raahave

    2013-01-01

    We introduce a new operator for general rationing problems in which, besides conflicting claims, individual baselines play an important role in the rationing process. The operator builds onto ideas of composition, which are not only frequent in rationing, but also in related problems...... such as bargaining, choice, and queuing. We characterize the operator and show how it preserves some standard axioms in the literature on rationing. We also relate it to recent contributions in such literature....

  11. CONTRIBUTIONS TO RATIONAL APPROXIMATION,

    Science.gov (United States)

    Some of the key results of linear Chebyshev approximation theory are extended to generalized rational functions. Prominent among these is Haar’s...linear theorem which yields necessary and sufficient conditions for uniqueness. Some new results in the classic field of rational function Chebyshev...Furthermore a Weierstrass type theorem is proven for rational Chebyshev approximation. A characterization theorem for rational trigonometric Chebyshev approximation in terms of sign alternation is developed. (Author)

  12. Rational design of hierarchically porous birnessite-type manganese dioxides nanosheets on different one-dimensional titania-based nanowires for high performance supercapacitors

    Science.gov (United States)

    Zhang, Yu Xin; Kuang, Min; Hao, Xiao Dong; Liu, Yan; Huang, Ming; Guo, Xiao Long; Yan, Jing; Han, Gen Quan; Li, Jing

    2014-12-01

    A facile and large-scale strategy of mesoporous birnessite-type manganese dioxide (MnO2) nanosheets on one-dimension (1D) H2Ti3O7 and anatase/TiO2 (B) nanowires (NWs) is developed for high performance supercapacitors. The morphological characteristics of MnO2 nanoflakes on H2Ti3O7 and anatase/TiO2 (B) NWs could be rationally designed with various characteristics (e.g., the sheet thickness, surface area). Interestingly, the MnO2/TiO2 NWs exhibit a more optimized electrochemical performance with specific capacitance of 120 F g-1 at current density of 0.1 A g-1 (based on MnO2 + TiO2) than MnO2/H2Ti3O7 NWs. An asymmetric supercapacitor of MnO2/TiO2//activated graphene (AG) yields a better energy density of 29.8 Wh kg-1 than MnO2/H2Ti3O7//AG asymmetric supercapacitor, while maintaining desirable cycling stability. Indeed, the pseudocapacitive difference is related to the substrates, unique structure and surface area. Especially, the anatase/TiO2 (B) mixed-phase system can provide good electronic conductivity and high utilization of MnO2 nanosheets.

  13. 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.

    Science.gov (United States)

    Castiñeira Reis, Marta; López, Carlos Silva; Kraka, Elfi; Cremer, Dieter; Faza, Olalla Nieto

    2016-09-06

    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.

  14. Rational Design and Synthesis of Carboxylate Gemini Surfactants with an Excellent Aggregate Behavior for Nano-La2O3 Morphology-Controllable Preparation.

    Science.gov (United States)

    Liao, Xueming; Gao, Zhinong; Xia, Yan; Niu, Fei; Zhai, Wenzhong

    2017-04-04

    A series of carboxylate gemini surfactants (CGS, C n -Φ-C n , n = 12, 14, 16, 18) with diphenyl ketone as a spacer group were prepared using a simple and feasible synthetic method. These CGS exhibited an excellent surface activity with extremely low critical micelle concentration (CMC) value (approximately 10 -5 mol/L), good performance in reducing surface tension (nearly 30 mN/m), and the ability of molecular self-assembly into different aggregate morphologies via adjusting the concentrations, which is attributed to the introduction of diphenyl ketone and carboxylic acid ammonium salt in the molecular structure. Moreover, the surface activity and self-assembly ability of CGS were further optimized by tuning the length of the tail chain. These excellent properties imply that CGS can be a soft template to prepare nanomaterials, especially in morphology-controllable synthesis. By adjusting the concentration of one of CGS (C 12 -Φ-C 12 ), nano-La 2 O 3 particles with diverse morphologies were obtained, including spherical shape, bead-chain shape, rod shape, velvet-antler shape, cedar shape, and bowknot shape. This work offers a vital insight into the rational design of template agents for the development of morphology-controllable nanomaterials.

  15. Rational design of hierarchically porous birnessite-type manganese dioxides nanosheets on different one-dimensional titania-based nanowires for high performance supercapacitors

    KAUST Repository

    Zhang, Yu Xin

    2014-12-01

    A facile and large-scale strategy of mesoporous birnessite-type manganese dioxide (MnO2) nanosheets on one-dimension (1D) H2Ti 3O7 and anatase/TiO2 (B) nanowires (NWs) is developed for high performance supercapacitors. The morphological characteristics of MnO2 nanoflakes on H2Ti 3O7 and anatase/TiO2 (B) NWs could be rationally designed with various characteristics (e.g., the sheet thickness, surface area). Interestingly, the MnO2/TiO2 NWs exhibit a more optimized electrochemical performance with specific capacitance of 120 F g-1 at current density of 0.1 A g-1 (based on MnO 2 + TiO2) than MnO2/H2Ti 3O7 NWs. An asymmetric supercapacitor of MnO 2/TiO2//activated graphene (AG) yields a better energy density of 29.8 Wh kg-1 than MnO2/H2Ti 3O7//AG asymmetric supercapacitor, while maintaining desirable cycling stability. Indeed, the pseudocapacitive difference is related to the substrates, unique structure and surface area. Especially, the anatase/TiO2 (B) mixed-phase system can provide good electronic conductivity and high utilization of MnO2 nanosheets. © 2014 Elsevier B.V. All rights reserved.

  16. Rational Design, Synthesis and Evaluation of γ-CD-Containing Cross-Linked Polyvinyl Alcohol Hydrogel as a Prednisone Delivery Platform

    Directory of Open Access Journals (Sweden)

    Adolfo Marican

    2018-03-01

    Full Text Available This study describes the in-silico rational design, synthesis and evaluation of cross-linked polyvinyl alcohol hydrogels containing γ-cyclodextrin (γ-CDHSAs as platforms for the sustained release of prednisone (PDN. Through in-silico studies using semi-empirical quantum mechanical calculations, the effectiveness of 20 dicarboxylic acids to generate a specific cross-linked hydrogel capable of supporting different amounts of γ-cyclodextrin (γ-CD was evaluated. According to the interaction energies calculated with the in-silico studies, the hydrogel made from PVA cross-linked with succinic acids (SA was shown to be the best candidate for containing γ-CD. Later, molecular dynamics simulation studies were performed in order to evaluate the intermolecular interactions between PDN and three cross-linked hydrogel formulations with different proportions of γ-CD (2.44%, 4.76% and 9.1%. These three cross-linked hydrogels were synthesized and characterized. The loading and the subsequent release of PDN from the hydrogels were investigated. The in-silico and experimental results showed that the interaction between PDN and γ-CDHSA was mainly produced with the γ-CDs linked to the hydrogels. Thus, the unique structures and properties of γ-CDHSA demonstrated an interesting multiphasic profile that could be utilized as a promising drug carrier for controlled, sustained and localized release of PDN.

  17. Rational design and synthesis of yolk-shell ZnGa2O4@C nanostructure with enhanced lithium storage properties

    Science.gov (United States)

    Han, Nao; Xia, Yuguo; Han, Yanyang; Jiao, Xiuling; Chen, Dairong

    2018-03-01

    The ability to create hybrid nanostructure with synergistic effect and confined morphology to achieve high performance and long-term stability is high desirable in lithium ion batteries. Although transition metal oxides as anode material reveal high theoretical capacities, the significant volume changes during repeated lithium insertion and extraction cause pulverization of electrode materials, resulting in rapid fade in capacity. Herein, yolk-shell nanostructure of ZnGa2O4 encapsulated by amorphous carbon is rationally designed and synthesized through two-step surface coating followed by thermal treatment and etching process. It is noteworthy that ZnGa2O4@C with yolk-shell structure is superior to pristine ZnGa2O4 and ZnGa2O4@C with core-shell structure in term of lithium storage. The stable reversible capacity of yolk-shell ZnGa2O4@C can be retained at 657.2 mAh g-1 at current density of 1 A g-1 after completion of 300 cycles, which also reveals superior rate performance. The appropriate carbon shell and void space involved in the yolk-shell structure are considered to be the crucial factor in accommodating volume expansion as well as preserving the structural integrity of yolk-shell ZnGa2O4@C.

  18. Rational Design of Bacillus coagulans NL01 l-Arabinose Isomerase and Use of Its F279I Variant in d-Tagatose Production.

    Science.gov (United States)

    Zheng, Zhaojuan; Mei, Wending; Xia, Meijuan; He, Qin; Ouyang, Jia

    2017-06-14

    d-Tagatose is a prospective functional sweetener that can be produced by l-arabinose isomerase (AI) from d-galactose. To improve the activity of AI toward d-galactose, the AI of Bacillus coagulans was rationally designed on the basis of molecular modeling and docking. After alanine scanning and site-saturation mutagenesis, variant F279I that exhibited improved activity toward d-galactose was obtained. The optimal temperature and pH of F279I were determined to be 50 °C and 8.0, respectively. This variant possessed 1.4-fold catalytic efficiency compared with the wild-type (WT) enzyme. The recombinant Escherichia coli overexpressing F279I also showed obvious advantages over the WT in biotransformation. Under optimal conditions, 67.5 and 88.4 g L -1 d-tagatose could be produced from 150 and 250 g L -1 d-galactose, respectively, in 15 h. The biocatalyst constructed in this study presents a promising alternative for large-scale d-tagatose production.

  19. Development of a model for the rational design of molecular imprinted polymer: Computational approach for combined molecular dynamics/quantum mechanics calculations

    International Nuclear Information System (INIS)

    Dong Cunku; Li Xin; Guo Zechong; Qi Jingyao

    2009-01-01

    A new rational approach for the preparation of molecularly imprinted polymer (MIP) based on the combination of molecular dynamics (MD) simulations and quantum mechanics (QM) calculations is described in this work. Before performing molecular modeling, a virtual library of functional monomers was created containing forty frequently used monomers. The MD simulations were first conducted to screen the top three monomers from virtual library in each porogen-acetonitrile, chloroform and carbon tetrachloride. QM simulations were then performed with an aim to select the optimum monomer and progen solvent in which the QM simulations were carried out; the monomers giving the highest binding energies were chosen as the candidate to prepare MIP in its corresponding solvent. The acetochlor, a widely used herbicide, was chosen as the target analyte. According to the theoretical calculation results, the MIP with acetochlor as template was prepared by emulsion polymerization method using N,N-methylene bisacrylamide (MBAAM) as functional monomer and divinylbenzene (DVB) as cross-linker in chloroform. The synthesized MIP was then tested by equilibrium-adsorption method, and the MIP demonstrated high removal efficiency to the acetochlor. Mulliken charge distribution and 1 H NMR spectroscopy of the synthesized MIP provided insight on the nature of recognition during the imprinting process probing the governing interactions for selective binding site formation at a molecular level. We think the computer simulation method first proposed in this paper is a novel and reliable method for the design and synthesis of MIP.

  20. Rational design of a live attenuated dengue vaccine: 2'-o-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques.

    Directory of Open Access Journals (Sweden)

    Roland Züst

    Full Text Available 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.

  1. Rational design of tetraphenylethylene-based luminescent down-shifting molecules: photophysical studies and photovoltaic applications in a CdTe solar cell from small to large units.

    Science.gov (United States)

    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.

  2. Rational design of a bi-layered reduced graphene oxide film on polystyrene foam for solar-driven interfacial water evaporation

    KAUST Repository

    Shi, Le

    2016-12-20

    Solar-driven water evaporation has been emerging as a highly efficient way for utilizing solar energy for clean water production and wastewater treatment. Here we rationally designed and fabricated a bi-layered photothermal membrane with a porous film of reduced graphene oxide (rGO) on the top and polystyrene (PS) foam at the bottom. The top porous rGO layer acts as a light absorber to harvest and convert light efficiently to thermal energy and the bottom PS layer, which purposefully disintegrates water transport channels, acts as an excellent thermal barrier to minimize heat transfer to the nonevaporative bulk water. The optimized bi-layered membrane was able to produce water evaporation rate as high as 1.31 kg m−2 h−1 with light to evaporation conversion efficiency as high as 83%, which makes it a promising photothermal material in the literature. Furthermore, the experiments and theoretical simulation were both conducted to examine the relationship between the overall energy efficiency and the depth of the photothermal material underwater and the experimental and simulations results coincided with each other. Therefore, this work provides systematic evidence in support of the concept of the interfacial heating and shines important light on practical applications of solar-driven processes for clean water production.

  3. Personal Autonomy and Rational Suicide.

    Science.gov (United States)

    Webber, May A.; Shulman, Ernest

    That certain suicides (which can be designated as rational) ought not to be interfered with is closely tied to the notion of the "right to autonomy." Specifically it is because the individual in question has this right that interference is prohibited. A proper understanding of the right to autonomy, while essential to understanding why…

  4. Application of propensity scores to explore the effect of public reporting of medicine use information on rational drug use in China: a quasi-experimental design.

    Science.gov (United States)

    Zhang, Xiaopeng; Wang, Lijun; Zhang, Xinping

    2014-11-11

    Transparency has become a hottest topic and a growing movement in the health care system worldwide. This study used a quasi-experimental design method to explore whether public reporting of medicine use information can improve rational drug use. 20 township hospitals and 274 doctors of City Y in Hubei Province, China were divided into the intervention and control groups on the basis of their characteristics. In the intervention group, the values and rankings of the average expenditure per prescription, percentage of prescriptions requiring antibiotics and percentage of prescriptions requiring injections of each hospital and doctor were publicly released to patients and doctors in an appropriate format monthly. Data were gathered both four months before and after the intervention. Propensity score matching (PSM) was used to minimize the observed covariate (gender, age, experience, education level, title, and monthly income) differences in the doctors' characteristics. 108 pairs of doctors were obtained after PSM. Chi-square test and t-test were employed to explore the effect of public reporting of medicine use information on rational drug use. The study was approved by the Committee of Tongji Medical College, Hua Zhong University of Science and Technology (IORG No: IORG0003571). In baseline, the average expenditure per prescription of the 274 doctors was 42.82 RMB yuan (USD 6.97), the percentage of prescriptions requiring antibiotics was 63.00%, and the percentage of prescriptions requiring injections was 70.79%, all higher than the average of Hubei Province and the standard recommended by WHO. Before the intervention all the three indicators were all comparable (p > 0.05), whereas after the intervention, a significant difference (p < 0.05) was found for the percentage of prescriptions requiring injections between the intervention (64.66%) and control groups (70.52%). Irrational drug use remains a policy issue in township hospitals in the study area. We demonstrated

  5. Public policy, rationality and reason

    Directory of Open Access Journals (Sweden)

    Rodolfo Canto Sáenz

    2015-07-01

    Full Text Available This work suggests the incorporation of practical reason in the design, implementation and evaluation of public policies, alongside instrumental rationality. It takes two proposals that today point in this direction: Rawls distinction between reasonable (practical reason and rational (instrumental reason and what this author calls the CI Procedure (categorical imperative procedure and Habermas model of deliberative democracy. The main conclusion is that the analysis of public policies can not be limited to rather narrow limits of science, but requires the contribution of political and moral philosophy.

  6. Rational drug design for anti-cancer chemotherapy: multi-target QSAR models for the in silico discovery of anti-colorectal cancer agents.

    Science.gov (United States)

    Speck-Planche, Alejandro; Kleandrova, Valeria V; Luan, Feng; Cordeiro, M Natália D S

    2012-08-01

    The discovery of new and more potent anti-cancer agents constitutes one of the most active fields of research in chemotherapy. Colorectal cancer (CRC) is one of the most studied cancers because of its high prevalence and number of deaths. In the current pharmaceutical design of more efficient anti-CRC drugs, the use of methodologies based on Chemoinformatics has played a decisive role, including Quantitative-Structure-Activity Relationship (QSAR) techniques. However, until now, there is no methodology able to predict anti-CRC activity of compounds against more than one CRC cell line, which should constitute the principal goal. In an attempt to overcome this problem we develop here the first multi-target (mt) approach for the virtual screening and rational in silico discovery of anti-CRC agents against ten cell lines. Here, two mt-QSAR classification models were constructed using a large and heterogeneous database of compounds. The first model was based on linear discriminant analysis (mt-QSAR-LDA) employing fragment-based descriptors while the second model was obtained using artificial neural networks (mt-QSAR-ANN) with global 2D descriptors. Both models correctly classified more than 90% of active and inactive compounds in training and prediction sets. Some fragments were extracted from the molecules and their contributions to anti-CRC activity were calculated using mt-QSAR-LDA model. Several fragments were identified as potential substructural features responsible for the anti-CRC activity and new molecules designed from those fragments with positive contributions were suggested and correctly predicted by the two models as possible potent and versatile anti-CRC agents. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Rational Design of Composite Panels

    DEFF Research Database (Denmark)

    Riber, Hans Jørgen

    1996-01-01

    A non-linear structural model for composite panels is presented. The non-linear terms in the lateral displacements are modelled as an additional set of lateral loads acting on the panel. Hence the solution is reduced to that of an equivalent panel with small displacements In order to treat sandwich...... Norske Veritas', DNV, building rules concerning high-speed light craft, in which the panel scantlings are often restricted by a maximum lateral deflection connected with the panel span....

  8. On the road to metallic nanoparticles by rational design: bridging the gap between atomic-level theoretical modeling and reality by total scattering experiments

    Science.gov (United States)

    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

  9. Dissecting the functional role of key residues in triheme cytochrome PpcA: a path to rational design of G. sulfurreducens strains with enhanced electron transfer capabilities.

    Directory of Open Access Journals (Sweden)

    Leonor Morgado

    Full Text Available PpcA is the most abundant member of a family of five triheme cytochromes c7 in the bacterium Geobacter sulfurreducens (Gs and is the most likely carrier of electrons destined for outer surface during respiration on solid metal oxides, a process that requires extracellular electron transfer. This cytochrome has the highest content of lysine residues (24% among the family, and it was suggested to be involved in e-/H(+ energy transduction processes. In the present work, we investigated the functional role of lysine residues strategically located in the vicinity of each heme group. Each lysine was replaced by glutamine or glutamic acid to evaluate the effects of a neutral or negatively charged residue in each position. The results showed that replacing Lys9 (located near heme IV, Lys18 (near heme I or Lys22 (between hemes I and III has essentially no effect on the redox properties of the heme groups and are probably involved in redox partner recognition. On the other hand, Lys43 (near heme IV, Lys52 (between hemes III and IV and Lys60 (near heme III are crucial in the regulation of the functional mechanism of PpcA, namely in the selection of microstates that allow the protein to establish preferential e-/H(+ transfer pathways. The results showed that the preferred e-/H(+ transfer pathways are only established when heme III is the last heme to oxidize, a feature reinforced by a higher difference between its reduction potential and that of its predecessor in the order of oxidation. We also showed that K43 and K52 mutants keep the mechanistic features of PpcA by establishing preferential e-/H+ transfer pathways at lower reduction potential values than the wild-type protein, a property that can enable rational design of Gs strains with optimized extracellular electron transfer capabilities.

  10. Structural Exploration of Quinazolin-4(3H)-ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological Evaluation, and Molecular Docking Studies.

    Science.gov (United States)

    Ugale, Vinod G; Bari, Sanjay B

    2016-11-01

    Anticonvulsants effective against multiple seizures are of wide interest as antiepileptic drugs, especially if active against pharmaco-resistant seizures. Herein, we synthesized 16 different, rationally designed 2-((6,7-dimethoxy-4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-N-(substituted phenyl)acetamides and screened for anticonvulsant activities through in vivo experiments. Compound 4d emerged as prototype with excellent anti-seizure action in mice against electroshock, chemically induced and pharmaco-resistant 6-Hz seizure models with no symptoms of neurotoxicity and hepatotoxicity (ED 50  = 23.5 mg/kg, MES, mice, i.p.; ED 50  = 32.6 mg/kg, scPTZ, mice, i.p.; ED 50  = 45.2 mg/kg, 6-Hz, mice, i.p.; TD 50  = 325.9 mg/kg, mice, i.p.). In addition, investigation of compound 4l in mice for its pharmacological profile proved it as safer anticonvulsant, devoid of the side effects such as motor dysfunction and hepatotoxicity of classical antiepileptic drugs (ED 50  = 26.1 mg/kg, MES, mice, i.p.; ED 50  = 79.4 mg/kg, scPTZ, mice, i.p.; TD 50  = 361.2 mg/kg, mice, i.p.). We also predicted physiochemical and pharmacokinetic properties of structurally optimized quinazolin-4(3H)-ones by a computational protocol. A combination of in vivo anticonvulsant profile, ex vivo toxicity, and in silico studies suggested that the synthesized compounds may be useful as broad-spectrum anti-seizure drug candidates with favorable pharmacokinetic parameters. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Site-directed mutagenesis of α-L-rhamnosidase from Alternaria sp. L1 to enhance synthesis yield of reverse hydrolysis based on rational design.

    Science.gov (United States)

    Xu, Li; Liu, Xiaohong; Yin, Zhenhao; Liu, Qian; Lu, Lili; Xiao, Min

    2016-12-01

    The α-L-rhamnosidase catalyzes the hydrolytic release of rhamnose from polysaccharides and glycosides and is widely used due to its applications in a variety of industrial processes. Our previous work reported that a wild-type α-L-rhamnosidase (RhaL1) from Alternaria sp. L1 could synthesize rhamnose-containing chemicals (RCCs) though reverse hydrolysis reaction with inexpensive rhamnose as glycosyl donor. To enhance the yield of reverse hydrolysis reaction and to determine the amino acid residues essential for the catalytic activity of RhaL1, site-directed mutagenesis of 11 residues was performed in this study. Through rationally designed mutations, the critical amino acid residues which may form direct or solvent-mediated hydrogen bonds with donor rhamnose (Asp 252 , Asp 257 , Asp 264 , Glu 530 , Arg 548 , His 553 , and Trp 555 ) and may form the hydrophobic pocket in stabilizing donor (Trp 261 , Tyr 302 , Tyr 316 , and Trp 369 ) in active-site of RhaL1 were analyzed, and three positive mutants (W261Y, Y302F, and Y316F) with improved product yield stood out. From the three positive variants, mutant W261Y accelerated the reverse hydrolysis with a prominent increase (43.7 %) in relative yield compared to the wild-type enzyme. Based on the 3D structural modeling, we supposed that the improved yield of mutant W261Y is due to the adjustment of the spatial position of the putative catalytic acid residue Asp 257 . Mutant W261Y also exhibited a shift in the pH-activity profile in hydrolysis reaction, indicating that introducing of a polar residue in the active site cavity may affect the catalysis behavior of the enzyme.

  12. Technique on rationalization of using electricity and cases

    International Nuclear Information System (INIS)

    1988-04-01

    This book deals with rationalization of using electric and cases. It is divided into four parts. The first part introduces necessity and of progression rationalization of using electric. The second part describes the technique on rationalization of using electric with management of electric energy. The third part depicts domestic cases of rationalization on using of electric such as substation and motor. The last part also introduces foreign cases of rationalization on using of electric with measure of generator circuit, design of motor, design of lighting and design of other equipment.

  13. Bounded Rationality and Budgeting

    OpenAIRE

    Ibrahim, Mukdad

    2016-01-01

    This article discusses the theory of bounded rationality which had been introduced by Herbert Simon in the 1950s. Simon introduced the notion of bounded rationality stating that while decision-makers strive for rationality, they are limited by the effect of the environment, their information process capacity and by the constraints on their information storage and retrieval capabilities. Moreover, this article tries to specifically blend this notion into budgeting, using the foundations of inc...

  14. Determinants of Actor Rationality

    DEFF Research Database (Denmark)

    Ellegaard, Chris

    Industrial companies must exercise influence on their suppliers (or supplier actors). Actor rationality is a central theme connected to this management task. In this article, relevant literature is studied with the purpose of shedding light on determinants of actor rationality. Two buyer-supplier...... relations are investigated in a multiple case study, leading to the proposal of various additional factors that determine and shape actor rationality. Moreover a conceptual model of rationality determinants in the buyer-supplier relation is proposed, a model that may help supply managers analyse...

  15. Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3

    DEFF Research Database (Denmark)

    Bunch, Lennart; Nielsen, Birgitte; Jensen, Anders A.

    2006-01-01

    The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S)-pyroglut......The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S...

  16. Guidelines for Rational Cancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Byunghee Yoo

    2017-12-01

    Full Text Available Traditionally, cancer therapy has relied on surgery, radiation therapy, and chemotherapy. In recent years, these interventions have become increasingly replaced or complemented by more targeted approaches that are informed by a deeper understanding of the underlying biology. Still, the implementation of fully rational patient-specific drug design appears to be years away. Here, we present a vision of rational drug design for cancer that is defined by two major components: modularity and image guidance. We suggest that modularity can be achieved by combining a nanocarrier and an oligonucleotide component into the therapeutic. Image guidance can be incorporated into the nanocarrier component by labeling with a specific imaging reporter, such as a radionuclide or contrast agent for magnetic resonance imaging. While limited by the need for additional technological advancement in the areas of cancer biology, nanotechnology, and imaging, this vision for the future of cancer therapy can be used as a guide to future research endeavors.

  17. NMR investigations of structural and dynamics features of natively unstructured drug peptide - salmon calcitonin: implication to rational design of potent sCT analogs.

    Science.gov (United States)

    Rawat, Atul; Kumar, Dinesh

    2013-01-01

    Backbone dynamics and conformational properties of drug peptide salmon calcitonin have been studied in aqueous solution using nuclear magnetic resonance (NMR). Although salmon calcitonin (sCT) is largely unfolded in solution (as has been reported in several circular dichroism studies), the secondary H(α) chemical shifts and three bond H(N) -H(α) coupling constants indicated that most of the residues of the peptide are populating the α-helical region of the Ramachandran (ϕ, ψ) map. Further, the peptide in solution has been found to exhibit multiple conformational states exchanging slowly on the NMR timescale (10(2) -10(3)  s(-1) ), inferred by the multiple chemical shift assignments in the region Leu4-Leu12 and around Pro23 (for residues Gln20-Tyr22 and Arg24). Possibly, these slowly exchanging multiple conformational states might inhibit symmetric self-association of the peptide and, in part, may account for its reduced aggregation propensity compared with human calcitonin (which lacks this property). The (15) N NMR-relaxation data revealed (i) the presence of slow (microsecond-to-millisecond) timescale dynamics in the N-terminal region (Cys1-Ser5) and core residues His17 and Asn26 and (ii) the presence of high frequency (nanosecond-to-picosecond) motions in the C-terminal arm. Put together, the various results suggested that (i) the flexible C-terminal of sCT (from Thr25-Thr31) is involved in identification of specific target receptors, (ii) whereas the N-terminal of sCT (from Cys1-Gln20) in solution - exhibiting significant amount of conformational plasticity and strong bias towards biologically active α-helical structure - facilitates favorable conformational adaptations while interacting with the intermembrane domains of these target receptors. Thus, we believe that the structural and dynamics features of sCT presented here will be useful guiding attributes for the rational design of biologically active sCT analogs. Copyright © 2012 European Peptide

  18. Relative Contribution of Th1 and Th17 Cells in Adaptive Immunity to Bordetella pertussis: Towards the Rational Design of an Improved Acellular Pertussis Vaccine

    Science.gov (United States)

    Ross, Pádraig J.; Allen, Aideen C.; Walsh, Kevin; Misiak, Alicja; Lavelle, Ed C.; McLoughlin, Rachel M.; Mills, Kingston H. G.

    2013-01-01

    Whooping cough caused by Bordetella pertussis is a re-emerging infectious disease despite the introduction of safer acellular pertussis vaccines (Pa). One explanation for this is that Pa are less protective than the more reactogenic whole cell pertussis vaccines (Pw) that they replaced. Although Pa induce potent antibody responses, and protection has been found to be associated with high concentrations of circulating IgG against vaccine antigens, it has not been firmly established that host protection induced with this vaccine is mediated solely by humoral immunity. The aim of this study was to examine the relative contribution of Th1 and Th17 cells in host immunity to infection with B. pertussis and in immunity induced by immunization with Pw and Pa and to use this information to help rationally design a more effective Pa. Our findings demonstrate that Th1 and Th17 both function in protective immunity induced by infection with B. pertussis or immunization with Pw. In contrast, a current licensed Pa, administered with alum as the adjuvant, induced Th2 and Th17 cells, but weak Th1 responses. We found that IL-1 signalling played a central role in protective immunity induced with alum-adsorbed Pa and this was associated with the induction of Th17 cells. Pa generated strong antibody and Th2 responses, but was fully protective in IL-4-defective mice, suggesting that Th2 cells were dispensable. In contrast, Pa failed to confer protective immunity in IL-17A-defective mice. Bacterial clearance mediated by Pa-induced Th17 cells was associated with cell recruitment to the lungs after challenge. Finally, protective immunity induced by an experimental Pa could be enhanced by substituting alum with a TLR agonist that induces Th1 cells. Our findings demonstrate that alum promotes protective immunity through IL-1β-induced IL-17A production, but also reveal that optimum protection against B. pertussis requires induction of Th1, but not Th2 cells. PMID:23592988

  19. Two Concepts of Rationality

    Directory of Open Access Journals (Sweden)

    Danny Frederick

    2010-02-01

    Full Text Available The dominant tradition in Western philosophy sees rationality as dictating. Thus rationality may require that we believe the best explanation and simple conceptual truths and that we infer in accordance with evident rules of inference. I argue that, given what we know about the growth of knowledge, this authoritarian concept of rationality leads to absurdities and should be abandoned. I then outline a libertarian concept of rationality, derived from Popper, which eschews the dictates and which sees a rational agent as one who questions, criticises, conjectures and experiments. I argue that, while the libertarian approach escapes the absurdities of the authoritarian, it requires two significant developments and an important clarification to be made fully consistent with itself.

  20. Exploring rationality in schizophrenia

    DEFF Research Database (Denmark)

    Revsbech, Rasmus; Mortensen, Erik Lykke; Owen, Gareth

    2015-01-01

    Background Empirical studies of rationality (syllogisms) in patients with schizophrenia have obtained different results. One study found that patients reason more logically if the syllogism is presented through an unusual content. Aims To explore syllogism-based rationality in schizophrenia. Meth...... differences became non-significant. Conclusions When taking intelligence and neuropsychological performance into account, patients with schizophrenia and controls perform similarly on syllogism tests of rationality.......Background Empirical studies of rationality (syllogisms) in patients with schizophrenia have obtained different results. One study found that patients reason more logically if the syllogism is presented through an unusual content. Aims To explore syllogism-based rationality in schizophrenia. Method...... Thirty-eight first-admitted patients with schizophrenia and 38 healthy controls solved 29 syllogisms that varied in presentation content (ordinary v. unusual) and validity (valid v. invalid). Statistical tests were made of unadjusted and adjusted group differences in models adjusting for intelligence...

  1. Irrational Rationality of Terrorism

    Directory of Open Access Journals (Sweden)

    Robert Nalbandov

    2013-12-01

    Full Text Available The present article deals with the ontological problem of applying the rational choice frameworks to the study of terrorism. It testing the application of the rational choice to the “old” (before the end of the Cold War and the “new” (after the end of the Cold War terrorisms. It starts with analyzing the fundamentals of rationality and applies it at two levels: the individual (actors and group (collective via two outlooks: tactical (short-term and strategic (long-term. The main argument of the article is that while the “old” terrorism can be explained by the rational choice theory its “new” version represents a substantial departure from rationality.

  2. Respect for rational autonomy.

    Science.gov (United States)

    Walker, Rebecca L

    2009-12-01

    The standard notion of autonomy in medical ethics does not require that autonomous choices not be irrational. The paper gives three examples of seemingly irrational patient choices and discusses how a rational autonomy analysis differs from the standard view. It then considers whether a switch to the rational autonomy view would lead to overriding more patient decisions but concludes that this should not be the case. Rather, a determination of whether individual patient decisions are autonomous is much less relevant than usually considered in determining whether health care providers must abide by these decisions. Furthermore, respect for rational autonomy entails strong positive requirements of respect for the autonomy of the person as a rational decision maker. The rationality view of autonomy is conceptually stronger than the standard view, allows for a more nuanced understanding of the practical moral calculus involved in respecting patient autonomy, and promotes positive respect for patient autonomy.

  3. Bilayer porous scaffold based on poly-(ε-caprolactone) nanofibrous membrane and gelatin sponge for favoring cell proliferation

    International Nuclear Information System (INIS)

    Zhou Zhihua; Zhou Yang; Chen Yiwang; Nie Huarong; Wang Yang; Li Fan; Zheng Yan

    2011-01-01

    Electrospun poly-(ε-caprolactone) (PCL) nanofibers has been widely used in the medical prosthesis. However, poor hydrophilicity and the lack of natural recognition sites for covalent cell-recognition signal molecules to promote cell attachment have limited its utility as tissue scaffolds. In this study, Bilayer porous scaffolds based on PCL electrospun membranes and gelatin (GE) sponges were fabricated through soft hydrolysis of PCL electrospun followed by grafting gelatin onto the fiber surface, through crosslinking and freeze drying treatment of additional gelatin coat and grafted gelatin surface. GE sponges were stably anchored on PCL membrane surface with the aid of grafted GE molecules. The morphologies of bilayer porous scaffolds were observed through SEM. The contact angle of the scaffolds was 0°, the mechanical properties of scaffolds were measured by tensile test, Young's moduli of PCL scaffolds before and after hydrolysis are 66-77.3 MPa and 62.3-75.4 MPa, respectively. Thus, the bilayer porous scaffolds showed excellent hydrophilic surface and desirable mechanical strength due to the soft hydrolysis and GE coat. The cell culture results showed that the adipose derived mesenchymal stem cells did more favor to adhere and grow on the bilayer porous scaffolds than on PCL electrospun membranes. The better cell affinity of the final bilayer scaffolds not only attributed to the surface chemistry but also the introduction of bilayer porous structure.

  4. Bilayer porous scaffold based on poly-({epsilon}-caprolactone) nanofibrous membrane and gelatin sponge for favoring cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Zhou Zhihua; Zhou Yang [Department of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China); Chen Yiwang, E-mail: ywchen@ncu.edu.cn [Department of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China); Institute of Polymers, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China); Nie Huarong, E-mail: niehr@iccas.ac.cn [Institute of Polymers, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China); Wang Yang [First Affiliated Hospital, Nanchang University, 17 Yongwaizheng Road, Nanchang 330006 (China); Li Fan; Zheng Yan [Institute of Polymers, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China)

    2011-12-15

    Electrospun poly-({epsilon}-caprolactone) (PCL) nanofibers has been widely used in the medical prosthesis. However, poor hydrophilicity and the lack of natural recognition sites for covalent cell-recognition signal molecules to promote cell attachment have limited its utility as tissue scaffolds. In this study, Bilayer porous scaffolds based on PCL electrospun membranes and gelatin (GE) sponges were fabricated through soft hydrolysis of PCL electrospun followed by grafting gelatin onto the fiber surface, through crosslinking and freeze drying treatment of additional gelatin coat and grafted gelatin surface. GE sponges were stably anchored on PCL membrane surface with the aid of grafted GE molecules. The morphologies of bilayer porous scaffolds were observed through SEM. The contact angle of the scaffolds was 0 Degree-Sign , the mechanical properties of scaffolds were measured by tensile test, Young's moduli of PCL scaffolds before and after hydrolysis are 66-77.3 MPa and 62.3-75.4 MPa, respectively. Thus, the bilayer porous scaffolds showed excellent hydrophilic surface and desirable mechanical strength due to the soft hydrolysis and GE coat. The cell culture results showed that the adipose derived mesenchymal stem cells did more favor to adhere and grow on the bilayer porous scaffolds than on PCL electrospun membranes. The better cell affinity of the final bilayer scaffolds not only attributed to the surface chemistry but also the introduction of bilayer porous structure.

  5. Edible Scaffolds Based on Non-Mammalian Biopolymers for Myoblast Growth

    Directory of Open Access Journals (Sweden)

    Javier Enrione

    2017-12-01

    Full Text Available In vitro meat has recently emerged as a new concept in food biotechnology. Methods to produce in vitro meat generally involve the growth of muscle cells that are cultured on scaffolds using bioreactors. Suitable scaffold design and manufacture are critical to downstream culture and meat production. Most current scaffolds are based on mammalian-derived biomaterials, the use of which is counter to the desire to obviate mammal slaughter in artificial meat production. Consequently, most of the knowledge is related to the design and control of scaffold properties based on these mammalian-sourced materials. To address this, four different scaffold materials were formulated using non-mammalian sources, namely, salmon gelatin, alginate, and additives including gelling agents and plasticizers. The scaffolds were produced using a freeze-drying process, and the physical, mechanical, and biological properties of the scaffolds were evaluated. The most promising scaffolds were produced from salmon gelatin, alginate, agarose, and glycerol, which exhibited relatively large pore sizes (~200 μm diameter and biocompatibility, permitting myoblast cell adhesion (~40% and growth (~24 h duplication time. The biodegradation profiles of the scaffolds were followed, and were observed to be less than 25% after 4 weeks. The scaffolds enabled suitable myogenic response, with high cell proliferation, viability, and adequate cell distribution throughout. This system composed of non-mammalian edible scaffold material and muscle-cells is promising for the production of in vitro meat.

  6. Development of biodegradable scaffolds based on magnetically guided assembly of magnetic sugar particles.

    Science.gov (United States)

    Hu, Chengzhi; Uchida, Tomoyuki; Tercero, Carlos; Ikeda, Seiichi; Ooe, Katsutoshi; Fukuda, Toshio; Arai, Fumihito; Negoro, Makoto; Kwon, Guiryong

    2012-05-31

    Biodegradable scaffolds with controlled pore layout and porosity have great significance in tissue engineering for cell penetration, tissue ingrowth, vascularization, and nutrient delivery. Porogen leaching has been commonly used to control pore size, pore structure and porosity in the scaffold. In this paper we focus on the use/development of two magnetically guided porogen assembly methods using magnetic sugar particles (MSPs) for scaffold fabrication. First, a patterning device is utilized to align MSPs following designed templates. Then a magnetic sheet film is fabricated by mixing poly(vinyl alcohol, PVA) and NdFeB powder for steering the MSPs. After poly(l-lactide-co-ɛ-caprolactone) (PLCL) casting and removal of the sugar template, a scaffold with spherical pores is obtained. The surface and the inner structure of the scaffolds are evaluated using light and electron micrographs showing their interconnection of pores, pore wall morphology and porosity. Single layer scaffolds with the size of 8mm in width and 10mm in length were constructed with controllable pore diameters in the ranges of 105-150 μm, 250-300 μm and 425-500 μm. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. [Rational use of medicines].

    Science.gov (United States)

    Helali, A

    2006-12-01

    Every body speaks about inappropriate use of medicines and each one gives his own explanation. Politicians are telling about the waste of medicines and the money of their national budget. Citizens are saying that the physicians prescribe more than necessary for treatment and blame them as one part of the financial burden weighting on their family budget. Physicians give different explanation and think that the rational use of medicines is a sort of pressure to limit their freedom to prescribe what it seems to them necessary and better for their patients. Pharmacists dispensing medicines consider the prescription as a physician's prerogative and prefer to stay neutral in this debate. Within this large range of opinions, it is difficult to find general consensus, so that every body take care to not declare his proper opinion about the subject, the causes and the adequate solutions. Finally no changes take place in this issue. However, neither the government as responsible for the citizen's health, nor the health professionals and international organisations, are facing their complete obligations toward the populations by ensuring to them that the medicines are administered according to the health need of the patients, efficacious and safe , in doses that meet their own individual requirements, for an adequate period of time, and at the lower cost, and be secured against misuse by the pharmacist before the delivery to the patients. This is a worthwhile programme, but unfortunately without designate takers or promoters until now.

  8. Rational points on varieties

    CERN Document Server

    Poonen, Bjorn

    2017-01-01

    This book is motivated by the problem of determining the set of rational points on a variety, but its true goal is to equip readers with a broad range of tools essential for current research in algebraic geometry and number theory. The book is unconventional in that it provides concise accounts of many topics instead of a comprehensive account of just one-this is intentionally designed to bring readers up to speed rapidly. Among the topics included are Brauer groups, faithfully flat descent, algebraic groups, torsors, étale and fppf cohomology, the Weil conjectures, and the Brauer-Manin and descent obstructions. A final chapter applies all these to study the arithmetic of surfaces. The down-to-earth explanations and the over 100 exercises make the book suitable for use as a graduate-level textbook, but even experts will appreciate having a single source covering many aspects of geometry over an unrestricted ground field and containing some material that cannot be found elsewhere. The origins of arithmetic (o...

  9. Plural rationalities and risk

    International Nuclear Information System (INIS)

    James, P.; Thompson, M.

    1989-01-01

    Like many social scientists, we attribute public unwillingness to accept certain low probability risks not to 'irrationality' but rather to the everyday application of qualitative as well as quantitative criteria. Just as most people buying a video or hi-fi do not base their decision solely on price or performance data but also consider such intangibles as design and the reputation of the manufacturer, individuals faced with a given risk take into account not merely the probability of harm but also the credibility and trustworthiness of whoever generates the information and manages the safety and other precautions which ensure its accuracy. To analyse these qualitative dimensions we utilise the grid/-group methodology developed by the cultural anthropologist Mary Douglas, and her co-workers. Douglas identifies four basic forms of society and four associated 'thought worlds' which serve to legitimise and reproduce them. Differences in concepts of human cognition, time and many other variables between the different thought worlds are so profound that they can be regarded as different kinds of rationality. The acceptability of risks is partially determined by the extent to which they support or threaten the existence of the different societies. (author)

  10. MRI evaluation of a new scaffold-based allogenic chondrocyte implantation for cartilage repair

    International Nuclear Information System (INIS)

    Dhollander, A.A.M.; Huysse, W.C.J.; Verdonk, P.C.M.; Verstraete, K.L.; Verdonk, R.; Verbruggen, G.; Almqvist, K.F.

    2010-01-01

    Aim: The present study was designed to evaluate the implantation of alginate beads containing human mature allogenic chondrocytes for the treatment of symptomatic cartilage defects of the knee. MRI was used for the morphological analysis of cartilage repair. The correlation between MRI findings and clinical outcome was also studied. Methods: A biodegradable, alginate-based biocompatible scaffold containing human mature allogenic chondrocytes was used for the treatment of symptomatic chondral and osteochondral lesions in the knee. Twenty-one patients were prospectively evaluated with use of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Visual Analogue Scale (VAS) for pain preoperatively and at 3, 6, 9 and 12 months of follow-up. Of the 21 patients, 12 had consented to follow the postoperative MRI evaluation protocol. MRI data were analyzed based on the original MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) and modified MOCART scoring system. The correlation between the clinical outcome and MRI findings was evaluated. Results: A statistically significant clinical improvement became apparent after 6 months and patients continued to improve during the 12 months of follow-up. One of the two MRI scoring systems that were used, showed a statistically significant deterioration of the repair tissue at 1 year of follow-up. Twelve months after the operation complete filling or hypertrophy was found in 41.6%. Bone-marrow edema and effusion were seen in 41.7% and 25% of the study patients, respectively. We did not find a consistent correlation between the MRI criteria and the clinical results. Discussion: The present study confirmed the primary role of MRI in the evaluation of cartilage repair. Two MOCART-based scoring systems were used in a longitudinal fashion and allowed a practical and morphological evaluation of the repair tissue. However, the correlation between clinical outcome and MRI findings was poor. Further

  11. MRI evaluation of a new scaffold-based allogenic chondrocyte implantation for cartilage repair

    Energy Technology Data Exchange (ETDEWEB)

    Dhollander, A.A.M., E-mail: Aad.Dhollander@Ugent.b [Department of Orthopaedic Surgery and Traumatology, Ghent University Hospital, De Pintelaan 185, 1P5, B9000 Gent (Belgium); Huysse, W.C.J., E-mail: Wouter.Huysse@Ugent.b [Department of Radiology, Ghent University Hospital, De Pintelaan 185, -1K12 IB, B9000 Gent (Belgium); Verdonk, P.C.M., E-mail: pverdonk@yahoo.co [Department of Orthopaedic Surgery and Traumatology, Ghent University Hospital, De Pintelaan 185, 1P5, B9000 Gent (Belgium); Verstraete, K.L., E-mail: Koenraad.Verstraete@Ugent.b [Department of Radiology, Ghent University Hospital, De Pintelaan 185, -1K12 IB, B9000 Gent (Belgium); Verdonk, R., E-mail: Rene.Verdonk@Ugent.b [Department of Orthopaedic Surgery and Traumatology, Ghent University Hospital, De Pintelaan 185, 1P5, B9000 Gent (Belgium); Verbruggen, G., E-mail: Gust.Verbruggen@Ugent.b [Laboratory of Connective Tissue Biology, Department of Rheumatology, Ghent University Hospital, De Pintelaan 185, Ghent (Belgium); Almqvist, K.F., E-mail: Fredrik.Almqvist@Ugent.b [Department of Orthopaedic Surgery and Traumatology, Ghent University Hospital, De Pintelaan 185, 1P5, B9000 Gent (Belgium)

    2010-07-15

    Aim: The present study was designed to evaluate the implantation of alginate beads containing human mature allogenic chondrocytes for the treatment of symptomatic cartilage defects of the knee. MRI was used for the morphological analysis of cartilage repair. The correlation between MRI findings and clinical outcome was also studied. Methods: A biodegradable, alginate-based biocompatible scaffold containing human mature allogenic chondrocytes was used for the treatment of symptomatic chondral and osteochondral lesions in the knee. Twenty-one patients were prospectively evaluated with use of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Visual Analogue Scale (VAS) for pain preoperatively and at 3, 6, 9 and 12 months of follow-up. Of the 21 patients, 12 had consented to follow the postoperative MRI evaluation protocol. MRI data were analyzed based on the original MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) and modified MOCART scoring system. The correlation between the clinical outcome and MRI findings was evaluated. Results: A statistically significant clinical improvement became apparent after 6 months and patients continued to improve during the 12 months of follow-up. One of the two MRI scoring systems that were used, showed a statistically significant deterioration of the repair tissue at 1 year of follow-up. Twelve months after the operation complete filling or hypertrophy was found in 41.6%. Bone-marrow edema and effusion were seen in 41.7% and 25% of the study patients, respectively. We did not find a consistent correlation between the MRI criteria and the clinical results. Discussion: The present study confirmed the primary role of MRI in the evaluation of cartilage repair. Two MOCART-based scoring systems were used in a longitudinal fashion and allowed a practical and morphological evaluation of the repair tissue. However, the correlation between clinical outcome and MRI findings was poor. Further

  12. History of Economic Rationalities

    DEFF Research Database (Denmark)

    This book concentrates upon how economic rationalities have been embedded into particular historical practices, cultures, and moral systems. Through multiple case-studies, situated in different historical contexts of the modern West, the book shows that the development of economic rationalities...... takes place in the meeting with other regimes of thought, values, and moral discourses. The book offers new and refreshing insights, ranging from the development of early economic thinking to economic aspects and concepts in the works of classical thinkers such as Thomas Hobbes, John Locke and Karl Marx......, to the role of economic reasoning in contemporary policies of art and health care. With economic rationalities as the read thread, the reader is offered a unique chance of historical self-awareness and recollection of how economic rationality became the powerful ideological and moral force that it is today....

  13. Rationing medical education.

    African Journals Online (AJOL)

    This paper discussed the pros and cons of the application of rationing to medical education and the different ... Even though some stakeholders in medical education might be taken aback at .... Walsh K. Online educational tools to improve the.

  14. Crab Rationalization Permit Program

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Crab Rationalization Program (Program) allocates BSAI crab resources among harvesters, processors, and coastal communities. The North Pacific Fishery Management...

  15. THE HICKSIAN RATIONAL CONSUMER

    OpenAIRE

    Manuel FERNÁNDEZ-GRELA

    2005-01-01

    The aim of this paper is to trace the evolution of the concept of ''rational consumer'' in Hicks's writings. After being one of the pioneers in the introduction of rationality assumptions about consumer behaviour in economic models, Hicks gradually developed a sceptical view about some of the uses to which those assumptions were put into. The focus of the paper is on continuity in Hicksian views, providing a picture of gradual changes in the long series of Hicks's works

  16. Biocomposite scaffolds based on electrospun poly(3-hydroxybutyrate) nanofibers and electrosprayed hydroxyapatite nanoparticles for bone tissue engineering applications

    International Nuclear Information System (INIS)

    Ramier, Julien; Bouderlique, Thibault; Stoilova, Olya; Manolova, Nevena; Rashkov, Iliya; Langlois, Valérie; Renard, Estelle; Albanese, Patricia; Grande, Daniel

    2014-01-01

    The electrospinning technique combined with the electrospraying process provides a straightforward and versatile approach for the fabrication of novel nanofibrous biocomposite scaffolds with structural, mechanical, and biological properties potentially suitable for bone tissue regeneration. In this comparative investigation, three types of poly(3-hydroxybutyrate) (PHB)-based scaffolds were engineered: (i) PHB mats by electrospinning of a PHB solution, (ii) mats of PHB/hydroxyapatite nanoparticle (nHA) blends by electrospinning of a mixed solution containing PHB and nHAs, and (iii) mats constituted of PHB nanofibers and nHAs by simultaneous electrospinning of a PHB solution and electrospraying of a nHA dispersion. Scaffolds based on PHB/nHA blends displayed improved mechanical properties compared to those of neat PHB mats, due to the incorporation of nHAs within the fibers. The electrospinning/electrospraying approach afforded biocomposite scaffolds with lower mechanical properties, due to their higher porosity, but they displayed slightly better biological properties. In the latter case, the bioceramic, i.e. nHAs, largely covered the fiber surface, thus allowing for a direct exposure to cells. The 21 day-monitoring through the use of MTS assays and SEM analyses demonstrated that human mesenchymal stromal cells (hMSCs) remained viable on PHB/nHA biocomposite scaffolds and proliferated continuously until reaching confluence. - Highlights: • Three different types of PHB-based scaffolds are engineered and thoroughly investigated. • The combination of electrospinning and electrospraying affords original nanofibrous biocomposite scaffolds. • PHB-based scaffolds show a strong capability of supporting viable cell development for 21 days

  17. Biocomposite scaffolds based on electrospun poly(3-hydroxybutyrate) nanofibers and electrosprayed hydroxyapatite nanoparticles for bone tissue engineering applications

    Energy Technology Data Exchange (ETDEWEB)

    Ramier, Julien [Institut de Chimie et des Matériaux Paris-Est, UMR 7182 CNRS, Université Paris-Est Créteil, 2, rue Henri Dunant, 94320 Thiais (France); Bouderlique, Thibault [Laboratoire “Croissance, Réparation et Régénération Tissulaires”, EAC 7149 CNRS, Université Paris-Est Créteil, 61, avenue du Général de Gaulle, 94010 Créteil (France); Stoilova, Olya; Manolova, Nevena; Rashkov, Iliya [Laboratory of Bioactive Polymers, Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev St., bl. 103A, BG-1113 Sofia (Bulgaria); Langlois, Valérie; Renard, Estelle [Institut de Chimie et des Matériaux Paris-Est, UMR 7182 CNRS, Université Paris-Est Créteil, 2, rue Henri Dunant, 94320 Thiais (France); Albanese, Patricia [Laboratory of Bioactive Polymers, Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev St., bl. 103A, BG-1113 Sofia (Bulgaria); Grande, Daniel, E-mail: grande@icmpe.cnrs.fr [Institut de Chimie et des Matériaux Paris-Est, UMR 7182 CNRS, Université Paris-Est Créteil, 2, rue Henri Dunant, 94320 Thiais (France)

    2014-05-01

    The electrospinning technique combined with the electrospraying process provides a straightforward and versatile approach for the fabrication of novel nanofibrous biocomposite scaffolds with structural, mechanical, and biological properties potentially suitable for bone tissue regeneration. In this comparative investigation, three types of poly(3-hydroxybutyrate) (PHB)-based scaffolds were engineered: (i) PHB mats by electrospinning of a PHB solution, (ii) mats of PHB/hydroxyapatite nanoparticle (nHA) blends by electrospinning of a mixed solution containing PHB and nHAs, and (iii) mats constituted of PHB nanofibers and nHAs by simultaneous electrospinning of a PHB solution and electrospraying of a nHA dispersion. Scaffolds based on PHB/nHA blends displayed improved mechanical properties compared to those of neat PHB mats, due to the incorporation of nHAs within the fibers. The electrospinning/electrospraying approach afforded biocomposite scaffolds with lower mechanical properties, due to their higher porosity, but they displayed slightly better biological properties. In the latter case, the bioceramic, i.e. nHAs, largely covered the fiber surface, thus allowing for a direct exposure to cells. The 21 day-monitoring through the use of MTS assays and SEM analyses demonstrated that human mesenchymal stromal cells (hMSCs) remained viable on PHB/nHA biocomposite scaffolds and proliferated continuously until reaching confluence. - Highlights: • Three different types of PHB-based scaffolds are engineered and thoroughly investigated. • The combination of electrospinning and electrospraying affords original nanofibrous biocomposite scaffolds. • PHB-based scaffolds show a strong capability of supporting viable cell development for 21 days.

  18. Design and Evaluation of an Energy-Dense, Light-Weight Combat Ration to Sustain Land Forces Involved in High-Intensity, Short-Duration Operations

    Science.gov (United States)

    2015-03-01

    group sessions centred on popular jack rations such as retorted fish and salami-type items as well as noodles , other pasta, confectionery and energy...Amount consumed Consumed Partially consumed Not consumed nil response Palatability 0% 20% 40% 60% 80% 100% Coffee, Instant Tea bag SCM sugar Pe rc... Instant Tea bag SCM sugar Pe rc en t o f r es po nd an ts Too much Enough Not enough nil response Amount consumed 0% 20% 40% 60% 80% 100% Coffee, Instant

  19. Design, development, mechanistic elucidation, and rational optimization of a tandem Ireland Claisen/Cope rearrangement reaction for rapid access to the (iso)cyclocitrinol core.

    Science.gov (United States)

    Plummer, Christopher W; Wei, Carolyn S; Yozwiak, Carrie E; Soheili, Arash; Smithback, Sara O; Leighton, James L

    2014-07-16

    An approach to the synthesis of the (iso)cyclocitrinol core structure is described. The key step is a tandem Ireland Claisen/Cope rearrangement sequence, wherein the Ireland Claisen rearrangement effects ring contraction to a strained 10-membered ring, and that strain in turn drives the Cope rearrangement under unusually mild thermal conditions. A major side product was identified as resulting from an unexpected and remarkably facile [1,3]-sigmatropic rearrangement, and a tactic to disfavor the [1,3] pathway and increase the efficiency of the tandem reaction was rationally devised.

  20. Development of a Rational Design Space for Optimizing Mixing Conditions for Formation of Adhesive Mixtures for Dry-Powder Inhaler Formulations.

    Science.gov (United States)

    Sarkar, Saurabh; Minatovicz, Bruna; Thalberg, Kyrre; Chaudhuri, Bodhisattwa

    2017-01-01

    The purpose of the present study was to develop guidance toward rational choice of blenders and processing conditions to make robust and high performing adhesive mixtures for dry-powder inhalers and to develop quantitative experimental approaches for optimizing the process. Mixing behavior of carrier (LH100) and AstraZeneca fine lactose in high-shear and low-shear double cone blenders was systematically investigated. Process variables impacting the mixing performance were evaluated for both blenders. The performance of the blenders with respect to the mixing time, press-on forces, static charging, and abrasion of carrier fines was monitored, and for some of the parameters, distinct differences could be detected. A comparison table is presented, which can be used as a guidance to enable rational choice of blender and process parameters based on the user requirements. Segregation of adhesive mixtures during hopper discharge was also investigated. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  1. Geometric Rationalization for Freeform Architecture

    KAUST Repository

    Jiang, Caigui

    2016-06-20

    The emergence of freeform architecture provides interesting geometric challenges with regards to the design and manufacturing of large-scale structures. To design these architectural structures, we have to consider two types of constraints. First, aesthetic constraints are important because the buildings have to be visually impressive. Sec- ond, functional constraints are important for the performance of a building and its e cient construction. This thesis contributes to the area of architectural geometry. Specifically, we are interested in the geometric rationalization of freeform architec- ture with the goal of combining aesthetic and functional constraints and construction requirements. Aesthetic requirements typically come from designers and architects. To obtain visually pleasing structures, they favor smoothness of the building shape, but also smoothness of the visible patterns on the surface. Functional requirements typically come from the engineers involved in the construction process. For exam- ple, covering freeform structures using planar panels is much cheaper than using non-planar ones. Further, constructed buildings have to be stable and should not collapse. In this thesis, we explore the geometric rationalization of freeform archi- tecture using four specific example problems inspired by real life applications. We achieve our results by developing optimization algorithms and a theoretical study of the underlying geometrical structure of the problems. The four example problems are the following: (1) The design of shading and lighting systems which are torsion-free structures with planar beams based on quad meshes. They satisfy the functionality requirements of preventing light from going inside a building as shad- ing systems or reflecting light into a building as lighting systems. (2) The Design of freeform honeycomb structures that are constructed based on hex-dominant meshes with a planar beam mounted along each edge. The beams intersect without

  2. Rationalization with ruled surfaces in architecture

    DEFF Research Database (Denmark)

    Steenstrup, Kasper Hornbak

    This thesis addresses the problems of rationalizing and segmenting large scale 3D models, and how to handle difficult production constraints in this area. The design choices when constructing large scale architecture are influenced by the budget. Therefore I strive to minimize the amount of time...... and material needed for production. This makes advanced free form architecture viable for low cost projects, allowing the architects to realize their designs. By pre-cutting building blocks using hot wire robots, the amount of milling necessary can be reduced drastically. I do this by rationalizing...

  3. Consumer rationality in choice

    NARCIS (Netherlands)

    Conlon, B.J.

    2001-01-01

    The dissertation concentrates on consumer choice and the ability of current modelling approaches to capture the underlying behaviour of the individual decision-makers. The standard assumption of a rational utility maximising individual and its implications for observed behaviour are examined and

  4. Universal and Relative Rationality

    Directory of Open Access Journals (Sweden)

    Nathaniel Goldberg

    2009-01-01

    Full Text Available In this paper I illustrate how a basic kind of universal rationality can be profitably combined with undeniable instances of relativism. I do so by engaging Michael Friedman’s recent response to a challenge from Thomas Kuhn.

  5. The rational complementarity problem

    NARCIS (Netherlands)

    Heemels, W.P.M.H.; Schumacher, J.M.; Weiland, S.

    1999-01-01

    An extension of the linear complementarity problem (LCP) of mathematical programming is the so-called rational complementarity problem (RCP). This problem occurs if complementarity conditions are imposed on input and output variables of linear dynamical input/state/output systems. The resulting

  6. Rational equity bubbles

    OpenAIRE

    Zhou, Ge

    2012-01-01

    This paper discusses the existence of a bubble in the pricing of an asset that pays positive dividends. I show that rational bubbles can exist in a growing economy. The existence of bubbles depends on the relative magnitudes of risk aversion to consumption and to wealth. Furthermore, I examine how an exogenous shock in technology might trigger bubbles.

  7. Ideal Theory, Real Rationality

    DEFF Research Database (Denmark)

    Flyvbjerg, Bent

    Understanding rationality and power are key to understanding actual political and administrative behavior. Political and administrative theory that ignores this fact stand in danger of being at best irrelevant or, at worst part of the problem it whishes to solve. The paper presents Jürgen Habermas...

  8. Diagnosis, Dogmatism, and Rationality.

    Science.gov (United States)

    Rabinowitz, Jonathan; Efron, Noah J.

    1997-01-01

    Presents findings suggesting that misdiagnoses frequently stem from flaws in human information processing, particularly in collecting and using information. Claims that improved diagnostic tools will not remedy the problem. Drawing on the work of Karl Popper and Robin Collingwood, proposes operational principles to ensure a rational diagnostic…

  9. Hegel's phenomenology of rationality

    DEFF Research Database (Denmark)

    Huggler, Jørgen

    2009-01-01

    The aim of this chapter is to elucidate Hegel's conception of rationality in the Phänomenologie des Geistes (1807), and to defend the thesis that he is an author engaged in discussion with a wide variety of sources. He uses sceptical reasoning to form a line of argument with a necessary progression...

  10. A rationally designed composite of alternating strata of Si nanoparticles and graphene: a high-performance lithium-ion battery anode.

    Science.gov (United States)

    Sun, Fu; Huang, Kai; Qi, Xiang; Gao, Tian; Liu, Yuping; Zou, Xianghua; Wei, Xiaolin; Zhong, Jianxin

    2013-09-21

    We have successfully fabricated a free-standing Si-re-G (reduced graphene) alternating stratum structure composite through a repeated process of filtering liquid exfoliated graphene oxide and uniformly dispersed Si solution, followed by the reduction of graphene oxide. The as-prepared free-standing flexible alternating stratum structure composite was directly evaluated as the anode for rechargeable lithium half-cells without adding any polymer binder, conductive additives or using current collectors. The half cells based on this new alternating structure composite exhibit an unexpected capacity of 1500 mA h g(-1) after 100 cycles at 1.35 A g(-1). Our rationally proposed strategy has incorporated the long cycle life of carbon and the high lithium-storage capacity of Si into one entity using the feasible and scalable vacuum filtration technique, rendering this new protocol as a readily applicable means of addressing the practical application challenges associated with the next generation of rechargeable lithium-ion batteries.

  11. Capital Requirements and Credit Rationing

    OpenAIRE

    Itai Agur

    2010-01-01

    This paper analyzes the trade-off between financial stability and credit rationing that arises when increasing capital requirements. It extends the Stiglitz-Weiss model of credit rationing to allow for bank default. Bank capital structure then matters for lending incentives. With default and rationing endogenous, optimal capital requirements can be analyzed. Introducing bank financiers, the paper also shows that uninsured funding raises the sensitivity of rationing to capital requirements. In...

  12. Rationality and ritual

    International Nuclear Information System (INIS)

    Wynne, B.

    1982-01-01

    The book concerns the Windscale Public Inquiry, held to investigate the application by British Nuclear Fuels to build a 1200 tonne per year thermal oxide reprocessing plant (THORP) for spent nuclear fuels from Britain and overseas. The subject is discussed under the headings: introduction (international dimensions; the Windscale Inquiry; conflict resolution and social drama; public debate and the sociology of knowledge); the decision-making legacy; oxide reprocessing - the background; the public inquiry tradition - a comparative perspective; the emergence of THORP from a private to a public issue (local and national planning politics); the process and impact of the Inquiry (opposition groups); judicial rationality, expert conflict, and political authority); the rationality and politics of analysis (proliferation; radiation risks; relative risks; the Ravenglass issue; discharge targets; general radiation protection arrangements); conclusion. (U.K.)

  13. Rational management of epilepsy.

    Science.gov (United States)

    Viswanathan, Venkataraman

    2014-09-01

    Management of epilepsies in children has improved considerably over the last decade, all over the world due to the advances seen in the understanding of the patho-physiology of epileptogenesis, availability of both structural and functional imaging studies along with better quality EEG/video-EEG recordings and the availability of a plethora of newer anti-epileptic drugs which are tailormade to act on specific pathways. In spite of this, there is still a long way to go before one is able to be absolutely rational about which drug to use for which type of epilepsy. There have been a lot of advances in the area of epilepsy surgery and is certainly gaining ground for specific cases. Better understanding of the genetic basis of epilepsies will hopefully lead to a more rational treatment plan in the future. Also, a lot of work needs to be done to dispel various misunderstandings and myths about epilepsy which still exists in our country.

  14. Multivariate rational data fitting

    Science.gov (United States)

    Cuyt, Annie; Verdonk, Brigitte

    1992-12-01

    Sections 1 and 2 discuss the advantages of an object-oriented implementation combined with higher floating-point arithmetic, of the algorithms available for multivariate data fitting using rational functions. Section 1 will in particular explain what we mean by "higher arithmetic". Section 2 will concentrate on the concepts of "object orientation". In sections 3 and 4 we shall describe the generality of the data structure that can be dealt with: due to some new results virtually every data set is acceptable right now, with possible coalescence of coordinates or points. In order to solve the multivariate rational interpolation problem the data sets are fed to different algorithms depending on the structure of the interpolation points in then-variate space.

  15. Models for Rational Number Bases

    Science.gov (United States)

    Pedersen, Jean J.; Armbruster, Frank O.

    1975-01-01

    This article extends number bases to negative integers, then to positive rationals and finally to negative rationals. Methods and rules for operations in positive and negative rational bases greater than one or less than negative one are summarized in tables. Sample problems are explained and illustrated. (KM)

  16. Rational Unified Process

    OpenAIRE

    Kopal, Nils

    2016-01-01

    In this German seminar paper, which was written in the year 2011 at the University of Duisburg for a Bachelor Colloquium in Applied computer science, we show a brief overview of the Rational Unified Process (RUP). Thus, interested students or generally interested people in software development gain a first impression of RUP. The paper includes a survey and overview of the underlying process structure, the phases of the process, its workflows, and describes the always by the RUP developers pos...

  17. Maps of Bounded Rationality

    OpenAIRE

    Kahneman, Daniel

    2002-01-01

    The work cited by the Nobel committee was done jointly with the late Amos Tversky (1937-1996) during a long and unusually close collaboration. Together, we explored the psychology of intuitive beliefs and choices and examined their bounded rationality. This essay presents a current perspective on the three major topics of our joint work: heuristics of judgment, risky choice, and framing effects. In all three domains we studied intuitions - thoughts and preferences that come to mind quickly an...

  18. Emotional Theory of Rationality

    OpenAIRE

    Garcés, Mario; Finkel, Lucila

    2011-01-01

    In recent decades, it has been definitely established the existence of a close relationship between the emotional phenomena and rational processes, but we still do not have a unified definition, or effective models to describe any of them well. To advance our understanding of the mechanisms governing the behavior of living beings we must integrate multiple theories, experiments and models from both fields. In this paper we propose a new theoretical framework that allows integrating and unders...

  19. On hereditarily rational functions

    OpenAIRE

    Nowak, Krzysztof Jan

    2012-01-01

    In this paper, we give a short proof of a theorem by Koll\\'{a}r on hereditarily rational functions. This is an answer to his appeal to find an elementary proof which does not rely so much on resolution of singularities. Our approach does not make use of desingularization techniques. Instead, we apply a stronger version of the \\L{}ojasiewicz inequality. Moreover, this allows us to sharpen Koll\\'{a}r's theorem.

  20. Three Cyanide-Bridged One-Dimensional Single Chain Co"I"I"I-Mn"I"I Complexes: Rational Design, Synthesis, Crystal Structures and Magnetic Properties

    International Nuclear Information System (INIS)

    Zhang, Daopeng; Zhao, Zengdian; Wang, Ping; Chen, Xia

    2012-01-01

    Two pyridinecarboxamide dicyanidecobalt(III) building blocks and two mononuclear seven-coordinated macrocycle manganese(II) compounds have been rationally selected to assemble cyanide-bridged heterobimetallic complexes, resulting in three cyanide-bridged Co"I"I"I-Mn"I"I complexes. Single X-ray diffraction analysis show that these complexes {[Mn(L"1)][Co(bpb)]}ClO_4·CH_3OH·0.5H_2O (1), {[Mn(L"2)][Co(bpb)]}ClO_4·0.5CH_3OH (2) and {[Mn(L"1)][Cobpmb]}ClO_4·H_2O (3) (L"1 = 3,6-diazaoctane-1,8-diamine, L"2 = 3,6-dioxaoctano-1,8- diamine: bpb"2"- = 1,2-bis(pyridine-2-carboxamido)benzenate, bpmb"2"- = 1,2-bis(pyridine-2-carboxamido)-4- methyl-benzenate) all present predictable one-dimensional single chain structures. The molecular structures of these one-dimensional complexes consists of alternating units of [Mn(L)]"2"+ (L = L"1 or L"2) and [Co(L')(CN)_2]"- (L' = bpb"2"-, or bpmb"2"-), forming a cyanide-bridged cationic polymeric chain with free ClO_4"- as the balance anion. The coordination geometry of manganese(II) ion in the three one-dimensional complexes is a slightly distorted pentagonal-bipyrimidal with two cyanide nitrogen atoms at the trans positions and N_5 or N_3O_2 coordinating mode at the equatorial plane from ligand L"1 or L"2. Investigation over magnetic properties of these complexes reveals that the very weak magnetic coupling between neighboring Mn(II) ions connected by the diamagnetic dicyanidecobalt(III) building block. A best-fit to the magnetic susceptibility of complex 1 leads to the magnetic coupling constants J = .0.084(3) cm"-"1

  1. Probability and rational choice

    Directory of Open Access Journals (Sweden)

    David Botting

    2014-05-01

    Full Text Available http://dx.doi.org/10.5007/1808-1711.2014v18n1p1 In this paper I will discuss the rationality of reasoning about the future. There are two things that we might like to know about the future: which hypotheses are true and what will happen next. To put it in philosophical language, I aim to show that there are methods by which inferring to a generalization (selecting a hypothesis and inferring to the next instance (singular predictive inference can be shown to be normative and the method itself shown to be rational, where this is due in part to being based on evidence (although not in the same way and in part on a prior rational choice. I will also argue that these two inferences have been confused, being distinct not only conceptually (as nobody disputes but also in their results (the value given to the probability of the hypothesis being not in general that given to the next instance and that methods that are adequate for one are not by themselves adequate for the other. A number of debates over method founder on this confusion and do not show what the debaters think they show.

  2. Rationality and drug use: an experimental approach.

    Science.gov (United States)

    Blondel, Serge; Lohéac, Youenn; Rinaudo, Stéphane

    2007-05-01

    In rational addiction theory, higher discount rates encourage drug use. We test this hypothesis in the general framework of rationality and behaviour under risk. We do so using an experimental design with real monetary incentives. The decisions of 34 drug addicts are compared with those of a control group. The decisions of drug users (DU) are not any less consistent with standard theories of behaviour over time and under risk. Further, there is no difference in the estimated discount rate between drug users and the control group, but the former do appear to be more risk-seeking.

  3. Are security analysts rational? a literature review

    OpenAIRE

    Peixinho, Rúben; Coelho, Luís; Taffler, Richard J.

    2005-01-01

    Rational choice theory and bounded rationality constitute the basis for the discussion in several areas regarding human rationality. In finance, this discussion has been made between traditional finance and behavioural finance approach, which have different perspectives concerning market agents’ rationality. This paper reviews several studies addressing rationality among security analysts. The analysis shows that analysts’systematic optimism seems to be inconsistent with rationality....

  4. The rational design of a novel potent analogue of the 5’-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity

    Science.gov (United States)

    Machrouhi, Fouzia; Ouhamou, Nouara; Laderoute, Keith; Calaoagan, Joy; Bukhtiyarova, Marina; Ehrlich, Paula J.; Klon, Anthony E.

    2010-01-01

    We have designed and synthesized analogues of compound C, a non-specific inhibitor of 5’-AMP-activated protein kinase (AMPK), using a computational fragment-based drug design (FBDD) approach. Synthesizing only twenty-seven analogues yielded a compound that was equipotent to compound C in the inhibition of the human AMPK (hAMPK) α2 subunit in the heterotrimeric complex in vitro, exhibited significantly improved selectivity against a subset of relevant kinases, and demonstrated enhanced cellular inhibition of AMPK. PMID:20932747

  5. Propriedade de fluxo e característica de escoabilidade de rações avícolas para dimensionamento de silos Flow properties and flowability characteristics of poultry rations for design of silos

    Directory of Open Access Journals (Sweden)

    José Pinheiro Lopes Neto

    2007-06-01

    Full Text Available O conhecimento das propriedades físicas e de fluxo dos produtos é de extrema importância no que se refere ao seu manuseio e processamento. Com a correta aplicação desses conhecimentos, é possível dimensionar de forma racional os sistemas de transporte e armazenagem utilizados, prevendo, assim, o tipo de fluxo ideal para cada operação. Este trabalho teve como objetivo determinar as propriedades físicas e de fluxo de três diferentes rações avícolas e avaliar suas influências nas características geométricas de tremonhas. Na obtenção dos dados, foi utilizado o aparelho de cisalhamento direto de translação (célula de cisalhamento de Jenike e duas superfícies de parede: aço liso e rugoso. Para determinar o índice de fluxo (ff c e o diâmetro mínimo do orifício de descarga (D, adotou-se a metodologia de Jenike enquanto que para o ângulo mínimo de inclinação da tremonha cônica, utilizou-se a metodologia de Enstad. Com base nos resultados obtidos, conclui-se que as Rações A e B foram classificadas como produtos coesivos enquanto que a Ração C apresentou os menores ângulos de inclinação da tremonha e maiores diâmetros de orifício de descarga.The knowledge about the physical and flow properties of industrial powders is very important to their handling and processing. With the right application of this information, it's possible to design conveyors and storage systems to predict the ideal kind of flow for each operation. This work had the objective to determinate the physical and flow properties of different kinds of poultry rations and to evaluate their influences on geometric characteristics of hoppers. For that, it was used the direct shear apparatus based on Jenike shear cell and two friction surfaces: smooth and rough steel walls. To determinate the index flow (ff c and minimum hopper opening diameter (D, was used the Jenike's methodology. For the minimum conical hopper angle, was used the mathematical method

  6. Rational design of biophysical imaging protocols to measure the level of intensity of massive delocalized infections under severe HIV-induced immunodeficiency: configuration of novel radioimmunoscintigraphy modalities with single-photon emission tomography (SPECT) and positron emission tomography (PET)

    International Nuclear Information System (INIS)

    Nazarea, A.D.

    1996-01-01

    Severe immunosupression brought about by critical depletion of CD4 + -lymphocytes in individuals suffering from HIV infection leads inevitably to the onset of multiple-agent opportunistic infections (ARC: the AIDS-related complex). Such opportunistic infections eventually become heterogeneously delocalized (disseminated) and an idea f their variety and number can be gleaned from the listing under clinical category C of the 1993 CDC Revised Classification System for HIV infections. This causes widespread oxygen free radical (principally superoxide and hydroxyl free radical) burst due to the up-switching of the hexose monophosphate (HMP) shunt as a result of the generalized activation, by the massive infection load, of NADPH oxidase, a constitutive enzyme that is present in the cell membranes of all granulocytes and mononuclear phagocytic cells. However the very short (reactive) lifetimes of superoxide and hydroxyl free radicals in the cellular milieu preclude their use as a convenient in vivo biomarkers if the level of phagocytosis (or HMP up-switching) were to be utilized as a correlative measure of the level of intensity of delocalized infections in ARC in any non-invasive whole-body imaging protocol. In the present contribution, we report a rational schema for a molecularly specific an self-consistent correlative measure of the intensity of multiple-agent, delocalized infections arising from severe HIV-induced immunodeficiency. The schema is based on the quantitative parametrization of the level of on-going degranulation activity of neutrophils in the granulocyte population. The rationally designed modalities rest on specificity inherent in radioimmunoscintigraphy, in particular on the ligand of radionuclide-tagged antibodies to the neutrophil proteinases HLE (human leukocytic elastase: EC.3.4.21.37) and cat G (cathepsin G: EC.3.4.21.20). In this work, these molecular probes are specifically configured to lend themselves as convenient in vivo biomarkers both in

  7. Rational design of a conformation-switchable Ca2+- and Tb3+-binding protein without the use of multiple coupled metal-binding sites.

    Science.gov (United States)

    Li, Shunyi; Yang, Wei; Maniccia, Anna W; Barrow, Doyle; Tjong, Harianto; Zhou, Huan-Xiang; Yang, Jenny J

    2008-10-01

    Ca2+, as a messenger of signal transduction, regulates numerous target molecules via Ca2+-induced conformational changes. Investigation into the determinants for Ca2+-induced conformational change is often impeded by cooperativity between multiple metal-binding sites or protein oligomerization in naturally occurring proteins. To dissect the relative contributions of key determinants for Ca2+-dependent conformational changes, we report the design of a single-site Ca2+-binding protein (CD2.trigger) created by altering charged residues at an electrostatically sensitive location on the surface of the host protein rat Cluster of Differentiation 2 (CD2).CD2.trigger binds to Tb3+ and Ca2+ with dissociation constants of 0.3 +/- 0.1 and 90 +/- 25 microM, respectively. This protein is largely unfolded in the absence of metal ions at physiological pH, but Tb3+ or Ca2+ binding results in folding of the native-like conformation. Neutralization of the charged coordination residues, either by mutation or protonation, similarly induces folding of the protein. The control of a major conformational change by a single Ca2+ ion, achieved on a protein designed without reliance on sequence similarity to known Ca2+-dependent proteins and coupled metal-binding sites, represents an important step in the design of trigger proteins.

  8. Rational design and synthesis of altered peptide ligands based on human myelin oligodendrocyte glycoprotein 35-55 epitope: inhibition of chronic experimental autoimmune encephalomyelitis in mice.

    Science.gov (United States)

    Tselios, Theodore; Aggelidakis, Mihalis; Tapeinou, Anthi; Tseveleki, Vivian; Kanistras, Ioannis; Gatos, Dimitrios; Matsoukas, John

    2014-11-04

    Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system and is an animal model of multiple sclerosis (MS). Although the etiology of MS remains unclear, there is evidence T-cell recognition of immunodominant epitopes of myelin proteins, such as the 35-55 epitope of myelin oligodendrocyte glycoprotein (MOG), plays a pathogenic role in the induction of chronic EAE. Cyclization of peptides is of great interest since the limited stability of linear peptides restricts their potential use as therapeutic agents. Herein, we have designed and synthesized a number of linear and cyclic peptides by mutating crucial T cell receptor (TCR) contact residues of the human MOG35-55 epitope. In particular, we have designed and synthesized cyclic altered peptide ligands (APLs) by mutating Arg41 with Ala or Arg41 and Arg46 with Ala. The peptides were synthesized in solid phase on 2-chlorotrityl chloride resin (CLTR-Cl) using the Fmoc/t-Bu methodology. The purity of final products was verified by RP-HPLC and their identification was achieved by ESI-MS. It was found that the substitutions of Arg at positions 41 and 46 with Ala results in peptide analogues that reduce the severity of MOG-induced EAE clinical symptoms in C57BL/6 mice when co-administered with mouse MOG35-55 peptide at the time of immunization.

  9. Rational Approximations to Rational Models: Alternative Algorithms for Category Learning

    Science.gov (United States)

    Sanborn, Adam N.; Griffiths, Thomas L.; Navarro, Daniel J.

    2010-01-01

    Rational models of cognition typically consider the abstract computational problems posed by the environment, assuming that people are capable of optimally solving those problems. This differs from more traditional formal models of cognition, which focus on the psychological processes responsible for behavior. A basic challenge for rational models…

  10. Realization theory for rational systems: Minimal rational realizations

    NARCIS (Netherlands)

    J. Nemcová (Jana); J.H. van Schuppen (Jan)

    2010-01-01

    htmlabstractThe study of realizations of response maps is a topic of control and system theory. Realization theory is used in system identification and control synthesis. A minimal rational realization of a given response map p is a rational realization of p such that the dimension of its state

  11. Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists

    DEFF Research Database (Denmark)

    Manera, Clementina; Saccomanni, Giuseppe; Adinolfi, Barbara

    2009-01-01

    The CB(2) receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, new 1,8-naphthyridin-2(1H)-on-3-carboxamide......-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB(2) agonists....... derivatives were designed, synthesized, and tested for their affinities toward the human CB(1) and CB(2) cannabinoid receptors. Some of the reported compounds showed a subnanomolar CB(2) affinity with a CB(1)/CB(2) selectivity ratio greater than 200 (compounds 6, 12, cis-12, 13, and cis-13). Further studies...

  12. Rational design of DKK3 structure-based small peptides as antagonists of Wnt signaling pathway and in silico evaluation of their efficiency.

    Directory of Open Access Journals (Sweden)

    Mansour Poorebrahim

    Full Text Available Dysregulated Wnt signaling pathway is highly associated with the pathogenesis of several human cancers. Dickkopf proteins (DKKs are thought to inhibit Wnt signaling pathway through binding to lipoprotein receptor-related protein (LRP 5/6. In this study, based on the 3-dimensional (3D structure of DKK3 Cys-rich domain 2 (CRD2, we have designed and developed several peptide inhibitors of Wnt signaling pathway. Modeller 9.15 package was used to predict 3D structure of CRD2 based on the Homology modeling (HM protocol. After refinement and minimization with GalaxyRefine and NOMAD-REF servers, the quality of selected models was evaluated utilizing VADAR, SAVES and ProSA servers. Molecular docking studies as well as literature-based information revealed two distinct boxes located at CRD2 which are actively involved in the DKK3-LRP5/6 interaction. A peptide library was constructed conducting the backrub sequence tolerance scanning protocol in Rosetta3.5 according to the DKK3-LRP5/6 binding sites. Seven tolerated peptides were chosen and their binding affinity and stability were improved by some logical amino acid substitutions. Molecular dynamics (MD simulations of peptide-LRP5/6 complexes were carried out using GROMACS package. After evaluation of binding free energies, stability, electrostatic potential and some physicochemical properties utilizing computational approaches, three peptides (PEP-I1, PEP-I3 and PEP-II2 demonstrated desirable features. However, all seven improved peptides could sufficiently block the Wnt-binding site of LRP6 in silico. In conclusion, we have designed and improved several small peptides based on the LRP6-binding site of CRD2 of DKK3. These peptides are highly capable of binding to LRP6 in silico, and may prevent the formation of active Wnt-LRP6-Fz complex.

  13. Suicide: rationality and responsibility for life.

    Science.gov (United States)

    Ho, Angela Onkay

    2014-03-01

    Death by suicide is widely held as an undesirable outcome. Most Western countries place emphasis on patient autonomy, a concept of controversy in relation to suicide. This paper explores the tensions between patients' rights and many societies' overarching desire to prevent suicide, while clarifying the relations between mental disorders, mental capacity, and rational suicide. A literature search was conducted using search terms of suicide and ethics in the PubMed and LexisNexis Academic databases. Article titles and abstracts were reviewed and deemed relevant if the paper addressed topics of rational suicide, patient autonomy or rights, or responsibility for life. Further articles were found from reference lists and by suggestion from preliminary reviewers of this paper. Suicidal behaviour in a person cannot be reliably predicted, yet various associations and organizations have developed standards of care for managing patients exhibiting suicidal behaviour. The responsibility for preventing suicide tends to be placed on the treating clinician. In cases where a person is capable of making treatment decisions--uninfluenced by any mental disorder--there is growing interest in the concept of rational suicide. There is much debate about whether suicide can ever be rational. Designating suicide as an undesirable event that should never occur raises the debate of who is responsible for one's life and runs the risk of erroneously attributing blame for suicide. While upholding patient rights of autonomy in psychiatric care is laudable, cases of suicidality warrant a delicate consideration of clinical judgment, duty of care, and legal obligations.

  14. Rational and design of an overfeeding protocol in constitutional thinness: Understanding the physiology, metabolism and genetic background of resistance to weight gain.

    Science.gov (United States)

    Ling, Yiin; Galusca, Bogdan; Hager, Jorg; Feasson, Leonard; Valsesia, Armand; Epelbaum, Jacques; Alexandre, Virginie; Wynn, Emma; Dinet, Cécile; Palaghiu, Radu; Peoc'h, Michel; Boirie, Yves; Montaurier, Christophe; Estour, Bruno; Germain, Natacha

    2016-10-01

    Constitutional thinness (CT) is a natural state of underweight (13-17.5kg/m 2 ) without the presence of any eating disorders and abnormal hormonal profile, and with preserved menses in women. We previously conducted a four-week fat overfeeding study showing weight gain resistance in CT women and one of our main results was the identification of an energy gap: a positive energy balance (higher energy intake than energy expenditure). This new overfeeding study is designed to confirm the energy gap and propose mechanistic hypothesis. A 2-week overfeeding (daily consumption of one bottle of Renutryl ® Booster (600kcal, 30g protein, 72g carbohydrate, 21g fat) on top of the dietary intake) is performed to compare 15 women and men in each CT group (Body Mass Index [BMI]controls (BMI 20-25kg/m 2 ). Bodyweight, food intake, energy expenditure (canopy, calorimetric chamber and Actiheart), body composition (DXA), appetite regulatory hormone profiles after a test meal, proteomics, metabolomics, urinary metabolic profiles, stool microbiome and lipids, fat and muscle transcriptomics are monitored before and after overfeeding. Data inter-linking will be able to be established with results of this study. The findings could possibly open to therapeutic approaches to help CT patients to gain weight as well as provide a better understanding of energy regulation with regard to treat obesity (resistance to weight loss), a mirror image of CT (resistance to weight gain). Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. Rational Design and Multibiological Profiling of Novel Donepezil-Trolox Hybrids against Alzheimer's Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties.

    Science.gov (United States)

    Cai, Pei; Fang, Si-Qiang; Yang, Xue-Lian; Wu, Jia-Jia; Liu, Qiao-Hong; Hong, Hao; Wang, Xiao-Bing; Kong, Ling-Yi

    2017-11-15

    A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC 50 = 0.54 μM) and hMAO-B (IC 50 = 4.3 μM), significant antioxidant activity (41.33 μM IC 50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Aβ 1-42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H 2 O 2 , rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl 3 induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer's drug.

  16. Catalytic Hydrogenation and Hydrodeoxygenation of Furfural over Pt(111): A Model System for the Rational Design and Operation of Practical Biomass Conversion Catalysts.

    Science.gov (United States)

    Taylor, Martin J; Jiang, Li; Reichert, Joachim; Papageorgiou, Anthoula C; Beaumont, Simon K; Wilson, Karen; Lee, Adam F; Barth, Johannes V; Kyriakou, Georgios

    2017-04-20

    Furfural is a key bioderived platform chemical whose reactivity under hydrogen atmospheres affords diverse chemical intermediates. Here, temperature-programmed reaction spectrometry and complementary scanning tunneling microscopy (STM) are employed to investigate furfural adsorption and reactivity over a Pt(111) model catalyst. Furfural decarbonylation to furan is highly sensitive to reaction conditions, in particular, surface crowding and associated changes in the adsorption geometry: furfural adopts a planar geometry on clean Pt(111) at low coverage, tilting at higher coverage to form a densely packed furfural adlayer. This switch in adsorption geometry strongly influences product selectivity. STM reveals the formation of hydrogen-bonded networks for planar furfural, which favor decarbonylation on clean Pt(111) and hydrogenolysis in the presence of coadsorbed hydrogen. Preadsorbed hydrogen promotes furfural hydrogenation to furfuryl alcohol and its subsequent hydrogenolysis to methyl furan, while suppressing residual surface carbon. Furfural chemistry over Pt is markedly different from that over Pd, with weaker adsorption over the former affording a simpler product distribution than the latter; Pd catalyzes a wider range of chemistry, including ring-opening to form propene. Insight into the role of molecular orientation in controlling product selectivity will guide the design and operation of more selective and stable Pt catalysts for furfural hydrogenation.

  17. Serendipitous discovery of potent human head and neck squamous cell carcinoma anti-cancer molecules: A fortunate failure of a rational molecular design.

    Science.gov (United States)

    Zagni, Chiara; Pistarà, Venerando; Oliveira, Luciana A; Castilho, Rogerio M; Romeo, Giovanni; Chiacchio, Ugo; Rescifina, Antonio

    2017-12-01

    Histone deacetylase inhibitors (HDACis) play an important role as valuable drugs targeted to cancer therapy: several HDACis are currently being tested in clinical trials. Two new potential HDACis 1a and 1d, characterized by the presence of a biphenyl-4-sulfonamide group as a connection unit between the N-{4-[(E)-(2-formylhydrazinylidene)methyl]-3-hydroxyphenyl} and the 2-hydroxy-N-(trifluoroacetyl)benzamide moiety, respectively, as two zinc-binding group (ZBG), have been designed, synthesized and tested for their biological activity. Surprisingly, compounds 1a and 12, this last exclusively obtained in place of 1d, exhibited a very low HDAC inhibitory activity. A serendipitous assay of these two compounds, conducted on three chemoresistant cell lines of head and neck squamous cell carcinoma (HNSCC), showed their antiproliferative activity at low nanomolar concentrations, better than cisplatin. In vitro, biological assays indicated that compounds 1a and 12 are able to increase acetylation of histone H3 and to interfere with the PI3K/Akt/mTOR pathway by inducing the accumulation of PTEN protein. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. A Rationally Designed TNF-α Epitope-Scaffold Immunogen Induces Sustained Antibody Response and Alleviates Collagen-Induced Arthritis in Mice.

    Directory of Open Access Journals (Sweden)

    Li Zhang

    Full Text Available The TNF-α biological inhibitors have significantly improved the clinical outcomes of many autoimmune diseases, in particular rheumatoid arthritis. However, the practical uses are limited due to high costs and the risk of anti-drug antibody responses. Attempts to develop anti-TNF-α vaccines have generated encouraging data in animal models, however, data from clinical trials have not met expectations. In present study, we designed a TNF-α epitope-scaffold immunogen DTNF7 using the transmembrane domain of diphtheria toxin, named DTT as a scaffold. Molecular dynamics simulation shows that the grafted TNF-α epitope is entirely surface-exposed and presented in a native-like conformation while the rigid helical structure of DTT is minimally perturbed, thereby rendering the immunogen highly stable. Immunization of mice with alum formulated DTNF7 induced humoral responses against native TNF-α, and the antibody titer was sustained for more than 6 months, which supports a role of the universal CD4 T cell epitopes of DTT in breaking self-immune tolerance. In a mouse model of rheumatoid arthritis, DTNF7-alum vaccination markedly delayed the onset of collagen-induced arthritis, and reduced incidence as well as clinical score. DTT is presumed safe as an epitope carrier because a catalytic inactive mutant of diphtheria toxin, CRM197 has good clinical safety records as an active vaccine component. Taken all together, we show that DTT-based epitope vaccine is a promising strategy for prevention and treatment of autoimmune diseases.

  19. Rational design for enhancing inflammation-responsive in vivo chemiluminescence via nanophotonic energy relay to near-infrared AIE-active conjugated polymer.

    Science.gov (United States)

    Seo, Young Hun; Singh, Ajay; Cho, Hong-Jun; Kim, Youngsun; Heo, Jeongyun; Lim, Chang-Keun; Park, Soo Young; Jang, Woo-Dong; Kim, Sehoon

    2016-04-01

    H2O2-specific peroxalate chemiluminescence is recognized as a potential signal for sensitive in vivo imaging of inflammation but the effect of underlying peroxalate-emitter energetics on its efficiency has rarely been understood. Here we report a simple nanophotonic way of boosting near-infrared chemiluminescence with no need of complicated structural design and synthesis of an energetically favored emitter. The signal enhancement was attained from the construction of a nanoparticle imaging probe (∼26 nm in size) by dense nanointegration of multiple molecules possessing unique photonic features, i.e., i) a peroxalate as a chemical fuel generating electronic excitation energy in response to inflammatory H2O2, ii) a low-bandgap conjugated polymer as a bright near-infrared emitter showing aggregation-induced emission (AIE), and iii) an energy gap-bridging photonic molecule that relays the chemically generated excitation energy to the emitter for its efficient excitation. From static and kinetic spectroscopic studies, a green-emissive BODIPY dye has proven to be an efficient relay molecule to bridge the energy gap between the AIE polymer and the chemically generated excited intermediate of H2O2-reacted peroxalates. The energy-relayed nanointegration of AIE polymer and peroxalate in water showed a 50-times boosted sensing signal compared to their dissolved mixture in THF. Besides the high H2O2 detectability down to 10(-9) M, the boosted chemiluminescence presented a fairly high tissue penetration depth (>12 mm) in an ex vivo condition, which enabled deep imaging of inflammatory H2O2 in a hair-covered mouse model of peritonitis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Toward a Rational Design of Bioactive Glasses with Optimal Structural Features: Composition–Structure Correlations Unveiled by Solid-State NMR and MD Simulations

    Science.gov (United States)

    2013-01-01

    The physiological responses of silicate-based bioactive glasses (BGs) are known to depend critically on both the P content (nP) of the glass and its silicate network connectivity (N̅BOSi). However, while the bioactivity generally displays a nonmonotonic dependence on nP itself, recent work suggest that it is merely the net orthophosphate content that directly links to the bioactivity. We exploit molecular dynamics (MD) simulations combined with 31P and 29Si solid-state nuclear magnetic resonance (NMR) spectroscopy to explore the quantitative relationships between N̅BOSi, nP, and the silicate and phosphate speciations in a series of Na2O–CaO–SiO2–P2O5 glasses spanning 2.1 ≤ N̅BOSi ≤ 2.9 and variable P2O5 contents up to 6.0 mol %. The fractional population of the orthophosphate groups remains independent of nP at a fixed N̅BOSi-value, but is reduced slightly as N̅BOSi increases. Nevertheless, P remains predominantly as readily released orthophosphate ions, whose content may be altered essentially independently of the network connectivity, thereby offering a route to optimize the glass bioactivity. We discuss the observed composition-structure links in relation to known composition-bioactivity correlations, and define how Na2O–CaO–SiO2–P2O5 compositions exhibiting an optimal bioactivity can be designed by simultaneously altering three key parameters: the silicate network connectivity, the (ortho)phosphate content, and the nNa/nCa molar ratio. PMID:24364818

  1. Theoretical studies of optics and charge transport in organic conducting oligomers and polymers: Rational design of improved transparent and conducting polymers

    Science.gov (United States)

    Hutchison, Geoffrey Rogers

    Theoretical studies on a variety of oligo- and polyheterocycles elucidate their optical and charge transport properties, suggesting new, improved transparent conductive polymers. First-principles calculations provide accurate methodologies for predicting both optical band gaps of neutral and cationic oligomers and intrinsic charge transfer rates. Multidimensional analysis reveals important motifs in chemical tailorability of oligoheterocycle optical and charge transport properties. The results suggest new directions for design of novel materials. Using both finite oligomer and infinite polymer calculations, the optical band gaps in polyheterocycles follow a modified particle-in-a-box formalism, scaling approximately as 1/N (where N is the number of monomer units) in short chains, saturating for long chains. Calculations demonstrate that band structure changes upon heteroatom substitution, (e.g., from polythiophene to polypyrrole) derive from heteroatom electron affinity. Further investigation of chemical variability in substituted oligoheterocycles using multidimensional statistics reveals the interplay between heteroatom and substituent in correlations between structure and redox/optical properties of neutral and cationic species. A linear correlation between band gaps of neutral and cationic species upon oxidation of conjugated oligomers, shows redshifts of optical absorption for most species and blueshifts for small band gap species. Interstrand charge-transport studies focus on two contributors to hopping-style charge transfer rates: internal reorganization energy and the electronic coupling matrix element. Statistical analysis of chemical variability of reorganization energies in oligoheterocycles proves the importance of reorganization energy in determining intrinsic charge transfer rates (e.g., charge mobility in unsubstituted oligothiophenes). Computed bandwidths across several oligothiophene crystal packing motifs show similar electron and hole bandwidths

  2. Rational Design of a Water-Storable Hierarchical Architecture Decorated with Amorphous Barium Oxide and Nickel Nanoparticles as a Solid Oxide Fuel Cell Anode with Excellent Sulfur Tolerance.

    Science.gov (United States)

    Song, Yufei; Wang, Wei; Ge, Lei; Xu, Xiaomin; Zhang, Zhenbao; Julião, Paulo Sérgio Barros; Zhou, Wei; Shao, Zongping

    2017-11-01

    Solid oxide fuel cells (SOFCs), which can directly convert chemical energy stored in fuels into electric power, represent a useful technology for a more sustainable future. They are particularly attractive given that they can be easily integrated into the currently available fossil fuel infrastructure to realize an ideal clean energy system. However, the widespread use of the SOFC technology is hindered by sulfur poisoning at the anode caused by the sulfur impurities in fossil fuels. Therefore, improving the sulfur tolerance of the anode is critical for developing SOFCs for use with fossil fuels. Herein, a novel, highly active, sulfur-tolerant anode for intermediate-temperature SOFCs is prepared via a facile impregnation and limited reaction protocol. During synthesis, Ni nanoparticles, water-storable BaZr 0.4 Ce 0.4 Y 0.2 O 3- δ (BZCY) perovskite, and amorphous BaO are formed in situ and deposited on the surface of a Sm 0.2 Ce 0.8 O 1.9 (SDC) scaffold. More specifically, a porous SDC scaffold is impregnated with a well-designed proton-conducting perovskite oxide liquid precursor with the nominal composition of Ba(Zr 0.4 Ce 0.4 Y 0.2 ) 0.8 Ni 0.2 O 3- δ (BZCYN), calcined and reduced in hydrogen. The as-synthesized hierarchical architecture exhibits high H 2 electro-oxidation activity, excellent operational stability, superior sulfur tolerance, and good thermal cyclability. This work demonstrates the potential of combining nanocatalysts and water-storable materials in advanced electrocatalysts for SOFCs.

  3. Rational customs clearance technology choice

    OpenAIRE

    Shramenko, N.; Andriets, V.

    2008-01-01

    Issues concerning cargo delivery efficiencyincrease by choice of rational customs clearance technology have been considered. Three possible variants of customs clearance andmethods which allow to define the most rational version of cargo delivery in international road communication based on main efficiency criteria for definite distance have been presented.

  4. Differential Rationality and Personal Development.

    Science.gov (United States)

    Fincher, Cameron

    This publication discusses differential rationality; it asserts that the development of institutions, professions, and individuals involves the differentiation of forms and styles of thinking and knowing that are, in various ways, idiosyncratic. Based on this understanding, differential rationality can be seen as a developmental construct that…

  5. Rationality problem for algebraic tori

    CERN Document Server

    Hoshi, Akinari

    2017-01-01

    The authors give the complete stably rational classification of algebraic tori of dimensions 4 and 5 over a field k. In particular, the stably rational classification of norm one tori whose Chevalley modules are of rank 4 and 5 is given. The authors show that there exist exactly 487 (resp. 7, resp. 216) stably rational (resp. not stably but retract rational, resp. not retract rational) algebraic tori of dimension 4, and there exist exactly 3051 (resp. 25, resp. 3003) stably rational (resp. not stably but retract rational, resp. not retract rational) algebraic tori of dimension 5. The authors make a procedure to compute a flabby resolution of a G-lattice effectively by using the computer algebra system GAP. Some algorithms may determine whether the flabby class of a G-lattice is invertible (resp. zero) or not. Using the algorithms, the suthors determine all the flabby and coflabby G-lattices of rank up to 6 and verify that they are stably permutation. The authors also show that the Krull-Schmidt theorem for G-...

  6. Product differentiation under bounded rationality

    NARCIS (Netherlands)

    Vermeulen, B.; Poutré, La J.A.; Kok, de A.G.; Pyka, A.; Handa, H.; Ishibuchi, H.; Ong, Y.-S.; Tan, K.-C.

    2015-01-01

    We study product differentiation equilibria and dynamics on the Salop circle under bounded rationality. Due to bounded rationality, firms tend to agglomerate in pairs. Upon adding a second tier of component suppliers, downstream assemblers may escape pairwise horizontal agglomeration. Moreover, we

  7. The concept of rational suicide.

    Science.gov (United States)

    Mayo, D J

    1986-05-01

    Suicide has been condemned in our culture in one way or another since Augustine offered theological arguments against it in the sixth century. More recently, theological condemnation has given way to the view that suicidal behavior must always be symptomatic of emotional disturbance and mental illness. However, suicide has not always been viewed so negatively. In other times and cultures, it has been held that circumstances might befall a person in which suicide would be a perfectly rational course of action, in the same sense that any other course of action could be rational: that it could be sensible, i.e., defensible by good reasons, or that it could be in keeping with the agent's fundamental interests. Indiscriminate use of modern life-sustaining technologies has renewed interest in the possibility of rational suicide. Today proponents of rational suicide tend to equate the rationality of suicide with the competence of the decision to commit suicide.

  8. Limited rationality and strategic interaction

    DEFF Research Database (Denmark)

    Fehr, Ernst; Tyran, Jean-Robert

    2008-01-01

    Much evidence suggests that people are heterogeneous with regard to their abilities to make rational, forward-looking decisions. This raises the question as to when the rational types are decisive for aggregate outcomes and when the boundedly rational types shape aggregate results. We examine...... this question in the context of a long-standing and important economic problem: the adjustment of nominal prices after an anticipated monetary shock. Our experiments suggest that two types of bounded rationality-money illusion and anchoring-are important behavioral forces behind nominal inertia. However......, depending on the strategic environment, bounded rationality has vastly different effects on aggregate price adjustment. If agents' actions are strategic substitutes, adjustment to the new equilibrium is extremely quick, whereas under strategic complementarity, adjustment is both very slow and associated...

  9. Rational Design and Synthesis of Biologically Active Disubstituted 2(3H) Furanones and Pyrrolone Derivatives as Potent and Safer Non Steroidal Anti-inflammatory Agents.

    Science.gov (United States)

    Khokra, S L; Khan, S A; Choudhary, D; Hasan, S M; Ahmad, A; Husain, Asif

    2016-01-01

    Furanone and pyrrolone heterocyclic ring system represent important and interesting classes of bioactive compounds. Medicinal chemists use these heterocycyclic moieties as scaffolds in drug design and discovery. A series of 3-arylidene-5-(naphthalene-2-yl)-furan-2(3H)-ones (2a-j) were synthesized by incorporating pharmacophore of COX-2 inhibitor rofecoxib and naphthyl ring of naproxen as potential non steroidal anti-inflammatory agents. These furanone derivatives were subsequently reacted with dry ammonia gas and benzylamine to furnish corresponding 3-arylidene-5-(naphthlen-2-yl)-1H-pyrrol-2(3H)-ones (3a-e) and 3-arylidene-1-benzyl-5- (naphthalene-2-yl)-1H-pyrrol-2(3H)-ones (4a-e), respectively. The newly prepared heterocyclics were screened for their expected in-vivo biological activities including anti-inflammatory, analgesic and ulcerogenic actions in rodents. The COX-2 inhibitory behavior of synthesized compounds was also assessed via automated docking studies. The chemical structure of the synthesized compounds was characterized by using modern spectroscopic techniques. Result of in-vivo pharmacological studies demonstrated that almost all N-Benzyl-pyrrol-2(3H)-ones (4a-e) showed better anti-inflammatory and analgesic activities in comparison with the other two series of furan-2(3H)-ones and pyrrol- 2(3H)-ones. The moldock score value of the tested compounds was found in the range of -116.66 to -170.328 and was better than the standard drug. Among all the synthesized compounds, only nine compounds (2d, 2g, 2h, 3d, 4a, 4b, 4c, 4d and 4e) exhibited potent anti-inflammatory and analgesic activities with significantly reduced gastrointestinal toxicity in various animal models in comparison to standard drug, diclofenac. Therefore, it is recommended to explore the potential of the synthesized compounds as lead candidates for the development of new therapeutic agents.

  10. Optical pH Sensor Covering the Range from pH 0-14 Compatible with Mobile-Device Readout and Based on a Set of Rationally Designed Indicator Dyes.

    Science.gov (United States)

    Gotor, Raúl; Ashokkumar, Pichandi; Hecht, Mandy; Keil, Karin; Rurack, Knut

    2017-08-15

    In this work, a family of pH-responsive fluorescent probes has been designed in a rational manner with the aid of quantum chemistry tools, covering the entire pH range from 0-14. Relying on the boron-dipyrromethene (BODIPY) core, all the probes as well as selected reference dyes display very similar spectroscopic properties with ON-OFF fluorescence switching responses, facilitating optical readout in simple devices used for detection and analysis. Embedding of the probes and reference dyes into hydrogel spots on a plastic strip yielded a test strip that reversibly indicates pH with a considerably small uncertainty of ∼0.1 pH units. These strips are not only reusable but, combined with a 3D-printed case that can be attached to a smartphone, the USB port of which drives the integrated LED used for excitation, allows for autonomous operation in on-site or in-the-field applications; the developed Android application software ("app") further simplifies operation for unskilled users.

  11. Metabolism and resistance of Fusarium spp. to the manzamine alkaloids via a putative retro pictet-spengler reaction and utility of the rational design of antimalarial and antifungal agents.

    Science.gov (United States)

    Kasanah, Noer; Farr, Lorelei Lucas; Gholipour, Abbas; Wedge, David E; Hamann, Mark T

    2014-08-01

    As a part of our continuing investigation of the manzamine alkaloids we studied the in vitro activity of the β-carboline containing manzamine alkaloids against Fusarium solani, Fusarium oxysporium, and Fusarium proliferatum by employing several bioassay techniques including one-dimensional direct bioautography, dilution, and plate susceptibility, and microtiter broth assays. In addition, we also studied the metabolism of the manzamine alkaloids by Fusarium spp. in order to facilitate the redesign of the compounds to prevent resistance of Fusarium spp. through metabolism. The present research reveals that the manzamine alkaloids are inactive against Fusarium spp. and the fungi transform manzamines via hydrolysis, reduction, and a retro Pictet-Spengler reaction. This is the first report to demonstrate an enzymatically retro Pictet-Spengler reaction. The results of this study reveal the utility of the rational design of metabolically stable antifungal agents from this class and the development of manzamine alkaloids as antimalarial drugs through the utilization of Fusarium's metabolic products to reconstruct the molecule.

  12. A rationally designed self-standing V2O5 electrode for high voltage non-aqueous all-solid-state symmetric (2.0 V) and asymmetric (2.8 V) supercapacitors.

    Science.gov (United States)

    Ghosh, Meena; Vijayakumar, Vidyanand; Soni, Roby; Kurungot, Sreekumar

    2018-05-10

    The maximum capacitive potential window of certain pseudocapacitive materials cannot be accessed in aqueous electrolytes owing to the low dissociation potential of 1.2 V possessed by water molecules. However, the inferior pseudocapacitance exhibited by the commonly used electrode materials when integrated with non-aqueous electrolytes still remains a challenge in the development of supercapacitors (SC). Proper selection of materials for the electrode and a rational design process are indeed important to overcome these practical intricacies so that such systems can perform well with non-aqueous electrolytes. We address this challenge by fabricating a prototype all-solid-state device designed with high-capacitive V2O5 as the electrode material along with a Li-ion conducting organic electrolyte. V2O5 is synthesized on a pre-treated carbon-fibre paper by adopting an electrochemical deposition technique that effects an improved contact resistance. A judicious electrode preparation strategy makes it possible to overcome the constraints of the low ionic and electrical conductivities imposed by the electrolyte and electrode material, respectively. The device, assembled in a symmetrical fashion, achieves a high specific capacitance of 406 F g-1 (at 1 A g-1). The profitable aspect of using an organic electrolyte is also demonstrated with an asymmetric configuration by using activated carbon as the positive and V2O5 as the negative electrode materials, respectively. The asymmetric device displays a wide working-voltage window of 2.8 V and delivers a high energy density of 102.68 W h kg-1 at a power density of 1.49 kW kg-1. Moreover, the low equivalent series resistance of 9.9 Ω and negligible charge transfer resistance are observed in the impedance spectra, which is a key factor that accounts for such an exemplary performance.

  13. Discrete Choice and Rational Inattention

    DEFF Research Database (Denmark)

    Fosgerau, Mogens; Melo, Emerson; de Palma, André

    2017-01-01

    This paper establishes a general equivalence between discrete choice and rational inattention models. Matejka and McKay (2015, AER) showed that when information costs are modelled using the Shannon entropy, the result- ing choice probabilities in the rational inattention model take the multinomial...... logit form. We show that when information costs are modelled using a class of generalized entropies, then the choice probabilities in any rational inattention model are observationally equivalent to some additive random utility discrete choice model and vice versa. This equivalence arises from convex...

  14. Testing bounded rationality against full rationality in job changing behavior

    OpenAIRE

    Contini, Bruno; Morini, Matteo

    2007-01-01

    In this paper we question the hypothesis of full rationality in the context of job changing behaviour, via simple econometric explorations on microdata drawn from WHIP (Worker Histories Italian Panel). Workers' performance is compared at the end of a three-year time window that starts when choices are expressed, under the accepted notion that the main driving forces of job change are future real wages and expected job quality. Bounded rationality suggests that individuals will search for new ...

  15. Testing Bounded Rationality Against Full Rationality in Job Changing Behavior

    OpenAIRE

    Bruno Contini

    2008-01-01

    In this paper I question the hypothesis of full rationality in the context of job changing behaviour, via simple econometric explorations on microdata drawn from WHIP (Worker Histories Italian Panel). Workers’ performance is compared at the end of a three-year time window that starts when choices are expressed, under the accepted notion that the main driving forces of job change are future real wages and expected job quality. Bounded rationality suggests that individuals will search for new o...

  16. Rational design of fiber forming supramolecular structures

    Science.gov (United States)

    Wang, Benjamin K; Kanahara, Satoko M

    2016-01-01

    Recent strides in the development of multifunctional synthetic biomimetic materials through the self-assembly of multi-domain peptides and proteins over the past decade have been realized. Such engineered systems have wide-ranging application in bioengineering and medicine. This review focuses on fundamental fiber forming α-helical coiled-coil peptides, peptide amphiphiles, and amyloid-based self-assembling peptides; followed by higher order collagen- and elastin-mimetic peptides with an emphasis on chemical / biological characterization and biomimicry. PMID:27022140

  17. Rational Design of Rho Protein Inhibitors

    National Research Council Canada - National Science Library

    Rojas, Rafael J

    2006-01-01

    Rho GTPases are molecular switches that fluctuate between on and off states. When active, these proteins function to remodel the actin cytoskeleton by interacting with a number of downstream effector molecules...

  18. Rational Design of Rho Protein Inhibitors

    National Research Council Canada - National Science Library

    Rojas, Rafael J

    2005-01-01

    Rho GTPases are molecular switches that fluctuate between on and off states. When active, these proteins function to remodel the actin cytoskeleton by interacting with a number of downstream effector molecules...

  19. Rational Design of Rho Protein Inhibitors

    National Research Council Canada - National Science Library

    Rojas, Rafael J

    2006-01-01

    ... nucleotide exchange factors (RhoGEFs). We have developed a high throughput screening strategy identify novel inhibitors of Rho activation are currently following up on several compounds which appear to selectively inhibit Rho activation. These compounds may form the basis of future drug development strategies for the treatment of metastatic breast cancer.

  20. Rational Design of Rho Protein Inhibitors

    National Research Council Canada - National Science Library

    Rojas, Rafael J

    2005-01-01

    ... nucleotide exchange factors (RhoGEFs). We have developed a high throughput screening strategy identify novel inhibitors of Rho activation are currently following up on several compounds which appear to selectively inhibit Rho activation. These compounds may form the basis of future drug development strategies for the treatment of metastatic breast cancer.

  1. Design, Development and Rationalization of Sarpagandha Ghanvati

    Science.gov (United States)

    Pundarikakshudu, K.; Bhatt, C. J.

    2015-01-01

    Sarpagandha ghanvati is a classical Ayurvedic formulation widely prescribed for anxiety and insomnia. It contains Sarpagandha (roots of Rauwolfia serpentina L. (Benth.) Ex Kurz; Family: Apocyanaceae), Khurasani ajowan (Hyocyamus niger L.; Family: Solanaceae) seeds, Jatamansi (Nardostachys jatamansi DC. Family: Valerianaceae) roots and Pipplamul (root of Piper longum L.; Family: Piperaceae). The objective of this study was to make a comparative evaluation of Ghanvatis and tablets of this formulation. Two tablet formulations were prepared; one incorporating only powders of all ingredients; the other with ethanol extracts of the first three ingredients and powder of Piper longum root. Similarly, two types of Sarpagandha ghanvati pills were prepared; one as per Ayurvedic Formulary of India; the other with ethanol extracts of the first three ingredients and powder of Piper longum root. Alcohol extracted 0.22% w/w of total alkaloids as against 0.061% w/w extracted by water. Tablets prepared with powders of all the ingredients had friability more than 3.0% where as those prepared with ethanol extract had very low friability. Ghanvatis, prepared as per the Ayurvedic formulary, did not show reserpine although other alkaloids were present. They showed less content uniformity and lower drug release. Ethanol extracted reserpine along with other alkaloids. Ghanvatis made with the alcoholic extracts exhibited better content uniformity and drug release than the traditional formulation. Tablets prepared with powders or extracts of the ingredients exhibited good content uniformity but the release of alkaloids from the tablets of powders was only 80%. Tablets of the extracts had good content uniformity with 90% release of the total alkaloids. Tablets prepared with alcoholic extracts using 1% polyvinylpyrrolidone as binder and 5% dried starch powder as disintegrating agent confirmed to all the requirements. Thus, the study shows tablets made with the extracts are superior to Ghanvatis and powder tablets. PMID:26798180

  2. Rational design of nanomaterials for water treatment

    KAUST Repository

    Li, Renyuan; Zhang, Lianbin; Wang, Peng

    2015-01-01

    The ever-increasing human demand for safe and clean water is gradually pushing conventional water treatment technologies to their limits and it is now a popular perception that the solutions to the existing and future water challenges will highly

  3. Design, Development and Rationalization of Sarpagandha Ghanvati.

    Science.gov (United States)

    Pundarikakshudu, K; Bhatt, C J

    2015-01-01

    Sarpagandha ghanvati is a classical Ayurvedic formulation widely prescribed for anxiety and insomnia. It contains Sarpagandha (roots of Rauwolfia serpentina L. (Benth.) Ex Kurz; Family: Apocyanaceae), Khurasani ajowan (Hyocyamus niger L.; Family: Solanaceae) seeds, Jatamansi (Nardostachys jatamansi DC. Family: Valerianaceae) roots and Pipplamul (root of Piper longum L.; Family: Piperaceae). The objective of this study was to make a comparative evaluation of Ghanvatis and tablets of this formulation. Two tablet formulations were prepared; one incorporating only powders of all ingredients; the other with ethanol extracts of the first three ingredients and powder of Piper longum root. Similarly, two types of Sarpagandha ghanvati pills were prepared; one as per Ayurvedic Formulary of India; the other with ethanol extracts of the first three ingredients and powder of Piper longum root. Alcohol extracted 0.22% w/w of total alkaloids as against 0.061% w/w extracted by water. Tablets prepared with powders of all the ingredients had friability more than 3.0% where as those prepared with ethanol extract had very low friability. Ghanvatis, prepared as per the Ayurvedic formulary, did not show reserpine although other alkaloids were present. They showed less content uniformity and lower drug release. Ethanol extracted reserpine along with other alkaloids. Ghanvatis made with the alcoholic extracts exhibited better content uniformity and drug release than the traditional formulation. Tablets prepared with powders or extracts of the ingredients exhibited good content uniformity but the release of alkaloids from the tablets of powders was only 80%. Tablets of the extracts had good content uniformity with 90% release of the total alkaloids. Tablets prepared with alcoholic extracts using 1% polyvinylpyrrolidone as binder and 5% dried starch powder as disintegrating agent confirmed to all the requirements. Thus, the study shows tablets made with the extracts are superior to Ghanvatis and powder tablets.

  4. Rational design of gene-based vaccines.

    Science.gov (United States)

    Barouch, Dan H

    2006-01-01

    Vaccine development has traditionally been an empirical discipline. Classical vaccine strategies include the development of attenuated organisms, whole killed organisms, and protein subunits, followed by empirical optimization and iterative improvements. While these strategies have been remarkably successful for a wide variety of viruses and bacteria, these approaches have proven more limited for pathogens that require cellular immune responses for their control. In this review, current strategies to develop and optimize gene-based vaccines are described, with an emphasis on novel approaches to improve plasmid DNA vaccines and recombinant adenovirus vector-based vaccines. Copyright 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  5. Rational Design of Nanobody80 Loop Peptidomimetics

    DEFF Research Database (Denmark)

    Martin, Charlotte; Moors, Samuel L C; Danielsen, Mia

    2017-01-01

    G protein-coupled receptors (GPCRs) play an important role in many cellular responses; as such, their mechanism of action is of utmost interest. To gain insight into the active conformation of GPCRs, the X-ray crystal structures of nanobody (Nb)-stabilized β2 -adrenergic receptor (β2 AR) have been......-hairpin conformation. Syntheses, conformational analysis, binding and functional in vitro assays, as well as internalization experiments, were performed. We demonstrate that peptidomimetics can structurally mimic the CDR3 loop of a nanobody and its function by inhibiting G protein coupling as measured by partial...

  6. Moral Credentialing and the Rationalization of Misconduct

    Science.gov (United States)

    Brown, Ryan P.; Tamborski, Michael; Wang, Xiaoqian; Barnes, Collin D.; Mumford, Michael D.; Connelly, Shane; Devenport, Lynn D.

    2010-01-01

    Recent studies lead to the paradoxical conclusion that the act of affirming one’s egalitarian or pro-social values and virtues might subsequently facilitate prejudiced or self-serving behavior, an effect previously referred to as “moral credentialing.” The present study extends this paradox to the domain of academic misconduct and investigates the hypothesis that such an effect might be limited by the extent to which misbehavior is rationalizable. Using a paradigm designed to investigate deliberative and rationalized forms of cheating (von Hippel, Lakin, & Shakarchi, 2005), we found that when participants had credentialed themselves (versus a non-close acquaintance) via a set of hypothetical moral dilemmas, they were more likely to cheat on a subsequent math task, but only if cheating was highly rationalizable. When cheating was difficult to rationalize, moral credentialing had almost no impact on cheating. PMID:21503267

  7. Rational reconstructions of modern physics

    CERN Document Server

    Mittelstaedt, Peter

    2013-01-01

    Newton’s classical physics and its underlying ontology are loaded with several metaphysical hypotheses that cannot be justified by rational reasoning nor by experimental evidence. Furthermore, it is well known that some of these hypotheses are not contained in the great theories of Modern Physics, such as the theory of Special Relativity and Quantum Mechanics. This book shows that, on the basis of Newton’s classical physics and by rational reconstruction, the theory of Special Relativity as well as Quantum Mechanics can be obtained by partly eliminating or attenuating the metaphysical hypotheses. Moreover, it is shown that these reconstructions do not require additional hypotheses or new experimental results. In the second edition the rational reconstructions are completed with respect to General Relativity and Cosmology. In addition, the statistics of quantum objects is elaborated in more detail with respect to the rational reconstruction of quantum mechanics. The new material completes the approach of t...

  8. Rational-Emotive Staff Development.

    Science.gov (United States)

    Forman, Susan G.; Forman, Bruce D.

    1980-01-01

    The application of Rational-Emotive Therapy principles and techniques in in-service education for school personnel is discussed. Teacher and counselor participation in a staff development program is described. (Author)

  9. Geometry optimization of a fibrous scaffold based on mathematical modelling and CFD simulation of a dynamic cell culture

    DEFF Research Database (Denmark)

    Tajsoleiman, Tannaz; J. Abdekhodaie, Mohammad; Gernaey, Krist

    2016-01-01

    simulation of cartilage cell culture under a perfusion flow, which allows not only to characterize the supply of nutrients and metabolic products inside a fibrous scaffold, but also to assess the overall culture condition and predict the cell growth rate. Afterwards, the simulation results supported finding...... an optimized design of the scaffold within a new mathematical optimization algorithm that is proposed. The main concept of this optimization routine isto maintain a large effective surface while simultaneously keeping the shear stress levelin an operating range that is expected to be supporting growth....... Therewith, it should bepossible to gradually reach improved culture efficiency as defined in the objective function....

  10. Management between Rationality and Irrationality

    OpenAIRE

    Cene Bavec

    2012-01-01

    In the paper, we discuss theoretical and practical aspects of management and its rational and irrational behavior in the light of traditional management theories and contemporary social theories and theories of complexity. We exposed differences between middle and top management, where rationality is ascribed mainly to middle management, while top management often acts on seemingly irrational way. For the part of this irrationality, we cannot blame management because it originates from the na...

  11. Choice, internal consistency, and rationality

    OpenAIRE

    Aditi Bhattacharyya; Prasanta K. Pattanaik; Yongsheng Xu

    2010-01-01

    The classical theory of rational choice is built on several important internal consistency conditions. In recent years, the reasonableness of those internal consistency conditions has been questioned and criticized, and several responses to accommodate such criticisms have been proposed in the literature. This paper develops a general framework to accommodate the issues raised by the criticisms of classical rational choice theory, and examines the broad impact of these criticisms from both no...

  12. Methods of Monitoring Cell Fate and Tissue Growth in Three-Dimensional Scaffold-Based Strategies for In Vitro Tissue Engineering.

    Science.gov (United States)

    Leferink, Anne M; van Blitterswijk, Clemens A; Moroni, Lorenzo

    2016-08-01

    In the field of tissue engineering, there is a need for methods that allow assessing the performance of tissue-engineered constructs noninvasively in vitro and in vivo. To date, histological analysis is the golden standard to retrieve information on tissue growth, cellular distribution, and cell fate on tissue-engineered constructs after in vitro cell culture or on explanted specimens after in vivo applications. Yet, many advances have been made to optimize imaging techniques for monitoring tissue-engineered constructs with a sub-mm or μm resolution. Many imaging modalities have first been developed for clinical applications, in which a high penetration depth has been often more important than lateral resolution. In this study, we have reviewed the current state of the art in several imaging approaches that have shown to be promising in monitoring cell fate and tissue growth upon in vitro culture. Depending on the aimed tissue type and scaffold properties, some imaging methods are more applicable than others. Optical methods are mostly suited for transparent materials such as hydrogels, whereas magnetic resonance-based methods are mostly applied to obtain contrast between hard and soft tissues regardless of their transparency. Overall, this review shows that the field of imaging in scaffold-based tissue engineering is developing at a fast pace and has the potential to overcome the limitations of destructive endpoint analysis.

  13. Interpolation of rational matrix functions

    CERN Document Server

    Ball, Joseph A; Rodman, Leiba

    1990-01-01

    This book aims to present the theory of interpolation for rational matrix functions as a recently matured independent mathematical subject with its own problems, methods and applications. The authors decided to start working on this book during the regional CBMS conference in Lincoln, Nebraska organized by F. Gilfeather and D. Larson. The principal lecturer, J. William Helton, presented ten lectures on operator and systems theory and the interplay between them. The conference was very stimulating and helped us to decide that the time was ripe for a book on interpolation for matrix valued functions (both rational and non-rational). When the work started and the first partial draft of the book was ready it became clear that the topic is vast and that the rational case by itself with its applications is already enough material for an interesting book. In the process of writing the book, methods for the rational case were developed and refined. As a result we are now able to present the rational case as an indepe...

  14. Rationally designed chimeric peptide of met-enkephalin and FMRFa-[D-Ala2,p-Cl-Phe4]YFa induce multiple opioid receptors mediated antinociception and up-regulate their expression.

    Science.gov (United States)

    Vats, Ishwar Dutt; Chaudhary, Snehlata; Sharma, Ahuti; Nath, Mahendra; Pasha, Santosh

    2010-07-25

    The physiological role of NPFF/FMRFa family of peptides appears to be complex and exact mechanism of action of these peptides is not yet completely understood. In same line of scrutiny, another analog of YGGFMKKKFMRFamide (YFa), a chimeric peptide of met-enkephalin and FMRFamide, was rationally designed and synthesized which contain D-alanine and p-Cl-phenylalanine residues at 2nd and 4th positions, respectively i.e., Y-(D-Ala)-G-(p-Cl-Phe)-MKKKFMRFamide ([D-Ala(2), p-Cl-Phe(4)]YFa) in order to achieve improved bioavailability and blood brain barrier penetration. Therefore, present study investigates the possible antinociceptive effect of [D-Ala(2), p-Cl-Phe(4)]YFa on intra-peritoneal (i.p.) administration using tail-flick test in rats followed by its opioid receptor(s) specificity using mu, delta and kappa receptor antagonists. Further, its antinociceptive effect was examined during 6 days of chronic i.p. treatment and assessed effect of this treatment on differential expression of opioid receptors. [D-Ala(2), p-Cl-Phe(4)]YFa in comparison to parent peptide YFa, induce significantly higher dose dependent antinociception in rats which was mediated by all three opioid receptors (mu, delta and kappa). Importantly, it induced comparable antinociception in rats throughout the chronic i.p. treatment and significantly up-regulated the overall expression (mRNA and protein) of mu, delta and kappa opioid receptors. Therefore, pharmacological and molecular behavior of [D-Ala(2), p-Cl-Phe(4)]YFa demonstrate that incorporation of D-alanine and p-Cl-phenylalanine residues at appropriate positions in chimeric peptide leads to altered opioid receptor selectivity and enhanced antinociceptive potency, relative to parent peptide. (c) 2010 Elsevier B.V. All rights reserved.

  15. Love and rationality: on some possible rational effects of love

    Directory of Open Access Journals (Sweden)

    Gustavo Ortiz-Millán

    Full Text Available In this paper I defend the idea that rather than disrupting rationality, as the common-sense conception has done it, love may actually help us to develop rational ways of thinking and acting. I make the case for romantic or erotic love, since this is the kind of love that is more frequently associated with irrationality in acting and thinking. I argue that this kind of love may make us develop epistemic and practical forms of rationality. Based on an analysis of its characteristic action tendencies, I argue that love may help us to develop an instrumental form of rationality in determining the best means to achieve the object of love. It may also narrow down the number of practical considerations that may help us to achieve our goals. Finally, love may generate rational ways of belief-formation by framing the parameters taken into account in perception and attention, and by bringing into light only a small portion of the epistemic information available. Love may make us perceive reality more acutely.

  16. Rational Decision Making as Performative Praxis: Explaining Rationality's Éternel Retour

    OpenAIRE

    Cabantous, L.; Gond, J-P.

    2011-01-01

    Organizational theorists built their knowledge of decision making through a progressive critique of rational choice theory. Their positioning towards rationality, however, is at odds with the observation of rationality persistence in organizational life. This paper addresses this paradox. It proposes a new perspective on rationality that allows the theorizing of the production of rational decisions by organizations. To account for rationality's éternel retour, we approach rational decision ma...

  17. Rationing medical education | Walsh | African Health Sciences

    African Journals Online (AJOL)

    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 ...

  18. Strategy selection as rational metareasoning.

    Science.gov (United States)

    Lieder, Falk; Griffiths, Thomas L

    2017-11-01

    Many contemporary accounts of human reasoning assume that the mind is equipped with multiple heuristics that could be deployed to perform a given task. This raises the question of how the mind determines when to use which heuristic. To answer this question, we developed a rational model of strategy selection, based on the theory of rational metareasoning developed in the artificial intelligence literature. According to our model people learn to efficiently choose the strategy with the best cost-benefit tradeoff by learning a predictive model of each strategy's performance. We found that our model can provide a unifying explanation for classic findings from domains ranging from decision-making to arithmetic by capturing the variability of people's strategy choices, their dependence on task and context, and their development over time. Systematic model comparisons supported our theory, and 4 new experiments confirmed its distinctive predictions. Our findings suggest that people gradually learn to make increasingly more rational use of fallible heuristics. This perspective reconciles the 2 poles of the debate about human rationality by integrating heuristics and biases with learning and rationality. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  19. DISTRIBUTED RC NETWORKS WITH RATIONAL TRANSFER FUNCTIONS,

    Science.gov (United States)

    A distributed RC circuit analogous to a continuously tapped transmission line can be made to have a rational short-circuit transfer admittance and...one rational shortcircuit driving-point admittance. A subcircuit of the same structure has a rational open circuit transfer impedance and one rational ...open circuit driving-point impedance. Hence, rational transfer functions may be obtained while considering either generator impedance or load

  20. Rational points on elliptic curves

    CERN Document Server

    Silverman, Joseph H

    2015-01-01

    The theory of elliptic curves involves a pleasing blend of algebra, geometry, analysis, and number theory. This book stresses this interplay as it develops the basic theory, thereby providing an opportunity for advanced undergraduates to appreciate the unity of modern mathematics. At the same time, every effort has been made to use only methods and results commonly included in the undergraduate curriculum. This accessibility, the informal writing style, and a wealth of exercises make Rational Points on Elliptic Curves an ideal introduction for students at all levels who are interested in learning about Diophantine equations and arithmetic geometry. Most concretely, an elliptic curve is the set of zeroes of a cubic polynomial in two variables. If the polynomial has rational coefficients, then one can ask for a description of those zeroes whose coordinates are either integers or rational numbers. It is this number theoretic question that is the main subject of this book. Topics covered include the geometry and ...

  1. Rationality in the Cryptographic Model

    DEFF Research Database (Denmark)

    Hubacek, Pavel

    This thesis presents results in the field of rational cryptography. In the first part we study the use of cryptographic protocols to avoid mediation and binding commitment when implementing game theoretic equilibrium concepts. First, we concentrate on the limits of cryptographic cheap talk...... to implement correlated equilibria of two-player strategic games in a sequentially rational way. We show that there exist two-player games for which no cryptographic protocol can implement the mediator in a sequentially rational way; that is, without introducing empty threats. In the context of computational...... with appealing economic applications. Our implementation puts forward a notion of cryptographically blinded games that exploits the power of encryption to selectively restrict the information available to players about sampled action profiles, such that these desirable equilibria can be stably achieved...

  2. Human endothelial colony-forming cells expanded with an improved protocol are a useful endothelial cell source for scaffold-based tissue engineering.

    Science.gov (United States)

    Denecke, Bernd; Horsch, Liska D; Radtke, Stefan; Fischer, Johannes C; Horn, Peter A; Giebel, Bernd

    2015-11-01

    One of the major challenges in tissue engineering is to supply larger three-dimensional (3D) bioengineered tissue transplants with sufficient amounts of nutrients and oxygen and to allow metabolite removal. Consequently, artificial vascularization strategies of such transplants are desired. One strategy focuses on endothelial cells capable of initiating new vessel formation, which are settled on scaffolds commonly used in tissue engineering. A bottleneck in this strategy is to obtain sufficient amounts of endothelial cells, as they can be harvested only in small quantities directly from human tissues. Thus, protocols are required to expand appropriate cells in sufficient amounts without interfering with their capability to settle on scaffold materials and to initiate vessel formation. Here, we analysed whether umbilical cord blood (CB)-derived endothelial colony-forming cells (ECFCs) fulfil these requirements. In a first set of experiments, we showed that marginally expanded ECFCs settle and survive on different scaffold biomaterials. Next, we improved ECFC culture conditions and developed a protocol for ECFC expansion compatible with 'Good Manufacturing Practice' (GMP) standards. We replaced animal sera with human platelet lysates and used a novel type of tissue-culture ware. ECFCs cultured under the new conditions revealed significantly lower apoptosis and increased proliferation rates. Simultaneously, their viability was increased. Since extensively expanded ECFCs could still settle on scaffold biomaterials and were able to form tubular structures in Matrigel assays, we conclude that these ex vivo-expanded ECFCs are a novel, very potent cell source for scaffold-based tissue engineering. Copyright © 2013 John Wiley & Sons, Ltd.

  3. Facile fabrication of poly(L-lactic acid) microsphere-incorporated calcium alginate/hydroxyapatite porous scaffolds based on Pickering emulsion templates.

    Science.gov (United States)

    Hu, Yang; Ma, Shanshan; Yang, Zhuohong; Zhou, Wuyi; Du, Zhengshan; Huang, Jian; Yi, Huan; Wang, Chaoyang

    2016-04-01

    In this study, we develop a facile one-pot approach to the fabrication of poly(L-lactic acid) (PLLA) microsphere-incorporated calcium alginate (ALG-Ca)/hydroxyapatite (HAp) porous scaffolds based on HAp nanoparticle-stabilized oil-in-water Pickering emulsion templates, which contain alginate in the aqueous phase and PLLA in the oil phase. The emulsion aqueous phase is solidified by in situ gelation of alginate with Ca(2+) released from HAp by decreasing pH with slow hydrolysis of D-gluconic acid δ-lactone (GDL) to produce emulsion droplet-incorporated gels, followed by freeze-drying to form porous scaffolds containing microspheres. The pore structure of porous scaffolds can be adjusted by varying the HAp or GDL concentration. The compressive tests show that the increase of HAp or GDL concentration is beneficial to improve the compressive property of porous scaffolds, while the excessive HAp can lead to the decrease in compressive property. Moreover, the swelling behavior studies display that the swelling ratios of porous scaffolds reduce with increasing HAp or GDL concentration. Furthermore, hydrophobic drug ibuprofen (IBU) and hydrophilic drug bovine serum albumin (BSA) are loaded into the microspheres and scaffold matrix, respectively. In vitro drug release results indicate that BSA has a rapid release while IBU has a sustained release in the dual drug-loaded scaffolds. In vitro cell culture experiments verify that mouse bone mesenchymal stem cells can proliferate on the porous scaffolds well, indicating the good biocompatibility of porous scaffolds. All these results demonstrate that the PLLA microsphere-incorporated ALG-Ca/HAp porous scaffolds have a promising potential for tissue engineering and drug delivery applications. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Rational choice in field archaelology

    Directory of Open Access Journals (Sweden)

    Cătălin Pavel

    2011-11-01

    Full Text Available In the present article I attempt to apply advances in the study of instrumental and epistemic rationality to field archaeology in order to gain insights into the ways archaeologists reason. The cognitive processes, particularly processes of decision making, that enable archaeologists to conduct the excavation in the trench have not been adequately studied so far. I take my cues from two different bodies of theory. I first inquire into the potential that rational choice theory (RCT may have in modeling archaeological behaviour, and I define subjective expected utility, which archaeologists attempt to maximize, in terms of knowledge acquisition and social gain. Following Elster’s criticism of RCT, I conclude that RCT’s standards for rational action do not correspond with those ostensibly used in field archaeology, but that instrumental rationality has a prominent role in the “archaeological experiment”. I further explore if models proposed as reaction to RCT may account for archaeological decision making. I focus on fast and frugal heuristics, and search for archaeological illustrations for some of the cognitive biases that are better documented in psychological literature. I document confirmation and congruence biases, the endowment effect, observer-expectancy bias, illusory correlation, clustering illusion, sunk cost bias, and anchoring, among others and I propose that some of these biases are used as cognitive tools by archaeologists at work and retain epistemic value. However, I find formal logic to be secondary in the development of archaeological reasoning, with default logic and defeasible logic being used instead. I emphasize scientific knowledge as an actively negotiated social product of human inquiry, and conclude that to describe rationality in field archaeology a bounded rationality model is the most promising avenue of investigation.

  5. Rationalizing the Promotion of Non-Rational Behaviors in Organizations.

    Science.gov (United States)

    Smith, Peter A. C.; Sharma, Meenakshi

    2002-01-01

    Organizations must balance rational/technical efficiency and emotions. Action learning has been proven to be effective for developing emotional openness in the workplace. Facilitators of action learning should draw upon the disciplines of counseling, Gestalt, psychodynamics, and Eastern philosophies. (Contains 23 references.) (SK)

  6. Re-visions of rationality?

    Science.gov (United States)

    Newell, Ben R

    2005-01-01

    The appeal of simple algorithms that take account of both the constraints of human cognitive capacity and the structure of environments has been an enduring theme in cognitive science. A novel version of such a boundedly rational perspective views the mind as containing an 'adaptive toolbox' of specialized cognitive heuristics suited to different problems. Although intuitively appealing, when this version was proposed, empirical evidence for the use of such heuristics was scant. I argue that in the light of empirical studies carried out since then, it is time this 'vision of rationality' was revised. An alternative view based on integrative models rather than collections of heuristics is proposed.

  7. Mental health as rational autonomy.

    Science.gov (United States)

    Edwards, R B

    1981-08-01

    Rather than eliminate the terms "mental health and illness" because of the grave moral consequences of psychiatric labeling, conservative definitions are proposed and defended. Mental health is rational autonomy, and mental illness is the sustained loss of such. Key terms are explained, advantages are explored, and alternative concepts are criticized. The value and descriptive components of all such definitions are consciously acknowledged. Where rational autonomy is intact, mental hospitals and psychotherapists should not think of themselves as treating an illness. Instead, they are functioning as applied axiologists, moral educators, spiritual mentors, etc. They deal with what Szasz has called "personal, social, and ethical problems in living." But mental illness is real.

  8. Optimal public rationing and price response.

    Science.gov (United States)

    Grassi, Simona; Ma, Ching-To Albert

    2011-12-01

    We study optimal public health care rationing and private sector price responses. Consumers differ in their wealth and illness severity (defined as treatment cost). Due to a limited budget, some consumers must be rationed. Rationed consumers may purchase from a monopolistic private market. We consider two information regimes. In the first, the public supplier rations consumers according to their wealth information (means testing). In equilibrium, the public supplier must ration both rich and poor consumers. Rationing some poor consumers implements price reduction in the private market. In the second information regime, the public supplier rations consumers according to consumers' wealth and cost information. In equilibrium, consumers are allocated the good if and only if their costs are below a threshold (cost effectiveness). Rationing based on cost results in higher equilibrium consumer surplus than rationing based on wealth. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Teaching Rational Decision-Making.

    Science.gov (United States)

    Woolever, Roberts

    1978-01-01

    Presented is an outline of a college course, "Education in American Society," that focused on teaching students rational decision-making skills while examining current issues in American Education. The outline is followed by student comments, reactions, and evaluations of the course. (JMD)

  10. Rational Suicide among the Elderly.

    Science.gov (United States)

    Humphry, Derek

    1992-01-01

    Contends that old age, in and of itself, should never need to be a cause for self-destruction. Further argues that suicide and assisted suicide carried out in the face of terminal illness causing unbearable suffering should be ethically and legally acceptable. Outlines a perspective on rational suicide among the elderly. (Author/NB)

  11. On a CO2 ration

    International Nuclear Information System (INIS)

    De Wit, P.

    2003-01-01

    In 2 years all the large energy companies in the European Union will have a CO2 ration, including a system to trade a shortage or surplus of emission rights. A cost effective system to reduce emission, provided that the government does not auction the emission rights [nl

  12. On Counting the Rational Numbers

    Science.gov (United States)

    Almada, Carlos

    2010-01-01

    In this study, we show how to construct a function from the set N of natural numbers that explicitly counts the set Q[superscript +] of all positive rational numbers using a very intuitive approach. The function has the appeal of Cantor's function and it has the advantage that any high school student can understand the main idea at a glance…

  13. Rationality, mental causation and social sciences

    Directory of Open Access Journals (Sweden)

    Mladenović Ivan

    2009-01-01

    Full Text Available The aim of this paper is to investigate the role of mental causation in the context of rational choice theory. The author defends psychological aspect of rational explanation against the challenge of contemporary reductive materialism.

  14. Rationality, mental causation and social sciences

    OpenAIRE

    Mladenović Ivan

    2009-01-01

    The aim of this paper is to investigate the role of mental causation in the context of rational choice theory. The author defends psychological aspect of rational explanation against the challenge of contemporary reductive materialism.

  15. Strategy of Rational Use of Energy

    International Nuclear Information System (INIS)

    1994-09-01

    In the decade of the eighty, especially in order to this decade and so far, the Rational Use of Energy have not constituted a high-priority option and of present time for Colombia. The last politicians were guided, to favor the energy consumption with low prices of the coal, of the electricity, of those derived of the petroleum, growing subsidy to the gasoline and transfer of the productive sector toward the social one. In the recovery of the electric sector, it is contributed alternatives to improve the quality of the service of the electric industries where measured technical and investments in the industrial, commercial sectors and public would allow to reduce short term the consumptions for 5 to 10%, without reducing the production levels or of service. In the construction sector , the efficient designs of buildings could avoid a growth too much express of the energy consumption. The rational use of energy and the handling of the electric demand, should be one of the tools bigger than the State and of the electric industry, as the technical measures of reduction of losses, to respond to the financial crisis of the energy public sector, while the private sector acquires capacity of enough investment. The Colombians companies, experience the necessity to improve their energy efficiency, like one of the important areas of reduction of their costs and of increase of their competitiveness, in front of other countries, especially Latin-American. As consequence of the economic opening, the companies should modernize their processes and administration methods, what means a reduction in the energy consumptions. The reduction of the polluting, specially atmospheric emissions (industries, vehicles), as well as to elimination of having undone dangerous and industrial residuals, it is a priority in Colombia all improvement of the energy efficiency, particularly in the industries, it is accompanied of a proportional reduction of polluting emissions. Then a politics of

  16. Love and rationality: on some possible rational effects of love

    Directory of Open Access Journals (Sweden)

    Gustavo Ortiz-Millán

    2007-01-01

    Full Text Available In this paper I defend the idea that rather than disrupting rationality, as the common-sense conception has done it, love may actually help us to develop rational ways of thinking and acting. I make the case for romantic or erotic love, since this is the kind of love that is more frequently associated with irrationality in acting and thinking. I argue that this kind of love may make us develop epistemic and practical forms of rationality. Based on an analysis of its characteristic action tendencies, I argue that love may help us to develop an instrumental form of rationality in determining the best means to achieve the object of love. It may also narrow down the number of practical considerations that may help us to achieve our goals. Finally, love may generate rational ways of belief-formation by framing the parameters taken into account in perception and attention, and by bringing into light only a small portion of the epistemic information available. Love may make us perceive reality more acutely.Neste artigo defendo a idéia de que, em vez de perturbar a racionalidade, como a concepção do senso comum o faz, o amor pode, na verdade, ajudar-nos a desenvolver modos racionais de pensar e agir. Dou bons argumentos para o amor romântico ou erótico, uma vez que esse é o tipo de amor que é mais freqüentemente associado à irracionalidade no agir e no pensar. Argumento que esse tipo de amor pode fazer-nos desenvolver formas epistêmicas e práticas de racionalidade. Com base em uma análise de suas tendências características para a ação, argumento que o amor pode ajudar-nos a desenvolver uma forma instrumental de racionalidade para se determinar o melhor meio de atingir o objeto de amor. Ele também pode limitar o número de considerações práticas que podem ajudar-nos a atingir os nossos objetivos. Finalmente, o amor pode gerar modos racionais de formação de crenças ao estruturar os parâmetros considerados na percepção e na aten

  17. Psychology and the Rationality of Emotion.

    Science.gov (United States)

    Clore, Gerald L

    2011-04-01

    Questions addressed by recent psychological research on emotion include questions about how thought shapes emotion and how emotion, in turn, shapes thought. Research on emotion and cognition paints a somewhat different picture than that seen in traditional discussions of passion and reason. This article reviews several aspects of this research, concentrating specifically on three views of rationality: Rationality as Process, Rationality as Product, and Rationality as Outcome.

  18. Lessons from Learning to Have Rational Expectations

    OpenAIRE

    Lindh, Thomas

    1989-01-01

    This paper reviews a growing literature investigating how economic agents may learn rational expectations. Fully rational learning requires implausible initial information assumptions, therefore some form of bounded rationality has come into focus. Such learning models often converge to rational expectations equilibria within certain bounds. Convergence analysis has been much simplified by methods from adaptive control theory. Learning stability as a correspondence principle show some promise...

  19. Psychology and the Rationality of Emotion*

    OpenAIRE

    Clore, Gerald L.

    2011-01-01

    Questions addressed by recent psychological research on emotion include questions about how thought shapes emotion and how emotion, in turn, shapes thought. Research on emotion and cognition paints a somewhat different picture than that seen in traditional discussions of passion and reason. This article reviews several aspects of this research, concentrating specifically on three views of rationality: Rationality as Process, Rationality as Product, and Rationality as Outcome.

  20. Psychology and the Rationality of Emotion*

    Science.gov (United States)

    Clore, Gerald L.

    2014-01-01

    Questions addressed by recent psychological research on emotion include questions about how thought shapes emotion and how emotion, in turn, shapes thought. Research on emotion and cognition paints a somewhat different picture than that seen in traditional discussions of passion and reason. This article reviews several aspects of this research, concentrating specifically on three views of rationality: Rationality as Process, Rationality as Product, and Rationality as Outcome. PMID:25125770

  1. Rational use of diagnostic radiology

    International Nuclear Information System (INIS)

    Racoveanu, N.T.; Volodin, V.

    1992-01-01

    The escalating number of radiodiagnostic investigations has, as a consequence, an increase in medical irradiation of patients and of cost of radiological services. Radiologists in USA and UK have since early 1970 questioned the efficacy of various radiological investigations and produced substantial evidence that more rational approaches are necessary. WHO initiated, in 1977, a programme in this direction which has issued four technical reports which give practical recommendations on how to rationalize the use of radiological examinations. Three main directions are considered: (1) Abandonment of routine radiological examinations, as procedures with no clinical or epidemiologic significance and which represent a waste of resources and patient dose. (2) Patient selection for various radiological investigations based on clinical criteria (high, intermediate, low yield). Selected patients have an increased prevalence of the given disease and the predictive value of radiological investigation is much higher. (3) Use of diagnostic algorithms with higher cost/efficiency and risk/benefit ratios, improving the outcome of radiological examinations

  2. Electricity rationing and public response

    International Nuclear Information System (INIS)

    Souza, Leonardo Rocha; Soares, Lacir Jorge

    2007-01-01

    This paper studies the electricity load demand behavior during the 2001 rationing period, which was implemented because of the Brazilian energy crisis. The hourly data refers to a utility situated in the southeast of the country. We use the model proposed by Soares and Souza [Soares, L.J. and Souza, L.R. (2006), 'Forecasting electricity demand using generalized long memory', International Journal of Forecasting, 22, 17-28.], making use of generalized long memory to model the seasonal behavior of the load. The rationing period is shown to have imposed a structural break in the series, decreasing the load at about 20%. Even so, the forecast accuracy is decreased only marginally, and the forecasts rapidly readapt to the new situation. The structural break, as well as the forecast errors from this model, also permits verifying the public response to pieces of information released regarding the crisis. (Author)

  3. Rational maps, monopoles and skyrmions

    International Nuclear Information System (INIS)

    Houghton, C.J.; Manton, N.S.

    1998-01-01

    We discuss the similarities between BPS monopoles and skyrmions, and point to an underlying connection in terms of rational maps between Riemann spheres. This involves the introduction of a new ansatz for Skyrme fields. We use this to construct good approximations to several known skyrmions, including all the minimal energy configurations up to baryon number nine, and some new solutions such as a baryon number seventeen Skyrme field with the truncated icosahedron structure of a buckyball. The new approach is also used to understand the low-lying vibrational modes of skyrmions, which are required for quantization. Along the way we discover an interesting Morse function on the space of rational maps which may be of use in understanding the Sen forms on the monopole moduli spaces. (orig.)

  4. Bounded Rationality in Transposition Processes

    DEFF Research Database (Denmark)

    Vollaard, Hans; Martinsen, Dorte Sindbjerg

    2014-01-01

    Studies explaining the timeliness and correctness of the transposition of EU directives into national legislation have provided rather inconclusive findings. They do not offer a clear-cut prediction concerning the transposition of the patients’ rights directive, which is one of the first that con......Studies explaining the timeliness and correctness of the transposition of EU directives into national legislation have provided rather inconclusive findings. They do not offer a clear-cut prediction concerning the transposition of the patients’ rights directive, which is one of the first...... that concerns the organisation and financing of national healthcare systems. This article applies the perspective of bounded rationality to explain (irregularities in) the timely and correct transposition of EU directives. The cognitive and organisational constraints long posited by the bounded rationality...

  5. Rational approximations for tomographic reconstructions

    International Nuclear Information System (INIS)

    Reynolds, Matthew; Beylkin, Gregory; Monzón, Lucas

    2013-01-01

    We use optimal rational approximations of projection data collected in x-ray tomography to improve image resolution. Under the assumption that the object of interest is described by functions with jump discontinuities, for each projection we construct its rational approximation with a small (near optimal) number of terms for a given accuracy threshold. This allows us to augment the measured data, i.e., double the number of available samples in each projection or, equivalently, extend (double) the domain of their Fourier transform. We also develop a new, fast, polar coordinate Fourier domain algorithm which uses our nonlinear approximation of projection data in a natural way. Using augmented projections of the Shepp–Logan phantom, we provide a comparison between the new algorithm and the standard filtered back-projection algorithm. We demonstrate that the reconstructed image has improved resolution without additional artifacts near sharp transitions in the image. (paper)

  6. Rational Thinking in School-Based Practice

    Science.gov (United States)

    Clark, Mary Kristen; Flynn, Perry

    2011-01-01

    Purpose: We reflect on Alan Kamhi's (2011) prologue on balancing certainty and uncertainty as it pertains to school-based practice. Method: In schools, rational thinking depends on effective team processes, much like professional learning communities. We consider the conditions that are required for rational thinking and how rational team dialogue…

  7. Book Selection, Collection Development, and Bounded Rationality.

    Science.gov (United States)

    Schwartz, Charles A.

    1989-01-01

    Reviews previously proposed schemes of classical rationality in book selection, describes new approaches to rational choice behavior, and presents a model of book selection based on bounded rationality in a garbage can decision process. The role of tacit knowledge and symbolic content in the selection process are also discussed. (102 references)…

  8. RATGRAPH: Computer Graphing of Rational Functions.

    Science.gov (United States)

    Minch, Bradley A.

    1987-01-01

    Presents an easy-to-use Applesoft BASIC program that graphs rational functions and any asymptotes that the functions might have. Discusses the nature of rational functions, graphing them manually, employing a computer to graph rational functions, and describes how the program works. (TW)

  9. Rationality and the Logic of Good Reasons.

    Science.gov (United States)

    Fisher, Walter R.

    This paper contends that the rationality of the logic of good reasons is constituted in its use. To support this claim, the paper presents an analysis of the relationship between being reasonable and being rational. It then considers how following the logic of good reasons leads to rationality in the behavior of individuals and groups; the latter…

  10. Information Transmission and Rational Inattention

    OpenAIRE

    Antonella Tutino

    2015-01-01

    We study the problem of optimal communication strategy between a fully informed agent and a rationally inattentive agent. The fully informed agent observes a sequence of shocks and transmits a message to the limited-capacity agent who takes a set of actions in response to the message. The problem of the informed agent is to seek the optimal signaling strategy that induces a behavior consistent with minimal welfare loss, uniformly over a given class of bounded utility functions. We characteriz...

  11. Rational Asset Pricing Bubbles Revisited

    OpenAIRE

    Jan Werner

    2012-01-01

    Price bubble arises when the price of an asset exceeds the asset's fundamental value, that is, the present value of future dividend payments. The important result of Santos and Woodford (1997) says that price bubbles cannot exist in equilibrium in the standard dynamic asset pricing model with rational agents as long as assets are in strictly positive supply and the present value of total future resources is finite. This paper explores the possibility of asset price bubbles when either one of ...

  12. Kant on empiricism and rationalism

    OpenAIRE

    Vanzo, Alberto

    2013-01-01

    This paper aims to correct some widely held misconceptions concerning Kant's role in the formation of a widespread narrative of early modern philosophy. According to this narrative, which dominated the English-speaking world throughout the twentieth century, the early modern period was characterized by the development of two rival schools: René Descartes's, Baruch Spinoza's, and G. W. Leibniz's rationalism; and John Locke's, George Berkeley's, and David Hume's empiricism. Empiricists and rati...

  13. Rational approximation of vertical segments

    Science.gov (United States)

    Salazar Celis, Oliver; Cuyt, Annie; Verdonk, Brigitte

    2007-08-01

    In many applications, observations are prone to imprecise measurements. When constructing a model based on such data, an approximation rather than an interpolation approach is needed. Very often a least squares approximation is used. Here we follow a different approach. A natural way for dealing with uncertainty in the data is by means of an uncertainty interval. We assume that the uncertainty in the independent variables is negligible and that for each observation an uncertainty interval can be given which contains the (unknown) exact value. To approximate such data we look for functions which intersect all uncertainty intervals. In the past this problem has been studied for polynomials, or more generally for functions which are linear in the unknown coefficients. Here we study the problem for a particular class of functions which are nonlinear in the unknown coefficients, namely rational functions. We show how to reduce the problem to a quadratic programming problem with a strictly convex objective function, yielding a unique rational function which intersects all uncertainty intervals and satisfies some additional properties. Compared to rational least squares approximation which reduces to a nonlinear optimization problem where the objective function may have many local minima, this makes the new approach attractive.

  14. Ventilation, good indoor air quality and rational use of energy

    DEFF Research Database (Denmark)

    Clausen, Geo; Fernandes, E. D. O.; DeGids, W.

    2003-01-01

    The aim of this report is to provide information and advice to policy and decission makers, researchers, architects, designers, and manufacturers on strategies for achieving a good balance between good indoor air quality (IAQ) and the rational use of Energy in buildings, available guidelines...

  15. Decision-Making: Are Plants More Rational than Animals?

    Science.gov (United States)

    Schmid, Bernhard

    2016-07-25

    A new study presents a novel experimental design and allows a test of risk sensitivity in plants. Faced with a choice between constant and variable resource supply, they make a rational decision for the option that maximizes fitness, a fact rarely observed in animals. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Rational optimization of reliability and safety policies

    International Nuclear Information System (INIS)

    Melchers, Robert E.

    2001-01-01

    Optimization of structures for design has a long history, including optimization using numerical methods and optimality criteria. Much of this work has considered a subset of the complete design optimization problem--that of the technical issues alone. The more general problem must consider also non-technical issues and, importantly, the interplay between them and the parameters which influence them. Optimization involves optimal setting of design or acceptance criteria and, separately, optimal design within the criteria. In the modern context of probability based design codes this requires probabilistic acceptance criteria. The determination of such criteria involves more than the nominal code failure probability approach used for design code formulation. A more general view must be taken and a clear distinction must be made between those matters covered by technical reliability and non-technical reliability. The present paper considers this issue and outlines a framework for rational optimization of structural and other systems given the socio-economic and political systems within which optimization must be performed

  17. WHO and rational reduction of patient dose

    International Nuclear Information System (INIS)

    Hanson, G.

    1995-01-01

    WHO activities aimed at reducing patient dose, while maintaining satisfactory image quality, include rational use of diagnostic imaging, effective choices for examination, equipment design and specification, quality assurance, and guidance for regulatory authorities and radiological personnel. To assist its Member States in developing a rational policy concerning imaging services WHO provides guidance through publications, its network of Collaborating Centres, and its expert advisers. Because approximately 2/3 of the world's population lacked diagnostic imaging services, early in the 1960s WHO became concerned with basic radiology. After several unsuccessful approaches WHO concentrated on development of the Basic Radiological System (WHO-BRS). Following a workshop held in Neuherberg, Germany, a guide for Quality Assurance in Diagnostic Radiology was published by WHO in 1982. A similar guide for Quality Assurance in Nuclear Medicine was also published in 1982. In collaboration with other international organisations WHO is preparing revised editions of both the Basic Safety Standards for Radiation Protection, and the five-volume Manual on Radiation Protection in Hospitals and General Practice. Regarding future needs, within any health care system there is a spectrum of imaging requirements ranging from the most essential to the most complex. Issues to be resolved involve the clinical decision-making process through which diagnostic imaging examinations are produced and the optimum mixture of imaging modalities. (Author)

  18. Probabilistic approach to rationalization of plants maintenance

    International Nuclear Information System (INIS)

    Kasai, Masao; Notoya, Junichi; Uchimoto, Tetsuya; Miya, Kenzo

    2001-01-01

    Since there are a lot of equipments in large plants, their safety and reliability cannot be kept as high level as designed without maintenance activities. Then preventive maintenance is intensively executed in some large plants. However, it will be inefficient to perform the preventive maintenance blindly. To make maintenance activities effective, it is essential to identify the critical equipments influencing plant safety and/or reliability and carry out the maintenance by focusing attentions on these equipments. It needs quantitative analyses to identify the critical equipments based on the data of failure rates. However, complete data set of failure rates cannot necessarily be available for some plants such as nuclear power plants. In this study, we carry out the reliability analysis for generic LNG plant and calculate various quantitative risk importance measures for each equipment. We propose rather qualitative representations for some quantitative measures, considering the situation without complete data set and conclude that it is possible to rationalize maintenance procedure by using these rather qualitative measures, though the level of rationalization is of course limited. (author)

  19. Rational Behavior Training: A Seven Lesson Sequence for Teaching Rational Behavior Skills to Students with Social and Emotional Disabilities.

    Science.gov (United States)

    Patton, Patricia Lucey

    This seven lesson curriculum sequence is designed to help teachers teach principles of Rational Behavior Training (RBT) which targets thinking behaviors, feeling behaviors, and behavioral responses to the environment. The program is appropriate for students with social and emotional disabilities and also develops reading, writing, spelling,…

  20. Coherent states and rational surfaces

    International Nuclear Information System (INIS)

    Brody, Dorje C; Graefe, Eva-Maria

    2010-01-01

    The state spaces of generalized coherent states associated with special unitary groups are shown to form rational curves and surfaces in the space of pure states. These curves and surfaces are generated by the various Veronese embeddings of the underlying state space into higher dimensional state spaces. This construction is applied to the parameterization of generalized coherent states, which is useful for practical calculations, and provides an elementary combinatorial approach to the geometry of the coherent state space. The results are extended to Hilbert spaces with indefinite inner products, leading to the introduction of a new kind of generalized coherent states.

  1. Grade Expectations: Rationality and Overconfidence

    Science.gov (United States)

    Magnus, Jan R.; Peresetsky, Anatoly A.

    2018-01-01

    Confidence and overconfidence are essential aspects of human nature, but measuring (over)confidence is not easy. Our approach is to consider students' forecasts of their exam grades. Part of a student's grade expectation is based on the student's previous academic achievements; what remains can be interpreted as (over)confidence. Our results are based on a sample of about 500 second-year undergraduate students enrolled in a statistics course in Moscow. The course contains three exams and each student produces a forecast for each of the three exams. Our models allow us to estimate overconfidence quantitatively. Using these models we find that students' expectations are not rational and that most students are overconfident, in agreement with the general literature. Less obvious is that overconfidence helps: given the same academic achievement students with larger confidence obtain higher exam grades. Female students are less overconfident than male students, their forecasts are more rational, and they are also faster learners in the sense that they adjust their expectations more rapidly. PMID:29375449

  2. Reappraisal of Rational Choice Theory

    Directory of Open Access Journals (Sweden)

    Katalin Martinas

    2013-01-01

    Full Text Available The value of rational choice theory (RCT for the social sciences has long been contested. Much time has been spent by economists and critics on the pervasive but elusive concept of rationality. The critiques mainly challenge the basis of the utility theorem. Several articles on the misuse of mathematics in economics have already appeared in the literature. As N. Bouleau stated, “On several occasions, however, one feels that the criticism is that the math is being misused and should be developed in some other direction (e.g. a statistical analysis of the financial tendencies that polarize wealth and income, or a study of the positive feedback mechanisms, etc.. This leaves certain dissatisfaction – on a philosophical level.” The aim of this paper is to present a decision theory, yields intention (logos and valuation (existence. Here we present a new mathematical representation of RCT, which leads to a dynamic economic theory. We discuss the philosophical or meta-economical problems, which are needed for the successful applications of mathematics.

  3. Grade Expectations: Rationality and Overconfidence

    Directory of Open Access Journals (Sweden)

    Jan R. Magnus

    2018-01-01

    Full Text Available Confidence and overconfidence are essential aspects of human nature, but measuring (overconfidence is not easy. Our approach is to consider students' forecasts of their exam grades. Part of a student's grade expectation is based on the student's previous academic achievements; what remains can be interpreted as (overconfidence. Our results are based on a sample of about 500 second-year undergraduate students enrolled in a statistics course in Moscow. The course contains three exams and each student produces a forecast for each of the three exams. Our models allow us to estimate overconfidence quantitatively. Using these models we find that students' expectations are not rational and that most students are overconfident, in agreement with the general literature. Less obvious is that overconfidence helps: given the same academic achievement students with larger confidence obtain higher exam grades. Female students are less overconfident than male students, their forecasts are more rational, and they are also faster learners in the sense that they adjust their expectations more rapidly.

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

    Science.gov (United States)

    Jeschek, Markus; Gerngross, Daniel; Panke, Sven

    2016-03-31

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

  5. Simplifications of rational matrices by using UML

    OpenAIRE

    Tasić, Milan B.; Stanimirović, Ivan P.

    2013-01-01

    The simplification process on rational matrices consists of simplifying each entry represented by a rational function. We follow the classic approach of dividing the numerator and denominator polynomials by their common GCD polynomial, and provide the activity diagram in UML for this process. A rational matrix representation as the quotient of a polynomial matrix and a polynomial is also discussed here and illustrated via activity diagrams. Also, a class diagram giving the links between the c...

  6. Freedom and Rationality : Rousseau on Citizenship

    OpenAIRE

    Salvat, Christophe

    2008-01-01

    This paper deals with Rousseau's idea of freedom in terms of rationality and deliberation. It gives support to Berlin's interpretation of the general will as a rational and objective will but dismisses the idea that Rousseau's theory necessarily leads to authoritarianism. The general will, publicly expressed by the law, may be defined as the rational and self-regarding will agents would have if put in an independent and objective state, i.e. the state of nature. The general and the particular...

  7. Rational-Emotive Therapy versus Systematic Desensitization: A Comment on Moleski and Tosi.

    Science.gov (United States)

    Atkinson, Leslie

    1983-01-01

    Questioned the statistical analyses of the Moleski and Tosi investigation of rational-emotive therapy versus systematic desensitization. Suggested means for lowering the error rate through a more efficient experimental design. Recommended a reanalysis of the original data. (LLL)

  8. Rational Drug Use of Nurses

    Directory of Open Access Journals (Sweden)

    Mehtap Sahingoz

    2013-02-01

    Full Text Available ABSTRACT Objective: At this study to be aimed to assess status of the knowledge of nurses who working in public and private health institutions in Sivas province use of medication fort he treatment during their illnesses and patients and the attitudes of rational drug application. Matherials and methods: the researc planned to attend 750 nurses but it has been completed with participation of 641 nurses (Reaching rate 85,5%. This is a descriptive and cross-sectional study. in the study data were collected with a questionaire, percentages stated and chi square test was used for analysis. Results: %95,3 of nurses were females and mean age of them 29.21±4.85 years. The rate of contacting a doktor in case of illness is higher in 39.1% of nurses in the 21-30 age group and 48.6% of nurses working in primary care institutions. The level of self-treating is higher in 45.5 % of nurses working less than a year in profession .In the case of illness, 53% of nurses stated that they had left the medicine when signs of disease over. %98.8 of nurses expressed that they know effects of drugs used and 99.1% of them stated they know the side effects of drugs used. The entire group of postgraduate education status stated that they have not received the drug recommended by others. The level of suggesting a drug to someone else fort he same disease is higher in 65.8% of the group 31 years and older and group working over 40 hours per week. It were determined that used in consultation with the physician 65.2% of nurses antibiotics, 87.5% of them weiht loss drug and 82.7% of them contraceptive . 99.5% of the nurses have expressed that they inform to patients about use of their medications. Among the issues that expressed informations took place the application form of drugs (51.0 %and information of need to consult one if deemed one unexpected effect (59.6% . Also has been identified that of nurses acquired inform about drugs from drug book (vademecum (87.5 % and they

  9. Rational Choice and the Framing of Decisions.

    Science.gov (United States)

    1986-05-29

    survival in a competitive environment , and a minority of rational individuals can sometimes impose rationality on the whole market. Third, the...intuitive appeal of the axioms of rational choice makes it plausible that the theory derived from these axioms should provide an acceptable account of choice...rn-use U? RATIONAL CHOICE AMD THE FINNING OF KCISIOUS(U mi/ STANFORD UNIV CR A TYERSEY ET AL. 29 NAYN4-S4-K-S61SWICLASS IF lED FO 5/10S IL EEEEEEEE

  10. Rationality in Machiavelli and in Kant

    Directory of Open Access Journals (Sweden)

    Vadim Chaly

    2016-11-01

    Full Text Available The paper contains interpretation and comparative analysis of Machiavelli’s and Kant’s conceptions on rationality as two prime examples of “realist” and “idealist” modes of agency. Kantian model of rationality is viewed as an augmentation of the Machiavellian one, not an opposition to it. To elaborate the point, Robert Aumann’s model of act-rationality and rulerationality is applied to the two philosophical models. Kantian practical reason is interpreted as an addition to Aumann’s instrumental rationality, providing rules for rules, or “rule-rule-rationality”.

  11. Rational use of diagnostic radiology

    International Nuclear Information System (INIS)

    Racoveanu, N.T.; Volodin, V.

    1992-01-01

    Radiologists in USA and UK have since early 1970 questioned the efficacy of various radiological investigations and produced substantial evidence that more rational approaches are necessary. WHO initiated, in 1977, a programme which has issued four technical reports giving practical recommendations on how to rationalise the use of radiological examinations. Three main directions are considered: (1) Abandonment of routine radiological examinations, as procedures with no clinical or epidemiologic significance and which represent a waste of resources and patient dose. (2) Patient selection for various radiological investigations based on clinical criteria (high, intermediate, low yield). Selected patients have an increased prevalence of the given disease and the predictive value of radiological investigation is much higher. (3) Use of diagnostic algorithms with higher cost/efficiency and risk/benefit ratios, improving the outcome of radiological examinations. (author)

  12. RATIONAL PHARMACOTHERAPY IN TAKOTSUBO CARDIOMYOPATHY

    Directory of Open Access Journals (Sweden)

    S. Marchev

    2012-01-01

    Full Text Available Rational pharmacotherapy in Takotsubo cardiomyopathy is based on clinical picture and data of functional and laboratory investigations of concrete patient. In patients with hypotension and moderate-to-severe left ventricle outflow tract obstruction inotropic agents must not to be used because they can worsen the degree of obstruction. In these patients beta blockers can improve hemodynamics by causing resolution of the obstruction. If intraventricular thrombus is detected, anticoagulation for at least 3 months is recommended. The duration of anticoagulant therapy may be modified depending on the extent of cardiac function recovery and thrombus resolution. For patients without thrombus but with severe left ventricular dysfunction, anticoagulation is recommended until the akinesis or dyskinesis has resolved but not more than 3 months.

  13. Max Weber's Types of Rationality: Cornerstones for the Analysis of Rationalization Processes in History.

    Science.gov (United States)

    Kalberg, Stephen

    1980-01-01

    Explores rationality in Max Weber's works and identifies four types of rationality which play major roles in his writing--practical, theoretical, substantive, and formal. Implications for society and education are discussed. (DB)

  14. Inaugurating Rationalization: Three Field Studies Find Increased Rationalization When Anticipated Realities Become Current.

    Science.gov (United States)

    Laurin, Kristin

    2018-04-01

    People will often rationalize the status quo, reconstruing it in an exaggeratedly positive light. They will even rationalize the status quo they anticipate, emphasizing the upsides and minimizing the downsides of sociopolitical realities they expect to take effect. Drawing on recent findings on the psychological triggers of rationalization, I present results from three field studies, one of which was preregistered, testing the hypothesis that an anticipated reality becoming current triggers an observable boost in people's rationalizations. San Franciscans rationalized a ban on plastic water bottles, Ontarians rationalized a targeted smoking ban, and Americans rationalized the presidency of Donald Trump, more in the days immediately after these realities became current compared with the days immediately before. Additional findings show evidence for a mechanism underlying these behaviors and rule out alternative accounts. These findings carry implications for scholarship on rationalization, for understanding protest behavior, and for policymakers.

  15. Is It Rational to Assume that Infants Imitate Rationally? A Theoretical Analysis and Critique

    Science.gov (United States)

    Paulus, Markus

    2012-01-01

    It has been suggested that preverbal infants evaluate the efficiency of others' actions (by applying a "principle of rational action") and that they imitate others' actions rationally. The present contribution presents a conceptual analysis of the claim that preverbal infants imitate rationally. It shows that this ability rests on at least three…

  16. Children's selective trust decisions: rational competence and limiting performance factors.

    Science.gov (United States)

    Hermes, Jonas; Behne, Tanya; Bich, Anna Elisa; Thielert, Christa; Rakoczy, Hannes

    2018-03-01

    Recent research has amply documented that even preschoolers learn selectively from others, preferring, for example, reliable over unreliable and competent over incompetent models. It remains unclear, however, what the cognitive foundations of such selective learning are, in particular, whether it builds on rational inferences or on less sophisticated processes. The current study, therefore, was designed to test directly the possibility that children are in principle capable of selective learning based on rational inference, yet revert to simpler strategies such as global impression formation under certain circumstances. Preschoolers (N = 75) were shown pairs of models that either differed in their degree of competence within one domain (strong vs. weak or knowledgeable vs. ignorant) or were both highly competent, but in different domains (e.g., strong vs. knowledgeable model). In the test trials, children chose between the models for strength- or knowledge-related tasks. The results suggest that, in fact, children are capable of rational inference-based selective trust: when both models were highly competent, children preferred the model with the competence most predictive and relevant for a given task. However, when choosing between two models that differed in competence on one dimension, children reverted to halo-style wide generalizations and preferred the competent models for both relevant and irrelevant tasks. These findings suggest that the rational strategies for selective learning, that children master in principle, can get masked by various performance factors. © 2017 John Wiley & Sons Ltd.

  17. Rational Design of High-Performance Wide-Bandgap (≈2 eV) Polymer Semiconductors as Electron Donors in Organic Photovoltaics Exhibiting High Open Circuit Voltages (≈1 V).

    Science.gov (United States)

    Chochos, Christos L; Katsouras, Athanasios; Gasparini, Nicola; Koulogiannis, Chrysanthos; Ameri, Tayebeh; Brabec, Christoph J; Avgeropoulos, Apostolos

    2017-01-01

    Systematic optimization of the chemical structure of wide-bandgap (≈2.0 eV) "donor-acceptor" copolymers consisting of indacenodithiophene or indacenodithieno[3,2-b]thiophene as the electron-rich unit and thieno[3,4-c]pyrrole-4,6-dione as the electron-deficient moiety in terms of alkyl side chain engineering and distance of the electron-rich and electron-deficient monomers within the repeat unit of the polymer chain results in high-performance electron donor materials for organic photovoltaics. Specifically, preliminary results demonstrate extremely high open circuit voltages (V oc s) of ≈1.0 V, reasonable short circuit current density (J sc ) of around 11 mA cm -2 , and moderate fill factors resulting in efficiencies close to 6%. All the devices are fabricated in an inverted architecture with the photoactive layer processed by doctor blade equipment, showing the compatibility with roll-to-roll large-scale manufacturing processes. From the correlation of the chemical structure-optoelectronic properties-photovoltaic performance, a rational guide toward further optimization of the chemical structure in this family of copolymers, has been achieved. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Rationing in health systems: A critical review.

    Science.gov (United States)

    Keliddar, Iman; Mosadeghrad, Ali Mohammad; Jafari-Sirizi, Mehdi

    2017-01-01

    Background: It is difficult to provide health care services to all those in need of such services due to limited resources and unlimited demands. Thus, priority setting and rationing have to be applied. This study aimed at critically examining the concept of rationing in health sector and identifying its purposes, influencing factors, mechanisms, and outcomes. Methods: The critical interpretive synthesis methodology was used in this study. PubMed, Cochrane, and Proquest databases were searched using the related key words to find related documents published between 1970 and 2015. In total, 161 published reports were reviewed and included in the study. Thematic content analysis was applied for data analysis. Results: Health services rationing means restricting the access of some people to useful or potentially useful health services due to budgetary limitation. The inherent features of the health market and health services, limited resources, and unlimited needs necessitate health services rationing. Rationing can be applied in 4 levels: health care policy- makers, health care managers, health care providers, and patients. Health care rationing can be accomplished through fixed budget, benefit package, payment mechanisms, queuing, copayments, and deductibles. Conclusion: This paper enriched our understanding of health services rationing and its mechanisms at various levels and contributed to the literature by broadly conceptualizing health services rationing.

  19. Fiber sources for complete calf starter rations.

    Science.gov (United States)

    Murdock, F R; Wallenius, R W

    1980-11-01

    Complete calf starter rations containing either 1) alfalfa hay, 2) cottonseed hulls, or 3) alfalfa-beet pulp as sources of fiber were fed to Holstein heifer calves at two locations on a limited milk program from 3 days to 12 wk of age. Rations were isonitrogenous and similar in content of crude fiber and acid detergent fiber. Although growth and development were normal on all rations, calves fed the cottonseed hull ration consumed more starter and gained more body weight than calves fed the other sources of fiber. The similarity of feed efficiencies, rumen pH, and molar ratios of volatile fatty acids between rations indicated no appreciable differences in rumen development or function. The growth response of calves fed the cottonseed hull ration appeared to be a result of better ration acceptability for which no reason was evident. Calves raised at Puyallup gained more body weight than calves at Pullman, and these gains were made more efficiently. These location effects may be related to seasonal differences and greater demands for production of body heat. Although the incidence of scours was less for calves fed alfalfa hay starter, the incidence and severity of bloat were higher for that ration.

  20. The Problem of Rational Moral Enlistment

    Science.gov (United States)

    Tillson, John

    2017-01-01

    How can one bring children to recognize the requirements of morality without resorting only to non-rational means of persuasion (i.e. what rational ground can be offered to children for their moral enlistment)? Michael Hand has recently defended a foundationalist approach to answering this question and John White has responded by (a) criticizing…