Milk Production, Physiological Condition and Performance of Etawa Crossbreed Goats Feed by Ration Supplemented with Mangosteen Peel Flour

NASA Astrophysics Data System (ADS)

Dzarnisa; Rachmadi, D.; Azhar, A.; Fakhrur Riza, R.; Hidayati, A.

2018-02-01

Study on the effect of the addition of mangosteen (Garcinia mangostana L.) peel flour on physiological condition and performance of Etawa crossbreed goats was done. This was to grant the use of mangosteen peel flour that rich of antioxidants and has variety good benefits for health as feed additive for cattle. This study used a Complete Randomized Block Design consisting of 4 treatment groups and 4 replications each. Subjects were 16 female Etawa crossbreed goats randomly designed into treatments group based on lactation periods. Subjects were feed with traditional rations (control, A), traditional rations and 2.5% mangosteen peel flour (B), tradition rations and 5% mangosteen peel flour (C), and traditional rations and 7,5 % mangosteen peel flour (D). Data on performance (milk production) and physiological condition (respiratory frequency, rectal temperature, and heart rate) obtained were analyzed using analysis of variance (ANOVA). The results showed that the addition of mangosteen peel flour as food additive in the rations resulted in variations in the milk production, physiological condition (rectal temperature, heart rate and respiration frequency) and performances (daily weigh gain, food consumption, ration conversion and breast volume) of Etawa crossbreed goats, but significant effect was only observed in the respiration frequency. The addition of 2.5% mangosteen peel flour in the ration caused the best, expected effects on milk production physiological condition and performance of Etawa crossbreed goats.

Recombinant and epitope-based vaccines on the road to the market and implications for vaccine design and production.

PubMed

Oyarzún, Patricio; Kobe, Bostjan

2016-03-03

Novel vaccination approaches based on rational design of B- and T-cell epitopes - epitope-based vaccines - are making progress in the clinical trial pipeline. The epitope-focused recombinant protein-based malaria vaccine (termed RTS,S) is a next-generation approach that successfully reached phase-III trials, and will potentially become the first commercial vaccine against a human parasitic disease. Progress made on methods such as recombinant DNA technology, advanced cell-culture techniques, immunoinformatics and rational design of immunogens are driving the development of these novel concepts. Synthetic recombinant proteins comprising both B- and T-cell epitopes can be efficiently produced through modern biotechnology and bioprocessing methods, and can enable the induction of large repertoires of immune specificities. In particular, the inclusion of appropriate CD4+ T-cell epitopes is increasingly considered a key vaccine component to elicit robust immune responses, as suggested by results coming from HIV-1 clinical trials. In silico strategies for vaccine design are under active development to address genetic variation in pathogens and several broadly protective "universal" influenza and HIV-1 vaccines are currently at different stages of clinical trials. Other methods focus on improving population coverage in target populations by rationally considering specificity and prevalence of the HLA proteins, though a proof-of-concept in humans has not been demonstrated yet. Overall, we expect immunoinformatics and bioprocessing methods to become a central part of the next-generation epitope-based vaccine development and production process.

Rational design for the stability improvement of Armillariella tabescens β-mannanase MAN47 based on N-glycosylation modification.

PubMed

Hu, Weixiong; Liu, Xiaoyun; Li, Yufeng; Liu, Daling; Kuang, Zhihe; Qian, Chuiwen; Yao, Dongsheng

2017-02-01

β-Mannanase has been widely used in industries such as food and feed processing and thus has been a target enzyme for biotechnological development. In this study, we sought to improve the stability and protease resistance of a recombinant β-mannanase, MAN47 from Armillariella tabescens, through rationally designed N-glycosylation. Based on homology modeling, molecular docking, secondary structure analysis and glycosylation feasibility analysis, an enhanced aromatic sequon sequence was introduced into specific MAN47 loop regions to facilitate N-glycosylation. The mutant enzymes were expressed in Pichia pastoris SMD1168, and their thermal stability, pH stability, trypsin resistance and pepsin resistance were determined. Two mutant MAN47 enzymes, g-123 and g-347, were glycosylated as expected when expressed in yeast, and their thermal stability, pH stability, and protease resistance were significantly improved compared to the wild-type enzyme. An enzyme with multiple stability characterizations has broad prospects in practical applications, and the rational design N-glycosylation strategy may have applications in simultaneously improving several properties of other biotechnological targets. Copyright © 2016 Elsevier Inc. All rights reserved.

Experiential versus rational training: a comparison of student attitudes toward homosexuality.

PubMed

Guth, Lorraine J; Lopez, David F; Rojas, Julio; Clements, Kimberly D; Tyler, J Michael

2004-01-01

Based on Epstein's (1994a) cognitive-experiential self-theory, two new training interventions were designed to teach students about gay, lesbian and bisexual issues. The efficacy of these theoretically based interventions was assessed in a short-term (7-week, three occasion) longitudinal study. Fifty undergraduate psychology students were randomly assigned to one of three treatment groups: Rational Training, Experiential Training, or Control Group. A residualized change score procedure was used to analyze change in levels of sexual prejudice and affect across the three types of measurement (pre-test, post-test, and follow-up). A 3 (Rational Training, Experiential Training, Control Group) x 2 (Low Sexual Prejudice, High Sexual Prejudice) MANOVA revealed that after the training, participants in the Experiential Group (affective training) had more accepting attitudes toward homosexuality compared to the Control Group. In addition, participants in the Experiential Group experienced more positive affect compared to the Rational and Control Groups and experienced more negative affect compared to the Rational Group. Findings are discussed and suggestions for future research are provided.

Combining Adaptive Hypermedia with Project and Case-Based Learning

ERIC Educational Resources Information Center

Papanikolaou, Kyparisia; Grigoriadou, Maria

2009-01-01

In this article we investigate the design of educational hypermedia based on constructivist learning theories. According to the principles of project and case-based learning we present the design rational of an Adaptive Educational Hypermedia system prototype named MyProject; learners working with MyProject undertake a project and the system…

Final Report: Rational Design of Anode Surface Chemistry in Microbial Fuel Cells for Improved Exoelectrogen Attachment and Electron Transfer

DTIC Science & Technology

2015-12-21

SECURITY CLASSIFICATION OF: The overall goal of this project is to determine how electrode surface chemistry can be rationally designed to decrease...2015 Approved for Public Release; Distribution Unlimited Final Report: Rational Design of Anode Surface Chemistry in Microbial Fuel Cells for...ABSTRACT Final Report: Rational Design of Anode Surface Chemistry in Microbial Fuel Cells for Improved Exoelectrogen Attachment and Electron Transfer

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

PubMed

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.

Multitarget drug discovery projects in CNS diseases: quantitative systems pharmacology as a possible path forward.

PubMed

Geerts, Hugo; Kennis, Ludo

2014-01-01

Clinical development in brain diseases has one of the lowest success rates in the pharmaceutical industry, and many promising rationally designed single-target R&D projects fail in expensive Phase III trials. By contrast, successful older CNS drugs do have a rich pharmacology. This article will provide arguments suggesting that highly selective single-target drugs are not sufficiently powerful to restore complex neuronal circuit homeostasis. A rationally designed multitarget project can be derisked by dialing in an additional symptomatic treatment effect on top of a disease modification target. Alternatively, we expand upon a hypothetical workflow example using a humanized computer-based quantitative systems pharmacology platform. The hope is that incorporating rationally multipharmacology drug discovery could potentially lead to more impactful polypharmacy drugs.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Makabe, Koki; Koide, Shohei

2009-06-17

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

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

PubMed

Migliniene, Ieva; Ostasevicius, Vytautas; Gaidys, Rimvydas; Dauksevicius, Rolanas; Janusas, Giedrius; Jurenas, Vytautas; Krasauskas, Povilas

2017-12-12

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.

Molecular Docking of Enzyme Inhibitors: A Computational Tool for Structure-Based Drug Design

ERIC Educational Resources Information Center

Rudnitskaya, Aleksandra; Torok, Bela; Torok, Marianna

2010-01-01

Molecular docking is a frequently used method in structure-based rational drug design. It is used for evaluating the complex formation of small ligands with large biomolecules, predicting the strength of the bonding forces and finding the best geometrical arrangements. The major goal of this advanced undergraduate biochemistry laboratory exercise…

Medicinal chemistry inspired fragment-based drug discovery.

PubMed

Lanter, James; Zhang, Xuqing; Sui, Zhihua

2011-01-01

Lead generation can be a very challenging phase of the drug discovery process. The two principal methods for this stage of research are blind screening and rational design. Among the rational or semirational design approaches, fragment-based drug discovery (FBDD) has emerged as a useful tool for the generation of lead structures. It is particularly powerful as a complement to high-throughput screening approaches when the latter failed to yield viable hits for further development. Engagement of medicinal chemists early in the process can accelerate the progression of FBDD efforts by incorporating drug-friendly properties in the earliest stages of the design process. Medium-chain acyl-CoA synthetase 2b and ketohexokinase are chosen as examples to illustrate the importance of close collaboration of medicinal chemists, crystallography, and modeling. Copyright © 2011 Elsevier Inc. All rights reserved.

Toward a rational, value-based drug benefit for Medicare.

PubMed

Lopert, Ruth; Moon, Marilyn

2007-01-01

A major challenge facing Congress is what changes, if any, to make to Medicare Part D. With the apparent failure of the Democrats' attempt to remove the prohibition on government intervention in drug price negotiations, the party's next steps are unclear. One suggested option is a plan administered by the Centers for Medicare and Medicaid Services (CMS), to compete with private plans and facilitate a transition to a more rational structure. We discuss issues surrounding the design of such a mechanism and how it might provide a transition toward a more rational and sustainable drug benefit in the longer term.

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

PubMed

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

2016-05-11

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

Towards the rational design of the Py5-ligand framework for ruthenium-based water oxidation catalysts.

PubMed

Schilling, Mauro; Böhler, Michael; Luber, Sandra

2018-05-21

In order to rationally design water oxidation catalysts (WOCs), an in-depth understanding of the reaction mechanism is essential. In this study we showcase the complexity of catalytic water oxidation, by elucidating how modifications of the pentapyridyl (Py5) ligand-framework influence the thermodynamics and kinetics of the process. In the reaction mechanism the pyridine-water exchange was identified as a key reaction which appears to determine the reactivity of the Py5-WOCs. Exploring the capabilities of in silico design we show which modifications of the ligand framework appear promising when attempting to improve the catalytic performance of WOCs derived from Py5.

Modeling corneal surfaces with rational functions for high-speed videokeratoscopy data compression.

PubMed

Schneider, Martin; Iskander, D Robert; Collins, Michael J

2009-02-01

High-speed videokeratoscopy is an emerging technique that enables study of the corneal surface and tear-film dynamics. Unlike its static predecessor, this new technique results in a very large amount of digital data for which storage needs become significant. We aimed to design a compression technique that would use mathematical functions to parsimoniously fit corneal surface data with a minimum number of coefficients. Since the Zernike polynomial functions that have been traditionally used for modeling corneal surfaces may not necessarily correctly represent given corneal surface data in terms of its optical performance, we introduced the concept of Zernike polynomial-based rational functions. Modeling optimality criteria were employed in terms of both the rms surface error as well as the point spread function cross-correlation. The parameters of approximations were estimated using a nonlinear least-squares procedure based on the Levenberg-Marquardt algorithm. A large number of retrospective videokeratoscopic measurements were used to evaluate the performance of the proposed rational-function-based modeling approach. The results indicate that the rational functions almost always outperform the traditional Zernike polynomial approximations with the same number of coefficients.

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

NASA Astrophysics Data System (ADS)

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

2013-04-01

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

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

PubMed

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

2013-04-01

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). 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. 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. Our findings point to the potential value of model-based rational design of feedback controllers for Parkinson's disease.

The Web-Based DNA Vaccine Database DNAVaxDB and Its Usage for Rational DNA Vaccine Design.

PubMed

Racz, Rebecca; He, Yongqun

2016-01-01

A DNA vaccine is a vaccine that uses a mammalian expression vector to express one or more protein antigens and is administered in vivo to induce an adaptive immune response. Since the 1990s, a significant amount of research has been performed on DNA vaccines and the mechanisms behind them. To meet the needs of the DNA vaccine research community, we created DNAVaxDB ( http://www.violinet.org/dnavaxdb ), the first Web-based database and analysis resource of experimentally verified DNA vaccines. All the data in DNAVaxDB, which includes plasmids, antigens, vaccines, and sources, is manually curated and experimentally verified. This chapter goes over the detail of DNAVaxDB system and shows how the DNA vaccine database, combined with the Vaxign vaccine design tool, can be used for rational design of a DNA vaccine against a pathogen, such as Mycobacterium bovis.

Design flood hydrograph estimation procedure for small and fully-ungauged basins

NASA Astrophysics Data System (ADS)

Grimaldi, S.; Petroselli, A.

2013-12-01

The Rational Formula is the most applied equation in practical hydrology due to its simplicity and the effective compromise between theory and data availability. Although the Rational Formula is affected by several drawbacks, it is reliable and surprisingly accurate considering the paucity of input information. However, after more than a century, the recent computational, theoretical, and large-scale monitoring progresses compel us to try to suggest a more advanced yet still empirical procedure for estimating peak discharge in small and ungauged basins. In this contribution an alternative empirical procedure (named EBA4SUB - Event Based Approach for Small and Ungauged Basins) based on the common modelling steps: design hyetograph, rainfall excess, and rainfall-runoff transformation, is described. The proposed approach, accurately adapted for the fully-ungauged basin condition, provides a potentially better estimation of the peak discharge, a design hydrograph shape, and, most importantly, reduces the subjectivity of the hydrologist in its application.

APPLICATION OF STEEL PIPE PILE LOADING TESTS TO DESIGN VERIFICATION OF FOUNDATION OF THE TOKYO GATE BRIDGE

NASA Astrophysics Data System (ADS)

Saitou, Yutaka; Kikuchi, Yoshiaki; Kusakabe, Osamu; Kiyomiya, Osamu; Yoneyama, Haruo; Kawakami, Taiji

Steel sheet pipe pile foundations with large diameter steel pipe sheet pile were used for the foundation of the main pier of the Tokyo Gateway bridge. However, as for the large diameter steel pipe pile, the bearing mechanism including a pile tip plugging effect is still unclear due to lack of the practical examinations even though loading tests are performed on Trans-Tokyo Bay Highway. In the light of the foregoing problems, static pile loading tests both vertical and horizontal directions, a dynamic loading test, and cone penetration tests we re conducted for determining proper design parameters of the ground for the foundations. Design parameters were determined rationally based on the tests results. Rational design verification was obtained from this research.

Project-Based Pedagogy for the Facilitation of Webpage Design

ERIC Educational Resources Information Center

Jakovljevic, Maria; Ankiewicz, Piet

2016-01-01

Real issues of web design and development include many problem-solving tasks. There are, however, some inadequacies associated with the implementation of appropriate pedagogy for organised and structured instruction that supports the rational problem-solving paradigm. The purpose of this article is to report on a study for the design and…

The equivalence of a human observer and an ideal observer in binary diagnostic tasks

NASA Astrophysics Data System (ADS)

He, Xin; Samuelson, Frank; Gallas, Brandon D.; Sahiner, Berkman; Myers, Kyle

2013-03-01

The Ideal Observer (IO) is "ideal" for given data populations. In the image perception process, as the raw images are degraded by factors such as display and eye optics, there is an equivalent IO (EIO). The EIO uses the statistical information that exits the perception/cognitive degradations as the data. We assume a human observer who received sufficient training, e.g., radiologists, and hypothesize that such a human observer can be modeled as if he is an EIO. To measure the likelihood ratio (LR) distributions of an EIO, we formalize experimental design principles that encourage rationality based on von Neumann and Morgenstern's (vNM) axioms. We present examples to show that many observer study design refinements, although motivated by empirical principles explicitly, implicitly encourage rationality. Our hypothesis is supported by a recent review paper on ROC curve convexity by Pesce, Metz, and Berbaum. We also provide additional evidence based on a collection of observer studies in medical imaging. EIO theory shows that the "sub-optimal" performance of a human observer can be mathematically formalized in the form of an IO, and measured through rationality encouragement.

Nano-array based monolithic catalysts: Concept, rational materials design and tunable catalytic performance

DOE PAGES

Ren, Zheng; Guo, Yanbing; Gao, Pu-Xian

2015-03-20

Monolithic catalysts, also known as structured catalysts, represent an important catalyst configuration widely used in automotive, chemical, and energy industries. However, several issues associated with washcoat based monolithic catalyst preparation are ever present, such as compromised materials utilization efficiency due to a less-than-ideal wash coating process, difficulty in precise and optimum microstructure control and lack of structure-property correlation. Here, in this mini-review, we introduce the concept of nano-array catalyst, a new type of monolithic catalyst featuring high catalyst utilization efficiency, good thermal/mechanical robustness, and catalytic performance tunability. A comprehensive overview is presented with detailed discussion of the strategies for nano-arraymore » catalyst preparation and rational catalytic activity adjustment enabled by the well-defined nano-array geometry. Specifically their scalable fabrication processes are reviewed in conjunction with discussion of their various catalytic oxidation reaction performances at low temperature. Finally, we hope this review will serve as a timely and useful research guide for rational design and utilization of the new type of monolithic catalysts.« less

Structural optimization of large ocean-going structures

NASA Technical Reports Server (NTRS)

Hughes, O. F.

1984-01-01

Ocean-going vehicles and platforms are among the largest structures in the world and are subjected to relatively harsh conditions of motions and loads. Some of them, such as semi-submersible platforms, are a relatively new type of structure and hence there is no formal, well evolved and established structural design code as there is for more traditional structures. More recently, efforts have also been made to develop a design method of this type for ships and other ocean structures. One of the many advantages of a rationally based design method is versatility; it can be used for structures that have widely differing purposes, measures of merit, shapes and sizes. The purpose is to describe a rationally based design method that has been developed within the field of ocean structures, in order that persons dealing with other types of structure can judge whether and to what extent its various features may be useful for those other types. Also, even though some features may not be applicable they might stimulate some useful ideas.

Rational design based synthetic polyepitope DNA vaccine for eliciting HIV-specific CD8+ T cell responses.

PubMed

Bazhan, S I; Karpenko, L I; Ilyicheva, T N; Belavin, P A; Seregin, S V; Danilyuk, N K; Antonets, D V; Ilyichev, A A

2010-04-01

Advances in defining HIV-1 CD8+ T cell epitopes and understanding endogenous MHC class I antigen processing enable the rational design of polyepitope vaccines for eliciting broadly targeted CD8+ T cell responses to HIV-1. Here we describe the construction and comparison of experimental DNA vaccines consisting of ten selected HLA-A2 epitopes from the major HIV-1 antigens Env, Gag, Pol, Nef, and Vpr. The immunogenicity of designed gene constructs was assessed after double DNA prime, single vaccinia virus boost immunization of HLA-A2 transgenic mice. We compared a number of parameters including different strategies for fusing ubiquitin to the polyepitope and including spacer sequences between epitopes to optimize proteasome liberation and TAP transport. It was demonstrated that the vaccine construct that induced in vitro the largest number of [peptide-MHC class I] complexes was also the most immunogenic in the animal experiments. This most immunogenic vaccine construct contained the N-terminal ubiquitin for targeting the polyepitope to the proteasome and included both proteasome liberation and TAP transport optimized spacer sequences that flanked the epitopes within the polyepitope construct. The immunogenicity of determinants was strictly related to their affinities for HLA-A2. Our finding supports the concept of rational vaccine design based on detailed knowledge of antigen processing. Copyright 2010 Elsevier Ltd. All rights reserved.

User involvement in the construction of a mental health charter: an exercise in communicative rationality?

PubMed

Hodge, Suzanne M

2009-09-01

This paper uses Jürgen Habermas's Theory of Communicative Action as a lens through which to examine the development of a local mental health charter. To assess whether the Charter represents the product of a communicatively rational process. RESEARCH DESIGN AND SETTING: The paper is based on an analysis of the text of the Charter, and on documentation relating to its development, including notes of discussion groups used to identify its themes. An analysis of the notes of the discussion groups against the text of the Charter shows that the Charter's themes are based broadly on the views generated in the discussion groups. However, they also draw on norms derived from wider discourses not reflected in the discussion groups, and exclude other specific local issues. The strength of feeling expressed in the discussion groups is also toned down in the language of the Charter. The development of the Charter was based on a participatory process that can be said to have contained elements of both communicative and strategic rationality. The strategic rationality involved in translating service users' views into language that would be acceptable to those working in the system can be seen as necessary for the Charter to succeed in bringing about change. In drawing also on communicatively generated norms from the wider public sphere the Charter can be seen as reflecting a form of generalized communicative rationality. The Charter represents a 'sluice' by which communicative rationality is drawn into the mental health system.

Rational drug therapy education in clinical phase carried out by task-based learning

PubMed Central

Bilge, S. Sırrı; Akyüz, Bahar; Ağrı, Arzu Erdal; Özlem, Mıdık

2017-01-01

Objectives: Irrational drug use results in drug interactions, treatment noncompliance, and drug resistance. Rational pharmacotherapy education is being implemented in many faculties of medicine. Our aim is to introduce rational pharmacotherapy education by clinicians and to evaluate task-based rational drug therapy education in the clinical context. Methods: The Kirkpatrick's evaluation model was used for the evaluation of the program. The participants evaluated the program in terms of constituents of the program, utilization, and contribution to learning. Voluntary participants responded to the evaluation forms after the educational program. Data are evaluated using both quantitative and qualitative tools. SPSS (version 21) used for quantitative data for determining mean and standard deviation values. Descriptive qualitative analysis approach is used for the analysis of open-ended questions. Results: It was revealed that the program and its components have been favorable. A total 95.9% of the students consider the education to be beneficial. Simulated patients practice and personal drug choice/problem-based learning sessions were appreciated by the students in particular. 93.9% of the students stated that all students of medicine should undergo this educational program. Among the five presentations contained in the program, “The Principles of Prescribing” received the highest points (9 ± 1.00) from participating students in general evaluation of the educational program. Conclusion: This study was carried out to improve task-based rational drug therapy education. According to feedback from the students concerning content, method, resource, assessment, and program design; some important changes, especially in number of facilitators and indications, are made in rational pharmacotherapy education in clinical task-based learning program. PMID:28458432

Rational Design Methodology.

DTIC Science & Technology

1978-09-01

This report describes an effort to specify a software design methodology applicable to the Air Force software environment . Available methodologies...of techniques for proof of correctness, design specification, and performance assessment of static designs. The rational methodology selected is a

Do Students Use Contextual Protective Behaviors to Reduce Alcohol-Related Sexual Risk? Examination of a Dual-Process Decision-Making Model

PubMed Central

Scaglione, Nichole M.; Hultgren, Brittney A.; Reavy, Racheal; Mallett, Kimberly A.; Turrisi, Rob; Cleveland, Michael J.; Sell, Nichole M.

2015-01-01

Objective Recent studies suggest drinking protective behaviors (DPBs) and contextual protective behaviors (CPBs) can uniquely reduce alcohol-related sexual risk in college students. Few studies have examined CPBs independently, and even fewer have utilized theory to examine modifiable psychosocial predictors of students’ decisions to use CPBs. The current study used a prospective design to examine 1) rational and reactive pathways and psychosocial constructs predictive of CPB use, and 2) how gender might moderate these influences in a sample of college students. Method Students (n = 508) completed web-based baseline (mid-spring semester) and 1- and 6-month follow-up assessments of CPB use; psychosocial constructs (expectancies, normative beliefs, attitudes, and self-concept); and rational and reactive pathways (intentions and willingness). Regression was used to examine rational and reactive influences as proximal predictors of CPB use at the 6-month follow-up. Subsequent path analyses examined the effects of psychosocial constructs, as distal predictors of CPB use, mediated through the rational and reactive pathways. Results Both rational (intentions to use CPB) and reactive (willingness to use CPB) influences were significantly associated with increased CPB use. The examined distal predictors were found to effect CPB use differentially through the rational and reactive pathways. Gender did not significantly moderate any relationships within in the model. Discussion Findings suggest potential entry points for increasing CPB use that include both rational and reactive pathways. Overall, this study demonstrates the mechanisms underlying how to increase the use of CPBs in programs designed to reduce alcohol-related sexual consequences and victimization. PMID:26415062

Do students use contextual protective behaviors to reduce alcohol-related sexual risk? Examination of a dual-process decision-making model.

PubMed

Scaglione, Nichole M; Hultgren, Brittney A; Reavy, Racheal; Mallett, Kimberly A; Turrisi, Rob; Cleveland, Michael J; Sell, Nichole M

2015-09-01

Recent studies suggest drinking protective behaviors (DPBs) and contextual protective behaviors (CPBs) can uniquely reduce alcohol-related sexual risk in college students. Few studies have examined CPBs independently, and even fewer have utilized theory to examine modifiable psychosocial predictors of students' decisions to use CPBs. The current study used a prospective design to examine (a) rational and reactive pathways and psychosocial constructs predictive of CPB use and (b) how gender might moderate these influences in a sample of college students. Students (n = 508) completed Web-based baseline (mid-Spring semester) and 1- and 6-month follow-up assessments of CPB use; psychosocial constructs (expectancies, normative beliefs, attitudes, and self-concept); and rational and reactive pathways (intentions and willingness). Regression was used to examine rational and reactive influences as proximal predictors of CPB use at the 6-month follow-up. Subsequent path analyses examined the effects of psychosocial constructs, as distal predictors of CPB use, mediated through the rational and reactive pathways. Both rational (intentions to use CPB) and reactive (willingness to use CPB) influences were significantly associated with increased CPB use. The examined distal predictors were found to effect CPB use differentially through the rational and reactive pathways. Gender did not significantly moderate any relationships within in the model. Findings suggest potential entry points for increasing CPB use that include both rational and reactive pathways. Overall, this study demonstrates the mechanisms underlying how to increase the use of CPBs in programs designed to reduce alcohol-related sexual consequences and victimization. (c) 2015 APA, all rights reserved).

Nucleic acids for the rational design of reaction circuits.

PubMed

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.

Modern Vaccines/Adjuvants Formulation Session 6: Vaccine &Adjuvant Formulation & Production 15-17 May 2013, Lausanne, Switzerland.

PubMed

Fox, Christopher B

2013-09-01

The Modern Vaccines/Adjuvants Formulation meeting aims to fill a critical gap in current vaccine development efforts by bringing together formulation scientists and immunologists to emphasize the importance of rational formulation design in order to optimize vaccine and adjuvant bioactivity, safety, and manufacturability. Session 6 on Vaccine and Adjuvant Formulation and Production provided three examples of this theme, with speakers emphasizing the need for extensive physicochemical characterization of adjuvant-antigen interactions, the rational formulation design of a CD8+ T cell-inducing adjuvant based on immunological principles, and the development and production of a rabies vaccine by a developing country manufacturer. Throughout the session, the practical importance of sound formulation and manufacturing design accompanied by analytical characterization was highlighted.

Using Web-Based Instruction to Teach Music Theory in the Piano Studio: Defining, Designing, and Implementing an Integrative Approach

ERIC Educational Resources Information Center

Carney, Robert D.

2010-01-01

This dissertation rationalizes the best use of Web-based instruction (WBI) for teaching music theory to private piano students in the later primary grades. It uses an integrative research methodology for defining, designing, and implementing a curriculum that includes WBI. Research from the fields of music education, educational technology,…

A supermolecular building approach for the design and construction of metal-organic frameworks.

PubMed

Guillerm, Vincent; Kim, Dongwook; Eubank, Jarrod F; Luebke, Ryan; Liu, Xinfang; Adil, Karim; Lah, Myoung Soo; Eddaoudi, Mohamed

2014-08-21

In this review, we describe two recently implemented conceptual approaches facilitating the design and deliberate construction of metal–organic frameworks (MOFs), namely supermolecular building block (SBB) and supermolecular building layer (SBL) approaches. Our main objective is to offer an appropriate means to assist/aid chemists and material designers alike to rationally construct desired functional MOF materials, made-to-order MOFs. We introduce the concept of net-coded building units (net-cBUs), where precise embedded geometrical information codes uniquely and matchlessly a selected net, as a compelling route for the rational design of MOFs. This concept is based on employing pre-selected 0-periodic metal–organic polyhedra or 2-periodic metal–organic layers, SBBs or SBLs respectively, as a pathway to access the requisite net-cBUs. In this review, inspired by our success with the original rht-MOF, we extrapolated our strategy to other known MOFs via their deconstruction into more elaborate building units (namely polyhedra or layers) to (i) elucidate the unique relationship between edge-transitive polyhedra or layers and minimal edge-transitive 3-periodic nets, and (ii) illustrate the potential of the SBB and SBL approaches as a rational pathway for the design and construction of 3-periodic MOFs. Using this design strategy, we have also identified several new hypothetical MOFs which are synthetically targetable.

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

PubMed

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

2015-06-06

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

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

PubMed Central

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

2015-01-01

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

Design Decisions in Developing Learning Trajectories-Based Assessments in Mathematics: A Case Study

ERIC Educational Resources Information Center

Penuel, William R.; Confrey, Jere; Maloney, Alan; Rupp, André A.

2014-01-01

This article analyzes the design decisions of a team developing diagnostic assessments for a learning trajectory focused on rational number reasoning. The analysis focuses on the design rationale for key decisions about how to develop the cognitive assessments and related validity arguments within a fluid state and national policy context. The…

14 CFR 25.331 - Symmetric maneuvering conditions.

Code of Federal Regulations, 2010 CFR

2010-01-01

...) Maneuvering balanced conditions. Assuming the airplane to be in equilibrium with zero pitching acceleration..., based on a rational pitching control motion vs. time profile, must be established in which the design...

MIRATE: MIps RATional dEsign Science Gateway.

PubMed

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.

Virtual screening and rational drug design method using structure generation system based on 3D-QSAR and docking.

PubMed

Chen, H F; Dong, X C; Zen, B S; Gao, K; Yuan, S G; Panaye, A; Doucet, J P; Fan, B T

2003-08-01

An efficient virtual and rational drug design method is presented. It combines virtual bioactive compound generation with 3D-QSAR model and docking. Using this method, it is possible to generate a lot of highly diverse molecules and find virtual active lead compounds. The method was validated by the study of a set of anti-tumor drugs. With the constraints of pharmacophore obtained by DISCO implemented in SYBYL 6.8, 97 virtual bioactive compounds were generated, and their anti-tumor activities were predicted by CoMFA. Eight structures with high activity were selected and screened by the 3D-QSAR model. The most active generated structure was further investigated by modifying its structure in order to increase the activity. A comparative docking study with telomeric receptor was carried out, and the results showed that the generated structures could form more stable complexes with receptor than the reference compound selected from experimental data. This investigation showed that the proposed method was a feasible way for rational drug design with high screening efficiency.

Computational design of auxotrophy-dependent microbial biosensors for combinatorial metabolic engineering experiments.

PubMed

Tepper, Naama; Shlomi, Tomer

2011-01-21

Combinatorial approaches in metabolic engineering work by generating genetic diversity in a microbial population followed by screening for strains with improved phenotypes. One of the most common goals in this field is the generation of a high rate chemical producing strain. A major hurdle with this approach is that many chemicals do not have easy to recognize attributes, making their screening expensive and time consuming. To address this problem, it was previously suggested to use microbial biosensors to facilitate the detection and quantification of chemicals of interest. Here, we present novel computational methods to: (i) rationally design microbial biosensors for chemicals of interest based on substrate auxotrophy that would enable their high-throughput screening; (ii) predict engineering strategies for coupling the synthesis of a chemical of interest with the production of a proxy metabolite for which high-throughput screening is possible via a designed bio-sensor. The biosensor design method is validated based on known genetic modifications in an array of E. coli strains auxotrophic to various amino-acids. Predicted chemical production rates achievable via the biosensor-based approach are shown to potentially improve upon those predicted by current rational strain design approaches. (A Matlab implementation of the biosensor design method is available via http://www.cs.technion.ac.il/~tomersh/tools).

Developing and Testing Rational Models of Message Design.

ERIC Educational Resources Information Center

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…

Rational Design of Broad Spectrum Antibacterial Activity Based on a Clinically Relevant Enoyl-Acyl Carrier Protein (ACP) Reductase Inhibitor*

PubMed Central

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

2014-01-01

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

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

PubMed

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.

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

PubMed

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

2014-06-06

Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors, including CG400549. Based on these structures, we rationalize the 65-fold reduced affinity of CG400549 toward Escherichia coli versus S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

The Progress of Theory in Knowledge Organization.

ERIC Educational Resources Information Center

Smiraglia, Richard P.

2002-01-01

Presents a background on theory in knowledge organization, which has moved from an epistemic stance of pragmatism and rationalism (based on observation of the construction of retrieval tools), to empiricism (based on the results of empirical research). Discusses historicism, external validity, classification, user-interface design, and…

Evaluation of design flood frequency methods for Iowa streams : final report, June 2009.

DOT National Transportation Integrated Search

2009-06-01

The objective of this project was to assess the predictive accuracy of flood frequency estimation for small Iowa streams based : on the Rational Method, the NRCS curve number approach, and the Iowa Runoff Chart. The evaluation was based on : comparis...

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

PubMed Central

Brown, Ashley C.; Barker, Thomas H.

2013-01-01

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

Advances in visual representation of molecular potentials.

PubMed

Du, Qi-Shi; Huang, Ri-Bo; Chou, Kuo-Chen

2010-06-01

The recent advances in visual representations of molecular properties in 3D space are summarized, and their applications in molecular modeling study and rational drug design are introduced. The visual representation methods provide us with detailed insights into protein-ligand interactions, and hence can play a major role in elucidating the structure or reactivity of a biomolecular system. Three newly developed computation and visualization methods for studying the physical and chemical properties of molecules are introduced, including their electrostatic potential, lipophilicity potential and excess chemical potential. The newest application examples of visual representations in structure-based rational drug are presented. The 3D electrostatic potentials, calculated using the empirical method (EM-ESP), in which the classical Coulomb equation and traditional atomic partial changes are discarded, are highly consistent with the results by the higher level quantum chemical method. The 3D lipophilicity potentials, computed by the heuristic molecular lipophilicity potential method based on the principles of quantum mechanics and statistical mechanics, are more accurate and reliable than those by using the traditional empirical methods. The 3D excess chemical potentials, derived by the reference interaction site model-hypernetted chain theory, provide a new tool for computational chemistry and molecular modeling. For structure-based drug design, the visual representations of molecular properties will play a significant role in practical applications. It is anticipated that the new advances in computational chemistry will stimulate the development of molecular modeling methods, further enriching the visual representation techniques for rational drug design, as well as other relevant fields in life science.

Structure-Based Rational Design of a Toll-like Receptor 4 (TLR4) Decoy Receptor with High Binding Affinity for a Target Protein

PubMed Central

Lee, Sang-Chul; Hong, Seungpyo; Park, Keunwan; Jeon, Young Ho; Kim, Dongsup; Cheong, Hae-Kap; Kim, Hak-Sung

2012-01-01

Repeat proteins are increasingly attracting much attention as alternative scaffolds to immunoglobulin antibodies due to their unique structural features. Nonetheless, engineering interaction interface and understanding molecular basis for affinity maturation of repeat proteins still remain a challenge. Here, we present a structure-based rational design of a repeat protein with high binding affinity for a target protein. As a model repeat protein, a Toll-like receptor4 (TLR4) decoy receptor composed of leucine-rich repeat (LRR) modules was used, and its interaction interface was rationally engineered to increase the binding affinity for myeloid differentiation protein 2 (MD2). Based on the complex crystal structure of the decoy receptor with MD2, we first designed single amino acid substitutions in the decoy receptor, and obtained three variants showing a binding affinity (KD) one-order of magnitude higher than the wild-type decoy receptor. The interacting modes and contributions of individual residues were elucidated by analyzing the crystal structures of the single variants. To further increase the binding affinity, single positive mutations were combined, and two double mutants were shown to have about 3000- and 565-fold higher binding affinities than the wild-type decoy receptor. Molecular dynamics simulations and energetic analysis indicate that an additive effect by two mutations occurring at nearby modules was the major contributor to the remarkable increase in the binding affinities. PMID:22363519

Recent advances in rational approaches for enzyme engineering

PubMed Central

Steiner, Kerstin; Schwab, Helmut

2012-01-01

Enzymes are an attractive alternative in the asymmetric syntheses of chiral building blocks. To meet the requirements of industrial biotechnology and to introduce new functionalities, the enzymes need to be optimized by protein engineering. This article specifically reviews rational approaches for enzyme engineering and de novo enzyme design involving structure-based approaches developed in recent years for improvement of the enzymes’ performance, broadened substrate range, and creation of novel functionalities to obtain products with high added value for industrial applications. PMID:24688651

Serving two masters: quality teaching and learning versus economic rationalism.

PubMed

Kenny, A J; Kendall, S

2001-11-01

Nurse educators face the challenge of competing pressures. Programmes must be developed that more adequately prepare students to meet the demands of a changing and complex health care system. These programmes must reflect excellence in teaching and learning and this needs to be achieved within the constraints of economic rationalism. The design of a model based on principles of self directed learning assisted one university to deliver a high quality clinical skills programme. Copyright 2001 Harcourt Publishers Ltd.

User involvement in the construction of a mental health charter: an exercise in communicative rationality?

PubMed Central

Hodge, Suzanne M.

2009-01-01

Abstract Background  This paper uses Jürgen Habermas’s Theory of Communicative Action as a lens through which to examine the development of a local mental health charter. Objective  To assess whether the Charter represents the product of a communicatively rational process. Research design and setting  The paper is based on an analysis of the text of the Charter, and on documentation relating to its development, including notes of discussion groups used to identify its themes. Findings  An analysis of the notes of the discussion groups against the text of the Charter shows that the Charter’s themes are based broadly on the views generated in the discussion groups. However, they also draw on norms derived from wider discourses not reflected in the discussion groups, and exclude other specific local issues. The strength of feeling expressed in the discussion groups is also toned down in the language of the Charter. Discussion  The development of the Charter was based on a participatory process that can be said to have contained elements of both communicative and strategic rationality. The strategic rationality involved in translating service users’ views into language that would be acceptable to those working in the system can be seen as necessary for the Charter to succeed in bringing about change. In drawing also on communicatively generated norms from the wider public sphere the Charter can be seen as reflecting a form of generalized communicative rationality. Conclusion  The Charter represents a ‘sluice’ by which communicative rationality is drawn into the mental health system. PMID:19754689

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

PubMed

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

2016-02-25

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.

Biotrichotomy: The Neuroscientific and Neurobiological Systemology, Epistemology, and Methodology of the Tri-Squared Test and Tri-Center Analysis in Biostatistics

ERIC Educational Resources Information Center

Osler, James Edward

2015-01-01

This monograph provides a neuroscience-based systemological, epistemological, and methodological rational for the design of an advanced and novel parametric statistical analytics designed for the biological sciences referred to as "Biotrichotomy". The aim of this new arena of statistics is to provide dual metrics designed to analyze the…

Systems metabolic engineering: the creation of microbial cell factories by rational metabolic design and evolution.

PubMed

Furusawa, Chikara; Horinouchi, Takaaki; Hirasawa, Takashi; Shimizu, Hiroshi

2013-01-01

It is widely acknowledged that in order to establish sustainable societies, production processes should shift from petrochemical-based processes to bioprocesses. Because bioconversion technologies, in which biomass resources are converted to valuable materials, are preferable to processes dependent on fossil resources, the former should be further developed. The following two approaches can be adopted to improve cellular properties and obtain high productivity and production yield of target products: (1) optimization of cellular metabolic pathways involved in various bioprocesses and (2) creation of stress-tolerant cells that can be active even under severe stress conditions in the bioprocesses. Recent progress in omics analyses has facilitated the analysis of microorganisms based on bioinformatics data for molecular breeding and bioprocess development. Systems metabolic engineering is a new area of study, and it has been defined as a methodology in which metabolic engineering and systems biology are integrated to upgrade the designability of industrially useful microorganisms. This chapter discusses multi-omics analyses and rational design methods for molecular breeding. The first is an example of the rational design of metabolic networks for target production by flux balance analysis using genome-scale metabolic models. Recent progress in the development of genome-scale metabolic models and the application of these models to the design of desirable metabolic networks is also described in this example. The second is an example of evolution engineering with omics analyses for the creation of stress-tolerant microorganisms. Long-term culture experiments to obtain the desired phenotypes and omics analyses to identify the phenotypic changes are described here.

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

NASA Astrophysics Data System (ADS)

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.

Rational design of a colorimetric pH sensor from a soluble retinoic acid chaperone.

PubMed

Berbasova, Tetyana; Nosrati, Meisam; Vasileiou, Chrysoula; Wang, Wenjing; Lee, Kin Sing Stephen; Yapici, Ipek; Geiger, James H; Borhan, Babak

2013-10-30

Reengineering of cellular retinoic acid binding protein II (CRABPII) to be capable of binding retinal as a protonated Schiff base is described. Through rational alterations of the binding pocket, electrostatic perturbations of the embedded retinylidene chromophore that favor delocalization of the iminium charge lead to exquisite control in the regulation of chromophoric absorption properties, spanning the visible spectrum (474-640 nm). The pKa of the retinylidene protonated Schiff base was modulated from 2.4 to 8.1, giving rise to a set of proteins of varying colors and pH sensitivities. These proteins were used to demonstrate a concentration-independent, ratiometric pH sensor.

Design Principles for Covalent Organic Frameworks as Efficient Electrocatalysts in Clean Energy Conversion and Green Oxidizer Production.

PubMed

Lin, Chun-Yu; Zhang, Lipeng; Zhao, Zhenghang; Xia, Zhenhai

2017-05-01

Covalent organic frameworks (COFs), an emerging class of framework materials linked by covalent bonds, hold potential for various applications such as efficient electrocatalysts, photovoltaics, and sensors. To rationally design COF-based electrocatalysts for oxygen reduction and evolution reactions in fuel cells and metal-air batteries, activity descriptors, derived from orbital energy and bonding structures, are identified with the first-principle calculations for the COFs, which correlate COF structures with their catalytic activities. The calculations also predict that alkaline-earth metal-porphyrin COFs could catalyze the direct production of H 2 O 2 , a green oxidizer and an energy carrier. These predictions are supported by experimental data, and the design principles derived from the descriptors provide an approach for rational design of new electrocatalysts for both clean energy conversion and green oxidizer production. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Log D versus HPLC derived hydrophobicity: The development of predictive tools to aid in the rational design of bioactive peptoids

DOE PAGES

Bolt, H. L.; Williams, C. E. J.; Brooks, R. V.; ...

2017-01-13

Hydrophobicity has proven to be an extremely useful parameter in small molecule drug discovery programmes given that it can be used as a predictive tool to enable rational design. For larger molecules, including peptoids, where folding is possible, the situation is more complicated and the average hydrophobicity (as determined by RP-HPLC retention time) may not always provide an effective predictive tool for rational design. Herein, we report the first ever application of partitioning experiments to determine the log D values for a series of peptoids. By comparing log D and average hydrophobicities we highlight the potential advantage of employing themore » former as a predictive tool in the rational design of biologically active peptoids.« less

Rational, computer-enabled peptide drug design: principles, methods, applications and future directions.

PubMed

Diller, David J; Swanson, Jon; Bayden, Alexander S; Jarosinski, Mark; Audie, Joseph

2015-01-01

Peptides provide promising templates for developing drugs to occupy a middle space between small molecules and antibodies and for targeting 'undruggable' intracellular protein-protein interactions. Importantly, rational or in cerebro design, especially when coupled with validated in silico tools, can be used to efficiently explore chemical space and identify islands of 'drug-like' peptides to satisfy diverse drug discovery program objectives. Here, we consider the underlying principles of and recent advances in rational, computer-enabled peptide drug design. In particular, we consider the impact of basic physicochemical properties, potency and ADME/Tox opportunities and challenges, and recently developed computational tools for enabling rational peptide drug design. Key principles and practices are spotlighted by recent case studies. We close with a hypothetical future case study.

Log D versus HPLC derived hydrophobicity: The development of predictive tools to aid in the rational design of bioactive peptoids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bolt, H. L.; Williams, C. E. J.; Brooks, R. V.

Hydrophobicity has proven to be an extremely useful parameter in small molecule drug discovery programmes given that it can be used as a predictive tool to enable rational design. For larger molecules, including peptoids, where folding is possible, the situation is more complicated and the average hydrophobicity (as determined by RP-HPLC retention time) may not always provide an effective predictive tool for rational design. Herein, we report the first ever application of partitioning experiments to determine the log D values for a series of peptoids. By comparing log D and average hydrophobicities we highlight the potential advantage of employing themore » former as a predictive tool in the rational design of biologically active peptoids.« less

Rational design and synthesis of 2-anilinopyridinyl-benzothiazole Schiff bases as antimitotic agents.

PubMed

Shaik, Thokhir B; Hussaini, S M Ali; Nayak, V Lakshma; Sucharitha, M Lakshmi; Malik, M Shaheer; Kamal, Ahmed

2017-06-01

Based on our previous results and literature precedence, a series of 2-anilinopyridinyl-benzothiazole Schiff bases were rationally designed by performing molecular modeling experiments on some selected molecules. The binding energies of the docked molecules were better than the E7010, and the Schiff base with trimethoxy group on benzothiazole moiety, 4y was the best. This was followed by the synthesis of a series of the designed molecules by a convenient synthetic route and evaluation of their anticancer potential. Most of the compounds have shown significant growth inhibition against the tested cell lines and the compound 4y exhibited good antiproliferative activity with a GI 50 value of 3.8µM specifically against the cell line DU145. In agreement with the docking results, 4y exerted cytotoxicity by the disruption of the microtubule dynamics by inhibiting tubulin polymerization via effective binding into colchicine domain, comparable to E7010. Detailed binding modes of 4y with colchicine binding site of tubulin were studied by molecular docking. Furthermore, 4y induced apoptosis as evidenced by biological studies like mitochondrial membrane potential, caspase-3, and Annexin V-FITC assays. Copyright © 2017 Elsevier Ltd. All rights reserved.

Two-color SERS microscopy for protein co-localization in prostate tissue with primary antibody-protein A/G-gold nanocluster conjugates

NASA Astrophysics Data System (ADS)

Salehi, Mohammad; Schneider, Lilli; Ströbel, Philipp; Marx, Alexander; Packeisen, Jens; Schlücker, Sebastian

2014-01-01

SERS microscopy is a novel staining technique in immunohistochemistry, which is based on antibodies labeled with functionalized noble metal colloids called SERS labels or nanotags for optical detection. Conventional covalent bioconjugation of these SERS labels cannot prevent blocking of the antigen recognition sites of the antibody. We present a rational chemical design for SERS label-antibody conjugates which addresses this issue. Highly sensitive, silica-coated gold nanoparticle clusters as SERS labels are non-covalently conjugated to primary antibodies by using the chimeric protein A/G, which selectively recognizes the Fc part of antibodies and therefore prevents blocking of the antigen recognition sites. In proof-of-concept two-color imaging experiments for the co-localization of p63 and PSA on non-neoplastic prostate tissue FFPE specimens, we demonstrate the specificity and signal brightness of these rationally designed primary antibody-protein A/G-gold nanocluster conjugates.SERS microscopy is a novel staining technique in immunohistochemistry, which is based on antibodies labeled with functionalized noble metal colloids called SERS labels or nanotags for optical detection. Conventional covalent bioconjugation of these SERS labels cannot prevent blocking of the antigen recognition sites of the antibody. We present a rational chemical design for SERS label-antibody conjugates which addresses this issue. Highly sensitive, silica-coated gold nanoparticle clusters as SERS labels are non-covalently conjugated to primary antibodies by using the chimeric protein A/G, which selectively recognizes the Fc part of antibodies and therefore prevents blocking of the antigen recognition sites. In proof-of-concept two-color imaging experiments for the co-localization of p63 and PSA on non-neoplastic prostate tissue FFPE specimens, we demonstrate the specificity and signal brightness of these rationally designed primary antibody-protein A/G-gold nanocluster conjugates. Electronic supplementary information (ESI) available. See DOI: 10.1039/c3nr05890e

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

PubMed Central

Van Regenmortel, Marc H. V.

2018-01-01

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 rational design process. This is why the complexity of the human immune system prevents us from rationally designing an HIV vaccine by solving inverse problems. PMID:29387066

Reliability-based criteria for load and resistance factor design code for wood bridges

Treesearch

Chris Eamon; Andrzej S. Nowak; Michael A. Ritter; Joe Murphy

2000-01-01

Recently AASHTO adopted a load and resistance factor design code for highway bridges. The new code provides a rational basis for the design of steel and concrete structures. However, the calibration was not done for wood bridges. Therefore, there is a need to fill this gap. The development of statistical models for wood bridge structures is discussed. Recent test...

Combinatorial and high-throughput screening of materials libraries: review of state of the art.

PubMed

Potyrailo, Radislav; Rajan, Krishna; Stoewe, Klaus; Takeuchi, Ichiro; Chisholm, Bret; Lam, Hubert

2011-11-14

Rational materials design based on prior knowledge is attractive because it promises to avoid time-consuming synthesis and testing of numerous materials candidates. However with the increase of complexity of materials, the scientific ability for the rational materials design becomes progressively limited. As a result of this complexity, combinatorial and high-throughput (CHT) experimentation in materials science has been recognized as a new scientific approach to generate new knowledge. This review demonstrates the broad applicability of CHT experimentation technologies in discovery and optimization of new materials. We discuss general principles of CHT materials screening, followed by the detailed discussion of high-throughput materials characterization approaches, advances in data analysis/mining, and new materials developments facilitated by CHT experimentation. We critically analyze results of materials development in the areas most impacted by the CHT approaches, such as catalysis, electronic and functional materials, polymer-based industrial coatings, sensing materials, and biomaterials.

On the Numerical Formulation of Parametric Linear Fractional Transformation (LFT) Uncertainty Models for Multivariate Matrix Polynomial Problems

NASA Technical Reports Server (NTRS)

Belcastro, Christine M.

1998-01-01

Robust control system analysis and design is based on an uncertainty description, called a linear fractional transformation (LFT), which separates the uncertain (or varying) part of the system from the nominal system. These models are also useful in the design of gain-scheduled control systems based on Linear Parameter Varying (LPV) methods. Low-order LFT models are difficult to form for problems involving nonlinear parameter variations. This paper presents a numerical computational method for constructing and LFT model for a given LPV model. The method is developed for multivariate polynomial problems, and uses simple matrix computations to obtain an exact low-order LFT representation of the given LPV system without the use of model reduction. Although the method is developed for multivariate polynomial problems, multivariate rational problems can also be solved using this method by reformulating the rational problem into a polynomial form.

Rational Improvement of Molar Absorptivity Guided by Oscillator Strength: A Case Study with Furoindolizine-Based Core Skeleton.

PubMed

Lee, Youngjun; Jo, Ala; Park, Seung Bum

2015-12-21

The rational improvement of photophysical properties can be highly valuable for the discovery of novel organic fluorophores. Using our new design strategy guided by the oscillator strength, we developed a series of full-color-tunable furoindolizine analogs with improved molar absorptivity through the fusion of a furan ring into the indolizine-based Seoul fluorophore. The excellent correlation between the computable values (oscillator strength and theoretical S0 -S1 energy gap) and photophysical properties (molar absorptivity and emission wavelength) confirmed the effectualness of our design strategy. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Revealing Nucleic Acid Mutations Using Förster Resonance Energy Transfer-Based Probes

PubMed Central

Junager, Nina P. L.; Kongsted, Jacob; Astakhova, Kira

2016-01-01

Nucleic acid mutations are of tremendous importance in modern clinical work, biotechnology and in fundamental studies of nucleic acids. Therefore, rapid, cost-effective and reliable detection of mutations is an object of extensive research. Today, Förster resonance energy transfer (FRET) probes are among the most often used tools for the detection of nucleic acids and in particular, for the detection of mutations. However, multiple parameters must be taken into account in order to create efficient FRET probes that are sensitive to nucleic acid mutations. In this review; we focus on the design principles for such probes and available computational methods that allow for their rational design. Applications of advanced, rationally designed FRET probes range from new insights into cellular heterogeneity to gaining new knowledge of nucleic acid structures directly in living cells. PMID:27472344

The effects of changing ration ingredients on acid-base status, renal function, and macromineral metabolism.

PubMed

Delaquis, A M; Block, E

1995-09-01

Ten Holstein and 2 Ayrshire cows were used in a switchback design to compare diets based on alfalfa haylage and corn silage. Both diets had a similar cation-anion difference and contained 1% NaHCO3. Dietary treatment did not affect DMI, DM digestibility, milk production, or milk composition. Intake, absorption, and urinary excretion of N were significantly increased by the ration based on haylage, but the overall balance remained unaffected. Cows consuming haylage absorbed and excreted significantly more water than did cows consuming corn silage and consequently had significantly larger urine volumes. Blood volume was increased by the ration based on haylage. Intakes of Mg, K, Cl, and S differed between diets, but only K balance was increased by the diet based on haylage. The fractional excretion of K, Cl, and S in urine was increased by the diet based on haylage, demonstrating that the kidneys responded to the increased intakes by diminishing the reabsorption or by increasing the secretion of these minerals. Acid-base parameters for blood, urine, and milk were unaffected by dietary treatment. A diet based on alfalfa haylage, compared with a diet based on corn silage with similar cation-anion difference, resulted in different water and mineral metabolism but did not affect the acid-base status of cows in early lactation.

Basic principles for rational design of high-performance nanostructured silicon-based thermoelectric materials.

PubMed

Yang, Chun Cheng; Li, Sean

2011-12-23

Recently, nanostructured silicon-based thermoelectric materials have drawn great attention owing to their excellent thermoelectric performance in the temperature range around 450 °C, which is eminently applicable for concentrated solar thermal technology. In this work, a unified nanothermodynamic model is developed to investigate the predominant factors that determine the lattice thermal conductivity of nanocrystalline, nanoporous, and nanostructured bulk Si. A systematic study shows that the thermoelectric performance of these materials can be substantially enhanced by the following three basic principles: 1) artificial manipulation and optimization of roughness with surface/interface patterning/engineering; 2) grain-size reduction with innovative fabrication techniques in a controllable fashion; and 3) optimization of material parameters, such as bulk solid-vapor transition entropy, bulk vibrational entropy, dimensionality, and porosity, to decrease the lattice thermal conductivity. These principles may be used to rationally design novel nanostructured Si-based thermoelectric materials for renewable energy applications. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

PubMed

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.

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

PubMed

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.

Rational design of the exchange-spring permanent magnet.

PubMed

Jiang, J S; Bader, S D

2014-02-12

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

Structure-based engineering of a pectate lyase with improved specific activity for ramie degumming.

PubMed

Zhou, Zhanping; Liu, Yang; Chang, Zhenying; Wang, Huilin; Leier, André; Marquez-Lago, Tatiana T; Ma, Yanhe; Li, Jian; Song, Jiangning

2017-04-01

Biotechnological applications of microbial pectate lyases (Pels) in plant fiber processing are promising, eco-friendly substitutes for conventional chemical degumming processes. However, to potentiate the enzymes' use for industrial applications, resolving the molecular structure to elucidate catalytic mechanisms becomes necessary. In this manuscript, we report the high resolution (1.45 Å) crystal structure of pectate lyase (pelN) from Paenibacillus sp. 0602 in apo form. Through sequence alignment and structural superposition with other members of the polysaccharide lyase (PL) family 1 (PL1), we determined that pelN shares the characteristic right-handed β-helix and is structurally similar to other members of the PL1 family, while exhibiting key differences in terms of catalytic and substrate binding residues. Then, based on information from structure alignments with other PLs, we engineered a novel pelN. Our rational design yielded a pelN mutant with a temperature for enzymatic activity optimally shifted from 67.5 to 60 °C. Most importantly, this pelN mutant displayed both higher specific activity and ramie fiber degumming ability when compared with the wild-type enzyme. Altogether, our rational design method shows great potential for industrial applications. Moreover, we expect the reported high-resolution crystal structure to provide a solid foundation for future rational, structure-based engineering of genetically enhanced pelNs.

Molecular beacon sequence design algorithm.

PubMed

Monroe, W Todd; Haselton, Frederick R

2003-01-01

A method based on Web-based tools is presented to design optimally functioning molecular beacons. Molecular beacons, fluorogenic hybridization probes, are a powerful tool for the rapid and specific detection of a particular nucleic acid sequence. However, their synthesis costs can be considerable. Since molecular beacon performance is based on its sequence, it is imperative to rationally design an optimal sequence before synthesis. The algorithm presented here uses simple Microsoft Excel formulas and macros to rank candidate sequences. This analysis is carried out using mfold structural predictions along with other free Web-based tools. For smaller laboratories where molecular beacons are not the focus of research, the public domain algorithm described here may be usefully employed to aid in molecular beacon design.

14 CFR 29.427 - Unsymmetrical loads.

Code of Federal Regulations, 2010 CFR

2010-01-01

... conditions. (b) To meet the design criteria of paragraph (a) of this section, in the absence of more rational... selected so that the maximum design loads are obtained on each surface. In the absence of more rational...

14 CFR 27.427 - Unsymmetrical loads.

Code of Federal Regulations, 2010 CFR

2010-01-01

... conditions. (b) To meet the design criteria of paragraph (a) of this section, in the absence of more rational... selected so the maximum design loads are obtained on each surface. In the absence of more rational data...

In-vitro engineering of novel bioactivity in the natural enzymes

NASA Astrophysics Data System (ADS)

Tiwari, Vishvanath

2016-10-01

Enzymes catalyze various biochemical functions with high efficiency and specificity. In-vitro design of the enzyme leads to novel bioactivity in this natural biomolecule that give answers of some vital questions like crucial residues in binding with substrate, molecular evolution, cofactor specificity etc. Enzyme engineering technology involves directed evolution, rational designing, semi-rational designing and structure-based designing using chemical modifications. Similarly, combined computational and in-vitro evolution approaches together help in artificial designing of novel bioactivity in the natural enzyme. DNA shuffling, error prone PCR and staggered extension process are used to artificially redesign active site of enzyme, which can alter its efficiency and specificity. Modifications of the enzyme can lead to the discovery of new path of molecular evolution, designing of efficient enzymes, locating active sites and crucial residues, shift in substrate and cofactor specificity. The methods and thermodynamics of in-vitro designing of the enzyme are also discussed. Similarly, engineered thermophilic and psychrophilic enzymes attain substrate specificity and activity of mesophilic enzymes that may also be beneficial for industry and therapeutics.

Global asymptotic stabilisation of rational dynamical systems based on solving BMI

NASA Astrophysics Data System (ADS)

Esmaili, Farhad; Kamyad, A. V.; Jahed-Motlagh, Mohammad Reza; Pariz, Naser

2017-08-01

In this paper, the global asymptotic stabiliser design of rational systems is studied in detail. To develop the idea, the state equations of the system are transformed to a new coordinate via polynomial transformation and the state feedback control law. This in turn is followed by the satisfaction of the linear growth condition (i.e. Lipschitz at zero). Based on a linear matrix inequality solution, the system in the new coordinate is globally asymptotically stabilised and then, leading to the global asymptotic stabilisation of the primary system. The polynomial transformation coefficients are derived by solving the bilinear matrix inequality problem. To confirm the capability of this method, three examples are highlighted.

Study design requirements for RNA sequencing-based breast cancer diagnostics.

PubMed

Mer, Arvind Singh; Klevebring, Daniel; Grönberg, Henrik; Rantalainen, Mattias

2016-02-01

Sequencing-based molecular characterization of tumors provides information required for individualized cancer treatment. There are well-defined molecular subtypes of breast cancer that provide improved prognostication compared to routine biomarkers. However, molecular subtyping is not yet implemented in routine breast cancer care. Clinical translation is dependent on subtype prediction models providing high sensitivity and specificity. In this study we evaluate sample size and RNA-sequencing read requirements for breast cancer subtyping to facilitate rational design of translational studies. We applied subsampling to ascertain the effect of training sample size and the number of RNA sequencing reads on classification accuracy of molecular subtype and routine biomarker prediction models (unsupervised and supervised). Subtype classification accuracy improved with increasing sample size up to N = 750 (accuracy = 0.93), although with a modest improvement beyond N = 350 (accuracy = 0.92). Prediction of routine biomarkers achieved accuracy of 0.94 (ER) and 0.92 (Her2) at N = 200. Subtype classification improved with RNA-sequencing library size up to 5 million reads. Development of molecular subtyping models for cancer diagnostics requires well-designed studies. Sample size and the number of RNA sequencing reads directly influence accuracy of molecular subtyping. Results in this study provide key information for rational design of translational studies aiming to bring sequencing-based diagnostics to the clinic.

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

PubMed

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.

Directed molecular evolution to design advanced red fluorescent proteins.

PubMed

Subach, Fedor V; Piatkevich, Kiryl D; Verkhusha, Vladislav V

2011-11-29

Fluorescent proteins have become indispensable imaging tools for biomedical research. Continuing progress in fluorescence imaging, however, requires probes with additional colors and properties optimized for emerging techniques. Here we summarize strategies for development of red-shifted fluorescent proteins. We discuss possibilities for knowledge-based rational design based on the photochemistry of fluorescent proteins and the position of the chromophore in protein structure. We consider advances in library design by mutagenesis, protein expression systems and instrumentation for high-throughput screening that should yield improved fluorescent proteins for advanced imaging applications.

Does an outcome-based approach to continuing medical education improve physicians' competences in rational prescribing?

PubMed

Esmaily, Hamideh M; Savage, Carl; Vahidi, Rezagoli; Amini, Abolghasem; Dastgiri, Saeed; Hult, Hakan; Dahlgren, Lars Owe; Wahlstrom, Rolf

2009-11-01

Continuing medical education (CME) is compulsory in Iran, and traditionally it is lecture-based, which is mostly not successful. Outcome-based education has been proposed for CME programs. To evaluate the effectiveness of an outcome-based educational intervention with a new approach based on outcomes and aligned teaching methods, on knowledge and skills of general physicians (GPs) working in primary care compared with a concurrent CME program in the field of "Rational prescribing". The method used was cluster randomized controlled design. All GPs working in six cities in one province in Iran were invited to participate. The cities were matched and randomly divided into an intervention arm for education on rational prescribing with an outcome-based approach, and a control arm for a traditional program on the same topic. Knowledge and skills were assessed using a pre- and post-test, including case scenarios. In total, 112 GPs participated. There were significant improvements in knowledge and prescribing skills after the training in the intervention arm as well as in comparison with the changes in the control arm. The overall intervention effect was 26 percentage units. The introduction of an outcome-based approach in CME appears to be effective when creating programs to improve GPs' knowledge and skills.

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

PubMed

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.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thompson, Scott K.; Washburn, David G.; Frazee, James S.

2010-09-03

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

A systems approach to designing next generation vaccines: combining α-galactose modified antigens with nanoparticle platforms

NASA Astrophysics Data System (ADS)

Phanse, Yashdeep; Carrillo-Conde, Brenda R.; Ramer-Tait, Amanda E.; Broderick, Scott; Kong, Chang Sun; Rajan, Krishna; Flick, Ramon; Mandell, Robert B.; Narasimhan, Balaji; Wannemuehler, Michael J.

2014-01-01

Innovative vaccine platforms are needed to develop effective countermeasures against emerging and re-emerging diseases. These platforms should direct antigen internalization by antigen presenting cells and promote immunogenic responses. This work describes an innovative systems approach combining two novel platforms, αGalactose (αGal)-modification of antigens and amphiphilic polyanhydride nanoparticles as vaccine delivery vehicles, to rationally design vaccine formulations. Regimens comprising soluble αGal-modified antigen and nanoparticle-encapsulated unmodified antigen induced a high titer, high avidity antibody response with broader epitope recognition of antigenic peptides than other regimen. Proliferation of antigen-specific CD4+ T cells was also enhanced compared to a traditional adjuvant. Combining the technology platforms and augmenting immune response studies with peptide arrays and informatics analysis provides a new paradigm for rational, systems-based design of next generation vaccine platforms against emerging and re-emerging pathogens.

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

NASA Astrophysics Data System (ADS)

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.

Design Principles for the Atomic and Electronic Structure of Halide Perovskite Photovoltaic Materials: Insights from Computation.

PubMed

Berger, Robert F

2018-02-09

In the current decade, perovskite solar cell research has emerged as a remarkably active, promising, and rapidly developing field. Alongside breakthroughs in synthesis and device engineering, halide perovskite photovoltaic materials have been the subject of predictive and explanatory computational work. In this Minireview, we focus on a subset of this computation: density functional theory (DFT)-based work highlighting the ways in which the electronic structure and band gap of this class of materials can be tuned via changes in atomic structure. We distill this body of computational literature into a set of underlying design principles for the band gap engineering of these materials, and rationalize these principles from the viewpoint of band-edge orbital character. We hope that this perspective provides guidance and insight toward the rational design and continued improvement of perovskite photovoltaics. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rationally designed synthetic protein hydrogels with predictable mechanical properties.

PubMed

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.

Models for Rational Number Bases

ERIC Educational Resources Information Center

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)

Rational design of aptazyme riboswitches for efficient control of gene expression in mammalian cells

PubMed Central

Zhong, Guocai; Wang, Haimin; Bailey, Charles C; Gao, Guangping; Farzan, Michael

2016-01-01

Efforts to control mammalian gene expression with ligand-responsive riboswitches have been hindered by lack of a general method for generating efficient switches in mammalian systems. Here we describe a rational-design approach that enables rapid development of efficient cis-acting aptazyme riboswitches. We identified communication-module characteristics associated with aptazyme functionality through analysis of a 32-aptazyme test panel. We then developed a scoring system that predicts an aptazymes’s activity by integrating three characteristics of communication-module bases: hydrogen bonding, base stacking, and distance to the enzymatic core. We validated the power and generality of this approach by designing aptazymes responsive to three distinct ligands, each with markedly wider dynamic ranges than any previously reported. These aptayzmes efficiently regulated adeno-associated virus (AAV)-vectored transgene expression in cultured mammalian cells and mice, highlighting one application of these broadly usable regulatory switches. Our approach enables efficient, protein-independent control of gene expression by a range of small molecules. DOI: http://dx.doi.org/10.7554/eLife.18858.001 PMID:27805569

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ozolins, Vidvuds

Molecularly Engineered Energy Materials (MEEM) was established as an interdisciplinary cutting-edge UCLA-based research center uniquely equipped to attack the challenge of rationally designing, synthesizing and testing revolutionary new energy materials. Our mission was to achieve transformational improvements in the performance of materials via controlling the nano-and mesoscale structure using selectively designed, earth-abundant, inexpensive molecular building blocks. MEEM has focused on materials that are inherently abundant, can be easily assembled from intelligently designed building blocks (molecules, nanoparticles), and have the potential to deliver transformative economic benefits in comparison with the current crystalline-and polycrystalline-based energy technologies. MEEM addressed basic science issues relatedmore » to the fundamental mechanisms of carrier generation, energy conversion, as well as transport and storage of charge and mass in tunable, architectonically complex materials. Fundamental understanding of these processes will enable rational design, efficient synthesis and effective deployment of novel three-dimensional material architectures for energy applications. Three interrelated research directions were initially identified where these novel architectures hold great promise for high-reward research: solar energy generation, electrochemical energy storage, and materials for CO 2 capture. Of these, the first two remained throughout the project performance period, while carbon capture was been phased out in consultation and with approval from BES program manager.« less

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

PubMed

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.

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

PubMed Central

Zadpoor, Amir A.

2017-01-01

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. PMID:28757572

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

PubMed

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.

Drug delivery systems: optimising the structure of peptide carriers for synthetic antimicrobial drugs.

PubMed

Payne, J W

1986-01-01

This paper discusses the concept of smugglins, i.e., molecules that are formed by attaching to, or incorporating into, normal cell nutrients varied moieties as a means of transporting otherwise impermeant substances into cells. Examples of antimicrobial smugglins that use this principle in Nature are described. The rationally designed antibiotic smugglins investigated to date are critically reviewed. Criteria for the design of optimal peptide carriers for antimicrobial smugglins are considered. A computer-linked, continuous-flow system for rapid measurement of the kinetic parameters for substrate transport via peptide permeases is described which, together with current molecular, genetic and biochemical techniques, now provides the means to obtain the information on which rational design should be based; examples are given for Escherichia coli and Candida albicans. After an uncertain commercial start, it now seems likely that increasing understanding of the uptake processes and other relevant features will make drug targeting using peptide carriers an achievable goal. Certainly their widespread occurrence in Nature should provide added incentive for the design of synthetic smugglins.

TECHNOLOGY INTEGRATION FOR CONTAMINATED SITE REMEDIATION: CLEANUP GOALS & PERFORMANCE CRITERIA

EPA Science Inventory

There is a need to develop and field-test integrated remediation technologies that operate in a synergistic manner for cost-effective treatment of contaminated sites to achieve risk-based and rational endpoints. Aggressive technologies designed for rapid source-zone remediation m...

Advancing cancer drug discovery towards more agile development of targeted combination therapies.

PubMed

Carragher, Neil O; Unciti-Broceta, Asier; Cameron, David A

2012-01-01

Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of large chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' potency and selectivity profiles. However, high attrition of targeted agents in clinical development suggest that combinations of targeted agents will be most effective in treating solid tumors if the biological networks that permit cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and development strategies are suboptimal for the rational design and development of novel drug combinations. In this article, we highlight a series of emerging technologies supporting a less reductionist, more agile, drug-discovery and development approach for the rational design, validation, prioritization and clinical development of novel drug combinations.

Machine learning in the rational design of antimicrobial peptides.

PubMed

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.

Rational design of an enzyme mutant for anti-cocaine therapeutics

NASA Astrophysics Data System (ADS)

Zheng, Fang; Zhan, Chang-Guo

2008-09-01

(-)-Cocaine is a widely abused drug and there is no available anti-cocaine therapeutic. The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority. An ideal anti-cocaine medication would be to accelerate (-)-cocaine metabolism producing biologically inactive metabolites. The main metabolic pathway of cocaine in body is the hydrolysis at its benzoyl ester group. Reviewed in this article is the state-of-the-art computational design of high-activity mutants of human butyrylcholinesterase (BChE) against (-)-cocaine. The computational design of BChE mutants have been based on not only the structure of the enzyme, but also the detailed catalytic mechanisms for BChE-catalyzed hydrolysis of (-)-cocaine and (+)-cocaine. Computational studies of the detailed catalytic mechanisms and the structure-and-mechanism-based computational design have been carried out through the combined use of a variety of state-of-the-art techniques of molecular modeling. By using the computational insights into the catalytic mechanisms, a recently developed unique computational design strategy based on the simulation of the rate-determining transition state has been employed to design high-activity mutants of human BChE for hydrolysis of (-)-cocaine, leading to the exciting discovery of BChE mutants with a considerably improved catalytic efficiency against (-)-cocaine. One of the discovered BChE mutants (i.e., A199S/S287G/A328W/Y332G) has a ˜456-fold improved catalytic efficiency against (-)-cocaine. The encouraging outcome of the computational design and discovery effort demonstrates that the unique computational design approach based on the transition-state simulation is promising for rational enzyme redesign and drug discovery.

Evaluation of skill-based training program on rational drug treatment for medical interns

PubMed Central

Venkatesan, Murugan; Dongre, Amol R; Ganapathy, Kalaiselvan

2017-01-01

Context: A module-based training program for medical interns using World Health Organization guide for good prescription along with the individual feedback on their prescription was developed and implemented. Objective: The objective of the study was to obtain the medical interns’ reactions to newly developed skill-based training program on rational treatment. Study Setting: This study was conducted at the Department of Community Medicine. Participants: A total of 96 medical interns were included in the study. Study Design: A cross-sectional study consisting of retro-prefeedback and open-ended questions about self-assessment of perceived skill on rational treatment. Analysis: Collected data were entered in Epi Info (3.5.4) and analyzed. Results: After training, there was a significant increase in self-perceived posttest scores of setting up the therapeutic objective for the treatment (2.9–4.9), ability to select the correct drug (2.8–5.1), ability to select right dose, schedule, and duration of drugs (2.5–4.9). and overall prescription skill (2.9–4.9). There is a significant decrease in self-perceived scores in the skill of practicing polypharmacy (4.1–2.5). Conclusions: Overall, the training program was taken well and interns perceived their skill on rational treatment was improved as shown by the feedback. PMID:29564272

Protein mechanics: from single molecules to functional biomaterials.

PubMed

Li, Hongbin; Cao, Yi

2010-10-19

Elastomeric proteins act as the essential functional units in a wide variety of biomechanical machinery and serve as the basic building blocks for biological materials that exhibit superb mechanical properties. These proteins provide the desired elasticity, mechanical strength, resilience, and toughness within these materials. Understanding the mechanical properties of elastomeric protein-based biomaterials is a multiscale problem spanning from the atomistic/molecular level to the macroscopic level. Uncovering the design principles of individual elastomeric building blocks is critical both for the scientific understanding of multiscale mechanics of biomaterials and for the rational engineering of novel biomaterials with desirable mechanical properties. The development of single-molecule force spectroscopy techniques has provided methods for characterizing mechanical properties of elastomeric proteins one molecule at a time. Single-molecule atomic force microscopy (AFM) is uniquely suited to this purpose. Molecular dynamic simulations, protein engineering techniques, and single-molecule AFM study have collectively revealed tremendous insights into the molecular design of single elastomeric proteins, which can guide the design and engineering of elastomeric proteins with tailored mechanical properties. Researchers are focusing experimental efforts toward engineering artificial elastomeric proteins with mechanical properties that mimic or even surpass those of natural elastomeric proteins. In this Account, we summarize our recent experimental efforts to engineer novel artificial elastomeric proteins and develop general and rational methodologies to tune the nanomechanical properties of elastomeric proteins at the single-molecule level. We focus on general design principles used for enhancing the mechanical stability of proteins. These principles include the development of metal-chelation-based general methodology, strategies to control the unfolding hierarchy of multidomain elastomeric proteins, and the design of novel elastomeric proteins that exhibit stimuli-responsive mechanical properties. Moving forward, we are now exploring the use of these artificial elastomeric proteins as building blocks of protein-based biomaterials. Ultimately, we would like to rationally tailor mechanical properties of elastomeric protein-based materials by programming the molecular sequence, and thus nanomechanical properties, of elastomeric proteins at the single-molecule level. This step would help bridge the gap between single protein mechanics and material biomechanics, revealing how the mechanical properties of individual elastomeric proteins are translated into the properties of macroscopic materials.

Rational design of liposomal drug delivery systems, a review: Combined experimental and computational studies of lipid membranes, liposomes and their PEGylation.

PubMed

Bunker, Alex; Magarkar, Aniket; Viitala, Tapani

2016-10-01

Combined experimental and computational studies of lipid membranes and liposomes, with the aim to attain mechanistic understanding, result in a synergy that makes possible the rational design of liposomal drug delivery system (LDS) based therapies. The LDS is the leading form of nanoscale drug delivery platform, an avenue in drug research, known as "nanomedicine", that holds the promise to transcend the current paradigm of drug development that has led to diminishing returns. Unfortunately this field of research has, so far, been far more successful in generating publications than new drug therapies. This partly results from the trial and error based methodologies used. We discuss experimental techniques capable of obtaining mechanistic insight into LDS structure and behavior. Insight obtained purely experimentally is, however, limited; computational modeling using molecular dynamics simulation can provide insight not otherwise available. We review computational research, that makes use of the multiscale modeling paradigm, simulating the phospholipid membrane with all atom resolution and the entire liposome with coarse grained models. We discuss in greater detail the computational modeling of liposome PEGylation. Overall, we wish to convey the power that lies in the combined use of experimental and computational methodologies; we hope to provide a roadmap for the rational design of LDS based therapies. Computational modeling is able to provide mechanistic insight that explains the context of experimental results and can also take the lead and inspire new directions for experimental research into LDS development. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Róg. Copyright © 2016 Elsevier B.V. All rights reserved.

Computational approaches for rational design of proteins with novel functionalities

PubMed Central

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

2012-01-01

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

Mechanism of action of mRNA-based vaccines.

PubMed

Iavarone, Carlo; O'hagan, Derek T; Yu, Dong; Delahaye, Nicolas F; Ulmer, Jeffrey B

2017-09-01

The present review summarizes the growing body of work defining the mechanisms of action of this exciting new vaccine technology that should allow rational approaches in the design of next generation mRNA vaccines. Areas covered: Bio-distribution of mRNA, localization of antigen production, role of the innate immunity, priming of the adaptive immune response, route of administration and effects of mRNA delivery systems. Expert commentary: In the last few years, the development of RNA vaccines had a fast growth, the rising number of proof will enable rational approaches to improving the effectiveness and safety of this modern class of medicine.

Rational Emotive Education

ERIC Educational Resources Information Center

Knaus, William

1977-01-01

Rational Emotive Education--an outgrowth of theories developed by Albert Ellis--is a teaching design of mental health concepts and problem-solving activities designed to help students to approach and cope with their problems through experiential learning, via a structured, thematic sequence of emotive education lessons. (MJB)

Rational design and application of responsive alpha-helical peptide hydrogels.

PubMed

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

2009-07-01

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

Rational design and application of responsive α-helical peptide hydrogels

PubMed Central

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

2009-01-01

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

Rational design and application of responsive α-helical peptide hydrogels

NASA Astrophysics Data System (ADS)

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

2009-07-01

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

Chemical control of the viscoelastic properties of vinylogous urethane vitrimers

PubMed Central

Denissen, Wim; Droesbeke, Martijn; Nicolaÿ, Renaud; Leibler, Ludwik; Winne, Johan M.; Du Prez, Filip E.

2017-01-01

Vinylogous urethane based vitrimers are polymer networks that have the intrinsic property to undergo network rearrangements, stress relaxation and viscoelastic flow, mediated by rapid addition/elimination reactions of free chain end amines. Here we show that the covalent exchange kinetics significantly can be influenced by combination with various simple additives. As anticipated, the exchange reactions on network level can be further accelerated using either Brønsted or Lewis acid additives. Remarkably, however, a strong inhibitory effect is observed when a base is added to the polymer matrix. These effects have been mechanistically rationalized, guided by low-molecular weight kinetic model experiments. Thus, vitrimer elastomer materials can be rationally designed to display a wide range of viscoelastic properties. PMID:28317893

Synthetic and structural studies on syringolin A and B reveal critical determinants of selectivity and potency of proteasome inhibition

PubMed Central

Clerc, Jérôme; Groll, Michael; Illich, Damir J.; Bachmann, André S.; Huber, Robert; Schellenberg, Barbara; Dudler, Robert; Kaiser, Markus

2009-01-01

Syrbactins, a family of natural products belonging either to the syringolin or glidobactin class, are highly potent proteasome inhibitors. Although sharing similar structural features, they differ in their macrocyclic lactam core structure and exocyclic side chain. These structural variations critically influence inhibitory potency and proteasome subsite selectivity. Here, we describe the total synthesis of syringolin A and B, which together with enzyme kinetic and structural studies, allowed us to elucidate the structural determinants underlying the proteasomal subsite selectivity and binding affinity of syrbactins. These findings were used successfully in the rational design and synthesis of a syringolin A-based lipophilic derivative, which proved to be the most potent syrbactin-based proteasome inhibitor described so far. With a Ki′ of 8.65 ± 1.13 nM for the chymotryptic activity, this syringolin A derivative displays a 100-fold higher potency than the parent compound syringolin A. In light of the medicinal relevance of proteasome inhibitors as anticancer compounds, the present findings may assist in the rational design and development of syrbactin-based chemotherapeutics. PMID:19359491

TECHNOLOGY INTEGRATION FOR CONTAMINATED SITE REMEDIATION: CLEANUP GOALS AND PERFORMANCE CRITERIA

EPA Science Inventory

There is a need to develop and field-test integrated remediation technologies that operate in a synergistic manner for cost-effective treatment of contaminated sites to achieve risk-based and rational endpoints. Aggressive technologies designed for rapid source-zone remediation m...

Rational Design of a New Class of Toll-Like Receptor 4 (TLR4) Tryptamine Related Agonists by Means of the Structure- and Ligand-Based Virtual Screening for Vaccine Adjuvant Discovery.

PubMed

Honegr, Jan; Dolezal, Rafael; Malinak, David; Benkova, Marketa; Soukup, Ondrej; Almeida, Joyce S F D de; Franca, Tanos C C; Kuca, Kamil; Prymula, Roman

2018-01-04

In order to identify novel lead structures for human toll-like receptor 4 ( h TLR4) modulation virtual high throughput screening by a peta-flops-scale supercomputer has been performed. Based on the in silico studies, a series of 12 compounds related to tryptamine was rationally designed to retain suitable molecular geometry for interaction with the h TLR4 binding site as well as to satisfy general principles of drug-likeness. The proposed compounds were synthesized, and tested by in vitro and ex vivo experiments, which revealed that several of them are capable to stimulate h TLR4 in vitro up to 25% activity of Monophosphoryl lipid A. The specific affinity of the in vitro most potent substance was confirmed by surface plasmon resonance direct-binding experiments. Moreover, two compounds from the series show also significant ability to elicit production of interleukin 6.

Programmed coherent coupling in a synthetic DNA-based excitonic circuit

NASA Astrophysics Data System (ADS)

Boulais, Étienne; Sawaya, Nicolas P. D.; Veneziano, Rémi; Andreoni, Alessio; Banal, James L.; Kondo, Toru; Mandal, Sarthak; Lin, Su; Schlau-Cohen, Gabriela S.; Woodbury, Neal W.; Yan, Hao; Aspuru-Guzik, Alán; Bathe, Mark

2018-02-01

Natural light-harvesting systems spatially organize densely packed chromophore aggregates using rigid protein scaffolds to achieve highly efficient, directed energy transfer. Here, we report a synthetic strategy using rigid DNA scaffolds to similarly program the spatial organization of densely packed, discrete clusters of cyanine dye aggregates with tunable absorption spectra and strongly coupled exciton dynamics present in natural light-harvesting systems. We first characterize the range of dye-aggregate sizes that can be templated spatially by A-tracts of B-form DNA while retaining coherent energy transfer. We then use structure-based modelling and quantum dynamics to guide the rational design of higher-order synthetic circuits consisting of multiple discrete dye aggregates within a DX-tile. These programmed circuits exhibit excitonic transport properties with prominent circular dichroism, superradiance, and fast delocalized exciton transfer, consistent with our quantum dynamics predictions. This bottom-up strategy offers a versatile approach to the rational design of strongly coupled excitonic circuits using spatially organized dye aggregates for use in coherent nanoscale energy transport, artificial light-harvesting, and nanophotonics.

AMOVA ["Accumulative Manifold Validation Analysis"]: An Advanced Statistical Methodology Designed to Measure and Test the Validity, Reliability, and Overall Efficacy of Inquiry-Based Psychometric Instruments

ERIC Educational Resources Information Center

Osler, James Edward, II

2015-01-01

This monograph provides an epistemological rational for the Accumulative Manifold Validation Analysis [also referred by the acronym "AMOVA"] statistical methodology designed to test psychometric instruments. This form of inquiry is a form of mathematical optimization in the discipline of linear stochastic modelling. AMOVA is an in-depth…

Children's selective trust decisions: rational competence and limiting performance factors.

PubMed

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.

Applications of different design methodologies in navigation systems and development at JPL

NASA Technical Reports Server (NTRS)

Thurman, S. W.

1990-01-01

The NASA/JPL deep space navigation system consists of a complex array of measurement systems, data processing systems, and support facilities, with components located both on the ground and on-board interplanetary spacecraft. From its beginings nearly 30 years ago, this system has steadily evolved and grown to meet the demands for ever-increasing navigation accuracy placed on it by a succession of unmanned planetary missions. Principal characteristics of this system are its capabilities and great complexity. Three examples in the design and development of interplanetary space navigation systems are examined in order to make a brief assessment of the usefulness of three basic design theories, known as normative, rational, and heuristic. Evaluation of the examples indicates that a heuristic approach, coupled with rational-based mathematical and computational analysis methods, is used most often in problems such as orbit determination strategy development and mission navigation system design, while normative methods have seen only limited use is such applications as the development of large software systems and in the design of certain operational navigation subsystems.

Cure Cycle Design Methodology for Fabricating Reactive Resin Matrix Fiber Reinforced Composites: A Protocol for Producing Void-free Quality Laminates

NASA Technical Reports Server (NTRS)

Hou, Tan-Hung

2014-01-01

For the fabrication of resin matrix fiber reinforced composite laminates, a workable cure cycle (i.e., temperature and pressure profiles as a function of processing time) is needed and is critical for achieving void-free laminate consolidation. Design of such a cure cycle is not trivial, especially when dealing with reactive matrix resins. An empirical "trial and error" approach has been used as common practice in the composite industry. Such an approach is not only costly, but also ineffective at establishing the optimal processing conditions for a specific resin/fiber composite system. In this report, a rational "processing science" based approach is established, and a universal cure cycle design protocol is proposed. Following this protocol, a workable and optimal cure cycle can be readily and rationally designed for most reactive resin systems in a cost effective way. This design protocol has been validated through experimental studies of several reactive polyimide composites for a wide spectrum of usage that has been documented in the previous publications.

Abnormality, rationality, and sanity.

PubMed

Hertwig, Ralph; Volz, Kirsten G

2013-11-01

A growing body of studies suggests that neurological and mental abnormalities foster conformity to norms of rationality that are widely endorsed in economics and psychology, whereas normality stands in the way of rationality thus defined. Here, we outline the main findings of these studies, discuss their implications for experimental design, and consider how 'sane' some benchmarks of rationality really are. Copyright © 2013 Elsevier Ltd. All rights reserved.

Principles of Design for High Performing Organizations: An Assessment of the State of the Field of Organizational Design Research

DTIC Science & Technology

1994-03-01

asked whether the planned structure considered (a) all objectives, (b) all functions, (c) all relevant units of analysis such as the plant , the...literature and provides an integrative model of design for high perfor-ming organizations. The model is based on an analysis of current theories of...important midrange theories underlie much of the work on organizational analysis . 0 Systems Approaches. These approaches emphasize the rational, goal

The political economy of rationing health care in England and the US: the 'accidental logics' of political settlements.

PubMed

Bevan, Gwyn; Brown, Lawrence D

2014-07-01

This article considers how the 'accidental logics' of political settlements for the English National Health Service (NHS) and the Medicare and Medicaid programmes in the United States have resulted in different institutional arrangements and different implicit social contracts for rationing, which we define to be the denial of health care that is beneficial but is deemed to be too costly. This article argues that rationing is designed into the English NHS and designed out of US Medicare; and compares rationing for the elderly in the United States and in England for acute care, care at the end of life, and chronic care.

Rosetta comparative modeling for library design: Engineering alternative inducer specificity in a transcription factor.

PubMed

Jha, Ramesh K; Chakraborti, Subhendu; Kern, Theresa L; Fox, David T; Strauss, Charlie E M

2015-07-01

Structure-based rational mutagenesis for engineering protein functionality has been limited by the scarcity and difficulty of obtaining crystal structures of desired proteins. On the other hand, when high-throughput selection is possible, directed evolution-based approaches for gaining protein functionalities have been random and fortuitous with limited rationalization. We combine comparative modeling of dimer structures, ab initio loop reconstruction, and ligand docking to select positions for mutagenesis to create a library focused on the ligand-contacting residues. The rationally reduced library requirement enabled conservative control of the substitutions by oligonucleotide synthesis and bounding its size within practical transformation efficiencies (∼ 10(7) variants). This rational approach was successfully applied on an inducer-binding domain of an Acinetobacter transcription factor (TF), pobR, which shows high specificity for natural effector molecule, 4-hydroxy benzoate (4HB), but no native response to 3,4-dihydroxy benzoate (34DHB). Selection for mutants with high transcriptional induction by 34DHB was carried out at the single-cell level under flow cytometry (via green fluorescent protein expression under the control of pobR promoter). Critically, this selection protocol allows both selection for induction and rejection of constitutively active mutants. In addition to gain-of-function for 34DHB induction, the selected mutants also showed enhanced sensitivity and response for 4HB (native inducer) while no sensitivity was observed for a non-targeted but chemically similar molecule, 2-hydroxy benzoate (2HB). This is unique application of the Rosetta modeling protocols for library design to engineer a TF. Our approach extends applicability of the Rosetta redesign protocol into regimes without a priori precision structural information. © 2015 Wiley Periodicals, Inc.

Vaccines: From Empirical Development to Rational Design

PubMed Central

Rueckert, Christine; Guzmán, Carlos A.

2012-01-01

Infectious diseases are responsible for an overwhelming number of deaths worldwide and their clinical management is often hampered by the emergence of multi-drug-resistant strains. Therefore, prevention through vaccination currently represents the best course of action to combat them. However, immune escape and evasion by pathogens often render vaccine development difficult. Furthermore, most currently available vaccines were empirically designed. In this review, we discuss why rational design of vaccines is not only desirable but also necessary. We introduce recent developments towards specifically tailored antigens, adjuvants, and delivery systems, and discuss the methodological gaps and lack of knowledge still hampering true rational vaccine design. Finally, we address the potential and limitations of different strategies and technologies for advancing vaccine development. PMID:23144616

Constraint-based modeling in microbial food biotechnology

PubMed Central

Rau, Martin H.

2018-01-01

Genome-scale metabolic network reconstruction offers a means to leverage the value of the exponentially growing genomics data and integrate it with other biological knowledge in a structured format. Constraint-based modeling (CBM) enables both the qualitative and quantitative analyses of the reconstructed networks. The rapid advancements in these areas can benefit both the industrial production of microbial food cultures and their application in food processing. CBM provides several avenues for improving our mechanistic understanding of physiology and genotype–phenotype relationships. This is essential for the rational improvement of industrial strains, which can further be facilitated through various model-guided strain design approaches. CBM of microbial communities offers a valuable tool for the rational design of defined food cultures, where it can catalyze hypothesis generation and provide unintuitive rationales for the development of enhanced community phenotypes and, consequently, novel or improved food products. In the industrial-scale production of microorganisms for food cultures, CBM may enable a knowledge-driven bioprocess optimization by rationally identifying strategies for growth and stability improvement. Through these applications, we believe that CBM can become a powerful tool for guiding the areas of strain development, culture development and process optimization in the production of food cultures. Nevertheless, in order to make the correct choice of the modeling framework for a particular application and to interpret model predictions in a biologically meaningful manner, one should be aware of the current limitations of CBM. PMID:29588387

Physicians' evaluations of patients' decisions to refuse oncological treatment

PubMed Central

van Kleffens, T; van Leeuwen, E

2005-01-01

Objective: To gain insight into the standards of rationality that physicians use when evaluating patients' treatment refusals. Design of the study: Qualitative design with indepth interviews. Participants: The study sample included 30 patients with cancer and 16 physicians (oncologists and general practitioners). All patients had refused a recommended oncological treatment. Results: Patients base their treatment refusals mainly on personal values and/or experience. Physicians mainly emphasise the medical perspective when evaluating patients' treatment refusals. From a medical perspective, a patient's treatment refusal based on personal values and experience is generally evaluated as irrational and difficult to accept, especially when it concerns a curative treatment. Physicians have a different attitude towards non-curative treatments and have less difficulty accepting a patient's refusal of these treatments. Thus, an important factor in the physician's evaluation of a treatment refusal is whether the treatment refused is curative or non-curative. Conclusion: Physicians mainly use goal oriented and patients mainly value oriented rationality, but in the case of non-curative treatment refusal, physicians give more emphasis to value oriented rationality. A consensus between the value oriented approaches of patient and physician may then emerge, leading to the patient's decision being understood and accepted by the physician. The physician's acceptance is crucial to his or her attitude towards the patient. It contributes to the patient's feeling free to decide, and being understood and respected, and thus to a better physician–patient relationship. PMID:15738431

Rational design of the column of a heavy multipurpose machining center

NASA Astrophysics Data System (ADS)

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

2016-04-01

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

Linked magnolol dimer as a selective PPARγ agonist - Structure-based rational design, synthesis, and bioactivity evaluation.

PubMed

Dreier, Dominik; Latkolik, Simone; Rycek, Lukas; Schnürch, Michael; Dymáková, Andrea; Atanasov, Atanas G; Ladurner, Angela; Heiss, Elke H; Stuppner, Hermann; Schuster, Daniela; Mihovilovic, Marko D; Dirsch, Verena M

2017-10-20

The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and its hetero-dimerization partner retinoid X receptor α (RXRα) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPARγ to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPARγ and RXRα. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPARγ and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPARγ agonist in vitro with the purified PPARγ ligand binding domain (LBD) and in a cell-based nuclear receptor transactivation model in HEK293 cells. We determined the synthesized magnolol dimer to bind with much higher affinity to the purified PPARγ ligand binding domain than magnolol (K i values of 5.03 and 64.42 nM, respectively). Regarding their potency to transactivate a PPARγ-dependent luciferase gene both compounds were equally effective. This is likely due to the PPARγ specificity of the newly designed magnolol dimer and lack of RXRα-driven transactivation activity by this dimeric compound.

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

PubMed

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

2015-06-01

Neopullulanase, a glycosyl hydrolase from Bacillus stearothermophilus (bsNpl), is a potentially valuable enzyme for starch and detergent industries. However, as the protein is not active at elevated temperatures and high surfactant concentrations, we aimed to increase its stability by rational enzyme design. Nine potentially destabilizing cavities were identified in the crystal structure of the enzyme. Based on computational predictions, these cavities were filled by residues with bulkier side chains. The five Asp46Glu, Val239Leu, Val404Leu, Ser407Thr and Ala566Leu exchanges resulted in a drastic stabilization of bsNpl against inactivation by heat and detergents. The catalytic activity of the variants was identical to the wild-type enzyme. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Rational Thinking in School-Based Practice

ERIC Educational Resources Information Center

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…

Promoting evidence-based practice in pharmacies.

PubMed

Toklu, Hale Zerrin

2015-01-01

Evidence-based medicine aims to optimize decision-making by using evidence from well-designed and conducted research. The concept of reliable evidence is essential, since the number of electronic information resources is increasing in parallel to the increasing number and type of drugs on the market. The decision-making process is a complex and requires an extensive evaluation as well as the interpretation of the data obtained. Different sources provide different levels of evidence for decision-making. Not all the data have the same value as the evidence. Rational use of medicine requires that the patients receive "medicines appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community." Pharmacists have a crucial role in the health system to maintain the rational use of medicine and provide pharmaceutical care to patients, because they are the drug experts who are academically trained for this purpose. The rational use of the pharmacist's workforce will improve the outcome of pharmacotherapy as well as decreasing the global health costs.

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

PubMed

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.

The Rational Patient and Beyond: Implications for Treatment Adherence in People with Psychiatric Disabilities

PubMed Central

Corrigan, Patrick W.; Rüsch, Nicolas; Ben-Zeev, Dror; Sher, Tamara

2014-01-01

Purpose/Objective Many people with psychiatric disabilities do not benefit from evidence-based practices because they often do not seek out or fully adhere to them. One way psychologists have made sense of this rehabilitation and health decision process and subsequent behaviors (of which adherence might be viewed as one) is by proposing a “rational patient;” namely, that decisions are made deliberatively by weighing perceived costs and benefits of intervention options. Social psychological research, however, suggests limitations to a rational patient theory that impact models of health decision making. Design The research literature was reviewed for studies of rational patient models and alternative theories with empirical support. Special focus was on models specifically related to decisions about rehabilitation strategies for psychiatric disability. Results Notions of the rational patient evolved out of several psychological models including the health belief model, protection motivation theory, and theory of planned behavior. A variety of practice strategies evolved to promote rational decision making. However, research also suggests limitations to rational deliberations of health. (1) Rather than carefully and consciously considered, many health decisions are implicit, potentially occurring outside awareness. (2) Decisions are not always planful; often it is the immediate exigencies of a context rather than an earlier balance of costs and benefits that has the greatest effects. (3) Cool cognitions often do not dictate the process; emotional factors have an important role in health decisions. Each of these limitations suggests additional practice strategies that facilitate a person’s health decisions. Conclusions/Implications Old models of rational decision making need to be supplanted by multi-process models that explain supra-deliberative factors in health decisions and behaviors. PMID:24446671

Computerized pigment design based on property hypersurfaces

NASA Astrophysics Data System (ADS)

Halova, Jaroslava; Sulcova, Petra; Kupka, Karel

2007-05-01

Competition is tough in the pigment market. Rational pigment design has therefore a competitive advantage, saving time and money. The aim of this work is to provide methods that can assist in designing pigments with defined properties. These methods include partial least squares regression (PLSR), neural network (NN) and generalized regression ANOVA model. Authors show how PLS bi-plot can be used to identify market gaps poorly covered by pigment manufacturers, thus giving an opportunity to develop pigments with potentially profitable properties.

Additively Manufactured and Surface Biofunctionalized Porous Nitinol.

PubMed

Gorgin Karaji, Z; Speirs, M; Dadbakhsh, S; Kruth, J-P; Weinans, H; Zadpoor, A A; Amin Yavari, S

2017-01-18

Enhanced bone tissue regeneration and improved osseointegration are among the most important goals in design of multifunctional orthopedic biomaterials. In this study, we used additive manufacturing (selective laser melting) to develop multifunctional porous nitinol that combines superelasticity with a rationally designed microarchitecture and biofunctionalized surface. The rational design based on triply periodic minimal surfaces aimed to properly adjust the pore size, increase the surface area (thereby amplifying the effects of surface biofunctionalization), and resemble the curvature characteristics of trabecular bone. The surface of additively manufactured (AM) porous nitinol was biofunctionalized using polydopamine-immobilized rhBMP2 for better control of the release kinetics. The actual morphological properties of porous nitinol measured by microcomputed tomography (e.g., open/close porosity, and surface area) closely matched the design values. The superelasticity originated from the austenite phase formed in the nitinol porous structure at room temperature. Polydopamine and rhBMP2 signature peaks were confirmed by X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy tests. The release of rhBMP2 continued until 28 days. The early time and long-term release profiles were found to be adjustable independent of each other. In vitro cell culture showed improved cell attachment, cell proliferation, cell morphology (spreading, spindle-like shape), and cell coverage as well as elevated levels of ALP activity and increased calcium content for biofunctionalized surfaces as compared to as-manufactured specimens. The demonstrated functionalities of porous nitinol could be used as a basis for deployable orthopedic implants with rationally designed microarchitectures that maximize bone tissue regeneration performance by release of biomolecules with adjustable and well-controlled release profiles.

Critical fictive temperature for plasticity in metallic glasses

PubMed Central

Kumar, Golden; Neibecker, Pascal; Liu, Yan Hui; Schroers, Jan

2013-01-01

A long-sought goal in metallic glasses is to impart ductility without conceding their strength and elastic limit. The rational design of tough metallic glasses, however, remains challenging because of the inability of existing theories to capture the correlation between plasticity, composition and processing for a wide range of glass-forming alloys. Here we propose a phenomenological criterion based on a critical fictive temperature, Tfc, which can rationalize the effect of composition, cooling rate and annealing on room-temperature plasticity of metallic glasses. Such criterion helps in understanding the widespread mechanical behaviour of metallic glasses and reveals alloy-specific preparation conditions to circumvent brittleness. PMID:23443564

[Computational chemistry in structure-based drug design].

PubMed

Cao, Ran; Li, Wei; Sun, Han-Zi; Zhou, Yu; Huang, Niu

2013-07-01

Today, the understanding of the sequence and structure of biologically relevant targets is growing rapidly and researchers from many disciplines, physics and computational science in particular, are making significant contributions to modern biology and drug discovery. However, it remains challenging to rationally design small molecular ligands with desired biological characteristics based on the structural information of the drug targets, which demands more accurate calculation of ligand binding free-energy. With the rapid advances in computer power and extensive efforts in algorithm development, physics-based computational chemistry approaches have played more important roles in structure-based drug design. Here we reviewed the newly developed computational chemistry methods in structure-based drug design as well as the elegant applications, including binding-site druggability assessment, large scale virtual screening of chemical database, and lead compound optimization. Importantly, here we address the current bottlenecks and propose practical solutions.

Vector Design Tour de Force: Integrating Combinatorial and Rational Approaches to Derive Novel Adeno-associated Virus Variants

PubMed Central

Marsic, Damien; Govindasamy, Lakshmanan; Currlin, Seth; Markusic, David M; Tseng, Yu-Shan; Herzog, Roland W; Agbandje-McKenna, Mavis; Zolotukhin, Sergei

2014-01-01

Methodologies to improve existing adeno-associated virus (AAV) vectors for gene therapy include either rational approaches or directed evolution to derive capsid variants characterized by superior transduction efficiencies in targeted tissues. Here, we integrated both approaches in one unified design strategy of “virtual family shuffling” to derive a combinatorial capsid library whereby only variable regions on the surface of the capsid are modified. Individual sublibraries were first assembled in order to preselect compatible amino acid residues within restricted surface-exposed regions to minimize the generation of dead-end variants. Subsequently, the successful families were interbred to derive a combined library of ~8 × 105 complexity. Next-generation sequencing of the packaged viral DNA revealed capsid surface areas susceptible to directed evolution, thus providing guidance for future designs. We demonstrated the utility of the library by deriving an AAV2-based vector characterized by a 20-fold higher transduction efficiency in murine liver, now equivalent to that of AAV8. PMID:25048217

Dacarbazine-Loaded Hollow Mesoporous Silica Nanoparticles Grafted with Folic Acid for Enhancing Antimetastatic Melanoma Response.

PubMed

Liu, Qianqian; Xu, Nan; Liu, Liping; Li, Jun; Zhang, Yamin; Shen, Chen; Shezad, Khurram; Zhang, Lianbin; Zhu, Jintao; Tao, Juan

2017-07-05

Dacarbazine (DTIC) is one of the most important chemotherapeutic agents for the treatment of melanoma; however, its poor solubility, photosensitivity, instability, and serious toxicity to normal cells limit its clinical applications. In this article, we present a rationally designed nanocarrier based on hollow mesoporous silica nanoparticles (HMSNs) for the encapsulation and targeted release of DTIC for eradicating melanoma. The nanocarrier (DTIC@HMLBFs) is prepared by modifying HMSNs with carboxyl groups to enhance the loading of DTIC, followed by further enveloping of folic acid-grafted liposomes, which act as a melanoma active target for controlled and targeted drug release. In vitro, DTIC@HMLBFs exhibited the strongest cytotoxicity to melanoma cells compared with DTIC@HMSNs and free DTIC. The in vivo investigations demonstrate that the rationally designed nanocarrier loaded with DTIC achieves significant improvement against lung metastasis of melanoma via targeting melanoma cells and tumor-associated macrophages. This study provides a promising platform for the design and fabrication of multifunctional nanomedicines, which are potentially useful for the treatment of melanoma.

Rational Design of Au@Pt Multibranched Nanostructures as Bifunctional Nanozymes.

PubMed

Wu, Jiangjiexing; Qin, Kang; Yuan, Dan; Tan, Jun; Qin, Li; Zhang, Xuejin; Wei, Hui

2018-04-18

One of the current challenges in nanozyme-based nanotechnology is the utilization of multifunctionalities in one material. In this regard, Au@Pt nanoparticles (NPs) with excellent enzyme-mimicking activities due to the Pt shell and unique surface plasmon resonance features from the Au core have attracted enormous research interest. However, the unique surface plasmon resonance features from the Au core have not been widely utilized. The practical problem of the optical-damping nature of Pt hinders the research into the combination of Au@Pt NPs' enzyme-mimicking properties with their surface-enhanced Raman scattering (SERS) activities. Herein, we rationally tuned the Pt amount to achieve Au@Pt NPs with simultaneous plasmonic and enzyme-mimicking activities. The results showed that Au@Pt NPs with 2.5% Pt produced the highest Raman signal in 2 min, which benefited from the remarkably accelerated catalytic oxidation of 3,3',5,5'-tetramethylbenzidine with the decorated Pt and strong electric field retained from the Au core for SERS. This study not only demonstrates the great promise of combining bimetallic nanomaterials' multiple functionalities but also provides rational guidelines to design high-performance nanozymes for potential biomedical applications.

Should informed consent be based on rational beliefs?

PubMed Central

Savulescu, J; Momeyer, R W

1997-01-01

Our aim is to expand the regulative ideal governing consent. We argue that consent should not only be informed but also based on rational beliefs. We argue that holding true beliefs promotes autonomy. Information is important insofar as it helps a person to hold the relevant true beliefs. But in order to hold the relevant true beliefs, competent people must also think rationally. Insofar as information is important, rational deliberation is important. Just as physicians should aim to provide relevant information regarding the medical procedures prior to patients consenting to have those procedures, they should also assist patients to think more rationally. We distinguish between rational choice/action and rational belief. While autonomous choice need not necessarily be rational, it should be based on rational belief. The implication for the doctrine of informed consent and the practice of medicine is that, if physicians are to respect patient autonomy and help patients to choose and act more rationally, not only must they provide information, but they should care more about the theoretical rationality of their patients. They should not abandon their patients to irrationality. They should help their patients to deliberate more effectively and to care more about thinking rationally. We illustrate these arguments in the context of Jehovah's Witnesses refusing life-saving blood transfusions. Insofar as Jehovah's Witnesses should be informed of the consequences of their actions, they should also deliberate rationally about these consequences. PMID:9358347

Should informed consent be based on rational beliefs?

PubMed

Savulescu, J; Momeyer, R W

1997-10-01

Our aim is to expand the regulative ideal governing consent. We argue that consent should not only be informed but also based on rational beliefs. We argue that holding true beliefs promotes autonomy. Information is important insofar as it helps a person to hold the relevant true beliefs. But in order to hold the relevant true beliefs, competent people must also think rationally. Insofar as information is important, rational deliberation is important. Just as physicians should aim to provide relevant information regarding the medical procedures prior to patients consenting to have those procedures, they should also assist patients to think more rationally. We distinguish between rational choice/action and rational belief. While autonomous choice need not necessarily be rational, it should be based on rational belief. The implication for the doctrine of informed consent and the practice of medicine is that, if physicians are to respect patient autonomy and help patients to choose and act more rationally, not only must they provide information, but they should care more about the theoretical rationality of their patients. They should not abandon their patients to irrationality. They should help their patients to deliberate more effectively and to care more about thinking rationally. We illustrate these arguments in the context of Jehovah's Witnesses refusing life-saving blood transfusions. Insofar as Jehovah's Witnesses should be informed of the consequences of their actions, they should also deliberate rationally about these consequences.

Rational thinking in school-based practice.

PubMed

Clark, Mary Kristen; Flynn, Perry

2011-01-01

We reflect on Alan Kamhi's (2011) prologue on balancing certainty and uncertainty as it pertains to school-based practice. 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 confronts uncertainties. We provide suggestions for how this dialogue can be used throughout the individualized education program (IEP) process to lead to more positive experiences for all team members as well as improved student outcomes. Rational thinking in school-based practice may be manifest by closer adherence to the tenets [corrected] of the Individuals With Disabilities Education Improvement Act of 2004 (IDEIA), ultimately resulting in increased rational thought and improved student outcomes.

Non-parametric identification of multivariable systems: A local rational modeling approach with application to a vibration isolation benchmark

NASA Astrophysics Data System (ADS)

Voorhoeve, Robbert; van der Maas, Annemiek; Oomen, Tom

2018-05-01

Frequency response function (FRF) identification is often used as a basis for control systems design and as a starting point for subsequent parametric system identification. The aim of this paper is to develop a multiple-input multiple-output (MIMO) local parametric modeling approach for FRF identification of lightly damped mechanical systems with improved speed and accuracy. The proposed method is based on local rational models, which can efficiently handle the lightly-damped resonant dynamics. A key aspect herein is the freedom in the multivariable rational model parametrizations. Several choices for such multivariable rational model parametrizations are proposed and investigated. For systems with many inputs and outputs the required number of model parameters can rapidly increase, adversely affecting the performance of the local modeling approach. Therefore, low-order model structures are investigated. The structure of these low-order parametrizations leads to an undesired directionality in the identification problem. To address this, an iterative local rational modeling algorithm is proposed. As a special case recently developed SISO algorithms are recovered. The proposed approach is successfully demonstrated on simulations and on an active vibration isolation system benchmark, confirming good performance of the method using significantly less parameters compared with alternative approaches.

Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain.

PubMed

Denny, R Aldrin; Flick, Andrew C; Coe, Jotham; Langille, Jonathan; Basak, Arindrajit; Liu, Shenping; Stock, Ingrid; Sahasrabudhe, Parag; Bonin, Paul; Hay, Duncan A; Brennan, Paul E; Pletcher, Mathew; Jones, Lyn H; Chekler, Eugene L Piatnitski

2017-07-13

Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).

Design and Fabrication of N-Alkyl-Polyethylenimine-Stabilized Iron Oxide Nanoclusters for Gene Delivery

PubMed Central

Liu, Gang; Wang, Zhiyong; Lee, Seulki; Ai, Hua; Chen, Xiaoyuan

2013-01-01

With the rapid development of nanotechnology, inorganic magnetic nanoparticles, especially iron oxide nanoparticles (IOs), have emerged as great vehicles for biomedical diagnostic and therapeutic applications. In order to rationally design IO-based gene delivery nanovectors, surface modification is essential and determines the loading and release of the gene of interest. Here we highlight the basic concepts and applications of nonviral gene delivery vehicles based on low molecular weight N-alkyl polyethylenimine-stabilized IOs. The experimental protocols related to these topics are described in this chapter. PMID:22568910

Design and Construction for Community Health Service Precision Fund Appropriation System Based on Performance Management.

PubMed

Gao, Xing; He, Yao; Hu, Hongpu

2017-01-01

Allowing for the differences in economy development, informatization degree and characteristic of population served and so on among different community health service organizations, community health service precision fund appropriation system based on performance management is designed, which can provide support for the government to appropriate financial funds scientifically and rationally for primary care. The system has the characteristic of flexibility and practicability, in which there are five subsystems including data acquisition, parameter setting, fund appropriation, statistical analysis system and user management.

Optimal public rationing and price response.

PubMed

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.

Computational and Genomic Analysis of Mycobacteriophage: A Longitudinal Study of Technology Engineered Biology Courses That Implemented an Inquiry Based Laboratory Practice Designed to Enhance, Encourage, and Empower Student Learning

ERIC Educational Resources Information Center

Hollowell, Gail P.; Osler, James E.; Hester, April L.

2015-01-01

This paper provides an applied research rational for a longitudinal investigation that involved teaching a "Technology Engineered Science Education Course" via an Interactive Laboratory Based Genomics Curriculum. The Technology st Engineering [TE] methodology was first introduced at the SAPES: South Atlantic Philosophy of Education…

Towards the Rational Design of Nanoparticle Catalysts

NASA Astrophysics Data System (ADS)

Dash, Priyabrat

This research is focused on development of routes towards the rational design of nanoparticle catalysts. Primarily, it is focused on two main projects; (1) the use of imidazolium-based ionic liquids (ILs) as greener media for the design of quasi-homogeneous nanoparticle catalysts and (2) the rational design of heterogeneous-supported nanoparticle catalysts from structured nanoparticle precursors. Each project has different studies associated with the main objective of the design of nanoparticle catalysts. In the first project, imidazolium-based ionic liquids have been used for the synthesis of nanoparticle catalysts. In particular, studies on recyclability, reuse, mode-of-stability, and long-term stability of these ionic-liquid supported nanoparticle catalysts have been done; all of which are important factors in determining the overall "greenness" of such synthetic routes. Three papers have been published/submitted for this project. In the first publication, highly stable polymer-stabilized Au, Pd and bimetallic Au-Pd nanoparticle catalysts have been synthesized in imidazolium-based 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM]PF6) ionic liquid (Journal of Molecular Catalysis A: Chemical, 2008, 286, 114). The resulting nanoparticles were found to be effective and selective quasi-homogeneous catalysts towards a wide-range of hydrogenation reactions and the catalyst solution was reused for further catalytic reactions with minimal loss in activity. The synthesis of very pure and clean ILs has allowed a platform to study the effects of impurities in the imidazolium ILs on nanoparticle stability. In a later study, a new mode of stabilization was postulated where the presence of low amounts of 1-methylimidazole has substantial effects on the resulting stability of Au and Pd-Au nanoparticles in these ILs (Chemical Communications, 2009, 812). In further continuation of this study, a comparative study involving four stabilization protocols for nanoparticle stabilization in BMIMPF6 IL is described, and have shown that nanoparticle stability and catalytic activity of nanoparticles is dependent on the overall stability of the nanoparticles towards aggregation (manuscript submitted). The second major project is focused on synthesizing structurally well-defined supported catalysts by incorporating the nanoparticle precursors (both alloy and core shell) into oxide frameworks (TiO2 and Al2O 3), and examining their structure-property relationships and catalytic activity. a full article has been published on this project (Journal of Physical Chemistry C, 2009, 113, 12719) in which a route to rationally design supported catalysts from structured nanoparticle precursors with precise control over size, composition, and internal structure of the nanoparticles has been shown. In a continuation of this methodology for the synthesis of heterogeneous catalysts, efforts were carried out to apply the same methodology in imidazolium-based ILs as a one-pot media for the synthesis of supported-nanoparticle heterogeneous catalysts via the trapping of pre-synthesized nanoparticles into porous inorganic oxide materials. Nanoparticle catalysts in highly porous titania supports were synthesized using this methodology (manuscript to be submitted).

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

PubMed

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.

Generation and development of RNA ligase ribozymes with modular architecture through "design and selection".

PubMed

Fujita, Yuki; Ishikawa, Junya; Furuta, Hiroyuki; Ikawa, Yoshiya

2010-08-26

In vitro selection with long random RNA libraries has been used as a powerful method to generate novel functional RNAs, although it often requires laborious structural analysis of isolated RNA molecules. Rational RNA design is an attractive alternative to avoid this laborious step, but rational design of catalytic modules is still a challenging task. A hybrid strategy of in vitro selection and rational design has been proposed. With this strategy termed "design and selection," new ribozymes can be generated through installation of catalytic modules onto RNA scaffolds with defined 3D structures. This approach, the concept of which was inspired by the modular architecture of naturally occurring ribozymes, allows prediction of the overall architectures of the resulting ribozymes, and the structural modularity of the resulting ribozymes allows modification of their structures and functions. In this review, we summarize the design, generation, properties, and engineering of four classes of ligase ribozyme generated by design and selection.

A car theft deterrent system research based on ARM9

NASA Astrophysics Data System (ADS)

Zhang, Kaisheng; Liu, Jinhao; Fan, Lijun

2009-07-01

The traditional automotive burglarproof systems commonly only rely on the simple remote control to security which measures are not perfect and functions are too single. With the development of society, people tend to concern on the fingerprint recognition technology, GSM /GPRS wireless transmission technology, the idea of ARM9-based design of automobile burglarproof system is dependent on both of them. The S3C2410 microprocessor embedded system is used in this system, which is illuminated the idea of the control system design through the hardware and software. The spot use indicates that the high control precision, steady performance and the humanistic rational design of automotive burglarproof system.

FRET-based small-molecule fluorescent probes: rational design and bioimaging applications.

PubMed

Yuan, Lin; Lin, Weiying; Zheng, Kaibo; Zhu, Sasa

2013-07-16

Fluorescence imaging has emerged as a powerful tool for monitoring biomolecules within the context of living systems with high spatial and temporal resolution. Researchers have constructed a large number of synthetic intensity-based fluorescent probes for bio-imaging. However, intensity-based fluorescent probes have some limitations: variations in probe concentration, probe environment, and excitation intensity may influence the fluorescence intensity measurements. In principle, the use of ratiometric fluorescent probes can alleviate this shortcoming. Förster resonance energy transfer (FRET) is one of the most widely used sensing mechanisms for ratiometric fluorescent probes. However, the development of synthetic FRET probes with favorable photophysical properties that are also suitable for biological imaging applications remains challenging. In this Account, we review the rational design and biological applications of synthetic FRET probes, focusing primarily on studies from our laboratory. To construct useful FRET probes, it is a pre-requisite to develop a FRET platform with favorable photophysical properties. The design criteria of a FRET platform include (1) well-resolved absorption spectra of the donor and acceptor, (2) well-separated emission spectra of the donor and acceptor, (3) donors and acceptors with comparable brightness, (4) rigid linkers, and (5) near-perfect efficiency in energy transfer. With an efficient FRET platform in hand, it is then necessary to modulate the donor-acceptor distance or spectral overlap integral in an analyte-dependent fashion for development of FRET probes. Herein, we emphasize our most recent progress on the development of FRET probes by spectral overlap integral, in particular by changing the molar absorption coefficient of the donor dyes such as rhodamine dyes, which undergo unique changes in the absorption profiles during the ring-opening and -closing processes. Although partial success has been obtained in design of first-generation rhodamine-based FRET probes via modulation of acceptor molar absorption coefficient, further improvements in terms of versatility, sensitivity, and synthetic accessibility are required. To address these issues with the first-generation rhodamine-based FRET probes, we have proposed a strategy for the design of second-generation probes. As a demonstration, we have developed FRET imaging probes for diverse targets including Cu²⁺, NO, HOCl, cysteine, and H₂O₂. This discussion of the methods for successfully designing synthetic FRET probes underscores the rational basis for further development of new FRET probes as a molecular toolbox for probing and manipulating a wide variety of biomolecules in living systems.

High-Performance Non-Fullerene Organic Solar Cells Based on a Selenium-Containing Polymer Donor and a Twisted Perylene Bisimide Acceptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Tao; Meng, Dong; Cai, Yunhao

2016-04-23

A novel polymer donor (PBDTS-Se) is designed to match with a non-fullerene acceptor (SdiPBI-S). The corresponding solar cells show a high efficiency of 8.22%, which result from synergetic improvements of light harvesting, charge carrier transport and collection, and morphology. The results indicate that rational design of novel donor materials is important for non-fullerene organic solar cells.

MDO can help resolve the designer's dilemma. [multidisciplinary design optimization

NASA Technical Reports Server (NTRS)

Sobieszczanski-Sobieski, Jaroslaw; Tulinius, Jan R.

1991-01-01

Multidisciplinary design optimization (MDO) is presented as a rapidly growing body of methods, algorithms, and techniques that will provide a quantum jump in the effectiveness and efficiency of the quantitative side of design, and will turn that side into an environment in which the qualitative side can thrive. MDO borrows from CAD/CAM for graphic visualization of geometrical and numerical data, data base technology, and in computer software and hardware. Expected benefits from this methodology are a rational, mathematically consistent approach to hypersonic aircraft designs, designs pushed closer to the optimum, and a design process either shortened or leaving time available for different concepts to be explored.

Nutritional Criteria for Military Rations and Effects of Prolonged Feeding on Acceptability

NASA Technical Reports Server (NTRS)

Schnakenberg, D.

1985-01-01

Broad nutritional policies for operational rations are designed to insure that the nutritional content of the rations served will sustain combat effectiveness. Concern exists that these rations, although nutritionally complete, would become monotonous because of limited variety causing nutrient intake to decrease and body weight losses to occur with adverse effects on morale and combat effectiveness. Whenever possible, troops are now fed one or two hot meals per day containing fresh foods and a much greater variety of foods than are available in packaged rations. A laboratory test was conducted with student volunteers and the results are discussed.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

R Daher; M Coincon; M Fonvielle

2011-12-31

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

Coupled Triboelectric Nanogenerator Networks for Efficient Water Wave Energy Harvesting.

PubMed

Xu, Liang; Jiang, Tao; Lin, Pei; Shao, Jia Jia; He, Chuan; Zhong, Wei; Chen, Xiang Yu; Wang, Zhong Lin

2018-02-27

Water wave energy is a promising clean energy source, which is abundant but hard to scavenge economically. Triboelectric nanogenerator (TENG) networks provide an effective approach toward massive harvesting of water wave energy in oceans. In this work, a coupling design in TENG networks for such purposes is reported. The charge output of the rationally linked units is over 10 times of that without linkage. TENG networks of three different connecting methods are fabricated and show better performance for the ones with flexible connections. The network is based on an optimized ball-shell structured TENG unit with high responsivity to small agitations. The dynamic behavior of single and multiple TENG units is also investigated comprehensively to fully understand their performance in water. The study shows that a rational design on the linkage among the units could be an effective strategy for TENG clusters to operate collaboratively for reaching a higher performance.

Live Attenuated Influenza Vaccines by Computer-Aided Rational Design

PubMed Central

Mueller, Steffen; Coleman, J. Robert; Papamichail, Dimitris; Ward, Charles B.; Nimnual, Anjaruwee; Futcher, Bruce; Skiena, Steven; Wimmer, Eckard

2010-01-01

Influenza claims 250,000 - 500,000 lives annually worldwide. Despite existing vaccines and enormous efforts in biomedical research, these staggering numbers have not changed significantly over the last two decades1, motivating the search for new, more effective, vaccines that can be rapidly designed and easily produced. Using influenza virus strain A/PR/8/34, we describe a systematic, rational approach, termed Synthetic Attenuated Virus Engineering (SAVE), to develop new, efficacious live attenuated influenza virus vaccine candidates through genome-scale changes in codon pair bias. Attenuation is based on many hundreds of nucleotide changes across the viral genome, offering high genetic stability and a wide margin of safety. The method can be applied rapidly to any emerging influenza virus in its entirety, an advantage that is significant for dealing with seasonal epidemics and pandemic threats, such as H5N1- or 2009-H1N1 influenza. PMID:20543832

Structure-Based Design of Hepatitis C Virus Vaccines That Elicit Neutralizing Antibody Responses to a Conserved Epitope

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pierce, Brian G.; Boucher, Elisabeth N.; Piepenbrink, Kurt H.

Despite recent advances in therapeutic options, hepatitis C virus (HCV) remains a severe global disease burden, and a vaccine can substantially reduce its incidence. Due to its extremely high sequence variability, HCV can readily escape the immune response; thus, an effective vaccine must target conserved, functionally important epitopes. Using the structure of a broadly neutralizing antibody in complex with a conserved linear epitope from the HCV E2 envelope glycoprotein (residues 412 to 423; epitope I), we performed structure-based design of immunogens to induce antibody responses to this epitope. This resulted in epitope-based immunogens based on a cyclic defensin protein, asmore » well as a bivalent immunogen with two copies of the epitope on the E2 surface. We solved the X-ray structure of a cyclic immunogen in complex with the HCV1 antibody and confirmed preservation of the epitope conformation and the HCV1 interface. Mice vaccinated with our designed immunogens produced robust antibody responses to epitope I, and their serum could neutralize HCV. Notably, the cyclic designs induced greater epitope-specific responses and neutralization than the native peptide epitope. Beyond successfully designing several novel HCV immunogens, this study demonstrates the principle that neutralizing anti-HCV antibodies can be induced by epitope-based, engineered vaccines and provides the basis for further efforts in structure-based design of HCV vaccines. IMPORTANCEHepatitis C virus is a leading cause of liver disease and liver cancer, with approximately 3% of the world's population infected. To combat this virus, an effective vaccine would have distinct advantages over current therapeutic options, yet experimental vaccines have not been successful to date, due in part to the virus's high sequence variability leading to immune escape. In this study, we rationally designed several vaccine immunogens based on the structure of a conserved epitope that is the target of broadly neutralizing antibodies.In vivoresults in mice indicated that these antigens elicited epitope-specific neutralizing antibodies, with various degrees of potency and breadth. These promising results suggest that a rational design approach can be used to generate an effective vaccine for this virus.« less

Rational Design of Peptide-Functionalized Surface Plasmon Resonance Sensor for Specific Detection of TNT Explosive.

PubMed

Wang, Jin; Muto, Masaki; Yatabe, Rui; Onodera, Takeshi; Tanaka, Masayoshi; Okochi, Mina; Toko, Kiyoshi

2017-09-30

In this study, a rationally-designed 2,4,6-trinitrotoluene (TNT) binding peptide derived from an amino acid sequence of the complementarity-determining region (CDR) of an anti-TNT monoclonal antibody was used for TNT detection based on a maleimide-functionalized surface plasmon resonance (SPR) sensor. By antigen-docking simulation and screening, the TNT binding candidate peptides were obtained as TNTHCDR1 derived from the heavy chain of CDR1, TNTHCDR2 derived from CDR2, and TNTHCDR3 from CDR3 of an anti-TNT antibody. The binding events between candidate peptides and TNT were evaluated using the SPR sensor by direct determination based on the 3-aminopropyltriethoxysilane (APTES) surface. The TNT binding peptide was directly immobilized on the maleimide-functionalized sensor chip surface from N-γ-maleimidobutyryl-oxysuccinimide ester (GMBS). The results demonstrated that peptide TNTHCDR3 was identified and selected as a TNT binding peptide among the other two candidate peptides. Five kinds of TNT analogues were also investigated to testify the selectivity of TNT binding peptide TNTHCDR3. Furthermore, the results indicated that the APTES-GMBS-based SPR sensor chip procedure featured a great potential application for the direct detection of TNT.

Rational Design of Peptide-Functionalized Surface Plasmon Resonance Sensor for Specific Detection of TNT Explosive

PubMed Central

Wang, Jin; Muto, Masaki; Yatabe, Rui; Onodera, Takeshi; Okochi, Mina; Toko, Kiyoshi

2017-01-01

In this study, a rationally-designed 2,4,6-trinitrotoluene (TNT) binding peptide derived from an amino acid sequence of the complementarity-determining region (CDR) of an anti-TNT monoclonal antibody was used for TNT detection based on a maleimide-functionalized surface plasmon resonance (SPR) sensor. By antigen-docking simulation and screening, the TNT binding candidate peptides were obtained as TNTHCDR1 derived from the heavy chain of CDR1, TNTHCDR2 derived from CDR2, and TNTHCDR3 from CDR3 of an anti-TNT antibody. The binding events between candidate peptides and TNT were evaluated using the SPR sensor by direct determination based on the 3-aminopropyltriethoxysilane (APTES) surface. The TNT binding peptide was directly immobilized on the maleimide-functionalized sensor chip surface from N-γ-maleimidobutyryl-oxysuccinimide ester (GMBS). The results demonstrated that peptide TNTHCDR3 was identified and selected as a TNT binding peptide among the other two candidate peptides. Five kinds of TNT analogues were also investigated to testify the selectivity of TNT binding peptide TNTHCDR3. Furthermore, the results indicated that the APTES-GMBS-based SPR sensor chip procedure featured a great potential application for the direct detection of TNT. PMID:28973962

Rational Behavior Training: A Seven Lesson Sequence for Teaching Rational Behavior Skills to Students with Social and Emotional Disabilities.

ERIC Educational Resources Information Center

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,…

Rational Ignorance in Education: A Field Experiment in Student Plagiarism

ERIC Educational Resources Information Center

Dee, Thomas S.; Jacob, Brian A.

2012-01-01

Plagiarism appears to be a common problem among college students, yet there is little evidence on the effectiveness of interventions designed to minimize plagiarism. This study presents the results of a field experiment that evaluated the effects of a web-based educational tutorial in reducing plagiarism. We found that assignment to the treatment…

Deregulation of Feedback Inhibition of Phosphoenolpyruvate Carboxylase for Improved Lysine Production in Corynebacterium glutamicum

PubMed Central

Chen, Zhen; Bommareddy, Rajesh Reddy; Frank, Doinita; Rappert, Sugima

2014-01-01

Allosteric regulation of phosphoenolpyruvate carboxylase (PEPC) controls the metabolic flux distribution of anaplerotic pathways. In this study, the feedback inhibition of Corynebacterium glutamicum PEPC was rationally deregulated, and its effect on metabolic flux redistribution was evaluated. Based on rational protein design, six PEPC mutants were designed, and all of them showed significantly reduced sensitivity toward aspartate and malate inhibition. Introducing one of the point mutations (N917G) into the ppc gene, encoding PEPC of the lysine-producing strain C. glutamicum LC298, resulted in ∼37% improved lysine production. In vitro enzyme assays and 13C-based metabolic flux analysis showed ca. 20 and 30% increases in the PEPC activity and corresponding flux, respectively, in the mutant strain. Higher demand for NADPH in the mutant strain increased the flux toward pentose phosphate pathway, which increased the supply of NADPH for enhanced lysine production. The present study highlights the importance of allosteric regulation on the flux control of central metabolism. The strategy described here can also be implemented to improve other oxaloacetate-derived products. PMID:24334667

Deregulation of feedback inhibition of phosphoenolpyruvate carboxylase for improved lysine production in Corynebacterium glutamicum.

PubMed

Chen, Zhen; Bommareddy, Rajesh Reddy; Frank, Doinita; Rappert, Sugima; Zeng, An-Ping

2014-02-01

Allosteric regulation of phosphoenolpyruvate carboxylase (PEPC) controls the metabolic flux distribution of anaplerotic pathways. In this study, the feedback inhibition of Corynebacterium glutamicum PEPC was rationally deregulated, and its effect on metabolic flux redistribution was evaluated. Based on rational protein design, six PEPC mutants were designed, and all of them showed significantly reduced sensitivity toward aspartate and malate inhibition. Introducing one of the point mutations (N917G) into the ppc gene, encoding PEPC of the lysine-producing strain C. glutamicum LC298, resulted in ∼37% improved lysine production. In vitro enzyme assays and (13)C-based metabolic flux analysis showed ca. 20 and 30% increases in the PEPC activity and corresponding flux, respectively, in the mutant strain. Higher demand for NADPH in the mutant strain increased the flux toward pentose phosphate pathway, which increased the supply of NADPH for enhanced lysine production. The present study highlights the importance of allosteric regulation on the flux control of central metabolism. The strategy described here can also be implemented to improve other oxaloacetate-derived products.

Shape Engineering Boosts Magnetic Mesoporous Silica Nanoparticle-Based Isolation and Detection of Circulating Tumor Cells.

PubMed

Chang, Zhi-Min; Wang, Zheng; Shao, Dan; Yue, Juan; Xing, Hao; Li, Li; Ge, Mingfeng; Li, Mingqiang; Yan, Huize; Hu, Hanze; Xu, Qiaobing; Dong, Wen-Fei

2018-04-04

Magnetic mesoporous silica nanoparticles (M-MSNs) are attractive candidates for the immunomagnetic isolation and detection of circulating tumor cells (CTCs). Understanding of the interactions between the effects of the shape of M-MSNs and CTCs is crucial to maximize the binding capacity and capture efficiency as well as to facilitate the sensitivity and efficiency of detection. In this work, fluorescent M-MSNs were rationally designed with sphere and rod morphologies while retaining their robust fluorescence and uniform surface functionality. After conjugation with the antibody of epithelial cell adhesion molecule (EpCAM), both of the differently shaped M-MSNs-EpCAM obtained achieved efficient enrichment of CTCs and fluorescent-based detection. Importantly, rodlike M-MSNs exhibited faster immunomagnetic isolation as well as better performance in the isolation and detection of CTCs in spiked cells and real clinical blood samples than those of their spherelike counterparts. Our results showed that shape engineering contributes positively toward immunomagnetic isolation, which might open new avenues to the rational design of magnetic-fluorescent nanoprobes for the sensitive and efficient isolation and detection of CTCs.

Return period adjustment for runoff coefficients based on analysis in undeveloped Texas watersheds

USGS Publications Warehouse

Dhakal, Nirajan; Fang, Xing; Asquith, William H.; Cleveland, Theodore G.; Thompson, David B.

2013-01-01

The rational method for peak discharge (Qp) estimation was introduced in the 1880s. The runoff coefficient (C) is a key parameter for the rational method that has an implicit meaning of rate proportionality, and the C has been declared a function of the annual return period by various researchers. Rate-based runoff coefficients as a function of the return period, C(T), were determined for 36 undeveloped watersheds in Texas using peak discharge frequency from previously published regional regression equations and rainfall intensity frequency for return periods T of 2, 5, 10, 25, 50, and 100 years. The C(T) values and return period adjustments C(T)/C(T=10  year) determined in this study are most applicable to undeveloped watersheds. The return period adjustments determined for the Texas watersheds in this study and those extracted from prior studies of non-Texas data exceed values from well-known literature such as design manuals and textbooks. Most importantly, the return period adjustments exceed values currently recognized in Texas Department of Transportation design guidance when T>10  years.

Computer-Aided Structure Based Drug Design Approaches for the Discovery of New Anti-CHIKV Agents.

PubMed

Jadav, Surender Singh; Sinha, Barij Nayan; Hilgenfeld, Rolf; Jayaprakash, Venkatesan

2017-11-10

Chikungunya is a viral infection caused by Chikungunya virus (CHIKV), an arbovirus transmitted through mosquito (Aedes aegypti and Aedes albopictus) bite. The virus from sylvatic cycle in Africa mutated to new vector adaptation and became one of the major emerging and re-emerging viral infections in the past decade, affecting more than 40 countries. Efforts are being made by many researches to develop means to prevent and control the infection through vaccines and vector control strategy. On the other hand, search for novel chemotherapeutic agents for the treatment of infected patients is on. Approach of repurposed drug is one way of identifying an existing drug for the treatment of CHIKV infection. Review the history of CHIKV nsp2 protease inhibitors derived through structure-based computer-aided drug design along with phytochemicals identified as anti-CHIKV agents. A survey on CHIKV inhibitors reported till date has been carriedout. The data obtained were organized and discussed under natural substances and synthetic derivatives obtained as result of rational design. The review provides a well organized content in chronological order that has highly significant information for medicinal chemist who wish to explore the area of Anti-CHIKV drug design and development. Natural compounds with different scaffolds provides an opportunity to explore Ligand based drug design (LBDD), while rational drug design approaches provides opportunity to explore the Structure based drug design. From the presented mini-review, readers can understand that this area is less explored and has lots of potential in anti-CHIKVviral drug design & development. of reported literature inferred that, unlike other viral proteases, the nsP2 protease can be targeted for CHIKV viral inhibition. The HTVS process for the identification of anti-CHIK agents provided a few successive validated lead compounds against CHIKV infections. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Identification of key residues modulating the stereoselectivity of nitrile hydratase toward rac-mandelonitrile by semi-rational engineering.

PubMed

Cheng, Zhongyi; Peplowski, Lukasz; Cui, Wenjing; Xia, Yuanyuan; Liu, Zhongmei; Zhang, Jialei; Kobayashi, Michihiko; Zhou, Zhemin

2018-03-01

Optically pure compounds are important in the synthesis of fine chemicals. Using directed evolution of enzymes to obtain biocatalysts that can selectively produce high-value chiral chemicals is often time-, money-, and resource-intensive; traditional semi-rational designs based on structural data and docking experiments are still limited due to the lack of accurate selection of hot-spot residues. In this study, through ligand-protein collision counts based on steered molecular dynamics simulation, we accurately identified four residues related to improving nitrile hydratase stereoselectivity toward rac-mandelonitrile (MAN). All the four selected residues had numerous collisions with rac-MAN. Five mutants significantly shifting stereoselectivity towards (S)-MAN were obtained from site-saturation mutagenesis, one of them, at position βPhe37, exhibiting efficient production of (S)-MAN with 96.8% ee p , was isolated and further analyzed. The increased pulling force observed during SMD simulation was found to be in good coincidence with the formation of hydrogen bonds between (R)-MAN and residue βHis37. (R)-MAN had to break these barriers to enter the active site of nitrile hydratase and S selectivity was thus improved. The results indicated that combining steered molecular dynamics simulation with a traditional semi-rational design significantly reduced the select range of hot-spot residues for the evolution of NHase stereoselectivity, which could serve as an alternative for the modulation of enzyme stereoselectivity. © 2017 Wiley Periodicals, Inc.

Many faces of rationality: Implications of the great rationality debate for clinical decision-making.

PubMed

Djulbegovic, Benjamin; Elqayam, Shira

2017-10-01

Given that more than 30% of healthcare costs are wasted on inappropriate care, suboptimal care is increasingly connected to the quality of medical decisions. It has been argued that personal decisions are the leading cause of death, and 80% of healthcare expenditures result from physicians' decisions. Therefore, improving healthcare necessitates improving medical decisions, ie, making decisions (more) rational. Drawing on writings from The Great Rationality Debate from the fields of philosophy, economics, and psychology, we identify core ingredients of rationality commonly encountered across various theoretical models. Rationality is typically classified under umbrella of normative (addressing the question how people "should" or "ought to" make their decisions) and descriptive theories of decision-making (which portray how people actually make their decisions). Normative theories of rational thought of relevance to medicine include epistemic theories that direct practice of evidence-based medicine and expected utility theory, which provides the basis for widely used clinical decision analyses. Descriptive theories of rationality of direct relevance to medical decision-making include bounded rationality, argumentative theory of reasoning, adaptive rationality, dual processing model of rationality, regret-based rationality, pragmatic/substantive rationality, and meta-rationality. For the first time, we provide a review of wide range of theories and models of rationality. We showed that what is "rational" behaviour under one rationality theory may be irrational under the other theory. We also showed that context is of paramount importance to rationality and that no one model of rationality can possibly fit all contexts. We suggest that in context-poor situations, such as policy decision-making, normative theories based on expected utility informed by best research evidence may provide the optimal approach to medical decision-making, whereas in the context-rich circumstances other types of rationality, informed by human cognitive architecture and driven by intuition and emotions such as the aim to minimize regret, may provide better solution to the problem at hand. The choice of theory under which we operate is important as it determines both policy and our individual decision-making. © 2017 The Authors Journal of Evaluation in Clinical Practice Published by John Wiley & Sons Ltd.

Enhancing the response rate of strand displacement-based electrochemical aptamer sensors using bivalent binding aptamer-cDNA probes.

PubMed

Zhang, Ziping; Tao, Cancan; Yin, Jungang; Wang, Yunhui; Li, Yanshen

2018-04-30

Electrochemical aptamer (EA) sensors based on aptamer-cDNA duplex probes (cDNA: complementary DNA) and target induced strand displacement (TISD) recognition are sensitive, selective and capable of detecting a wide variety of target analytes. While substantial research efforts have focused on engineering of new signaling mechanisms for the improvement of sensor sensitivity, little attention was paid to the enhancement of sensor response rate. Typically, the previous TISD based EA sensors exhibited relatively long response times larger than 30min, which mainly resulted from the suboptimal aptamer-cDNA probe structure in which most of aptamer bases were paired to the cDNA bases. In an effort to improve the response rate of this type of sensors, we report here the rational engineering of a quickly responsive and sensitive aptamer-cDNA probe by employing the conception of bivalent interaction in supramolecular chemistry. We design a bivalent cDNA strand through linking two short monovalent cDNA sequences, and it is simultaneously hybridized to two electrode-immobilized aptamer probes to form a bivalent binding (BB) aptamer-cDNA probe. This class of BB probe possesses the advantages of less aptamer bases paired to the cDNA bases for quick response rate and good structural stability for high sensor sensitivity. By use of the rationally designed BB aptamer-cDNA probe, a TISD based EA sensor against ATP with significantly enhanced response rate (with a displacement equilibrium time of 4min) and high sensitivity was successfully constructed. We believe that our BB probe conception will help guide future designs and applications of TISD based EA sensors. Copyright © 2017 Elsevier B.V. All rights reserved.

Prediction and redesign of protein–protein interactions

PubMed Central

Lua, Rhonald C.; Marciano, David C.; Katsonis, Panagiotis; Adikesavan, Anbu K.; Wilkins, Angela D.; Lichtarge, Olivier

2014-01-01

Understanding the molecular basis of protein function remains a central goal of biology, with the hope to elucidate the role of human genes in health and in disease, and to rationally design therapies through targeted molecular perturbations. We review here some of the computational techniques and resources available for characterizing a critical aspect of protein function – those mediated by protein–protein interactions (PPI). We describe several applications and recent successes of the Evolutionary Trace (ET) in identifying molecular events and shapes that underlie protein function and specificity in both eukaryotes and prokaryotes. ET is a part of analytical approaches based on the successes and failures of evolution that enable the rational control of PPI. PMID:24878423

Many faces of rationality: Implications of the great rationality debate for clinical decision‐making

PubMed Central

Elqayam, Shira

2017-01-01

Abstract Given that more than 30% of healthcare costs are wasted on inappropriate care, suboptimal care is increasingly connected to the quality of medical decisions. It has been argued that personal decisions are the leading cause of death, and 80% of healthcare expenditures result from physicians' decisions. Therefore, improving healthcare necessitates improving medical decisions, ie, making decisions (more) rational. Drawing on writings from The Great Rationality Debate from the fields of philosophy, economics, and psychology, we identify core ingredients of rationality commonly encountered across various theoretical models. Rationality is typically classified under umbrella of normative (addressing the question how people “should” or “ought to” make their decisions) and descriptive theories of decision‐making (which portray how people actually make their decisions). Normative theories of rational thought of relevance to medicine include epistemic theories that direct practice of evidence‐based medicine and expected utility theory, which provides the basis for widely used clinical decision analyses. Descriptive theories of rationality of direct relevance to medical decision‐making include bounded rationality, argumentative theory of reasoning, adaptive rationality, dual processing model of rationality, regret‐based rationality, pragmatic/substantive rationality, and meta‐rationality. For the first time, we provide a review of wide range of theories and models of rationality. We showed that what is “rational” behaviour under one rationality theory may be irrational under the other theory. We also showed that context is of paramount importance to rationality and that no one model of rationality can possibly fit all contexts. We suggest that in context‐poor situations, such as policy decision‐making, normative theories based on expected utility informed by best research evidence may provide the optimal approach to medical decision‐making, whereas in the context‐rich circumstances other types of rationality, informed by human cognitive architecture and driven by intuition and emotions such as the aim to minimize regret, may provide better solution to the problem at hand. The choice of theory under which we operate is important as it determines both policy and our individual decision‐making. PMID:28730671

ProgrammingRationalAgents in GOAL

NASA Astrophysics Data System (ADS)

Hindriks, Koen V.

The agent programming language GOAL is a high-level programming language to program rational agents that derive their choice of action from their beliefsand goals. The language provides the basic building blocks to design and implementrationalagents by meansofa setofprogramming constructs. These programming constructs allow and facilitate the manipulation of an agent’sbeliefs and goals and to structure its decision-making. GOAL agents are called rational because they satisfy a numberof basic rationality constraints and because they decide to perform actions to further their goals based uponareasoning scheme derived from practical reasoning. The programming concepts of belief and goal incorporated into GOAL provide the basis for this form of reasoning and are similarto their common sense counterparts used everyday to explain the actions that we perform. In addition, GOAL provides the means for agents to focus their attention on specic goals and to communicate at the knowledge level. This provides an intuitive basis for writing high-level agent programs. At the same time these concepts and programming constructs have a well-dened, formal semantics. The formal semantics provides the basis for deninga verication framework for GOAL for verifying and reasoning about GOAL agents whichis similar to some of the wellknownagent logics introduced in the literature.

Application of the Quality by Design Approach to the Freezing Step of Freeze-Drying: Building the Design Space.

PubMed

Arsiccio, Andrea; Pisano, Roberto

2018-06-01

The present work shows a rational method for the development of the freezing step of a freeze-drying cycle. The current approach to the selection of freezing conditions is still empirical and nonsystematic, thus resulting in poor robustness of control strategy. The final aim of this work is to fill this gap, describing a rational procedure, based on mathematical modeling, for properly choosing the freezing conditions. Mechanistic models are used for the prediction of temperature profiles during freezing and dimension of ice crystals being formed. Mathematical description of the drying phase of freeze-drying is also coupled with the results obtained by freezing models, thus providing a comprehensive characterization of the lyophilization process. In this framework, deep understanding of the phenomena involved is required, and according to the Quality by Design approach, this knowledge can be used to build the design space. The step-by-step procedure for building the design space for freezing is thus described, and examples of applications are provided. The calculated design space is validated upon experimental data, and we show that it allows easy control of the freezing process and fast selection of appropriate operating conditions. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Design and fabrication of N-alkyl-polyethylenimine-stabilized iron oxide nanoclusters for gene delivery.

PubMed

Liu, Gang; Wang, Zhiyong; Lee, Seulki; Ai, Hua; Chen, Xiaoyuan

2012-01-01

With the rapid development of nanotechnology, inorganic magnetic nanoparticles, especially iron oxide nanoparticles (IOs), have emerged as great vehicles for biomedical diagnostic and therapeutic applications. In order to rationally design IO-based gene delivery nanovectors, surface modification is essential and determines the loading and release of the gene of interest. Here we highlight the basic concepts and applications of nonviral gene delivery vehicles based on low molecular weight N-alkyl polyethylenimine-stabilized IOs. The experimental protocols related to these topics are described in this chapter. Copyright © 2012 Elsevier Inc. All rights reserved.

Qualitative mechanism models and the rationalization of procedures

NASA Technical Reports Server (NTRS)

Farley, Arthur M.

1989-01-01

A qualitative, cluster-based approach to the representation of hydraulic systems is described and its potential for generating and explaining procedures is demonstrated. Many ideas are formalized and implemented as part of an interactive, computer-based system. The system allows for designing, displaying, and reasoning about hydraulic systems. The interactive system has an interface consisting of three windows: a design/control window, a cluster window, and a diagnosis/plan window. A qualitative mechanism model for the ORS (Orbital Refueling System) is presented to coordinate with ongoing research on this system being conducted at NASA Ames Research Center.

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

PubMed

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.

Structure-based approach to rationally design a chimeric protein for an effective vaccine against Group B Streptococcus infections.

PubMed

Nuccitelli, Annalisa; Cozzi, Roberta; Gourlay, Louise J; Donnarumma, Danilo; Necchi, Francesca; Norais, Nathalie; Telford, John L; Rappuoli, Rino; Bolognesi, Martino; Maione, Domenico; Grandi, Guido; Rinaudo, C Daniela

2011-06-21

Structural vaccinology is an emerging strategy for the rational design of vaccine candidates. We successfully applied structural vaccinology to design a fully synthetic protein with multivalent protection activity. In Group B Streptococcus, cell-surface pili have aroused great interest because of their direct roles in virulence and importance as protective antigens. The backbone subunit of type 2a pilus (BP-2a) is present in six immunogenically different but structurally similar variants. We determined the 3D structure of one of the variants, and experimentally demonstrated that protective antibodies specifically recognize one of the four domains that comprise the protein. We therefore constructed a synthetic protein constituted by the protective domain of each one of the six variants and showed that the chimeric protein protects mice against the challenge with all of the type 2a pilus-carrying strains. This work demonstrates the power of structural vaccinology and will facilitate the development of an optimized, broadly protective pilus-based vaccine against Group B Streptococcus by combining the uniquely generated chimeric protein with protective pilin subunits from two other previously identified pilus types. In addition, this work describes a template procedure that can be followed to develop vaccines against other bacterial pathogens.

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

PubMed

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.

Rational design of adjuvants targeting the C-type lectin Mincle.

PubMed

Decout, Alexiane; Silva-Gomes, Sandro; Drocourt, Daniel; Barbe, Sophie; André, Isabelle; Cueto, Francisco J; Lioux, Thierry; Sancho, David; Pérouzel, Eric; Vercellone, Alain; Prandi, Jacques; Gilleron, Martine; Tiraby, Gérard; Nigou, Jérôme

2017-03-07

The advances in subunit vaccines development have intensified the search for potent adjuvants, particularly adjuvants inducing cell-mediated immune responses. Identification of the C-type lectin Mincle as one of the receptors underlying the remarkable immunogenicity of the mycobacterial cell wall, via recognition of trehalose-6,6'-dimycolate (TDM), has opened avenues for the rational design of such molecules. Using a combination of chemical synthesis, biological evaluation, molecular dynamics simulations, and protein mutagenesis, we gained insight into the molecular bases of glycolipid recognition by Mincle. Unexpectedly, the fine structure of the fatty acids was found to play a key role in the binding of a glycolipid to the carbohydrate recognition domain of the lectin. Glucose and mannose esterified at O -6 by a synthetic α-ramified 32-carbon fatty acid showed agonist activity similar to that of TDM, despite their much simpler structure. Moreover, they were seen to stimulate proinflammatory cytokine production in primary human and murine cells in a Mincle-dependent fashion. Finally, they were found to induce strong Th1 and Th17 immune responses in vivo in immunization experiments in mice and conferred protection in a murine model of Mycobacterium tuberculosis infection. Here we describe the rational development of new molecules with powerful adjuvant properties.

Rational design of p53, an intrinsically unstructured protein, for the fabrication of novel molecular sensors.

PubMed

Geddie, Melissa L; O'Loughlin, Taryn L; Woods, Kristen K; Matsumura, Ichiro

2005-10-21

The dominant paradigm of protein engineering is structure-based site-directed mutagenesis. This rational approach is generally more effective for the engineering of local properties, such as substrate specificity, than global ones such as allostery. Previous workers have modified normally unregulated reporter enzymes, including beta-galactosidase, alkaline phosphatase, and beta-lactamase, so that the engineered versions are activated (up to 4-fold) by monoclonal antibodies. A reporter that could easily be "reprogrammed" for the facile detection of novel effectors (binding or modifying activities) would be useful in high throughput screens for directed evolution or drug discovery. Here we describe a straightforward and general solution to this potentially difficult design problem. The transcription factor p53 is normally regulated by a variety of post-translational modifications. The insertion of peptides into intrinsically unstructured domains of p53 generated variants that were activated up to 100-fold by novel effectors (proteases or antibodies). An engineered p53 was incorporated into an existing high throughput screen for the detection of human immunodeficiency virus protease, an arbitrarily chosen novel effector. These results suggest that the molecular recognition properties of intrinsically unstructured proteins are relatively easy to engineer and that the absence of crystal structures should not deter the rational engineering of this class of proteins.

Rational design of a dual-mode optical and chemical prodrug.

PubMed

McCoy, Colin P; Rooney, Clare; Jones, David S; Gorman, Sean P; Nieuwenhuyzen, Mark

2007-01-01

The purpose of this study is to demonstrate the rational design and behaviour of the first dual-mode optical and chemical prodrug, exemplified by an acetyl salicylic acid-based system. A cyclic 1,4-benzodioxinone prodrug was synthesised by reaction of 3,5-dimethoxybenzoin and acetyl salicoyl chloride with pyridine. After purification by column chromatography and recrystallization, characterization was achieved using infrared and NMR spectroscopies, mass spectrometry, elemental analysis and single crystal X-ray diffraction. Light-triggered drug liberation was characterised via UV-visible spectroscopy following low-power 365 nm irradiation for controlled times. Chemical drug liberation was characterised via UV-visible spectroscopy in pH 5.5 solution. The synthetic method yielded pure prodrug, with full supporting characterisation. Light-triggered drug liberation proceeded at a rate of 8.30x10(-2) s-1, while chemical, hydrolytic liberation proceeded independently at 1.89x10(-3) s-1. The photochemical and hydrolytic reactions were both quantitative. This study demonstrates the first rational dual-mode optical and chemical prodrug, using acetyl salicylic acid as a model, acting as a paradigm for future dual-mode systems. Photochemical drug liberation proceeds 44 times faster than chemical liberation, suggesting potential use in drug-eluting medical devices where an additional burst of drug is required at the onset of infection.

Modes of rationality in nursing documentation: biology, biography and the 'voice of nursing'.

PubMed

Hyde, Abbey; Treacy, Margaret P; Scott, P Anne; Butler, Michelle; Drennan, Jonathan; Irving, Kate; Byrne, Anne; MacNeela, Padraig; Hanrahan, Marian

2005-06-01

This article is based on a discourse analysis of the complete nursing records of 45 patients, and concerns the modes of rationality that mediated text-based accounts relating to patient care that nurses recorded. The analysis draws on the work of the critical theorist, Jurgen Habermas, who conceptualised rationality in the context of modernity according to two types: purposive rationality based on an instrumental logic, and value rationality based on ethical considerations and moral reasoning. Our analysis revealed that purposive rationality dominated the content of nursing documentation, as evidenced by a particularly bio-centric and modernist construction of the workings of the body within the texts. There was little reference in the documentation to central themes of contemporary nursing discourses, such as notions of partnership, autonomy, and self-determination, which are associated with value rationality. Drawing on Habermas, we argue that this nursing documentation depicted the colonisation of the sociocultural lifeworld by the bio-technocratic system. Where nurses recorded disagreements that patients had with medical regimes, the central struggle inherent in the project of modernity became transparent--the tension between the rational and instrumental control of people through scientific regulation and the autonomy of the subject. The article concludes by problematising communicative action within the context of nursing practice.

Grid Based Technologies for in silico Screening and Drug Design.

PubMed

Potemkin, Vladimir; Grishina, Maria

2018-03-08

Various techniques for rational drug design are presented in the paper. The methods are based on a substitution of antipharmacophore atoms of the molecules of training dataset by new atoms and/or group of atoms increasing the atomic bioactivity increments obtained at a SAR study. Furthermore, a design methodology based on the genetic algorithm DesPot for discrete optimization and generation of new drug candidate structures is described. Additionally, wide spectra of SAR approaches (3D/4D QSAR interior and exterior-based methods - BiS, CiS, ConGO, CoMIn, high-quality docking method - ReDock) using MERA force field and/or AlteQ quantum chemical method for correct prognosis of bioactivity and bioactive probability is described. The design methods are implemented now at www.chemosophia.com web-site for online computational services. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

PubMed

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.

Improving fermented quality of cider vinegar via rational nutrient feeding strategy.

PubMed

Qi, Zhengliang; Dong, Die; Yang, Hailin; Xia, Xiaole

2017-06-01

This work aimed to find a rational nutrient feeding strategy for cider vinegar fermentation based on adequate information on the nutritional requirement of acetic acid bacteria. Through single nutrient lack experiment assay, necessary nutrient recipe for Acetobacter pasteurianus CICIM B7003 in acetous fermentation was confirmed. Compounds from the essential nutrient recipe were tested further to find out the key substrates significantly influencing cider vinegar fermentation. The findings showed that aspartate, glutamate, proline and tryptophan should be considered in detail for optimizing nutritional composition of cider. Finally, a nutrient feeding strategy that simultaneously adds proline, glutamate, aspartate and tryptophan to form final concentrations of 0.02g/L, 0.03g/L, 0.01g/L and 0.005g/L in cider was achieved by orthogonal experiment design. Comparing to the original fermentation, the yield of acetic acid from alcohol reached 93.3% and the concentration of most volatile flavor compounds increased with the rational nutrient feeding strategy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Program Synthesizes UML Sequence Diagrams

NASA Technical Reports Server (NTRS)

Barry, Matthew R.; Osborne, Richard N.

2006-01-01

A computer program called "Rational Sequence" generates Universal Modeling Language (UML) sequence diagrams of a target Java program running on a Java virtual machine (JVM). Rational Sequence thereby performs a reverse engineering function that aids in the design documentation of the target Java program. Whereas previously, the construction of sequence diagrams was a tedious manual process, Rational Sequence generates UML sequence diagrams automatically from the running Java code.

Structure and Computation in Immunoreagent Design: From Diagnostics to Vaccines.

PubMed

Gourlay, Louise; Peri, Claudio; Bolognesi, Martino; Colombo, Giorgio

2017-12-01

Novel immunological tools for efficient diagnosis and treatment of emerging infections are urgently required. Advances in the diagnostic and vaccine development fields are continuously progressing, with reverse vaccinology and structural vaccinology (SV) methods for antigen identification and structure-based antigen (re)design playing increasingly relevant roles. SV, in particular, is predicted to be the front-runner in the future development of diagnostics and vaccines targeting challenging diseases such as AIDS and cancer. We review state-of-the-art methodologies for structure-based epitope identification and antigen design, with specific applicative examples. We highlight the implications of such methods for the engineering of biomolecules with improved immunological properties, potential diagnostic and/or therapeutic uses, and discuss the perspectives of structure-based rational design for the production of advanced immunoreagents. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity

PubMed Central

Sengupta, Poulomi; Basu, Sudipta; Soni, Shivani; Pandey, Ambarish; Roy, Bhaskar; Oh, Michael S.; Chin, Kenneth T.; Paraskar, Abhimanyu S.; Sarangi, Sasmit; Connor, Yamicia; Sabbisetti, Venkata S.; Kopparam, Jawahar; Kulkarni, Ashish; Muto, Katherine; Amarasiriwardena, Chitra; Jayawardene, Innocent; Lupoli, Nicola; Dinulescu, Daniela M.; Bonventre, Joseph V.; Mashelkar, Raghunath A.; Sengupta, Shiladitya

2012-01-01

Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC50 values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-RasLSL/+/Ptenfl/fl ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics. PMID:22733767

Solution Synthesis of Atomically Precise Graphene Nanoribbons

NASA Astrophysics Data System (ADS)

Shekhirev, Mikhail; Sinitskii, Alexander

2017-05-01

Bottom-up fabrication of narrow strips of graphene, also known as graphene nanoribbons or GNRs, is an attractive way to open a bandgap in semimetallic graphene. In this chapter, we review recent progress in solution-based synthesis of GNRs with atomically precise structures. We discuss a variety of atomically precise GNRs and highlight theoretical and practical aspects of their structural design and solution synthesis. These GNRs are typically synthesized through a polymerization of rationally designed molecular precursors followed by a planarization through a cyclodehydrogenation reaction. We discuss various synthetic techniques for polymerization and planarization steps, possible approaches for chemical modification of GNRs, and compare the properties of GNRs that could be achieved by different synthetic methods. We also discuss the importance of the rational design of molecular precursors to avoid isomerization during the synthesis and achieve GNRs that have only one possible structure. Significant attention in this chapter is paid to the methods of material characterization of solution-synthesized GNRs. The chapter is concluded with the discussion of the most significant challenges in the field and the future outlook.

Computerized structural mechanics for 1990's: Advanced aircraft needs

NASA Technical Reports Server (NTRS)

Viswanathan, A. V.; Backman, B. F.

1989-01-01

The needs for computerized structural mechanics (CSM) as seen from the standpoint of the aircraft industry are discussed. These needs are projected into the 1990's with special focus on the new advanced materials. Preliminary design/analysis, research, and detail design/analysis are identified as major areas. The role of local/global analyses in these different areas is discussed. The lessons learned in the past are used as a basis for the design of a CSM framework that could modify and consolidate existing technology and include future developments in a rational and useful way. A philosophy is stated, and a set of analyses needs driven by the emerging advanced composites is enumerated. The roles of NASA, the universities, and the industry are identified. Finally, a set of rational research targets is recommended based on both the new types of computers and the increased complexity the industry faces. Computerized structural mechanics should be more than new methods in structural mechanics and numerical analyses. It should be a set of engineering applications software products that combines innovations in structural mechanics, numerical analysis, data processing, search and display features, and recent hardware advances and is organized in a framework that directly supports the design process.

Computational design of hepatitis C vaccines using empirical fitness landscapes and population dynamics

NASA Astrophysics Data System (ADS)

Hart, Gregory; Ferguson, Andrew

Hepatitis C virus (HCV) afflicts 170 million people and kills 350,000 annually. Vaccination offers the most realistic and cost effective hope of controlling this epidemic. Despite 25 years of research, no vaccine is available. A major obstacle is the virus' extreme genetic variability and rapid mutational escape from immune pressure. Improvements in the vaccine design process are urgently needed. Coupling data mining and maximum entropy inference, we have developed a computational approach to translate sequence databases into empirical fitness landscapes. These landscapes explicitly connect viral genotype to phenotypic fitness and reveal vulnerable targets that can be exploited to rationally design vaccines. These landscapes represent the mutational ''playing field'' over which the virus evolves. We have integrated them with agent-based models of the viral mutational and host immune response, establishing a data-driven multi-scale immune simulator. We have used this simulator to perform in silico screening of HCV immunogens to rationally design vaccines to both cripple viral fitness and block escape. By systematically identifying a small number of promising vaccine candidates, these models can accelerate the search for a vaccine by massively reducing the experimental search space.

Improved Potency of Indole-Based NorA Efflux Pump Inhibitors: From Serendipity toward Rational Design and Development.

PubMed

Buonerba, Federica; Lepri, Susan; Goracci, Laura; Schindler, Bryan D; Seo, Susan M; Kaatz, Glenn W; Cruciani, Gabriele

2017-01-12

The NorA efflux pump is a potential drug target for reversal of resistance to selected antibacterial agents, and recently we described indole-based inhibitor candidates. Herein we report a second class of inhibitors derived from them but with significant differences in shape and size. In particular, compounds 13 and 14 are very potent inhibitors in that they demonstrated the lowest IC 50 values (2 μM) ever observed among all indole-based compounds we have evaluated.

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

PubMed

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

2016-01-01

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

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

PubMed

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.

The limits of intelligence in design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Papamichael, K.; Protzen, J.P.

1993-05-01

A new, comprehensive design theory is presented, applicable to all design domains such as engineering and industrial design, architecture, city and regional planning, and, in general, any goal-oriented activity that involves decision making. The design process is analyzed into fundamental activities that are characterized with respect to the nature of knowledge requirements and the degree to which they can be specified and delegated to others, in general, and to computers in particular. The characterization of design problems as ``wicked,`` or ``ill-defined,`` design has been understood as a rational activity, that is ``thinking before acting.`` The new theory presented in thismore » paper suggests that design is ``thinking and feeling while acting,`` supporting the position that design is only partially rational. Intelligence, ``natural`` or ``artificial,`` is only one of two requirements for design, the other being emotions. Design decisions are only partially inferred, that is, they are not entirely the product of reasoning. Rather, design decisions are based on judgment that requires the notion of ``good`` and ``bad,`` which is attributed to feelings, rather than thoughts. The presentation of the design theory extends to the implications associated with the limits of intelligence in design, which, in turn, become constraints on the potential role of computers in design. Many of the current development efforts in computer-aided design violate these constraints, especially in the implementation of expert systems and multi-criterion evaluation models. These violations are identified and discussed in detail. Finally, specific areas for further research and development in computer-aided design are presented and discussed.« less

Final Environmental Impact Statement for Development of Facilities to Support Basing US Pacific Fleet F/A-18E/F Aircraft on the West Coast of the United States, Volume 1.

DTIC Science & Technology

1998-05-01

ROG reactive organic compound RONA Record of Non -applicability RTV rational threshold value RWQCB Regional Water Quality Control Board SARA...over water. The ranges are either scheduled via a designated military or civilian controlling agency (for restricted or warning areas) or are used...operations areas (MOAs), and air traffic control authorized airspace (ATCAA). Airspace designations throughout the United States are controlled by the Federal

The effects of feeding rations that differ in fiber and fermentable starch within a day on milk production and the daily rhythm of feed intake and plasma hormones and metabolites in dairy cows.

PubMed

Niu, M; Ying, Y; Bartell, P A; Harvatine, K J

2017-01-01

A daily pattern of feed intake, milk synthesis, and plasma metabolites and hormones occurs in dairy cows fed a total mixed ration once or twice a day. The objective of this study was to determine if feeding multiple rations within a day, complementing these rhythms, would improve milk production. Twelve Holstein cows were used in a replicated 3×3 Latin square design with 21-d periods. Cows were housed in tie stalls with feed tubs, and feed weight was recorded every 10 s for observation of feeding behavior. Rations were a low fiber and high fermentable starch ration [LFHS; 27.4% neutral detergent fiber (NDF) and 31.7% starch based on 55.7% corn silage and 14.1% steam-flaked corn], a high fiber and low fermentable starch ration (HFLS; 31.7% NDF and 22.3% starch based on 44% corn silage, 26.3% alfalfa haylage, and no steam-flaked corn), and a total mixed ration that was a 1:3 ratio of LFHS and HFLS (30.7% NDF, 24.5% starch). The control treatment (CON) cows were fed the total mixed ration at 0700h, the high/low treatment (HL) fed HFLS ration at 0700h and LFHS ration at 2200h, and the low/high (LH) treatment fed LFHS ration at 0700h and HFLS ration at 1100h (LFHS and HFLS rations fed at a 1:3 ratio). No effect was found of treatment on daily milk, but LH decreased milk fat concentration and yield compared with HL (0.2 percentage units and 0.24kg, respectively). Daily dry matter and NDF intake and total-tract digestibility did not differ between treatments. The HL treatment reduced intake at the morning-conditioned meal after feeding and reduced intake before the evening feeding. A treatment by time of day interaction was found for fecal NDF and indigestible NDF concentration, blood urea nitrogen (BUN), plasma insulin, and fatty acid concentration, and body temperature. The CON and LH treatments increased the daily amplitude of fecal NDF by 1.0 and 1.1 percentage units compared with HL. Plasma insulin was higher in HL than CON at 0100 and 0400h, but lower at 1300 and 1900h. Plasma fatty acids were higher for CON than HL at 0700h and HL was lower than LH at 0400 and 1900h. Plasma BUN was higher for HL than control at 0100h, but lower at 1000h. Body temperature in CON and HL treatments followed a similar diurnal pattern, whereas body temperature for LH was lower than that of HL treatment at 1300 and 2300h. No daily rhythm was found of fecal indigestible NDF concentration, plasma glucose, or fatty acids detected in the HL treatment, and the amplitude of plasma insulin and BUN was lower for HL compared with CON (70 and 60% decrease, respectively). In conclusion, feeding 2 rations that differ in fiber and fermentable starch modifies diurnal rhythms in dairy cows. Furthermore, feeding a high fiber and low fermentable starch ration during the high intake period of the day may stabilize nutrient absorption across the day. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

[Concepts of rational taxonomy].

PubMed

Pavlinov, I Ia

2011-01-01

The problems are discussed related to development of concepts of rational taxonomy and rational classifications (taxonomic systems) in biology. Rational taxonomy is based on the assumption that the key characteristic of rationality is deductive inference of certain partial judgments about reality under study from other judgments taken as more general and a priory true. Respectively, two forms of rationality are discriminated--ontological and epistemological ones. The former implies inference of classifications properties from general (essential) properties of the reality being investigated. The latter implies inference of the partial rules of judgments about classifications from more general (formal) rules. The following principal concepts of ontologically rational biological taxonomy are considered: "crystallographic" approach, inference of the orderliness of organismal diversity from general laws of Nature, inference of the above orderliness from the orderliness of ontogenetic development programs, based on the concept of natural kind and Cassirer's series theory, based on the systemic concept, based on the idea of periodic systems. Various concepts of ontologically rational taxonomy can be generalized by an idea of the causal taxonomy, according to which any biologically sound classification is founded on a contentwise model of biological diversity that includes explicit indication of general causes responsible for that diversity. It is asserted that each category of general causation and respective background model may serve as a basis for a particular ontologically rational taxonomy as a distinctive research program. Concepts of epistemologically rational taxonomy and classifications (taxonomic systems) can be interpreted in terms of application of certain epistemological criteria of substantiation of scientific status of taxonomy in general and of taxonomic systems in particular. These concepts include: consideration of taxonomy consistency from the standpoint of inductive and hypothetico-deductive argumentation schemes and such fundamental criteria of classifications naturalness as their prognostic capabilities; foundation of a theory of "general taxonomy" as a "general logic", including elements of the axiomatic method. The latter concept constitutes a core of the program of general classiology; it is inconsistent due to absence of anything like "general logic". It is asserted that elaboration of a theory of taxonomy as a biological discipline based on the formal principles of epistemological rationality is not feasible. Instead, it is to be elaborated as ontologically rational one based on biologically sound metatheories about biological diversity causes.

Recoding aminoacyl-tRNA synthetases for synthetic biology by rational protein-RNA engineering.

PubMed

Hadd, Andrew; Perona, John J

2014-12-19

We have taken a rational approach to redesigning the amino acid binding and aminoacyl-tRNA pairing specificities of bacterial glutaminyl-tRNA synthetase. The four-stage engineering incorporates generalizable design principles and improves the pairing efficiency of noncognate glutamate with tRNA(Gln) by over 10(5)-fold compared to the wild-type enzyme. Better optimized designs of the protein-RNA complex include substantial reengineering of the globular core region of the tRNA, demonstrating a role for specific tRNA nucleotides in specifying the identity of the genetically encoded amino acid. Principles emerging from this engineering effort open new prospects for combining rational and genetic selection approaches to design novel aminoacyl-tRNA synthetases that ligate noncanonical amino acids onto tRNAs. This will facilitate reconstruction of the cellular translation apparatus for applications in synthetic biology.

Peer-based control in self-managing teams: linking rational and normative influence with individual and group performance.

PubMed

Stewart, Greg L; Courtright, Stephen H; Barrick, Murray R

2012-03-01

The authors use a multilevel framework to introduce peer-based control as a motivational state that emerges in self-managing teams. The authors specifically describe how peer-based rational control, which is defined as team members perceiving the distribution of economic rewards as dependent on input from teammates, extends and interacts with the more commonly studied normative control force of group cohesion to explain both individual and collective performance in teams. On the basis of data from 587 factory workers in 45 self-managing teams at 3 organizations, peer-based rational control corresponded with higher performance for both individuals and collective teams. Results further demonstrated that the rational and normative mechanism of peer-based control interacted to explain performance at both the individual and team levels. Increased peer-based rational control corresponded with higher individual and collective performance in teams with low cohesion, but the positive effects on performance were attenuated in cohesive teams.

Effect of feeding sorghum straw based complete rations with different roughage to concentrate ratio on dry matter intake, nutrient utilization, and nitrogen balance in Nellore ram lambs.

PubMed

Malisetty, Venkateswarlu; Yerradoddi, Ramana Reddy; Devanaboina, Nagalakshmi; Mallam, Mahender; Mitta, Pavani

2014-06-01

An experiment was conducted by feeding sorghum straw (Sorghum bicolor) based complete rations at roughage concentrate ratio 70:30 (CR-I), 60:40 (CR-II), 50:50 (CR-III), and 40:60 (CR-IV) for 180 days to find out suitable ratio of sorghum straw in the complete ration (mash form) on nutrient utilization and nitrogen balance in Nellore ram lambs. The DMI (g/day) increased significantly (P < 0.05) as level of concentrate increased in complete rations. No significant difference was found in digestibilities of proximate nutrients. However, CP digestibility was higher either significantly or nonsignificantly by 2.12, 5.50, and 9.36 %, respectively, in lambs fed with CR-II (P > 0.05), CR-III (P > 0.05), and CR-IV (P < 0.05) rations in comparison to lambs fed with CR-I ration. Furthermore, CP digestibility was higher by 7.09 and 3.66 % in lambs fed with CR-IV ration than those fed with CR-II (P < 0.05) and CR-III (P > 0.05) ration. The average CWC digestibility coefficients were comparable among four rations. The N intake (g/day) was significantly (P < 0.01) different and progressively increased by 31.46, 48.69, and 82.86 % in ram lambs fed with CR-II, CR-III, and CR-IV rations, respectively, in comparison to CR-I ration. The N balance (g/day) was higher either significantly or nonsignificantly by 34.46 (P > 0.05), 133.46 (P < 0.01), and 198.87 % (P < 0.01) with CR-II, CR-III, and CR-IV rations, respectively, in comparison to CR-I ration. Based on results, it is inferred that the level of sorghum straw in complete ration had no effect on digestibility of nutrients barring crude protein in Nellore ram lambs.

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

PubMed

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

2015-01-01

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

[Strategies to prevent bacteriophage infection in industrial fermentation].

PubMed

Shen, Juntao; Xiu, Zhilong

2017-12-25

During the development of bacteria-based biotechnology, bacteriophage infection is one of the constant threats and troublesome problems in industrial fermentation. The core of puzzled bacteriophage infection is a complex arm race of coevolution between bacteriophages and their hosts where bacteriophage has evolved lots of escaped ways against bacterial resistance mechanisms. The strategies of rationally designing factories and rotation of starter strains could reduce the risk of bacteriophage infection, but often fail to avoid. Genetic engineering to increase bacterial resistance is one of the strategies to prevent bacteriophage infection and more knowledge about bacteriophage and its host is needed. Recently, there are some new findings on bacterial resistance mechanisms which provide new solutions for bacteriophage infection. For example, it is possible for a rational design of resistant strains to use CRISPR-Cas based technologies just based on the sequences of bacteriophages. Moreover, it is also possible to avoid the escape of bacteriophage by iteratively building up resistance levels to generate robust industrial starter cultures. Quorum-sensing signal molecules have recently been proved to be involved in the interactions between bacteria and bacteriophages, which provides a possible way to solve bacteriophage infection from a population level. Finally, the rapid development of bacteriophage genome editing and synthetic biology will bring some new cues for preventing bacteriophage infection in industrial fermentation.

Treatment of ice cover and other thin elastic layers with the parabolic equation method.

PubMed

Collins, Michael D

2015-03-01

The parabolic equation method is extended to handle problems involving ice cover and other thin elastic layers. Parabolic equation solutions are based on rational approximations that are designed using accuracy constraints to ensure that the propagating modes are handled properly and stability constrains to ensure that the non-propagating modes are annihilated. The non-propagating modes are especially problematic for problems involving thin elastic layers. It is demonstrated that stable results may be obtained for such problems by using rotated rational approximations [Milinazzo, Zala, and Brooke, J. Acoust. Soc. Am. 101, 760-766 (1997)] and generalizations of these approximations. The approach is applied to problems involving ice cover with variable thickness and sediment layers that taper to zero thickness.

Rational assembly of nanoparticle superlattices with designed lattice symmetries

DOEpatents

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.

Rational Emotive Theory Applied to Groups

ERIC Educational Resources Information Center

Jacobs, Edward; Croake, James W.

1976-01-01

University students participated in five weeks of education/discussion based on rational emotive theory. The results indicated increased rational thinking, decreased anxiety, and fewer reported problems. (Author)

A decade of vaccines: Integrating immunology and vaccinology for rational vaccine design.

PubMed

D'Argenio, David A; Wilson, Christopher B

2010-10-29

Vaccination stands as one of the most successful public health measures of the last century. New approaches will be needed, however, to develop highly effective vaccines to prevent tuberculosis, HIV-AIDS, and malaria and to eradicate polio. Current advances in immunology and technology have set the stage for rational vaccine design to begin a "Decade of Vaccines." Copyright © 2010 Elsevier Inc. All rights reserved.

Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.

PubMed

Rahm, Fredrik; Viklund, Jenny; Trésaugues, Lionel; Ellermann, Manuel; Giese, Anja; Ericsson, Ulrika; Forsblom, Rickard; Ginman, Tobias; Günther, Judith; Hallberg, Kenth; Lindström, Johan; Persson, Lars Boukharta; Silvander, Camilla; Talagas, Antoine; Díaz-Sáez, Laura; Fedorov, Oleg; Huber, Kilian V M; Panagakou, Ioanna; Siejka, Paulina; Gorjánácz, Mátyás; Bauser, Marcus; Andersson, Martin

2018-03-22

Recent literature has both suggested and questioned MTH1 as a novel cancer target. BAY-707 was just published as a target validation small molecule probe for assessing the effects of pharmacological inhibition of MTH1 on tumor cell survival, both in vitro and in vivo. (1) In this report, we describe the medicinal chemistry program creating BAY-707, where fragment-based methods were used to develop a series of highly potent and selective MTH1 inhibitors. Using structure-based drug design and rational medicinal chemistry approaches, the potency was increased over 10,000 times from the fragment starting point while maintaining high ligand efficiency and drug-like properties.

Rational design of aerobic digestion systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rich, L.G.

1987-06-01

Deficiencies are identified in state-of-the-art procedures used in the design of systems for the aerobic digestion of waste-activated sludge solids. A procedure for the design of such systems on a rational basis is presented. Such a procedure not only includes a well-defined stabilization objective, but takes into account the stabilization that occurs in the activated sludge process. Related methods are discussed by which coefficients used in the design procedure can be evaluated. A design example is given. Further research and performance data derived from systems designed by the procedure are needed to better evaluate the parameters used and to testmore » the assumptions made in applying the procedure.« less

Rational design of aerobic digestion systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rich, L.G.

1987-06-01

Deficiencies are identified in state-of-the-art procedures used in the design of systems for the aerobic digestion of waste-activated sludge solids. A procedure for the design of such systems on a rational basis is presented. Such a procedure not only includes a well-defined stabilization objective, but takes into account the stabilization that occurs in the activated sludge process. Related methods are discussed by which coefficients used in the design procedure can be evaluated. A design example is given. Further research and performance data derived from systems designed by the procedure are needed to better evaluate the parameters used and to testmore » the assumptions made in applying the procedure. (Refs. 28).« less

Rational chemical design of the next generation of molecular imaging probes based on physics and biology: mixing modalities, colors and signals

PubMed Central

Longmire, Michelle R.; Ogawa, Mikako; Choyke, Peter L.

2012-01-01

In recent years, numerous in vivo molecular imaging probes have been developed. As a consequence, much has been published on the design and synthesis of molecular imaging probes focusing on each modality, each type of material, or each target disease. More recently, second generation molecular imaging probes with unique, multi-functional, or multiplexed characteristics have been designed. This critical review focuses on (i) molecular imaging using combinations of modalities and signals that employ the full range of the electromagnetic spectra, (ii) optimized chemical design of molecular imaging probes for in vivo kinetics based on biology and physiology across a range of physical sizes, (iii) practical examples of second generation molecular imaging probes designed to extract complementary data from targets using multiple modalities, color, and comprehensive signals (277 references). PMID:21607237

T Cell Determinants Incorporating [beta]-Amino Acid Residues Are Protease Resistant and Remain Immunogenic In Vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Webb, Andrew I.; Dunstone, Michelle A.; Williamson, Nicholas A.

2010-07-20

A major hurdle in designing successful epitope-based vaccines resides in the delivery, stability, and immunogenicity of the peptide immunogen. The short-lived nature of unmodified peptide-based vaccines in vivo limits their therapeutic application in the immunotherapy of cancers and chronic viral infections as well as their use in generating prophylactic immunity. The incorporation of {beta}-amino acids into peptides decreases proteolysis, yet its potential application in the rational design of T cell mimotopes is poorly understood. To address this, we have replaced each residue of the SIINFEKL epitope individually with the corresponding {beta}-amino acid and examined the resultant efficacy of these mimotopes.more » Some analogs displayed similar MHC binding and superior protease stability compared with the native epitope. Importantly, these analogs were able to generate cross-reactive CTLs in vivo that were capable of lysing tumor cells that expressed the unmodified epitope as a surrogate tumor Ag. Structural analysis of peptides in which anchor residues were substituted with {beta}-amino acids revealed the basis for enhanced MHC binding and retention of immunogenicity observed for these analogs and paves the way for future vaccine design using {beta}-amino acids. We conclude that the rational incorporation of {beta}-amino acids into T cell determinants is a powerful alternative to the traditional homologous substitution of randomly chosen naturally occurring {alpha}-amino acids, and these mimotopes may prove particularly useful for inclusion in epitope-based vaccines.« less

Distance Education Assessment Infrastructure and Process Design Based on International Standard 23988

ERIC Educational Resources Information Center

Shaffer, Steven C.

2012-01-01

Assessment is an important part of distance education (DE). As class sizes get larger and workloads increase, the IT infrastructure and processes used for DE assessments become more of an issue. Using the BS ISO/IEC 23988:2007 Standard for the use of technology in the delivery of assessments as a guide, this paper describes a rational approach to…

A Resource Guide for an Exploratory Curriculum for Three-Year Old Migrant Children.

ERIC Educational Resources Information Center

Hoffman, Stevie; Mottola, Niel

The rational for the curriculum design for three-year-old migrant children in an expanded-day educational program is presented. Consideration is given for each of the program phases, the learning environment, the rationale for a pre-service workshop and on-going in-service consultancy. This curriculum is based on the premise that, because of the…

Rational design of a pH-insensitive cyan fluorescent protein CyPet2 based on the CyPet crystal structure.

PubMed

Liu, Rui; Hu, Xiao-Jian; Ding, Yu

2017-06-01

The emission spectrum of widely used CyPet is pH-sensitive. In order to synthesize a pH-insensitive cyan fluorescent protein by rational design, we solved the crystal structures of CyPet under different pH conditions. The indole group of the CyPet chromophore adopts a cis-coplanar conformation in acidic and neutral conditions, while it converts to trans-coplanar under basic conditions. His148 and Glu222 play a vital role in this isomerization. The pH-sensitive chromophore isomerization and change in the emission spectrum can be explained by the coexistence of several different fluorescent states. We trap the chromophore in the trans conformation by A167I mutation (CyPet2), which also prevents the multiconformation of the seventh β-strand. CyPet2 exhibits an unchanged emission spectral shape as a function of pH. © 2017 Federation of European Biochemical Societies.

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

PubMed Central

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

2014-01-01

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

High-Performance Long-Term-Stable Dopant-Free Perovskite Solar Cells and Additive-Free Organic Solar Cells by Employing Newly Designed Multirole π-Conjugated Polymers.

PubMed

Kranthiraja, Kakaraparthi; Gunasekar, Kumarasamy; Kim, Hyunji; Cho, An-Na; Park, Nam-Gyu; Kim, Seonha; Kim, Bumjoon J; Nishikubo, Ryosuke; Saeki, Akinori; Song, Myungkwan; Jin, Sung-Ho

2017-06-01

Perovskite solar cells (PSCs) and organic solar cells (OSCs) are promising renewable light-harvesting technologies with high performance, but the utilization of hazardous dopants and high boiling additives is harmful to all forms of life and the environment. Herein, new multirole π-conjugated polymers (P1-P3) are developed via a rational design approach through theoretical hindsight, further successfully subjecting them into dopant-free PSCs as hole-transporting materials and additive-free OSCs as photoactive donors, respectively. Especially, P3-based PSCs and OSCs not only show high power conversion efficiencies of 17.28% and 8.26%, but also display an excellent ambient stability up to 30 d (for PSCs only), owing to their inherent superior optoelectronic properties in their pristine form. Overall, the rational approach promises to support the development of environmentally and economically sustainable PSCs and OSCs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Controlling resistant bacteria with a novel class of β-lactamase inhibitor peptides: from rational design to in vivo analyses

PubMed Central

Mandal, Santi M.; Migliolo, Ludovico; Silva, Osmar N.; Fensterseifer, Isabel C. M.; Faria-Junior, Celio; Dias, Simoni C.; Basak, Amit; Hazra, Tapas K.; Franco, Octávio L.

2014-01-01

Peptide rational design was used here to guide the creation of two novel short β-lactamase inhibitors, here named dBLIP-1 and -2, with length of five amino acid residues. Molecular modeling associated with peptide synthesis improved bactericidal efficacy in addition to amoxicillin, ampicillin and cefotaxime. Docked structures were consistent with calorimetric analyses against bacterial β-lactamases. These two compounds were further tested in mice. Whereas commercial antibiotics alone failed to cure mice infected with Staphylococcus aureus and Escherichia coli expressing β-lactamases, infection was cleared when treated with antibiotics in combination with dBLIPs, clearly suggesting that peptides were able to neutralize bacterial resistance. Moreover, immunological assays were also performed showing that dBLIPs were unable to modify mammalian immune response in both models, reducing the risks of collateral effects. In summary, the unusual peptides here described provide leads to overcome β-lactamase-based resistance, a remarkable clinical challenge. PMID:25109311

Rational design of novel TLR4 ligands by in silico screening and their functional and structural characterization in vitro.

PubMed

Honegr, Jan; Malinak, David; Dolezal, Rafael; Soukup, Ondrej; Benkova, Marketa; Hroch, Lukas; Benek, Ondrej; Janockova, Jana; Kuca, Kamil; Prymula, Roman

2018-02-25

The purpose of this study was to identify new small molecules that possess activity on human toll-like receptor 4 associated with the myeloid differentiation protein 2 (hTLR4/MD2). Following current rational drug design principles, we firstly performed a ligand and structure based virtual screening of more than 130 000 compounds to discover until now unknown class of hTLR4/MD2 modulators that could be used as novel type of immunologic adjuvants. The core of the in silico study was molecular docking of flexible ligands in a partially flexible hTLR4/MD2 receptor model using a peta-flops-scale supercomputer. The most promising substances resulting from this study, related to anthracene-succimide hybrids, were synthesized and tested. The best prepared candidate exhibited 80% of Monophosphoryl Lipid A in vitro agonistic activity in cell lines expressing hTLR4/MD2. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Rational design of a monomeric and photostable far-red fluorescent protein for fluorescence imaging in vivo.

PubMed

Yu, Dan; Dong, Zhiqiang; Gustafson, William Clay; Ruiz-González, Rubén; Signor, Luca; Marzocca, Fanny; Borel, Franck; Klassen, Matthew P; Makhijani, Kalpana; Royant, Antoine; Jan, Yuh-Nung; Weiss, William A; Guo, Su; Shu, Xiaokun

2016-02-01

Fluorescent proteins (FPs) are powerful tools for cell and molecular biology. Here based on structural analysis, a blue-shifted mutant of a recently engineered monomeric infrared fluorescent protein (mIFP) has been rationally designed. This variant, named iBlueberry, bears a single mutation that shifts both excitation and emission spectra by approximately 40 nm. Furthermore, iBlueberry is four times more photostable than mIFP, rendering it more advantageous for imaging protein dynamics. By tagging iBlueberry to centrin, it has been demonstrated that the fusion protein labels the centrosome in the developing zebrafish embryo. Together with GFP-labeled nucleus and tdTomato-labeled plasma membrane, time-lapse imaging to visualize the dynamics of centrosomes in radial glia neural progenitors in the intact zebrafish brain has been demonstrated. It is further shown that iBlueberry can be used together with mIFP in two-color protein labeling in living cells and in two-color tumor labeling in mice. © 2015 The Protein Society.

Strongly hyperpolarized gas from parahydrogen by rational design of ligand-capped nanoparticles

PubMed Central

Sharma, Ramesh; Bouchard, Louis-S

2012-01-01

The production of hyperpolarized fluids in continuous mode would broaden substantially the range of applications in chemistry, materials science, and biomedicine. Here we show that the rational design of a heterogeneous catalyst based on a judicious choice of metal type, nanoparticle size and surface decoration with appropriate ligands leads to highly efficient pairwise addition of dihydrogen across an unsaturated bond. This is demonstrated in a parahydrogen-induced polarization (PHIP) experiment by a 508-fold enhancement (±78) of a CH3 proton signal and a corresponding 1219-fold enhancement (±187) of a CH2 proton signal using nuclear magnetic resonance (1H-NMR). In contrast, bulk metal catalyst does not show this effect due to randomization of reacting dihydrogen. Our approach results in the largest gas-phase NMR signal enhancement by PHIP known to date. Sensitivity-enhanced NMR with this technique could be used to image microfluidic reactions in-situ, to probe nonequilibrium thermodynamics or for the study of metabolic reactions. PMID:22355789

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

NASA Astrophysics Data System (ADS)

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

2015-07-01

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

Priority setting in healthcare: towards guidelines for the program budgeting and marginal analysis framework.

PubMed

Peacock, Stuart J; Mitton, Craig; Ruta, Danny; Donaldson, Cam; Bate, Angela; Hedden, Lindsay

2010-10-01

Economists' approaches to priority setting focus on the principles of opportunity cost, marginal analysis and choice under scarcity. These approaches are based on the premise that it is possible to design a rational priority setting system that will produce legitimate changes in resource allocation. However, beyond issuing guidance at the national level, economic approaches to priority setting have had only a moderate impact in practice. In particular, local health service organizations - such as health authorities, health maintenance organizations, hospitals and healthcare trusts - have had difficulty implementing evidence from economic appraisals. Yet, in the context of making decisions between competing claims on scarce health service resources, economic tools and thinking have much to offer. The purpose of this article is to describe and discuss ten evidence-based guidelines for the successful design and implementation of a program budgeting and marginal analysis (PBMA) priority setting exercise. PBMA is a framework that explicitly recognizes the need to balance pragmatic and ethical considerations with economic rationality when making resource allocation decisions. While the ten guidelines are drawn from the PBMA framework, they may be generalized across a range of economic approaches to priority setting.

Comparing Proteolytic Fingerprints of Antigen-Presenting Cells during Allergen Processing.

PubMed

Hofer, Heidi; Weidinger, Tamara; Briza, Peter; Asam, Claudia; Wolf, Martin; Twaroch, Teresa E; Stolz, Frank; Neubauer, Angela; Dall, Elfriede; Hammerl, Peter; Jacquet, Alain; Wallner, Michael

2017-06-08

Endolysosomal processing has a critical influence on immunogenicity as well as immune polarization of protein antigens. In industrialized countries, allergies affect around 25% of the population. For the rational design of protein-based allergy therapeutics for immunotherapy, a good knowledge of T cell-reactive regions on allergens is required. Thus, we sought to analyze endolysosomal degradation patterns of inhalant allergens. Four major allergens from ragweed, birch, as well as house dust mites were produced as recombinant proteins. Endolysosomal proteases were purified by differential centrifugation from dendritic cells, macrophages, and B cells, and combined with allergens for proteolytic processing. Thereafter, endolysosomal proteolysis was monitored by protein gel electrophoresis and mass spectrometry. We found that the overall proteolytic activity of specific endolysosomal fractions differed substantially, whereas the degradation patterns of the four model allergens obtained with the different proteases were extremely similar. Moreover, previously identified T cell epitopes were assigned to endolysosomal peptides and indeed showed a good overlap with known T cell epitopes for all four candidate allergens. Thus, we propose that the degradome assay can be used as a predictor to determine antigenic peptides as potential T cell epitopes, which will help in the rational design of protein-based allergy vaccine candidates.

Comparing Proteolytic Fingerprints of Antigen-Presenting Cells during Allergen Processing

PubMed Central

Hofer, Heidi; Weidinger, Tamara; Briza, Peter; Asam, Claudia; Wolf, Martin; Twaroch, Teresa E.; Stolz, Frank; Neubauer, Angela; Dall, Elfriede; Hammerl, Peter; Jacquet, Alain; Wallner, Michael

2017-01-01

Endolysosomal processing has a critical influence on immunogenicity as well as immune polarization of protein antigens. In industrialized countries, allergies affect around 25% of the population. For the rational design of protein-based allergy therapeutics for immunotherapy, a good knowledge of T cell-reactive regions on allergens is required. Thus, we sought to analyze endolysosomal degradation patterns of inhalant allergens. Four major allergens from ragweed, birch, as well as house dust mites were produced as recombinant proteins. Endolysosomal proteases were purified by differential centrifugation from dendritic cells, macrophages, and B cells, and combined with allergens for proteolytic processing. Thereafter, endolysosomal proteolysis was monitored by protein gel electrophoresis and mass spectrometry. We found that the overall proteolytic activity of specific endolysosomal fractions differed substantially, whereas the degradation patterns of the four model allergens obtained with the different proteases were extremely similar. Moreover, previously identified T cell epitopes were assigned to endolysosomal peptides and indeed showed a good overlap with known T cell epitopes for all four candidate allergens. Thus, we propose that the degradome assay can be used as a predictor to determine antigenic peptides as potential T cell epitopes, which will help in the rational design of protein-based allergy vaccine candidates. PMID:28594355

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

PubMed Central

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

Rational Design of ZnO:H/ZnO Bilayer Structure for High-Performance Thin-Film Transistors.

PubMed

Abliz, Ablat; Huang, Chun-Wei; Wang, Jingli; Xu, Lei; Liao, Lei; Xiao, Xiangheng; Wu, Wen-Wei; Fan, Zhiyong; Jiang, Changzhong; Li, Jinchai; Guo, Shishang; Liu, Chuansheng; Guo, Tailiang

2016-03-01

The intriguing properties of zinc oxide-based semiconductors are being extensively studied as they are attractive alternatives to current silicon-based semiconductors for applications in transparent and flexible electronics. Although they have promising properties, significant improvements on performance and electrical reliability of ZnO-based thin film transistors (TFTs) should be achieved before they can be applied widely in practical applications. This work demonstrates a rational and elegant design of TFT, composed of poly crystalline ZnO:H/ZnO bilayer structure without using other metal elements for doping. The field-effect mobility and gate bias stability of the bilayer structured devices have been improved. In this device structure, the hydrogenated ultrathin ZnO:H active layer (∼3 nm) could provide suitable carrier concentration and decrease the interface trap density, while thick pure-ZnO layer could control channel conductance. Based on this novel structure, a high field-effect mobility of 42.6 cm(2) V(-1) s(-1), a high on/off current ratio of 10(8) and a small subthreshold swing of 0.13 V dec(-1) have been achieved. Additionally, the bias stress stability of the bilayer structured devices is enhanced compared to the simple single channel layer ZnO device. These results suggest that the bilayer ZnO:H/ZnO TFTs have a great potential for low-cost thin-film electronics.

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

NASA Astrophysics Data System (ADS)

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

2016-06-01

The separation of metallic (m-) and semiconducting (s-) single-walled carbon nanotubes (SWNTs) without causing contamination and damage is a major challenge for SWNT-based devices. As a facile and nondestructive tool, the use of a magnetic field could be an ideal strategy to separate m-/s-SWNTs, based on the difference of magnetic susceptibilities. Here, we designed a novel magnetic field-assisted floating catalyst chemical vapor deposition system to separate m-/s-SWNTs. Briefly, m-SWNTs are attracted toward the magnetic pole, leaving s-SWNTs on the substrate. By using this strategy, s-SWNTs with a purity of 99% could be obtained, which is enough to construct high-performance transistors with a mobility of 230 cm2 V-1 s-1 and an on/off ratio of 106. We also established a model to quantitatively calculate the percentage of m-SWNTs on the substrate and this model shows a good match with the experimental data. Furthermore, our rational design also provides a new avenue for the growth of SWNTs with specific chirality and manipulated arrangement due to the difference of magnetic susceptibilities between different diameters, chiralities, and types.The separation of metallic (m-) and semiconducting (s-) single-walled carbon nanotubes (SWNTs) without causing contamination and damage is a major challenge for SWNT-based devices. As a facile and nondestructive tool, the use of a magnetic field could be an ideal strategy to separate m-/s-SWNTs, based on the difference of magnetic susceptibilities. Here, we designed a novel magnetic field-assisted floating catalyst chemical vapor deposition system to separate m-/s-SWNTs. Briefly, m-SWNTs are attracted toward the magnetic pole, leaving s-SWNTs on the substrate. By using this strategy, s-SWNTs with a purity of 99% could be obtained, which is enough to construct high-performance transistors with a mobility of 230 cm2 V-1 s-1 and an on/off ratio of 106. We also established a model to quantitatively calculate the percentage of m-SWNTs on the substrate and this model shows a good match with the experimental data. Furthermore, our rational design also provides a new avenue for the growth of SWNTs with specific chirality and manipulated arrangement due to the difference of magnetic susceptibilities between different diameters, chiralities, and types. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr03928f

Randomness in the network inhibits cooperation based on the bounded rational collective altruistic decision

NASA Astrophysics Data System (ADS)

Ohdaira, Tetsushi

2014-07-01

Previous studies discussing cooperation employ the best decision that every player knows all information regarding the payoff matrix and selects the strategy of the highest payoff. Therefore, they do not discuss cooperation based on the altruistic decision with limited information (bounded rational altruistic decision). In addition, they do not cover the case where every player can submit his/her strategy several times in a match of the game. This paper is based on Ohdaira's reconsideration of the bounded rational altruistic decision, and also employs the framework of the prisoner's dilemma game (PDG) with sequential strategy. The distinction between this study and the Ohdaira's reconsideration is that the former covers the model of multiple groups, but the latter deals with the model of only two groups. Ohdaira's reconsideration shows that the bounded rational altruistic decision facilitates much more cooperation in the PDG with sequential strategy than Ohdaira and Terano's bounded rational second-best decision does. However, the detail of cooperation of multiple groups based on the bounded rational altruistic decision has not been resolved yet. This study, therefore, shows how randomness in the network composed of multiple groups affects the increase of the average frequency of mutual cooperation (cooperation between groups) based on the bounded rational altruistic decision of multiple groups. We also discuss the results of the model in comparison with related studies which employ the best decision.

Monotonicity preserving splines using rational cubic Timmer interpolation

NASA Astrophysics Data System (ADS)

Zakaria, Wan Zafira Ezza Wan; Alimin, Nur Safiyah; Ali, Jamaludin Md

2017-08-01

In scientific application and Computer Aided Design (CAD), users usually need to generate a spline passing through a given set of data, which preserves certain shape properties of the data such as positivity, monotonicity or convexity. The required curve has to be a smooth shape-preserving interpolant. In this paper a rational cubic spline in Timmer representation is developed to generate interpolant that preserves monotonicity with visually pleasing curve. To control the shape of the interpolant three parameters are introduced. The shape parameters in the description of the rational cubic interpolant are subjected to monotonicity constrained. The necessary and sufficient conditions of the rational cubic interpolant are derived and visually the proposed rational cubic Timmer interpolant gives very pleasing results.

Elucidating Solvation Structures for Rational Design of Multivalent Electrolytes-A Review.

PubMed

Rajput, Nav Nidhi; Seguin, Trevor J; Wood, Brandon M; Qu, Xiaohui; Persson, Kristin A

2018-04-26

Fundamental molecular-level understanding of functional properties of liquid solutions provides an important basis for designing optimized electrolytes for numerous applications. In particular, exhaustive knowledge of solvation structure, stability, and transport properties is critical for developing stable electrolytes for fast-charging and high-energy-density next-generation energy storage systems. Accordingly, there is growing interest in the rational design of electrolytes for beyond lithium-ion systems by tuning the molecular-level interactions of solvate species present in the electrolytes. Here we present a review of the solvation structure of multivalent electrolytes and its impact on the electrochemical performance of these batteries. A direct correlation between solvate species present in the solution and macroscopic properties of electrolytes is sparse for multivalent electrolytes and contradictory results have been reported in the literature. This review aims to illustrate the current understanding, compare results, and highlight future needs and directions to enable the deep understanding needed for the rational design of improved multivalent electrolytes.

Computational design optimization for microfluidic magnetophoresis

PubMed Central

Plouffe, Brian D.; Lewis, Laura H.; Murthy, Shashi K.

2011-01-01

Current macro- and microfluidic approaches for the isolation of mammalian cells are limited in both efficiency and purity. In order to design a robust platform for the enumeration of a target cell population, high collection efficiencies are required. Additionally, the ability to isolate pure populations with minimal biological perturbation and efficient off-chip recovery will enable subcellular analyses of these cells for applications in personalized medicine. Here, a rational design approach for a simple and efficient device that isolates target cell populations via magnetic tagging is presented. In this work, two magnetophoretic microfluidic device designs are described, with optimized dimensions and operating conditions determined from a force balance equation that considers two dominant and opposing driving forces exerted on a magnetic-particle-tagged cell, namely, magnetic and viscous drag. Quantitative design criteria for an electromagnetic field displacement-based approach are presented, wherein target cells labeled with commercial magnetic microparticles flowing in a central sample stream are shifted laterally into a collection stream. Furthermore, the final device design is constrained to fit on standard rectangular glass coverslip (60 (L)×24 (W)×0.15 (H) mm3) to accommodate small sample volume and point-of-care design considerations. The anticipated performance of the device is examined via a parametric analysis of several key variables within the model. It is observed that minimal currents (<500 mA) are required to generate magnetic fields sufficient to separate cells from the sample streams flowing at rate as high as 7 ml∕h, comparable to the performance of current state-of-the-art magnet-activated cell sorting systems currently used in clinical settings. Experimental validation of the presented model illustrates that a device designed according to the derived rational optimization can effectively isolate (∼100%) a magnetic-particle-tagged cell population from a homogeneous suspension even in a low abundance. Overall, this design analysis provides a rational basis to select the operating conditions, including chamber and wire geometry, flow rates, and applied currents, for a magnetic-microfluidic cell separation device. PMID:21526007

Target-cancer cell specific activatable fluorescence imaging Probes: Rational Design and in vivo Applications

PubMed Central

Kobayashi, Hisataka; Choyke, Peter L.

2010-01-01

CONSPECTUS Conventional imaging methods, such as angiography, computed tomography, magnetic resonance imaging and radionuclide imaging, rely on contrast agents (iodine, gadolinium, radioisotopes) that are “always on”. While these agents have proven clinically useful, they are not sufficiently sensitive because of the inadequate target to background ratio. A unique aspect of optical imaging is that fluorescence probes can be designed to be activatable, i.e. only “turned on” under certain conditions. These probes can be designed to emit signal only after binding a target tissue, greatly increasing sensitivity and specificity in the detection of disease. There are two basic types of activatable fluorescence probes; 1) conventional enzymatically activatable probes, which exist in the quenched state until activated by enzymatic cleavage mostly outside of the cells, and 2) newly designed target-cell specific activatable probes, which are quenched until activated in targeted cells by endolysosomal processing that results when the probe binds specific cell-surface receptors and is subsequently internalized. Herein, we present a review of the rational design and in vivo applications of target-cell specific activatable probes. Designing these probes based on their photo-chemical (e.g. activation strategy), pharmacological (e.g. biodistribution), and biological (e.g. target specificity) properties has recently allowed the rational design and synthesis of target-cell specific activatable fluorescence imaging probes, which can be conjugated to a wide variety of targeting molecules. Several different photo-chemical mechanisms have been utilized, each of which offers a unique capability for probe design. These include: self-quenching, homo- and hetero-fluorescence resonance energy transfer (FRET), H-dimer formation and photon-induced electron transfer (PeT). In addition, the repertoire is further expanded by the option for reversibility or irreversibility of the signal emitted using the aforementioned mechanisms. Given the wide range of photochemical mechanisms and properties, target-cell specific activatable probes possess considerable flexibility and can be adapted to specific diagnostic needs. Herein, we summarize the chemical, pharmacological, and biological basis of target-cell specific activatable imaging probes and discuss methods to successfully design such target-cell specific activatable probes for in vivo cancer imaging. PMID:21062101

Molecular switches in carbon-rich organometallic compounds: Theoretical aspects

NASA Astrophysics Data System (ADS)

Costuas, Karine

2015-01-01

Organometallic complexes associated with an appropriate choice of ancillary ligands reveal to have a wide range of physical properties leading to promising applications when incorporated in nano-size devices. The challenge is to design innovative multifunctional compounds based on redox active carbon-rich organometallics associated with spin carriers and/or photochromic units. A multidisciplinary approach in this area has proved to be efficient in a series a systems combining carbon-rich bridging ligands and redox metallic moieties. In this domain, the role of theoretical investigations based on quantum mechanics tools have a crucial role in rationalizing and in helping designing systems possessing target properties.

Design of monodisperse and well-defined polypeptide-based polyvalent inhibitors of anthrax toxin.

PubMed

Patke, Sanket; Boggara, Mohan; Maheshwari, Ronak; Srivastava, Sunit K; Arha, Manish; Douaisi, Marc; Martin, Jacob T; Harvey, Ian B; Brier, Matthew; Rosen, Tania; Mogridge, Jeremy; Kane, Ravi S

2014-07-28

The design of polyvalent molecules, presenting multiple copies of a specific ligand, represents a promising strategy to inhibit pathogens and toxins. The ability to control independently the valency and the spacing between ligands would be valuable for elucidating structure-activity relationships and for designing potent polyvalent molecules. To that end, we designed monodisperse polypeptide-based polyvalent inhibitors of anthrax toxin in which multiple copies of an inhibitory toxin-binding peptide were separated by flexible peptide linkers. By tuning the valency and linker length, we designed polyvalent inhibitors that were over four orders of magnitude more potent than the corresponding monovalent ligands. This strategy for the rational design of monodisperse polyvalent molecules may not only be broadly applicable for the inhibition of toxins and pathogens, but also for controlling the nanoscale organization of cellular receptors to regulate signaling and the fate of stem cells. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Book Selection, Collection Development, and Bounded Rationality.

ERIC Educational Resources Information Center

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)…

Adding liquid feed to a total mixed ration reduces feed sorting behavior and improves productivity of lactating dairy cows.

PubMed

DeVries, T J; Gill, R M

2012-05-01

This study was designed to determine the effect of adding a molasses-based liquid feed (LF) supplement to a total mixed ration (TMR) on the feed sorting behavior and production of dairy cows. Twelve lactating Holstein cows (88.2±19.5 DIM) were exposed, in a crossover design with 21-d periods, to each of 2 treatment diets: 1) control TMR and 2) control TMR with 4.1% dietary dry matter LF added. Dry matter intake (DMI), sorting, and milk yield were recorded for the last 7 d of each treatment period. Milk samples were collected for composition analysis for the last 3 d of each treatment period; these data were used to calculate 4% fat-corrected milk and energy-corrected milk yield. Sorting was determined by subjecting fresh feed and orts samples to particle separation and expressing the actual intake of each particle fraction as a percentage of the predicted intake of that fraction. Addition of LF did not noticeably change the nutrient composition of the ration, with the exception of an expected increase in dietary sugar concentration (from 4.0 to 5.4%). Liquid feed supplementation affected the particle size distribution of the ration, resulting in a lesser amount of short and a greater amount of fine particles. Cows sorted against the longest ration particles on both treatment diets; the extent of this sorting was greater on the control diet (55.0 vs. 68.8%). Dry matter intake was 1.4 kg/d higher when cows were fed the LF diet as compared with the control diet, resulting in higher acid-detergent fiber, neutral-detergent fiber, and sugar intakes. As a result of the increased DMI, cows tended to produce 1.9 kg/d more milk and produced 3.1 and 3.2 kg/d more 4% fat-corrected milk and energy-corrected milk, respectively, on the LF diet. As a result, cows tended to produce more milk fat (0.13 kg/d) and produced more milk protein (0.09 kg/d) on the LF diet. No difference between treatments was observed in the efficiency of milk production. Overall, adding a molasses-based LF to TMR can be used to decrease feed sorting, enhance DMI, and improve milk yield. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Geology and Design: Formal and Rational Connections

NASA Astrophysics Data System (ADS)

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.

Easy design of colorimetric logic gates based on nonnatural base pairing and controlled assembly of gold nanoparticles.

PubMed

Zhang, Li; Wang, Zhong-Xia; Liang, Ru-Ping; Qiu, Jian-Ding

2013-07-16

Utilizing the principles of metal-ion-mediated base pairs (C-Ag-C and T-Hg-T), the pH-sensitive conformational transition of C-rich DNA strand, and the ligand-exchange process triggered by DL-dithiothreitol (DTT), a system of colorimetric logic gates (YES, AND, INHIBIT, and XOR) can be rationally constructed based on the aggregation of the DNA-modified Au NPs. The proposed logic operation system is simple, which consists of only T-/C-rich DNA-modified Au NPs, and it is unnecessary to exquisitely design and alter the DNA sequence for different multiple molecular logic operations. The nonnatural base pairing combined with unique optical properties of Au NPs promises great potential in multiplexed ion sensing, molecular-scale computers, and other computational logic devices.

Dual kinase-bromodomain inhibitors for rationally designed polypharmacology

PubMed Central

Ciceri, Pietro; Müller, Susanne; O’Mahony, Alison; Fedorov, Oleg; Filippakopoulos, Panagis; Hunt, Jeremy P.; Lasater, Elisabeth A.; Pallares, Gabriel; Picaud, Sarah; Wells, Christopher; Martin, Sarah; Wodicka, Lisa M.; Shah, Neil P.; Treiber, Daniel K.; Knapp, Stefan

2014-01-01

Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multi-target profile has, however, necessitated the application of combination therapies, which can pose significant clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as novel targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase/bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, clinical PLK1 and JAK2/FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a novel strategy for rational single agent polypharmacological targeting. Furthermore, structure-activity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase/bromodomain inhibitors. PMID:24584101

TRO-2D - A code for rational transonic aerodynamic optimization

NASA Technical Reports Server (NTRS)

Davis, W. H., Jr.

1985-01-01

Features and sample applications of the transonic rational optimization (TRO-2D) code are outlined. TRO-2D includes the airfoil analysis code FLO-36, the CONMIN optimization code and a rational approach to defining aero-function shapes for geometry modification. The program is part of an effort to develop an aerodynamically smart optimizer that will simplify and shorten the design process. The user has a selection of drag minimization and associated minimum lift, moment, and the pressure distribution, a choice among 14 resident aero-function shapes, and options on aerodynamic and geometric constraints. Design variables such as the angle of attack, leading edge radius and camber, shock strength and movement, supersonic pressure plateau control, etc., are discussed. The results of calculations of a reduced leading edge camber transonic airfoil and an airfoil with a natural laminar flow are provided, showing that only four design variables need be specified to obtain satisfactory results.

Rationally reduced libraries for combinatorial pathway optimization minimizing experimental effort.

PubMed

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.

Effects of predation stress and food ration on perch gut microbiota.

PubMed

Zha, Yinghua; Eiler, Alexander; Johansson, Frank; Svanbäck, Richard

2018-02-06

Gut microbiota provide functions of importance to influence hosts' food digestion, metabolism, and protection against pathogens. Factors that affect the composition and functions of gut microbial communities are well studied in humans and other animals; however, we have limited knowledge of how natural food web factors such as stress from predators and food resource rations could affect hosts' gut microbiota and how it interacts with host sex. In this study, we designed a two-factorial experiment exposing perch (Perca fluviatilis) to a predator (pike, Esox lucius), and different food ratios, to examine the compositional and functional changes of perch gut microbiota based on 16S rRNA amplicon sequencing. We also investigated if those changes are host sex dependent. We showed that overall gut microbiota composition among individual perch significantly responded to food ration and predator presence. We found that species richness decreased with predator presence, and we identified 23 taxa from a diverse set of phyla that were over-represented when a predator was present. For example, Fusobacteria increased both at the lowest food ration and at predation stress conditions, suggesting that Fusobacteria are favored by stressful situations for the host. In concordance, both food ration and predation stress seemed to influence the metabolic repertoire of the gut microbiota, such as biosynthesis of other secondary metabolites, metabolism of cofactors, and vitamins. In addition, the identified interaction between food ration and sex emphasizes sex-specific responses to diet quantity in gut microbiota. Collectively, our findings emphasize an alternative state in gut microbiota with responses to changes in natural food webs depending on host sex. The obtained knowledge from this study provided us with an important perspective on gut microbiota in a food web context.

Caught between intending and doing: older people ideating on a self-chosen death

PubMed Central

van Wijngaarden, Els; Leget, Carlo; Goossensen, Anne

2016-01-01

Objectives The aim of this paper is to provide insight into what it means to live with the intention to end life at a self-chosen moment from an insider perspective. Setting Participants who lived independent or semidependent throughout the Netherlands. Participants 25 Dutch older citizens (mean age of 82 years) participated. They were ideating on a self-chosen death because they considered their lives to be no longer worth living. Inclusion criteria were that they: (1) considered their lives to be ‘completed’; (2) suffered from the prospect of living on; (3) currently wished to die; (4) were 70 years of age or older; (5) were not terminally ill; (6) considered themselves to be mentally competent; (7) considered their death wish reasonable. Design In this qualitative study, in-depth interviews were carried out in the participants’ everyday home environment (median lasting 1.56 h). Verbatim transcripts were analysed based on the principles of phenomenological thematic analysis. Results The liminality or ‘in-betweenness’ of intending and actually performing self-directed death (or not) is characterised as a constant feeling of being torn explicated by the following pairs of themes: (1) detachment and attachment; (2) rational and non-rational considerations; (3) taking control and lingering uncertainty; (4) resisting interference and longing for support; (5) legitimacy and illegitimacy. Conclusions Our findings show that the in-between period emerges as a considerable, existential challenge with both rational and non-rational concerns and thoughts, rather than a calculative, coherent sum of rational considerations. Our study highlights the need to take due consideration of all ambiguities and ambivalences present after a putatively rational decision has been made in order to develop careful policy and support for this particular group of older people. PMID:26781505

Rational-Emotive Therapy versus Systematic Desensitization: A Comment on Moleski and Tosi.

ERIC Educational Resources Information Center

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)

Incentives, equity and the Able Chooser Problem.

PubMed

Grill, Kalle

2017-03-01

Health incentive schemes aim to produce healthier behaviours in target populations. They may do so both by making incentivised options more salient and by making them less costly. Changes in costs only result in healthier behaviour if the individual rationally assesses the cost change and acts accordingly. Not all people do this well. Those who fail to respond rationally to incentives will typically include those who are least able to make prudent choices more generally. This group will typically include the least advantaged more generally, since disadvantage inhibits one's effective ability to choose well and since poor choices tend to cause or aggravate disadvantage. Therefore, within the target population, health benefits to the better off may come at the cost of aggravated inequity. This is one instance of a problem I name the Able Chooser Problem, previously emphasised by Richard Arneson in relation to coercive paternalism. I describe and discuss this problem by distinguishing between policy options and their effects on the choice situation of individuals. Both positive and negative incentives, as well as mandates that are less than perfectly effective, require some sort of rational deliberation and action and so face the Able Chooser Problem. In contrast, effective restriction of what options are physically available, as well as choice context design that makes some options more salient or appealing, does not demand rational agency. These considerations provide an equity-based argument for preferring smart design of our choice and living environment to incentives and mandates. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

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

PubMed Central

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

2016-01-01

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

Is Educational Policy Making Rational--and What Would that Mean, Anyway?

ERIC Educational Resources Information Center

Bredo, Eric

2009-01-01

In "Moderating the Debate: Rationality and the Promise of American Education," Michael Feuer raises concerns about the consequences of basing educational policy on the model of rational choice drawn from economics. Policy making would be better and more realistic, he suggests, if it were based on a newer procedural model drawn from cognitive…

A Large Size Chimeric Highly Immunogenic Peptide Presents Multistage Plasmodium Antigens as a Vaccine Candidate System against Malaria.

PubMed

Lozano, José Manuel; Varela, Yahson; Silva, Yolanda; Ardila, Karen; Forero, Martha; Guasca, Laura; Guerrero, Yuly; Bermudez, Adriana; Alba, Patricia; Vanegas, Magnolia; Patarroyo, Manuel Elkin

2017-11-01

Rational strategies for obtaining malaria vaccine candidates should include not only a proper selection of target antigens for antibody stimulation, but also a versatile molecular design based on ordering the right pieces from the complex pathogen molecular puzzle towards more active and functional immunogens. Classical Plasmodium falciparum antigens regarded as vaccine candidates have been selected as model targets in this study. Among all possibilities we have chosen epitopes of Pf CSP, STARP; MSA1 and Pf 155/RESA from pre- and erythrocyte stages respectively for designing a large 82-residue chimeric immunogen. A number of options aimed at diminishing steric hindrance for synthetic procedures were assessed based on standard Fmoc chemistry such as building block orthogonal ligation; pseudo-proline and microwave-assisted procedures, therefore the large-chimeric target was produced, characterized and immunologically tested. Antigenicity and functional in vivo efficacy tests of the large-chimera formulations administered alone or as antigen mixtures have proven the stimulation of high antibody titers, showing strong correlation with protection and parasite clearance of vaccinated BALB/c mice after being lethally challenged with both P. berghei -ANKA and P. yoelii 17XL malaria strains. Besides, 3D structure features shown by the large-chimera encouraged as to propose using these rational designed large synthetic molecules as reliable vaccine candidate-presenting systems.

Enhancement of the Power-Conversion Efficiency of Organic Solar Cells via Unveiling an Appropriate Rational Design Strategy in Indacenodithiophene- alt-quinoxaline π-Conjugated Polymers.

PubMed

Chochos, Christos L; Singh, Ranbir; Gregoriou, Vasilis G; Kim, Min; Katsouras, Athanasios; Serpetzoglou, Efthymis; Konidakis, Ioannis; Stratakis, Emmanuel; Cho, Kilwon; Avgeropoulos, Apostolos

2018-03-28

We report on the photovoltaic parameters, photophysical properties, optoelectronic properties, self-assembly, and morphology variations in a series of high-performance donor-acceptor (D-A) π-conjugated polymers based on indacenodithiophene and quinoxaline moieties as a function of the number-average molecular weight ([Formula: see text]), the nature of aryl substituents, and the enlargement of the polymer backbone. One of the most important outcome is that from the three optimization approaches followed to tune the chemical structure toward enhanced photovoltaic performance in bulk heterojunction solar cell devices with the fullerene derivative [6,6]-phenyl-C 71 -butyric acid methyl ester as the electron acceptor, the choice of the aryl substituent is the most efficient rational design strategy. Incorporation of thienyl rings as substituents versus phenyl rings accelerates the electron-hole extraction process to the respective electrode, despite the slightly lower recombination lifetime and, thus, improves the electrical performance of the device. Single-junction solar cells based on ThIDT-TQxT feature a maximum power-conversion efficiency of 7.26%. This study provides significant insights toward understanding of the structure-properties-performance relationship for D-A π-conjugated polymers in solid state, which provide helpful inputs for the design of next-generation polymeric semiconductors for organic solar cells with enhanced performance.

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

PubMed

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

2016-06-28

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

Correlating Reactivity and Selectivity to Cyclopentadienyl Ligand Properties in Rh(III)-Catalyzed C-H Activation Reactions: An Experimental and Computational Study.

PubMed

Piou, Tiffany; Romanov-Michailidis, Fedor; Romanova-Michaelides, Maria; Jackson, Kelvin E; Semakul, Natthawat; Taggart, Trevor D; Newell, Brian S; Rithner, Christopher D; Paton, Robert S; Rovis, Tomislav

2017-01-25

Cp X Rh(III)-catalyzed C-H functionalization reactions are a proven method for the efficient assembly of small molecules. However, rationalization of the effects of cyclopentadienyl (Cp X ) ligand structure on reaction rate and selectivity has been viewed as a black box, and a truly systematic study is lacking. Consequently, predicting the outcomes of these reactions is challenging because subtle variations in ligand structure can cause notable changes in reaction behavior. A predictive tool is, nonetheless, of considerable value to the community as it would greatly accelerate reaction development. Designing a data set in which the steric and electronic properties of the Cp X Rh(III) catalysts were systematically varied allowed us to apply multivariate linear regression algorithms to establish correlations between these catalyst-based descriptors and the regio-, diastereoselectivity, and rate of model reactions. This, in turn, led to the development of quantitative predictive models that describe catalyst performance. Our newly described cone angles and Sterimol parameters for Cp X ligands served as highly correlative steric descriptors in the regression models. Through rational design of training and validation sets, key diastereoselectivity outliers were identified. Computations reveal the origins of the outstanding stereoinduction displayed by these outliers. The results are consistent with partial η 5 -η 3 ligand slippage that occurs in the transition state of the selectivity-determining step. In addition to the instructive value of our study, we believe that the insights gained are transposable to other group 9 transition metals and pave the way toward rational design of C-H functionalization catalysts.

Options as information: rational reversals of evaluation and preference.

PubMed

Sher, Shlomi; McKenzie, Craig R M

2014-06-01

This article develops a rational analysis of an important class of apparent preference reversals-joint-separate reversals traditionally explained by the evaluability hypothesis. The "options-as-information" model considers a hypothetical rational actor with limited knowledge about the market distribution of a stimulus attribute. The actor's evaluations are formed via a 2-stage process-an inferential stage in which beliefs are updated on the basis of the sample of options received, followed by an assessment stage in which options are evaluated in light of these updated beliefs. This process generates joint-separate reversals in standard experimental designs. The normative model explains why the evaluability hypothesis works when it does, identifies boundary conditions for the hypothesis, and clarifies some common misconceptions about these effects. In particular, it implies that joint-separate reversals are not irrational; in fact, they are not preference reversals. However, in expanded designs where more than 2 options are jointly evaluated, the model predicts that genuine (and rational) preference reversals will sometimes emerge. Results of 3 experiments suggest an excellent fit between the rational actor model and the judgments of human actors in joint-separate experiments. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Nutrition for Health and Performance, 2000: Nutritional Guidance for Military Operations in Temperate and Extreme Environments.

DTIC Science & Technology

1999-12-01

processed , high-salt foods (read food labels). • If You Drink Alcoholic Beverages, Do So in Moderation - Alcoholic beverages supply calories but...military. Rations are made from "real foods" (commercially grown and processed ). Commercial brand name foods and military ration items are often...designed to simplify and streamline the process of providing group meals in the field by integrating components of A-Rations, and Heat & Serve (H & S

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

PubMed Central

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

Research on Bounded Rationality of Fuzzy Choice Functions

PubMed Central

Wu, Xinlin; Zhao, Yong

2014-01-01

The rationality of a fuzzy choice function is a hot research topic in the study of fuzzy choice functions. In this paper, two common fuzzy sets are studied and analyzed in the framework of the Banerjee choice function. The complete rationality and bounded rationality of fuzzy choice functions are defined based on the two fuzzy sets. An assumption is presented to study the fuzzy choice function, and especially the fuzzy choice function with bounded rationality is studied combined with some rationality conditions. Results show that the fuzzy choice function with bounded rationality also satisfies some important rationality conditions, but not vice versa. The research gives supplements to the investigation in the framework of the Banerjee choice function. PMID:24782677

Research on bounded rationality of fuzzy choice functions.

PubMed

Wu, Xinlin; Zhao, Yong

2014-01-01

The rationality of a fuzzy choice function is a hot research topic in the study of fuzzy choice functions. In this paper, two common fuzzy sets are studied and analyzed in the framework of the Banerjee choice function. The complete rationality and bounded rationality of fuzzy choice functions are defined based on the two fuzzy sets. An assumption is presented to study the fuzzy choice function, and especially the fuzzy choice function with bounded rationality is studied combined with some rationality conditions. Results show that the fuzzy choice function with bounded rationality also satisfies some important rationality conditions, but not vice versa. The research gives supplements to the investigation in the framework of the Banerjee choice function.

Methods for open innovation on a genome-design platform associating scientific, commercial, and educational communities in synthetic biology.

PubMed

Toyoda, Tetsuro

2011-01-01

Synthetic biology requires both engineering efficiency and compliance with safety guidelines and ethics. Focusing on the rational construction of biological systems based on engineering principles, synthetic biology depends on a genome-design platform to explore the combinations of multiple biological components or BIO bricks for quickly producing innovative devices. This chapter explains the differences among various platform models and details a methodology for promoting open innovation within the scope of the statutory exemption of patent laws. The detailed platform adopts a centralized evaluation model (CEM), computer-aided design (CAD) bricks, and a freemium model. It is also important for the platform to support the legal aspects of copyrights as well as patent and safety guidelines because intellectual work including DNA sequences designed rationally by human intelligence is basically copyrightable. An informational platform with high traceability, transparency, auditability, and security is required for copyright proof, safety compliance, and incentive management for open innovation in synthetic biology. GenoCon, which we have organized and explained here, is a competition-styled, open-innovation method involving worldwide participants from scientific, commercial, and educational communities that aims to improve the designs of genomic sequences that confer a desired function on an organism. Using only a Web browser, a participating contributor proposes a design expressed with CAD bricks that generate a relevant DNA sequence, which is then experimentally and intensively evaluated by the GenoCon organizers. The CAD bricks that comprise programs and databases as a Semantic Web are developed, executed, shared, reused, and well stocked on the secure Semantic Web platform called the Scientists' Networking System or SciNetS/SciNeS, based on which a CEM research center for synthetic biology and open innovation should be established. Copyright © 2011 Elsevier Inc. All rights reserved.

Depressive symptoms and occupational stress among Chinese female nurses: the mediating effects of social support and rational coping.

PubMed

Wu, Hui; Ge, Cui Xia; Sun, Wei; Wang, Jia Na; Wang, Lie

2011-10-01

The study reported here was designed to investigate the relationship between depressive symptoms and occupational stress in female nurses in China during the period June-July 2008. The hypothesis tested was that social support and rational coping would mediate the effects of occupational stress on depressive symptoms. Our structural equation modeling revealed that social support and rational coping were negatively correlated with depressive symptoms. Social support and rational coping mediated the effects of occupational stress on depressive symptoms. Role overload, role insufficiency, and role boundary were predictive of depressive symptoms. These results indicated that lessening occupational stress and strengthening social support and rational coping could decrease depressive symptoms among Chinese female nurses. Copyright © 2011 Wiley Periodicals, Inc.

Rational Design and Synthesis of γFe2 O3 @Au Magnetic Gold Nanoflowers for Efficient Cancer Theranostics.

PubMed

Huang, Jie; Guo, Miao; Ke, Hengte; Zong, Cheng; Ren, Bin; Liu, Gang; Shen, He; Ma, Yufei; Wang, Xiaoyong; Zhang, Hailu; Deng, Zongwu; Chen, Huabing; Zhang, Zhijun

2015-09-09

An γFe2 O3 @Au core/shell-type magnetic gold nanoflower-based theranostic nano-platform is developed. It is integrated with ultrasensitive surface-enhanced Raman scattering imaging, high-resolution photo-acoustics imaging, real-time magnetic resonance imaging, and photothermal therapy capabilities. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rational selection of experimental readout and intervention sites for reducing uncertainties in computational model predictions.

PubMed

Flassig, Robert J; Migal, Iryna; der Zalm, Esther van; Rihko-Struckmann, Liisa; Sundmacher, Kai

2015-01-16

Understanding the dynamics of biological processes can substantially be supported by computational models in the form of nonlinear ordinary differential equations (ODE). Typically, this model class contains many unknown parameters, which are estimated from inadequate and noisy data. Depending on the ODE structure, predictions based on unmeasured states and associated parameters are highly uncertain, even undetermined. For given data, profile likelihood analysis has been proven to be one of the most practically relevant approaches for analyzing the identifiability of an ODE structure, and thus model predictions. In case of highly uncertain or non-identifiable parameters, rational experimental design based on various approaches has shown to significantly reduce parameter uncertainties with minimal amount of effort. In this work we illustrate how to use profile likelihood samples for quantifying the individual contribution of parameter uncertainty to prediction uncertainty. For the uncertainty quantification we introduce the profile likelihood sensitivity (PLS) index. Additionally, for the case of several uncertain parameters, we introduce the PLS entropy to quantify individual contributions to the overall prediction uncertainty. We show how to use these two criteria as an experimental design objective for selecting new, informative readouts in combination with intervention site identification. The characteristics of the proposed multi-criterion objective are illustrated with an in silico example. We further illustrate how an existing practically non-identifiable model for the chlorophyll fluorescence induction in a photosynthetic organism, D. salina, can be rendered identifiable by additional experiments with new readouts. Having data and profile likelihood samples at hand, the here proposed uncertainty quantification based on prediction samples from the profile likelihood provides a simple way for determining individual contributions of parameter uncertainties to uncertainties in model predictions. The uncertainty quantification of specific model predictions allows identifying regions, where model predictions have to be considered with care. Such uncertain regions can be used for a rational experimental design to render initially highly uncertain model predictions into certainty. Finally, our uncertainty quantification directly accounts for parameter interdependencies and parameter sensitivities of the specific prediction.

Mechanism Design for Incentivizing Social Media Contributions

NASA Astrophysics Data System (ADS)

Singh, Vivek K.; Jain, Ramesh; Kankanhalli, Mohan

Despite recent advancements in user-driven social media platforms, tools for studying user behavior patterns and motivations remain primitive. We highlight the voluntary nature of user contributions and that users can choose when (and when not) to contribute to the common media pool. A Game theoretic framework is proposed to study the dynamics of social media networks where contribution costs are individual but gains are common. We model users as rational selfish agents, and consider domain attributes like voluntary participation, virtual reward structure, network effect, and public-sharing to model the dynamics of this interaction. The created model describes the most appropriate contribution strategy from each user's perspective and also highlights issues like 'free-rider' problem and individual rationality leading to irrational (i.e. sub-optimal) group behavior. We also consider the perspective of the system designer who is interested in finding the best incentive mechanisms to influence the selfish end-users so that the overall system utility is maximized. We propose and compare multiple mechanisms (based on optimal bonus payment, social incentive leveraging, and second price auction) to study how a system designer can exploit the selfishness of its users, to design incentive mechanisms which improve the overall task-completion probability and system performance, while possibly still benefiting the individual users.

Visualized and precise design of artificial small RNAs for regulating T7 RNA polymerase and enhancing recombinant protein folding in Escherichia coli.

PubMed

Zhao, Yujia; Fan, Jingjing; Li, Jinlin; Li, Jun; Zhou, Xiaohong; Li, Chun

2016-12-01

Small non-coding RNAs (sRNAs) have received much attention in recent years due to their unique biological properties, which can efficiently and specifically tune target gene expressions in bacteria. Inspired by natural sRNAs, recent works have proposed the use of artificial sRNAs (asRNAs) as genetic tools to regulate desired gene that has been applied in several fields, such as metabolic engineering and bacterial physiology studies. However, the rational design of asRNAs is still a challenge. In this study, we proposed structure and length as two criteria to implement rational visualized and precise design of asRNAs. T7 expression system was one of the most useful recombinant protein expression systems. However, it was deeply limited by the formation of inclusion body. To settle this problem, we designed a series of asRNAs to inhibit the T7 RNA polymerase (Gene1) expression to balance the rate between transcription and folding of recombinant protein. Based on the heterologous expression of Aspergillus oryzae Li-3 glucuronidase in E. coli , the asRNA-antigene1-17bp can effectively decrease the inclusion body and increase the enzyme activity by 169.9%.

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

PubMed

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.

Rational design of vaccine targets and strategies for HIV: a crossroad of statistical physics, biology, and medicine.

PubMed

Chakraborty, Arup K; Barton, John P

2017-03-01

Vaccination has saved more lives than any other medical procedure. Pathogens have now evolved that have not succumbed to vaccination using the empirical paradigms pioneered by Pasteur and Jenner. Vaccine design strategies that are based on a mechanistic understanding of the pertinent immunology and virology are required to confront and eliminate these scourges. In this perspective, we describe just a few examples of work aimed to achieve this goal by bringing together approaches from statistical physics with biology and clinical research.

New Concepts in Complex Regional Pain Syndrome

PubMed Central

Tajerian, Maral; Clark, J David

2015-01-01

SYNOPSIS Despite the severe pain and disability associated with Complex Regional Pain Syndrome (CRPS), our lack of understanding of the pathophysiological mechanisms supporting this enigmatic condition prevents the rational design of new therapies, a situation that is frustrating both to the physician and the patient. The following review will highlight some of the mechanisms thought to be involved in the pathophysiology of CRPS in preclinical models and CRPS patients, with the ultimate goal that understanding these mechanisms will lead to the design of efficacious, mechanism-based treatments available to the clinic. PMID:26611388

Rational design of vaccine targets and strategies for HIV: a crossroad of statistical physics, biology, and medicine

NASA Astrophysics Data System (ADS)

Chakraborty, Arup K.; Barton, John P.

2017-03-01

Vaccination has saved more lives than any other medical procedure. Pathogens have now evolved that have not succumbed to vaccination using the empirical paradigms pioneered by Pasteur and Jenner. Vaccine design strategies that are based on a mechanistic understanding of the pertinent immunology and virology are required to confront and eliminate these scourges. In this perspective, we describe just a few examples of work aimed to achieve this goal by bringing together approaches from statistical physics with biology and clinical research.

Systematic design for trait introgression projects.

PubMed

Cameron, John N; Han, Ye; Wang, Lizhi; Beavis, William D

2017-10-01

Using an Operations Research approach, we demonstrate design of optimal trait introgression projects with respect to competing objectives. We demonstrate an innovative approach for designing Trait Introgression (TI) projects based on optimization principles from Operations Research. If the designs of TI projects are based on clear and measurable objectives, they can be translated into mathematical models with decision variables and constraints that can be translated into Pareto optimality plots associated with any arbitrary selection strategy. The Pareto plots can be used to make rational decisions concerning the trade-offs between maximizing the probability of success while minimizing costs and time. The systematic rigor associated with a cost, time and probability of success (CTP) framework is well suited to designing TI projects that require dynamic decision making. The CTP framework also revealed that previously identified 'best' strategies can be improved to be at least twice as effective without increasing time or expenses.

Rationally designed chemokine-based toxin targeting the viral G protein-coupled receptor US28 potently inhibits cytomegalovirus infection in vivo

PubMed Central

Spiess, Katja; Jeppesen, Mads G.; Malmgaard-Clausen, Mikkel; Krzywkowski, Karen; Dulal, Kalpana; Cheng, Tong; Hjortø, Gertrud M.; Larsen, Olav; Burg, John S.; Jarvis, Michael A.; Christopher Garcia, K.; Zhu, Hua; Kledal, Thomas N.; Rosenkilde, Mette M.

2015-01-01

The use of receptor–ligand interactions to direct toxins to kill diseased cells selectively has shown considerable promise for treatment of a number of cancers and, more recently, autoimmune disease. Here we move the fusion toxin protein (FTP) technology beyond cancer/autoimmune therapeutics to target the human viral pathogen, human cytomegalovirus (HCMV), on the basis of its expression of the 7TM G protein-coupled chemokine receptor US28. The virus origin of US28 provides an exceptional chemokine-binding profile with high selectivity and improved binding for the CX3C chemokine, CX3CL1. Moreover, US28 is constitutively internalizing by nature, providing highly effective FTP delivery. We designed a synthetic CX3CL1 variant engineered to have ultra-high affinity for US28 and greater specificity for US28 than the natural sole receptor for CX3CL1, CX3CR1, and we fused the synthetic variant with the cytotoxic domain of Pseudomonas Exotoxin A. This novel strategy of a rationally designed FTP provided unparalleled anti-HCMV efficacy and potency in vitro and in vivo. PMID:26080445

Rational drug design and synthesis of molecules targeting the angiotensin II type 1 and type 2 receptors.

PubMed

Kellici, Tahsin F; Tzakos, Andreas G; Mavromoustakos, Thomas

2015-03-02

The angiotensin II (Ang II) type 1 and type 2 receptors (AT1R and AT2R) orchestrate an array of biological processes that regulate human health. Aberrant function of these receptors triggers pathophysiological responses that can ultimately lead to death. Therefore, it is important to design and synthesize compounds that affect beneficially these two receptors. Cardiovascular disease, which is attributed to the overactivation of the vasoactive peptide hormone Αng II, can now be treated with commercial AT1R antagonists. Herein, recent achievements in rational drug design and synthesis of molecules acting on the two AT receptors are reviewed. Quantitative structure activity relationships (QSAR) and molecular modeling on the two receptors aim to assist the search for new active compounds. As AT1R and AT2R are GPCRs and drug action is localized in the transmembrane region the role of membrane bilayers is exploited. The future perspectives in this field are outlined. Tremendous progress in the field is expected if the two receptors are crystallized, as this will assist the structure based screening of the chemical space and lead to new potent therapeutic agents in cardiovascular and other diseases.

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

PubMed

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.

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

PubMed

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 presented have applications for other materials with dityrosine crosslinks, which are found in nature as post-translational modificaitons, as well as in engineered matrices such as tyramine-substituted hyaluronic acid and recombinant resilin. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Prevalence and Determinants of Physician Bedside Rationing

PubMed Central

Hurst, Samia A; Slowther, Anne-Marie; Forde, Reidun; Pegoraro, Renzo; Reiter-Theil, Stella; Perrier, Arnaud; Garrett-Mayer, Elizabeth; Danis, Marion

2006-01-01

BACKGROUND Bedside rationing by physicians is controversial. The debate, however, is clouded by lack of information regarding the extent and character of bedside rationing. DESIGN, SETTING, AND PARTICIPANTS We developed a survey instrument to examine the frequency, criteria, and strategies used for bedside rationing. Content validity was assessed through expert assessment and scales were tested for internal consistency. The questionnaire was translated and administered to General Internists in Norway, Switzerland, Italy, and the United Kingdom. Logistic regression was used to identify the variables associated with reported rationing. RESULTS Survey respondents (N =656, response rate 43%) ranged in age from 28 to 82, and averaged 25 years in practice. Most respondents (82.3%) showed some degree of agreement with rationing, and 56.3% reported that they did ration interventions. The most frequently mentioned criteria for rationing were a small expected benefit (82.3%), low chances of success (79.8%), an intervention intended to prolong life when quality of life is low (70.6%), and a patient over 85 years of age (70%). The frequency of rationing by clinicians was positively correlated with perceived scarcity of resources (odds ratio [OR]=1.11, 95% confidence interval [CI] 1.06 to 1.16), perceived pressure to ration (OR=2.14, 95% CI 1.52 to 3.01), and agreement with rationing (OR=1.13, 95% CI 1.05 to 1.23). CONCLUSION Bedside rationing is prevalent in all surveyed European countries and varies with physician attitudes and resource availability. The prevalence of physician bedside rationing, which presents physicians with difficult moral dilemmas, highlights the importance of discussions regarding how to ration care in the most ethically justifiable manner. PMID:16836629

The Operator Construct of Rational Numbers in Childhood and Adolescence--An Exploratory Study

ERIC Educational Resources Information Center

Kieren, T. E.; Nelson, D.

1978-01-01

Based on a theory of rational numbers which sees the rational numbers construct of a person as potentially built on a number of subconstructs, this study explored the view of rational numbers as operators. Significant changes in performance level and quality appeared between ages 11 and 12 and 12 and 13. (JC)

Optimal feeding systems for small-scale dairy herds in the North West Province, South Africa.

PubMed

Manzana, N Patience; McCrindle, Cheryl M E; Sebei, P Julius; Prozesky, Leon

2014-07-09

Land redistribution was legislated in 1994; it was designed to resolve historical imbalances inland ownership in South Africa. Between 2002 and 2006, a longitudinal observational studywas conducted with 15 purposively selected small-scale dairy farmers in a land redistributionproject in Central North West Province. Four farmers left the project over the period. For thepurposes of this study, a small-scale dairy farm was defined as a farm that produces less than500 L of milk a day, irrespective of the number of cows or size of the farm. The study wasconducted in three phases. In the first phase, situational analysis using participatory ruralappraisal (PRA) and observation was used to outline the extent of the constraints and designappropriate interventions. Feeds that were used were tested and evaluated. In the secondphase, three different feeding systems were designed from the data obtained from PRA. Thesewere: (1) A semi-intensive farm-based ration using available crops, pastures and crop residueswith minimal rations purchased. (2) An intensive, zero-grazing dairy system using a totalmixed ration. (3) A traditional, extensive or dual-purpose system, where the calf drank fromthe cow until weaning and milking was done only once a day. In the third phase, adoptionwas monitored. By July 2006, all remaining farmers had changed to commercially formulatedrations or licks and the body condition score of the cows had improved. It was concluded thatveterinary extension based on PRA and a holistic systems approach was a good option forsuch complex problems. Mentoring by commercial dairy farmers, veterinary and extensionservices appeared to be viable. Further research should be done to optimise the traditionalmodel of dairy farming, as this was relatively profitable, had a lower risk and was less labourintensive.

Embedded real-time operating system micro kernel design

NASA Astrophysics Data System (ADS)

Cheng, Xiao-hui; Li, Ming-qiang; Wang, Xin-zheng

2005-12-01

Embedded systems usually require a real-time character. Base on an 8051 microcontroller, an embedded real-time operating system micro kernel is proposed consisting of six parts, including a critical section process, task scheduling, interruption handle, semaphore and message mailbox communication, clock managent and memory managent. Distributed CPU and other resources are among tasks rationally according to the importance and urgency. The design proposed here provides the position, definition, function and principle of micro kernel. The kernel runs on the platform of an ATMEL AT89C51 microcontroller. Simulation results prove that the designed micro kernel is stable and reliable and has quick response while operating in an application system.

The mechanism and design of sequencing batch reactor systems for nutrient removal--the state of the art.

PubMed

Artan, N; Wilderer, P; Orhon, D; Morgenroth, E; Ozgür, N

2001-01-01

The Sequencing Batch Reactor (SBR) process for carbon and nutrient removal is subject to extensive research, and it is finding a wider application in full-scale installations. Despite the growing popularity, however, a widely accepted approach to process analysis and modeling, a unified design basis, and even a common terminology are still lacking; this situation is now regarded as the major obstacle hindering broader practical application of the SBR. In this paper a rational dimensioning approach is proposed for nutrient removal SBRs based on scientific information on process stoichiometry and modelling, also emphasizing practical constraints in design and operation.

Personal Autonomy and Rational Suicide.

ERIC Educational Resources Information Center

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…

The Feminist Supervision Scale: A Rational/Theoretical Approach

ERIC Educational Resources Information Center

Szymanski, Dawn M.

2003-01-01

This article reports the development and psychometric properties of the Feminist Supervision Scale (FSS), a new scale designed to assess feminist supervision practices in clinical supervision. This 32-item measure was developed using a rational/theoretical approach of test construction and includes four subscales: (a) collaborative relationships,…

13C metabolic flux analysis: optimal design of isotopic labeling experiments.

PubMed

Antoniewicz, Maciek R

2013-12-01

Measuring fluxes by 13C metabolic flux analysis (13C-MFA) has become a key activity in chemical and pharmaceutical biotechnology. Optimal design of isotopic labeling experiments is of central importance to 13C-MFA as it determines the precision with which fluxes can be estimated. Traditional methods for selecting isotopic tracers and labeling measurements did not fully utilize the power of 13C-MFA. Recently, new approaches were developed for optimal design of isotopic labeling experiments based on parallel labeling experiments and algorithms for rational selection of tracers. In addition, advanced isotopic labeling measurements were developed based on tandem mass spectrometry. Combined, these approaches can dramatically improve the quality of 13C-MFA results with important applications in metabolic engineering and biotechnology. Copyright © 2013 Elsevier Ltd. All rights reserved.

The jABC Approach to Rigorous Collaborative Development of SCM Applications

NASA Astrophysics Data System (ADS)

Hörmann, Martina; Margaria, Tiziana; Mender, Thomas; Nagel, Ralf; Steffen, Bernhard; Trinh, Hong

Our approach to the model-driven collaborative design of IKEA's P3 Delivery Management Process uses the jABC [9] for model driven mediation and choreography to complement a RUP-based (Rational Unified Process) development process. jABC is a framework for service development based on Lightweight Process Coordination. Users (product developers and system/software designers) easily develop services and applications by composing reusable building-blocks into (flow-) graph structures that can be animated, analyzed, simulated, verified, executed, and compiled. This way of handling the collaborative design of complex embedded systems has proven to be effective and adequate for the cooperation of non-programmers and non-technical people, which is the focus of this contribution, and it is now being rolled out in the operative practice.

Designing and developing suppository formulations for anti-HIV drug delivery.

PubMed

Ham, Anthony S; Buckheit, Robert W

2017-08-01

Despite a long history of use for rectal and vaginal drug delivery, the current worldwide market for suppositories is limited primarily due to a lack of user acceptability. Therefore, virtually no rational pharmaceutical development of antiviral suppositories has been performed. However, suppositories offer several advantages over other antiviral dosage forms. Current suppository designs have integrated active pharmaceutical ingredients into existing formulation designs without optimization. As such, emerging suppository development has been focused on improving upon the existing classical design to enhance drug delivery and is poised to open suppository drug delivery to a broader range of drugs, including antiretroviral products. Thus, with continuing research into rational suppository design and development, there is significant potential for antiretroviral suppository drug delivery.

Professional practices and perception towards rational use of medicines according to WHO methodology in United Arab Emirates

PubMed Central

Abdul Rasool, Bazigha K.; Fahmy, Sahar A.; Abu-Gharbieh, Eman F.; Ali, Heyam S.

2009-01-01

Inappropriate prescribing reduces the quality of medical care and leads to a waste of resources. No study has been reported concerning rational drug use in United Arab Emirates, UAE, recently. Objectives assessing patterns of use and defining problems regarding the rational drug use.Setting baseline situational analysis study for practices in the health care system relevant to drug use. Method A descriptive pilot study, consisting of pharmacists, physicians and patients (100 of each of category) from four private hospitals, (12) medical clinics, (80) community pharmacies in addition to 150 prescriptions. A questionnaire of three sections was designed to include WHO indicators regarding patients, facility and prescribing patterns that are relevant to rational drug use was carried out in four emirates of the UAE in the period December 2008-Febreuary 2009. Results Consultation and dispensing times were 10 (SD=2.75) min and 68 (SD=9.7) seconds, respectively. Average no. of drugs per prescription was (2.9 + 0.97), % of prescriptions using generic name (7.35%), % of antibiotic containing prescriptions (31.1%), % of injection containing prescriptions (2.9%), adherence to Standard Treatment Protocols (46%), adherence to the essential drug list (64%), patient’s knowledge of correct dosage (55%), adequately labeled drugs (45%), patient’s information (65%). Conclusions Several areas of deficiency in rational drug use had been defined in the private sector through UAE that can be remedied through adopting several strategies such as adherence to national standard treatment guidelines and essential drug list based on treatments of choice, interaction between health care system and providing drugs information to consumers. PMID:25152796

Professional practices and perception towards rational use of medicines according to WHO methodology in United Arab Emirates.

PubMed

Rasool, Bazigha K Abdul; Fahmy, Sahar A; Abu-Gharbieh, Eman F; Ali, Heyam S

2010-01-01

Inappropriate prescribing reduces the quality of medical care and leads to a waste of resources. No study has been reported concerning rational drug use in United Arab Emirates, UAE, recently. assessing patterns of use and defining problems regarding the rational drug use.Setting baseline situational analysis study for practices in the health care system relevant to drug use. A descriptive pilot study, consisting of pharmacists, physicians and patients (100 of each of category) from four private hospitals, (12) medical clinics, (80) community pharmacies in addition to 150 prescriptions. A questionnaire of three sections was designed to include WHO indicators regarding patients, facility and prescribing patterns that are relevant to rational drug use was carried out in four emirates of the UAE in the period December 2008-Febreuary 2009. Consultation and dispensing times were 10 (SD=2.75) min and 68 (SD=9.7) seconds, respectively. Average no. of drugs per prescription was (2.9 + 0.97), % of prescriptions using generic name (7.35%), % of antibiotic containing prescriptions (31.1%), % of injection containing prescriptions (2.9%), adherence to Standard Treatment Protocols (46%), adherence to the essential drug list (64%), patient's knowledge of correct dosage (55%), adequately labeled drugs (45%), patient's information (65%). Several areas of deficiency in rational drug use had been defined in the private sector through UAE that can be remedied through adopting several strategies such as adherence to national standard treatment guidelines and essential drug list based on treatments of choice, interaction between health care system and providing drugs information to consumers.

Computer-aided rational design of the phosphotransferase system for enhanced glucose uptake in Escherichia coli

PubMed Central

Nishio, Yousuke; Usuda, Yoshihiro; Matsui, Kazuhiko; Kurata, Hiroyuki

2008-01-01

The phosphotransferase system (PTS) is the sugar transportation machinery that is widely distributed in prokaryotes and is critical for enhanced production of useful metabolites. To increase the glucose uptake rate, we propose a rational strategy for designing the molecular architecture of the Escherichia coli glucose PTS by using a computer-aided design (CAD) system and verified the simulated results with biological experiments. CAD supports construction of a biochemical map, mathematical modeling, simulation, and system analysis. Assuming that the PTS aims at controlling the glucose uptake rate, the PTS was decomposed into hierarchical modules, functional and flux modules, and the effect of changes in gene expression on the glucose uptake rate was simulated to make a rational strategy of how the gene regulatory network is engineered. Such design and analysis predicted that the mlc knockout mutant with ptsI gene overexpression would greatly increase the specific glucose uptake rate. By using biological experiments, we validated the prediction and the presented strategy, thereby enhancing the specific glucose uptake rate. PMID:18197177

Biologically relevant 3D tumor arrays: treatment response and the importance of stromal partners

NASA Astrophysics Data System (ADS)

Rizvi, Imran; Celli, Jonathan P.; Xu, Feng; Evans, Conor L.; Abu-Yousif, Adnan O.; Muzikansky, Alona; Elrington, Stefan A.; Pogue, Brian W.; Finkelstein, Dianne M.; Demirci, Utkan; Hasan, Tayyaba

2011-02-01

The development and translational potential of therapeutic strategies for cancer is limited, in part, by a lack of biological models that capture important aspects of tumor growth and treatment response. It is also becoming increasingly evident that no single treatment will be curative for this complex disease. Rationally-designed combination regimens that impact multiple targets provide the best hope of significantly improving clinical outcomes for cancer patients. Rapidly identifying treatments that cooperatively enhance treatment efficacy from the vast library of candidate interventions is not feasible, however, with current systems. There is a vital, unmet need to create cell-based research platforms that more accurately mimic the complex biology of human tumors than monolayer cultures, while providing the ability to screen therapeutic combinations more rapidly than animal models. We have developed a highly reproducible in vitro three-dimensional (3D) tumor model for micrometastatic ovarian cancer (OvCa), which in conjunction with quantitative image analysis routines to batch-process large datasets, serves as a high throughput reporter to screen rationally-designed combination regimens. We use this system to assess mechanism-based combination regimens with photodynamic therapy (PDT), which sensitizes OvCa to chemo and biologic agents, and has shown promise in clinic trials. We show that PDT synergistically enhances carboplatin efficacy in a sequence dependent manner. In printed heterocellular cultures we demonstrate that proximity of fibroblasts enhances 3D tumor growth and investigate co-cultures with endothelial cells. The principles described here could inform the design and evaluation of mechanism-based therapeutic options for a broad spectrum of metastatic solid tumors.

Diketopyrrolopyrrole-based carbon dots for photodynamic therapy.

PubMed

He, Haozhe; Zheng, Xiaohua; Liu, Shi; Zheng, Min; Xie, Zhigang; Wang, Yong; Yu, Meng; Shuai, Xintao

2018-06-01

The development of a simple and straightforward strategy to synthesize multifunctional carbon dots for photodynamic therapy (PDT) has been an emerging focus. In this work, diketopyrrolopyrrole-based fluorescent carbon dots (DPP CDs) were designed and synthesized through a facile one-pot hydrothermal method by using diketopyrrolopyrrole (DPP) and chitosan (CTS) as raw materials. DPP CDs not only maintained the ability of DPP to generate singlet oxygen (1O2) but also have excellent hydrophilic properties and outstanding biocompatibility. In vitro and in vivo experiments demonstrated that DPP CDs greatly inhibited the growth of tumor cells under laser irradiation (540 nm). This study highlights the potential of the rational design of CDs for efficient cancer therapy.

Designing Trials for Testing the Efficacy of Pre- Pro- and Synbiotics

NASA Astrophysics Data System (ADS)

Lewis, Stephen; Atkinson, Charlotte

Providing an evidence base for the rational delivery of medicines and treatments is the cornerstone of modern health care delivery. Much of this evidence base is gained through conducting clinical trials. Superficially, designing a clinical trial seems straightforward. However, in practice many unforeseen difficulties arise with long setting up times, poor recruitment rates and patients or interventions not behaving in the way expected. Unfortunately, clinical trials examining the efficacy of pre-, pro- and synbiotics have developed a reputation for being published in low impact journals and reaching unconvincing conclusions. As a generalization, the reason for this poor reputation is that the trials have tended to be too small and have not used meaningful clinical endpoints.

A smart T(1)-weighted MRI contrast agent for uranyl cations based on a DNAzyme-gadolinium conjugate.

PubMed

Xu, Weichen; Xing, Hang; Lu, Yi

2013-11-07

Rational design of smart MRI contrast agents with high specificity for metal ions remains a challenge. Here, we report a general strategy for the design of smart MRI contrast agents for detecting metal ions based on conjugation of a DNAzyme with a gadolinium complex. The 39E DNAzyme, which has high selectivity for UO2(2+), was conjugated to Gd(III)-DOTA and streptavidin. The binding of UO2(2+) to its 39E DNAzyme resulted in the dissociation of Gd(III)-DOTA from the large streptavidin, leading to a decrease of the T1 correlation time, and a change in the MRI signal.

Tunable assembly of amyloid-forming peptides into nanosheets as a retrovirus carrier.

PubMed

Dai, Bin; Li, Dan; Xi, Wenhui; Luo, Fang; Zhang, Xiang; Zou, Man; Cao, Mi; Hu, Jun; Wang, Wenyuan; Wei, Guanghong; Zhang, Yi; Liu, Cong

2015-03-10

Using and engineering amyloid as nanomaterials are blossoming trends in bionanotechnology. Here, we show our discovery of an amyloid structure, termed "amyloid-like nanosheet," formed by a key amyloid-forming segment of Alzheimer's Aβ. Combining multiple biophysical and computational approaches, we proposed a structural model for the nanosheet that is formed by stacking the amyloid fibril spines perpendicular to the fibril axis. We further used the nanosheet for laboratorial retroviral transduction enhancement and directly visualized the presence of virus on the nanosheet surface by electron microscopy. Furthermore, based on our structural model, we designed nanosheet-forming peptides with different functionalities, elucidating the potential of rational design for amyloid-based materials with novel architecture and function.

[Development of a basic ration out of commercial foods for nutrition in ground-based simulation experiments].

PubMed

Agureev, A N; Kalandarov, S; Bogatova, R I; Krivitsina, Z A; Vasil'eva, V F

2005-01-01

Food rations composed of canned products were given the physiological and hygienic evaluation in the context of their fitness for human volunteers in experiments with head-down bedrest in isolation and confinement. As a result, the food rations were proven to contain the desired quantities of nutrients. Evaluation of food fitness for human subjects was made based on the data of clinical-physiological and biochemical investigations. The rations met the energy and anabolic metabolism demands of human subjects during extreme chamber experiments and were favorable to maintaining good level of vital processes.

Community attitudes toward rationing ARVs: a qualitative study of justice and equity.

PubMed

Rennie, Stuart

2006-12-01

Medical rationing of anti-retroviral therapies (ARVs) may conflict with the right to health, but rationing is nevertheless a reality in developing countries. In this article, which is based on a poster presentation at the conference, Stuart Rennie presents the preliminary findings of a study on community attitudes towards rationing ARVs in the Democratic Republic of Congo (DRC).

Cognitive success: instrumental justifications of normative systems of reasoning.

PubMed

Schurz, Gerhard

2014-01-01

In the first part of the paper (sec. 1-4), I argue that Elqayam and Evan's (2011) distinction between normative and instrumental conceptions of cognitive rationality corresponds to deontological vs. teleological accounts in meta-ethics. I suggest that Elqayam and Evans' distinction be replaced by the distinction between a-priori intuition-based vs. a-posteriori success-based accounts of cognitive rationality. The value of cognitive success lies in its instrumental rationality for almost-all practical purposes. In the second part (sec. 5-7), I point out that the Elqayam and Evans's distinction between normative and instrumental rationality is coupled with a second distinction: between logically general vs. locally adaptive accounts of rationality. I argue that these are two independent distinctions that should be treated as independent dimensions. I also demonstrate that logically general systems of reasoning can be instrumentally justified. However, such systems can only be cognitively successful if they are paired with successful inductive reasoning, which is the area where the program of adaptive (ecological) rationality emerged, because there are no generally optimal inductive reasoning methods. I argue that the practical necessity of reasoning under changing environments constitutes a dilemma for ecological rationality, which I attempt to solve within a dual account of rationality.

Fundamental understanding and rational design of high energy structural microbatteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Yuxing; Li, Qiuyan; Cartmell, Samuel

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 inmore » designing the structural microbatteries for emerging technologies.« less

Rationalization of a nanoparticle-based nicotine nanovaccine as an effective next-generation nicotine vaccine: A focus on hapten localization.

PubMed

Zhao, Zongmin; Hu, Yun; Harmon, Theresa; Pentel, Paul; Ehrich, Marion; Zhang, Chenming

2017-09-01

A lipid-polymeric hybrid nanoparticle-based next-generation nicotine nanovaccine was rationalized in this study to combat nicotine addiction. A series of nanovaccines, which had nicotine-haptens localized on carrier protein (LPKN), nanoparticle surface (LPNK), or both (LPNKN), were designed to study the impact of hapten localization on their immunological efficacy. All three nanovaccines were efficiently taken up and processed by dendritic cells. LPNKN induced a significantly higher immunogenicity against nicotine and a significantly lower anti-carrier protein antibody level compared to LPKN and LPNK. Meanwhile, it was found that the anti-nicotine antibodies elicited by LPKN and LPNKN bind nicotine stronger than those elicited by LPKN, and LPNK and LPNKN resulted in a more balanced Th1-Th2 immunity than LPKN. Moreover, LPNKN exhibited the best ability to block nicotine from entering the brain of mice. Collectively, the results demonstrated that the immunological efficacy of the hybrid nanoparticle-based nicotine vaccine could be enhanced by modulating hapten localization, providing a promising strategy to combatting nicotine addiction. Copyright © 2017 Elsevier Ltd. All rights reserved.

In Silico Augmentation of the Drug Development Pipeline: Examples from the study of Acute Inflammation.

PubMed

An, Gary; Bartels, John; Vodovotz, Yoram

2011-03-01

The clinical translation of promising basic biomedical findings, whether derived from reductionist studies in academic laboratories or as the product of extensive high-throughput and -content screens in the biotechnology and pharmaceutical industries, has reached a period of stagnation in which ever higher research and development costs are yielding ever fewer new drugs. Systems biology and computational modeling have been touted as potential avenues by which to break through this logjam. However, few mechanistic computational approaches are utilized in a manner that is fully cognizant of the inherent clinical realities in which the drugs developed through this ostensibly rational process will be ultimately used. In this article, we present a Translational Systems Biology approach to inflammation. This approach is based on the use of mechanistic computational modeling centered on inherent clinical applicability, namely that a unified suite of models can be applied to generate in silico clinical trials, individualized computational models as tools for personalized medicine, and rational drug and device design based on disease mechanism.

The role of leader influence tactics and safety climate in engaging employees' safety participation.

PubMed

Clarke, Sharon; Ward, Katie

2006-10-01

This study examines the effect of leader influence tactics on employee safety participation in a U.K.-based manufacturing organization, examining the role of safety climate as a mediator. Structural equation modeling showed that leader influence tactics associated with a transformational leadership style had significant relationships with safety participation that were partially mediated by the safety climate (consultation) or fully mediated by the safety climate (inspirational appeals). In addition, leader influence tactics associated with a transactional leadership style had significant relationships with safety participation: rational persuasion (partially mediated by safety climate) and coalition tactics (direct effect). Thus, leaders may encourage safety participation using a combination of influence tactics, based on rational arguments, involvement in decision making, and generating enthusiasm for safety. The influence of building trust in managers is discussed as an underlying mechanism in this relationship. Practical implications are highlighted, including the design of leadership development programs, which may be particularly suited to high-reliability organizations.

Scheduled power tracking control of the wind-storage hybrid system based on the reinforcement learning theory

NASA Astrophysics Data System (ADS)

Li, Ze

2017-09-01

In allusion to the intermittency and uncertainty of the wind electricity, energy storage and wind generator are combined into a hybrid system to improve the controllability of the output power. A scheduled power tracking control method is proposed based on the reinforcement learning theory and Q-learning algorithm. In this method, the state space of the environment is formed with two key factors, i.e. the state of charge of the energy storage and the difference value between the actual wind power and scheduled power, the feasible action is the output power of the energy storage, and the corresponding immediate rewarding function is designed to reflect the rationality of the control action. By interacting with the environment and learning from the immediate reward, the optimal control strategy is gradually formed. After that, it could be applied to the scheduled power tracking control of the hybrid system. Finally, the rationality and validity of the method are verified through simulation examples.

Comparison of Peak-Flow Estimation Methods for Small Drainage Basins in Maine

USGS Publications Warehouse

Hodgkins, Glenn A.; Hebson, Charles; Lombard, Pamela J.; Mann, Alexander

2007-01-01

Understanding the accuracy of commonly used methods for estimating peak streamflows is important because the designs of bridges, culverts, and other river structures are based on these flows. Different methods for estimating peak streamflows were analyzed for small drainage basins in Maine. For the smallest basins, with drainage areas of 0.2 to 1.0 square mile, nine peak streamflows from actual rainfall events at four crest-stage gaging stations were modeled by the Rational Method and the Natural Resource Conservation Service TR-20 method and compared to observed peak flows. The Rational Method had a root mean square error (RMSE) of -69.7 to 230 percent (which means that approximately two thirds of the modeled flows were within -69.7 to 230 percent of the observed flows). The TR-20 method had an RMSE of -98.0 to 5,010 percent. Both the Rational Method and TR-20 underestimated the observed flows in most cases. For small basins, with drainage areas of 1.0 to 10 square miles, modeled peak flows were compared to observed statistical peak flows with return periods of 2, 50, and 100 years for 17 streams in Maine and adjoining parts of New Hampshire. Peak flows were modeled by the Rational Method, the Natural Resources Conservation Service TR-20 method, U.S. Geological Survey regression equations, and the Probabilistic Rational Method. The regression equations were the most accurate method of computing peak flows in Maine for streams with drainage areas of 1.0 to 10 square miles with an RMSE of -34.3 to 52.2 percent for 50-year peak flows. The Probabilistic Rational Method was the next most accurate method (-38.5 to 62.6 percent). The Rational Method (-56.1 to 128 percent) and particularly the TR-20 method (-76.4 to 323 percent) had much larger errors. Both the TR-20 and regression methods had similar numbers of underpredictions and overpredictions. The Rational Method overpredicted most peak flows and the Probabilistic Rational Method tended to overpredict peak flows from the smaller (less than 5 square miles) drainage basins and underpredict peak flows from larger drainage basins. The results of this study are consistent with the most comprehensive analysis of observed and modeled peak streamflows in the United States, which analyzed statistical peak flows from 70 drainage basins in the Midwest and the Northwest.

The application of powerful promoters to enhance gene expression in industrial microorganisms.

PubMed

Zhou, Shenghu; Du, Guocheng; Kang, Zhen; Li, Jianghua; Chen, Jian; Li, Huazhong; Zhou, Jingwen

2017-02-01

Production of useful chemicals by industrial microorganisms has been attracting more and more attention. Microorganisms screened from their natural environment usually suffer from low productivity, low stress resistance, and accumulation of by-products. In order to overcome these disadvantages, rational engineering of microorganisms to achieve specific industrial goals has become routine. Rapid development of metabolic engineering and synthetic biology strategies provide novel methods to improve the performance of industrial microorganisms. Rational regulation of gene expression by specific promoters is essential to engineer industrial microorganisms for high-efficiency production of target chemicals. Identification, modification, and application of suitable promoters could provide powerful switches at the transcriptional level for fine-tuning of a single gene or a group of genes, which are essential for the reconstruction of pathways. In this review, the characteristics of promoters from eukaryotic, prokaryotic, and archaea microorganisms are briefly introduced. Identification of promoters based on both traditional biochemical and systems biology routes are summarized. Besides rational modification, de novo design of promoters to achieve gradient, dynamic, and logic gate regulation are also introduced. Furthermore, flexible application of static and dynamic promoters for the rational engineering of industrial microorganisms is highlighted. From the perspective of powerful promoters in industrial microorganisms, this review will provide an extensive description of how to regulate gene expression in industrial microorganisms to achieve more useful goals.

The "Intentionality Measurement Instrument" [or "IMI"]: A Comprehensive Psychometric Instrument Based upon the Dual Quadrant Scalar Model of Intentionality That Is Designed to Measure Intent, Motive Type, and Disposition

ERIC Educational Resources Information Center

Osler, James Edward, II

2016-01-01

The overall aim of this paper is to provide an epistemological rational for the measurement of intentionality. The purpose of this narrative is to identify "Intentionality" as an arena of action in the dispositional learning domain can be measured using an "Intentionality Measurement Instrument" [also referred by the acronym…

People’s Republic of China Scientific Abstracts, No. 172

DTIC Science & Technology

1977-07-21

preventing rain seepage and rational illumination arrangement. The ventilation problem is solved if the multi-span plant building is chosen. In addition...This article is based on investigation and measurement of illumination in scores of plants . A large number of model experiments was carried out in...Electric Power TITLE: "Investigation and Discussion on Designing Multipurpose Work- shops in Power Plants " SOURCE: Peking CHIEN-CHU HSUEH-PAO

Auditing Rational Adversaries to Provably Manage Risks

DTIC Science & Technology

2012-05-23

series of white papers on accountability-based privacy governance in which one recommendation is that organisations should have in place policies and...that this state of affairs raises is how to design effective audit and punishment schemes. This paper articulates a desirable property and presents an...In this section, we provide an overview of our model using a motivating scenario that will serve as a running example for this paper . Consider a

Supported Pd nanoclusters with enhanced hydrogen spillover for NOx removal via H2-SCR: the elimination of "volcano-type" behaviour.

PubMed

Peng, Zhezhe; Li, Zongyuan; Liu, Yun-Quan; Yan, Shuai; Tong, Jianing; Wang, Duo; Ye, Yueyuan; Li, Shuirong

2017-05-30

A rational design of a Pd catalyst with highly dispersed Pd nanoclusters on an Al doped ceria-based oxide for low temperature selective catalytic reduction of NO x by hydrogen with excess O 2 was achieved. The supported Pd nanocluster shows a high hydrogen spillover ability and a NO x conversion of >84% within 100-300 °C.

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

NASA Astrophysics Data System (ADS)

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.

System of Objectified Judgement Analysis (SOJA) as a tool in rational and transparent drug-decision making.

PubMed

Janknegt, Robert; Scott, Mike; Mairs, Jill; Timoney, Mark; McElnay, James; Brenninkmeijer, Rob

2007-10-01

Drug selection should be a rational process that embraces the principles of evidence-based medicine. However, many factors may affect the choice of agent. It is against this background that the System of Objectified Judgement Analysis (SOJA) process for rational drug-selection was developed. This article describes how the information on which the SOJA process is based, was researched and processed.

Heuristics and Biases in Military Decision Making

DTIC Science & Technology

2010-10-01

rationality and is based on a linear, step-based model that generates a specific course of action and is useful for the examination of problems that...exhibit stability and are underpinned by assumptions of “technical- rationality .”5 The Army values MDMP as the sanctioned approach for solving...theory) which sought to describe human behavior as a rational maximization of cost-benefit decisions, Kahne- man and Tversky provided a simple

Economic reasoning and artificial intelligence.

PubMed

Parkes, David C; Wellman, Michael P

2015-07-17

The field of artificial intelligence (AI) strives to build rational agents capable of perceiving the world around them and taking actions to advance specified goals. Put another way, AI researchers aim to construct a synthetic homo economicus, the mythical perfectly rational agent of neoclassical economics. We review progress toward creating this new species of machine, machina economicus, and discuss some challenges in designing AIs that can reason effectively in economic contexts. Supposing that AI succeeds in this quest, or at least comes close enough that it is useful to think about AIs in rationalistic terms, we ask how to design the rules of interaction in multi-agent systems that come to represent an economy of AIs. Theories of normative design from economics may prove more relevant for artificial agents than human agents, with AIs that better respect idealized assumptions of rationality than people, interacting through novel rules and incentive systems quite distinct from those tailored for people. Copyright © 2015, American Association for the Advancement of Science.

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

PubMed Central

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

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

PubMed

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.

Attributional biases about the origins of attitudes: externality, emotionality, and rationality.

PubMed

Kenworthy, Jared B; Miller, Norman

2002-05-01

Pilot work and 3 studies investigated the ways people explain the origins of attitudes. Study I examined the use of 3 dimensions (externality, rationality, emotionality) to explain the origin of people's own, in-group, and out-group attitudes. Attributions for own attitudes were the least externally and emotionally based and the most rationally based. By comparison with the out-group, less externality, less emotionality, and more rationality also were attributed to in-group attitudes. Studies 2 and 3 examined the effects of intergroup threat on attributions for in- and out-group attitude positions. Under high threat, more externality and emotionality but less rationality were attributed to out-group attitudes than under low threat. Intergroup differentiation mediated the difference between out-group attributions under high and low threat.

Issues of Dynamic Coalition Formation Among Rational Agents

DTIC Science & Technology

2002-04-01

approaches of forming stable coalitions among rational agents. Issues and problems of dynamic coalition environments are discussed in section 3 while...2.2. 2.1.2 Coalition Algorithm, Coalition Formation Environment and Model Rational agents which are involved in a co-operative game (A,v) are...publicly available simulation environment for coalition formation among rational information agents based on selected classic coalition theories is, for

Multifunctional Self-Assembled Monolayers for Organic Field-Effect Transistors

NASA Astrophysics Data System (ADS)

Cernetic, Nathan

Organic field effect transistors (OFETs) have the potential to reach commercialization for a wide variety of applications such as active matrix display circuitry, chemical and biological sensing, radio-frequency identification devices and flexible electronics. In order to be commercially competitive with already at-market amorphous silicon devices, OFETs need to approach similar performance levels. Significant progress has been made in developing high performance organic semiconductors and dielectric materials. Additionally, a common route to improve the performance metric of OFETs is via interface modification at the critical dielectric/semiconductor and electrode/semiconductor interface which often play a significant role in charge transport properties. These metal oxide interfaces are typically modified with rationally designed multifunctional self-assembled monolayers. As means toward improving the performance metrics of OFETs, rationally designed multifunctional self-assembled monolayers are used to explore the relationship between surface energy, SAM order, and SAM dipole on OFET performance. The studies presented within are (1) development of a multifunctional SAM capable of simultaneously modifying dielectric and metal surface while maintaining compatibility with solution processed techniques (2) exploration of the relationship between SAM dipole and anchor group on graphene transistors, and (3) development of self-assembled monolayer field-effect transistor in which the traditional thick organic semiconductor is replaced by a rationally designed self-assembled monolayer semiconductor. The findings presented within represent advancement in the understanding of the influence of self-assembled monolayers on OFETs as well as progress towards rationally designed monolayer transistors.

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.

PubMed

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.

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

PubMed

Li, Yilin; Li, Zhipeng; Ablekim, Tursunjan; Ren, Tianhui; Dong, Wen-Ji

2014-12-21

A rational design strategy of novel fluorophores for luminescent down-shifting (LDS) application was proposed and tested in this paper. Three new fluorophores (1a-c) with specific intramolecular charge transfer (ICT) and aggregation-induced emission (AIE) characteristics were synthesized as LDS molecules for increasing the output short circuit current density (Jsc) of a CdTe solar cell. Photophysical studies of their solution and solid states, and photovoltaic measurements of their PMMA solid films applied on a CdTe solar cell suggested that the specific spectroscopic properties and Jsc enhancement effects of these molecules were highly related to their chemical structures. The Jsc enhancement effects of these fluorophores were measured on both a CdTe small cell and a large panel. An increase in the output Jsc by as high as 5.69% for a small cell and 8.88% for a large panel was observed. Compared to a traditional LDS molecule, Y083, these fluorophores exhibited more superior capabilities of LDS.

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

NASA Astrophysics Data System (ADS)

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

2014-09-01

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Chunlong; Qi, Jiahui; Tao, Jinhui

2014-09-05

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

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

PubMed Central

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

Reversed enantioselectivity of diisopropyl fluorophosphatase against organophosphorus nerve agents by rational design.

PubMed

Melzer, Marco; Chen, Julian C-H; Heidenreich, Anne; Gäb, Jürgen; Koller, Marianne; Kehe, Kai; Blum, Marc-Michael

2009-12-02

Diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris is an efficient and robust biocatalyst for the hydrolysis of a range of highly toxic organophosphorus compounds including the nerve agents sarin, soman, and cyclosarin. In contrast to the substrate diisopropyl fluorophosphate (DFP) the nerve agents possess an asymmetric phosphorus atom, which leads to pairs of enantiomers that display markedly different toxicities. Wild-type DFPase prefers the less toxic stereoisomers of the substrates which leads to slower detoxification despite rapid hydrolysis. Enzyme engineering efforts based on rational design yielded two quadruple enzyme mutants with reversed enantioselectivity and overall enhanced activity against tested nerve agents. The reversed stereochemical preference is explained through modeling studies and the crystal structures of the two mutants. Using the engineered mutants in combination with wild-type DFPase leads to significantly enhanced activity and detoxification, which is especially important for personal decontamination. Our findings may also be of relevance for the structurally related enzyme human paraoxonase (PON), which is of considerable interest as a potential catalytic in vivo scavenger in case of organophosphorus poisoning.

Effect of duration of fasting and a short-term high-roughage ration on the concentration of Escherichia coli biotype 1 in cattle feces.

PubMed

Jordan, D; McEwen, S A

1998-05-01

A field trial using cattle from a commercial feedlot was conducted to quantify the effect of duration of fasting and a temporary change in ration on the concentration of Escherichia coli biotype 1 in feces. A nested hierarchical design with repeated measures through time was used. Two groups of 20 British x European breed beef steers having reached slaughter weight (mean live weight 685 kg; SD 50 kg) were fed entirely on a high-energy ration typical of that used in the Ontario beef finishing industry or were switched for 4 days onto a high-roughage ration. This was followed by a period of fasting and water deprivation to mimic that which occurs prior to slaughter. Fecal samples were collected at 0, 24, and 48 h of fasting, and for each sample the total presumptive E. coli (biotype 1) CFU/g of feces was enumerated by spiral plating. Estimates of effect for the design factors were obtained by restricted maximum likelihood, and these were compared to robust counterparts obtained from generalized estimating equations. Results indicated that the ration, the duration of fasting, and their interaction had significant effects on total log E. coli concentration in feces. Cattle on the high-roughage ration for four days had a significantly lower initial log E. coli CFU/g of feces compared to cattle on the normal ration, but after 48 h of fasting they had a significantly higher concentration. It is concluded that while a temporary change in ration and duration of fasting does affect E. coli concentration in feces, these changes do not seem large enough to deliver a drastic improvement in beef carcass hygiene should they be incorporated in hazard analysis and critical control point (HACCP) plans for the preslaughter period of beef production.

Differential Rationality and Personal Development.

ERIC Educational Resources Information Center

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…

Open-Shell-Character-Based Molecular Design Principles: Applications to Nonlinear Optics and Singlet Fission.

PubMed

Nakano, Masayoshi

2017-01-01

Open-shell character, e. g., diradical character, is a quantum chemically well-defined quantity in ground-state molecular systems, which is not an observable but can quantify the degree of effective bond weakness in the chemical sense or electron correlation strength in the physical sense. Because this quantity also correlates to specific excited states, physicochemical properties concerned with those states are expected to strongly correlate to the open-shell character. This feature enables us to open a new path to revealing the mechanism of these properties as well as to realizing new design principles for efficient functional molecular systems. This account explains the open-shell-character-based molecular design principles and introduces their applications to the rational design of highly efficient nonlinear optical and singlet fission molecular systems. © 2017 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Refusals and Rejections: Designing Messages to Serve Multiple Goals.

ERIC Educational Resources Information Center

Saeki, Mimako; O'Keefe, Barbara J.

1994-01-01

Tests a rational model of the elaboration of themes found in rejection messages, using Japanese and American participants. Finds partial support for the initial rational model but notes two key revisions: identifies two new themes in rejection messages and suggests substantial differences in the way Americans and Japanese elaborate themes to serve…

Decision-Making: Are Plants More Rational than Animals?

PubMed

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.

Joint Tactics, Techniques, and Procedures for Joint Special Operations Task Force Operations

DTIC Science & Technology

2001-12-19

phase? Is a ration cycle proposed? •• Are fresh eggs, fresh fruits and vegetables, fresh meats, juices, milk , and canned soft-drink supplements to ration...measures designed to mislead the enemy by manipulation, distortion, or falsification of evidence to induce the enemy to react in a manner prejudicial to

Rational-operator-based depth-from-defocus approach to scene reconstruction.

PubMed

Li, Ang; Staunton, Richard; Tjahjadi, Tardi

2013-09-01

This paper presents a rational-operator-based approach to depth from defocus (DfD) for the reconstruction of three-dimensional scenes from two-dimensional images, which enables fast DfD computation that is independent of scene textures. Two variants of the approach, one using the Gaussian rational operators (ROs) that are based on the Gaussian point spread function (PSF) and the second based on the generalized Gaussian PSF, are considered. A novel DfD correction method is also presented to further improve the performance of the approach. Experimental results are considered for real scenes and show that both approaches outperform existing RO-based methods.

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

NASA Technical Reports Server (NTRS)

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

1994-01-01

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

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

PubMed

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.

Recent advances in medicinal chemistry of sulfonamides. Rational design as anti-tumoral, anti-bacterial and anti-inflammatory agents.

PubMed

Shah, Syed Shoaib Ahmad; Rivera, Gildardo; Ashfaq, Muhammad

2013-01-01

Now-a-days, cancer is becoming one of the major problems of public health in the world. Pharmacology treatment is a way to increase quality and long life. Predominantly, in last decade sulfonamide derivatives have been described as potential carbonic anhydrase inhibitors. In the present work, we describe recent advances during the last decade in medicinal chemistry of sulfonamides derivatives with some examples of rational design as anti-tumoral, antibacterial and anti-inflammatory agents. We show strategy design, structure-activity relationship, biological activity and advances of new sulfonamide compounds that have more health significance than some clinically used sulfonamides.

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

PubMed Central

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

2016-01-01

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

A rational design for hepatitis B virus X protein refolding and bioprocess development guided by second virial coefficient studies.

PubMed

Basu, Anindya; Chen, Wei Ning; Leong, Susanna Su Jan

2011-04-01

The hepatitis B virus X (HBx) protein is well known for its role in hepatitis B virus infection that often leads to hepatocellular carcinoma. Despite the clinical importance of HBx, there is little progress in anti-HBx drug development strategies due to shortage of HBx from native sources. Consistent expression of HBx as insoluble inclusion bodies within various expression systems has largely hindered HBx manufacturing via economical biosynthesis routes. Confronted by this roadblock, this study aims to quantitatively understand HBx protein behaviour in solution that will guide the rational development of a refolding-based bioprocess for HBx production. Second virial coefficient (SVC) measurements were employed to study the effects of varying physicochemical parameters on HBx intermolecular protein interaction. The SVC results suggest that covalent HBx aggregates play a key role in protein destabilisation during refolding. The use of an SVC-optimised refolding environment yielded bioactive and soluble HBx proteins from the denatured-reduced inclusion body state. This study provides new knowledge on HBx solubility behaviour in vitro, which is important in structure-function elucidation behaviour of this hydrophobic protein. Importantly, a rational refolding-based Escherichia coli bioprocess that can deliver purified and soluble HBx at large scale is successfully developed, which opens the way for rapid preparation of soluble HBx for further clinical and characterisation studies.

Symbolism and rationality in the politics of psychoactive substances.

PubMed

Room, Robin

2005-01-01

Psychoactive substances take on many symbolic meanings, and thus the politics of psychoactive substances has featured symbolic elements, or value-based rationality, alongside and often dominating instrumental rationality. Drawing particularly on the work of Joseph Gusfield and Nordic scholars, the chapter considers the symbolic dimension in the politics of substance use, even in Nordic countries celebrated for their societal commitment to knowledge-based policymaking, and its effects on the interplay of science and policy.

Application of a Genetic Algorithm and Multi Agent System to Explore Emergent Patterns of Social Rationality and a Distress-Based Model for Deceit in the Workplace

DTIC Science & Technology

2008-06-01

postponed the fulfillment of her own Masters Degree by at least 18 months so that I would have the opportunity to earn mine. She is smart , lovely...GENETIC ALGORITHM AND MULTI AGENT SYSTEM TO EXPLORE EMERGENT PATTERNS OF SOCIAL RATIONALITY AND A DISTRESS-BASED MODEL FOR DECEIT IN THE WORKPLACE...of a Genetic Algorithm and Mutli Agent System to Explore Emergent Patterns of Social Rationality and a Distress-Based Model for Deceit in the

Rational and experiential decision-making preferences of third-year student pharmacists.

PubMed

McLaughlin, Jacqueline E; Cox, Wendy C; Williams, Charlene R; Shepherd, Greene

2014-08-15

To examine the rational (systematic and rule-based) and experiential (fast and intuitive) decision-making preferences of student pharmacists, and to compare these preferences to the preferences of other health professionals and student populations. The Rational-Experiential Inventory (REI-40), a validated psychometric tool, was administered electronically to 114 third-year (P3) student pharmacists. Student demographics and preadmission data were collected. The REI-40 results were compared with student demographics and admissions data to identify possible correlations between these factors. Mean REI-40 rational scores were higher than experiential scores. Rational scores for younger students were significantly higher than students aged 30 years and older (p<0.05). No significant differences were found based on gender, race, or the presence of a prior degree. All correlations between REI-40 scores and incoming grade point average (GPA) and Pharmacy College Admission Test (PCAT) scores were weak. Student pharmacists favored rational decision making over experiential decision making, which was similar to results of studies done of other health professions.

Cognitive success: instrumental justifications of normative systems of reasoning

PubMed Central

Schurz, Gerhard

2014-01-01

In the first part of the paper (sec. 1–4), I argue that Elqayam and Evan's (2011) distinction between normative and instrumental conceptions of cognitive rationality corresponds to deontological vs. teleological accounts in meta-ethics. I suggest that Elqayam and Evans' distinction be replaced by the distinction between a-priori intuition-based vs. a-posteriori success-based accounts of cognitive rationality. The value of cognitive success lies in its instrumental rationality for almost-all practical purposes. In the second part (sec. 5–7), I point out that the Elqayam and Evans's distinction between normative and instrumental rationality is coupled with a second distinction: between logically general vs. locally adaptive accounts of rationality. I argue that these are two independent distinctions that should be treated as independent dimensions. I also demonstrate that logically general systems of reasoning can be instrumentally justified. However, such systems can only be cognitively successful if they are paired with successful inductive reasoning, which is the area where the program of adaptive (ecological) rationality emerged, because there are no generally optimal inductive reasoning methods. I argue that the practical necessity of reasoning under changing environments constitutes a dilemma for ecological rationality, which I attempt to solve within a dual account of rationality. PMID:25071624

Rapid communication: Computational simulation and analysis of a candidate for the design of a novel silk-based biopolymer.

PubMed

Golas, Ewa I; Czaplewski, Cezary

2014-09-01

This work theoretically investigates the mechanical properties of a novel silk-derived biopolymer as polymerized in silico from sericin and elastin-like monomers. Molecular Dynamics simulations and Steered Molecular Dynamics were the principal computational methods used, the latter of which applies an external force onto the system and thereby enables an observation of its response to stress. The models explored herein are single-molecule approximations, and primarily serve as tools in a rational design process for the preliminary assessment of properties in a new material candidate. © 2014 Wiley Periodicals, Inc.

Fundamental understanding and rational design of high energy structural microbatteries

DOE PAGES

Wang, Yuxing; Li, Qiuyan; Cartmell, Samuel; ...

2017-11-21

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 duringmore » the rolling process are discussed providing new insights in designing the structural microbatteries for emerging technologies.« less

Fundamental understanding and rational design of high energy structural microbatteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Yuxing; Li, Qiuyan; Cartmell, Samuel

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 duringmore » the rolling process are discussed providing new insights in designing the structural microbatteries for emerging technologies.« less

Submarine pipeline on-bottom stability. Volume 2: Software and manuals

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1998-12-01

The state-of-the-art in pipeline stability design has been changing very rapidly recent. The physics governing on-bottom stability are much better understood now than they were eight years. This is due largely because of research and large scale model tests sponsored by PRCI. Analysis tools utilizing this new knowledge have been developed. These tools provide the design engineer with a rational approach have been developed. These tools provide the design engineer with a rational approach for weight coating design, which he can use with confidence because the tools have been developed based on full scale and near full scale model tests.more » These tools represent the state-of-the-art in stability design and model the complex behavior of pipes subjected to both wave and current loads. These include: hydrodynamic forces which account for the effect of the wake (generated by flow over the pipe) washing back and forth over the pipe in oscillatory flow; and the embedment (digging) which occurs as a pipe resting on the seabed is exposed to oscillatory loadings and small oscillatory deflections. This report has been developed as a reference handbook for use in on-bottom pipeline stability analysis It consists of two volumes. Volume one is devoted descriptions of the various aspects of the problem: the pipeline design process; ocean physics, wave mechanics, hydrodynamic forces, and meteorological data determination; geotechnical data collection and soil mechanics; and stability design procedures. Volume two describes, lists, and illustrates the analysis software. Diskettes containing the software and examples of the software are also included in Volume two.« less

Parity for mental health and substance abuse care under managed care.

PubMed

Frank, Richard G.; McGuire, Thomas G.

1998-12-01

BACKGROUND: Parity in insurance coverage for mental health and substance abuse has been a key goal of mental health and substance abuse care advocates in the United States during most of the past 20 years. The push for parity began during the era of indemnity insurance and fee for service payment when benefit design was the main rationing device in health care. The central economic argument for enacting legislation aimed at regulating the insurance benefit was to address market failure stemming from adverse selection. The case against parity was based on inefficiency related to moral hazard. Empirical analyses provided evidence that ambulatory mental health services were considerably more responsive to the terms of insurance than were ambulatory medical services. AIMS: Our goal in this research is to reexamine the economics of parity in the light of recent changes in the delivery of health care in the United States. Specifically managed care has fundamentally altered the way in which health services are rationed. Benefit design is now only one mechanism among many that are used to allocate health care resources and control costs. We examine the implication of these changes for policies aimed at achieving parity in insurance coverage. METHOD: We develop a theoretical approach to characterizing rationing under managed care. We then analyze the traditional efficiency concerns in insurance, adverse selection and moral hazard in the context of policy aimed at regulating health and mental health benefits under private insurance. RESULTS: We show that since managed care controls costs and utilization in new ways parity in benefit design no longer implies equal access to and quality of mental health and substance abuse care. Because costs are controlled by management under managed care and not primarily by out of pocket prices paid by consumers, demand response recedes as an efficiency argument against parity. At the same time parity in benefit design may accomplish less with respect to providing a remedy to problems related to adverse selection.

Advances in drying: Volume 4

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mujumdar, A.S.

1987-01-01

Topics covered in this volume include recent thoughts in modeling of drying phenomena, use of computers in rational design of drying particulates, recent advances in drying of wood, and heat/mass transfer phenomena in drying of solids. As the readers will no doubt notice, special effort is made to ensure the truly international nature of the contents of this serial publication. As existing knowledge on drying and dryers becomes more widely and readily accessible, it is expected that more and more dryers will be designed rationally rather than built solely with the benefit of empiricism.

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

NASA Technical Reports Server (NTRS)

Carter, Daniel C. (Inventor)

1994-01-01

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

Gravimetric chemical sensors based on silica-based mesoporous organic-inorganic hybrids.

PubMed

Xu, Jiaqiang; Zheng, Qi; Zhu, Yongheng; Lou, Huihui; Xiang, Qun; Cheng, Zhixuan

2014-09-01

Silica-based mesoporous organic-inorganic hybrid material modified quartz crystal microbalance (QCM) sensors have been examined for their ability to achieve highly sensitive and selective detection. Mesoporous silica SBA-15 serves as an inorganic host with large specific surface area, facilitating gas adsorption, and thus leads to highly sensitive response; while the presence of organic functional groups contributes to the greatly improved specific sensing property. In this work, we summarize our efforts in the rational design and synthesis of novel sensing materials for the detection of hazardous substances, including simulant nerve agent, organic vapor, and heavy metal ion, and develop high-performance QCM-based chemical sensors.

Network-based Approaches in Pharmacology.

PubMed

Boezio, Baptiste; Audouze, Karine; Ducrot, Pierre; Taboureau, Olivier

2017-10-01

In drug discovery, network-based approaches are expected to spotlight our understanding of drug action across multiple layers of information. On one hand, network pharmacology considers the drug response in the context of a cellular or phenotypic network. On the other hand, a chemical-based network is a promising alternative for characterizing the chemical space. Both can provide complementary support for the development of rational drug design and better knowledge of the mechanisms underlying the multiple actions of drugs. Recent progress in both concepts is discussed here. In addition, a network-based approach using drug-target-therapy data is introduced as an example. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

PubMed

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.

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

PubMed

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.

Design and synthesis of type-III mimetics of ShK toxin

NASA Astrophysics Data System (ADS)

Baell, Jonathan B.; Harvey, Andrew J.; Norton, Raymond S.

2002-04-01

ShK toxin is a structurally defined, 35-residue polypeptide which blocks the voltage-gated Kv1.3 potassium channel in T-lymphocytes and has been identified as a possible immunosuppressant. Our interest lies in the rational design and synthesis of type-III mimetics of protein and polypeptide structure and function. ShK toxin is a challenging target for mimetic design as its binding epitope consists of relatively weakly binding residues, some of which are discontinuous. We discuss here our investigations into the design and synthesis of 1st generation, small molecule mimetics of ShK toxin and highlight any principles relevant to the generic design of type-III mimetics of continuous and discontinuous binding epitopes. We complement our approach with attempted pharmacophore-based database mining.

Specification for Visual Requirements of Work-Centered Software Systems

DTIC Science & Technology

2006-10-01

no person shall be subject to any penity for fallng to comply wih a collection of N ilo ration it does not display a currenty valid OMB control...work- aiding systems. Based on the design concept for a work- centered support system (WCSS), these software systems support user tasks and goals...through both direct and indirect aiding methods within the interface client. In order to ensure the coherent development and delivery of work- centered

Clearing the smoke around medical marijuana.

PubMed

Ware, M A

2011-12-01

The hazy world of "medical marijuana" continues to cry out for clear data on which to base medical decision making and rational policy design. In this issue of Clinical Pharmacology & Therapeutics, Abrams and colleagues report that vaporized cannabis does not meaningfully affect opioid plasma levels and may even augment the efficacy of oxycodone and morphine in patients with chronic non-cancer pain. This Commentary considers the implications of this work for clinical practice and further research initiatives.

A Snack-based Ration Containing Caffeine Increases Caloric Intake and Improves Cognitive Performance

DTIC Science & Technology

2011-05-01

of Environmental Medicine, Natick, MA. Volunteers who indicated that they were vegetarian , pregnant, or older than 55 yrs were excluded from...others in the group. The positive effects associated with the FSR® occurred despite little differences between the response of the diet groups to the...by the field exercise. The present study was designed so that blood caffeine levels would be distinctly different between diet groups at the time of

Aeroelastic Deflection of NURBS Geometry

NASA Technical Reports Server (NTRS)

Samareh, Jamshid A.

1998-01-01

The purpose of this paper is to present an algorithm for using NonUniform Rational B-Spline (NURBS) representation in an aeroelastic loop. The algorithm is based on creating a least-squares NURBS surface representing the aeroelastic defection. The resulting NURBS surfaces are used to update either the original Computer- Aided Design (CAD) model, Computational Structural Mechanics (CSM) grid or the Computational Fluid Dynamics (CFD) grid. Results are presented for a generic High-Speed Civil Transport (HSCT).

In silico design of supramolecules from their precursors: odd-even effects in cage-forming reactions.

PubMed

Jelfs, Kim E; Eden, Edward G B; Culshaw, Jamie L; Shakespeare, Stephen; Pyzer-Knapp, Edward O; Thompson, Hugh P G; Bacsa, John; Day, Graeme M; Adams, Dave J; Cooper, Andrew I

2013-06-26

We synthesize a series of imine cage molecules where increasing the chain length of the alkanediamine precursor results in an odd-even alternation between [2 + 3] and [4 + 6] cage macrocycles. A computational procedure is developed to predict the thermodynamically preferred product and the lowest energy conformer, hence rationalizing the observed alternation and the 3D cage structures, based on knowledge of the precursors alone.

In silico Design of Supramolecules from Their Precursors: Odd–Even Effects in Cage-Forming Reactions

PubMed Central

2013-01-01

We synthesize a series of imine cage molecules where increasing the chain length of the alkanediamine precursor results in an odd–even alternation between [2 + 3] and [4 + 6] cage macrocycles. A computational procedure is developed to predict the thermodynamically preferred product and the lowest energy conformer, hence rationalizing the observed alternation and the 3D cage structures, based on knowledge of the precursors alone. PMID:23745577

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

PubMed

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

2015-04-01

In this work, we sought to rationally design membrane-active peptides that are triggered by low pH to form macromolecular-sized pores in lipid bilayers. Such peptides could have broad utility in biotechnology and in nanomedicine as cancer therapeutics or drug delivery vehicles that promote release of macromolecules from endosomes. Our approach to rational design was to combine the properties of a pH-independent peptide, MelP5, which forms large pores allowing passage of macromolecules, with the properties of two pH-dependent membrane-active peptides, pHlip and GALA. We created two hybrid sequences, MelP5_Δ4 and MelP5_Δ6, by using the distribution of acidic residues on pHlip and GALA as a guide to insert acidic amino acids into the amphipathic helix of MelP5. We show that the new peptides bind to lipid bilayers and acquire secondary structure in a pH-dependent manner. The peptides also destabilize bilayers in a pH-dependent manner, such that lipid vesicles release the small molecules ANTS/DPX at low pH only. Thus, we were successful in designing pH-triggered pore-forming peptides. However, no macromolecular release was observed under any conditions. Therefore, we abolished the unique macromolecular poration properties of MelP5 by introducing pH sensitivity into its sequence. We conclude that the properties of pHlip, GALA, and MelP5 are additive, but only partially so. We propose that this lack of additivity is a limitation in the rational design of novel membrane-active peptides, and that high-throughput approaches to discovery will be critical for continued progress in the field. Copyright © 2015 Elsevier B.V. All rights reserved.

Rationing medical education.

PubMed

Walsh, Kieran

2016-03-01

The purpose of this paper is to discuss the role of rationing in medical education. Medical education is expensive and there is a limit to that which governments, funders or individuals can spend on it. Rationing involves the allocation of resources that are limited. This paper discussed the pros and cons of the application of rationing to medical education and the different forms of rationing that could be applied. Even though some stakeholders in medical education might be taken aback at the prospect of rationing, the truth is that rationing has always occurred in one form or another in medical education and in healthcare more broadly. Different types of rationing exist in healthcare professional education. For example rationing may be implicit or explicit or may be based on macro-allocation or micro-allocation decisions. Funding can be distributed equally among learners, or according to the needs of individual learners, or to ensure that overall usefulness is maximised. One final option is to allow the market to operate freely and to decide in that way. These principles of rationing can apply to individual learners or to institutions or departments or learning modes. Rationing is occurring in medical education, even though it might be implicit. It is worth giving consideration to methods of rationing and to make thinking about rationing more explicit.

Li4 Ti5 O12 Anode: Structural Design from Material to Electrode and the Construction of Energy Storage Devices.

PubMed

Chen, Zhijie; Li, Honsen; Wu, Langyuan; Lu, Xiaoxia; Zhang, Xiaogang

2018-03-01

Spinel Li 4 Ti 5 O 12 , known as a zero-strain material, is capable to be a competent anode material for promising applications in state-of-art electrochemical energy storage devices (EESDs). Compared with commercial graphite, spinel Li 4 Ti 5 O 12 offers a high operating potential of ∼1.55 V vs Li/Li + , negligible volume expansion during Li + intercalation process and excellent thermal stability, leading to high safety and favorable cyclability. Despite the merits of Li 4 Ti 5 O 12 been presented, there still remains the issue of Li 4 Ti 5 O 12 suffering from poor electronic conductivity, manifesting disadvantageous rate performance. Typically, a material modification process of Li 4 Ti 5 O 12 will be proposed to overcome such an issue. However, the previous reports have made few investigations and achievements to analyze the subsequent processes after a material modification process. In this review, we attempt to put considerable interest in complete device design and assembly process with its material structure design (or modification process), electrode structure design and device construction design. Moreover, we have systematically concluded a series of representative design schemes, which can be divided into three major categories involving: (1) nanostructures design, conductive material coating process and doping process on material level; (2) self-supporting or flexible electrode structure design on electrode level; (3) rational assembling of lithium ion full cell or lithium ion capacitor on device level. We believe that these rational designs can give an advanced performance for Li 4 Ti 5 O 12 -based energy storage device and deliver a deep inspiration. © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Knowledge Utilization Strategies in the Design and Implementation of New Schools--Symbolic Functions.

ERIC Educational Resources Information Center

Sieber, Sam D.

An examination of case studies suggests that rational processes were not entirely at work in the planning and conception of new, innovative schools. The rational model that serves as the foundation of our information systems assumes that a compelling professional need triggers a search for solutions; and, therefore, school personnel are eager to…

Tuning complement activation and pathway through controlled molecular architecture of dextran chains in nanoparticle corona.

PubMed

Coty, Jean-Baptiste; Eleamen Oliveira, Elquio; Vauthier, Christine

2017-11-05

The understanding of complement activation by nanomaterials is a key to a rational design of safe and efficient nanomedicines. This work proposed a systematic study investigating how molecular design of nanoparticle coronas made of dextran impacts on mechanisms that trigger complement activation. The nanoparticles used for this work consisted of dextran-coated poly(isobutylcyanoacrylate) (PIBCA) nanoparticles have already been thoroughly characterized. Their different capacity to trigger complement activation established on the cleavage of the protein C3 was also already described making these nanoparticles good models to investigate the relation between the molecular feature of their corona and the mechanism by which they triggered complement activation. Results of this new study show that complement activation pathways can be selected by distinct architectures formed by dextran chains composing the nanoparticle corona. Assumptions that explain the relation between complement activation mechanisms triggered by the nanoparticles and the nanoparticle corona molecular feature were proposed. These results are of interest to better understand how the design of dextran-coated nanomaterials will impact interactions with the complement system. It can open perspectives with regard to the selection of a preferential complement activation pathway or prevent the nanoparticles to activate the complement system, based on a rational choice of the corona configuration. Copyright © 2017 Elsevier B.V. All rights reserved.

Design and application of a CA-BDI model to determine farmers' land-use behavior.

PubMed

Liang, Xiaoying; Chen, Hai; Wang, Yanni; Song, Shixiong

2016-01-01

The belief-desire-intention (BDI) model has been widely used to construct reasoning systems for complex tasks in dynamic environments. We have designed a capabilities and abilities (CA)-BDI farmer decision-making model, which is an extension of the BDI architecture and includes internal representations for farmer household Capabilities and Abilities. This model is used to explore farmer learning mechanisms and to simulate the bounded rational decisions made by farmer households. Our case study focuses on the Gaoqu Commune of Mizhi County, Shaanxi Province, China, where scallion is one of the main cash crops. After comparing the differences between actual land-use changes from 2007 to 2009 and the simulation results, we analyze the validity of the model and discuss the potential and limitations of the farmer land-use decision-making model under three scenarios. Based on the design and implementation of the model, the following conclusions can be drawn: (1) the CA-BDI framework is an appropriate model for exploring learning mechanisms and simulating bounded rational decisions; and (2) local governments should encourage scallion planting by assisting scallion farmer cooperatives and farmers to understand the market risk, standardize the rules of their cooperation, and supervise the contracts made between scallion cooperatives and farmers.

Toward rational design of amines for CO2 capture: Substituent effect on kinetic process for the reaction of monoethanolamine with CO2.

PubMed

Xie, Hongbin; Wang, Pan; He, Ning; Yang, Xianhai; Chen, Jingwen

2015-11-01

Amines have been considered as promising candidates for post-combustion CO2 capture. A mechanistic understanding for the chemical processes involved in the capture and release of CO2 is important for the rational design of amines. In this study, the structural effects of amines on the kinetic competition among three typical products (carbamates, carbamic acids and bicarbonate) from amines+CO2 were investigated, in contrast to previous thermodynamic studies to tune the reaction of amines with CO2 based on desirable reaction enthalpy and reaction stoichiometry. We used a quantum chemical method to calculate the activation energies (Ea) for the reactions of a range of substituted monoethanolamines with CO2 covering three pathways to the three products. The results indicate that the formation of carbamates is the most favorable, among the three considered products. In addition, we found that the Ea values for all pathways linearly correlate with pKa of amines, and more importantly, the kinetic competition between carbamate and bicarbonate absorption pathways varies with pKa of the amines, i.e. stronger basicity results in less difference in Ea. These results highlight the importance of the consideration of kinetic competition among different reaction pathways in amine design. Copyright © 2015. Published by Elsevier B.V.

Rational Design of Hyperbranched Nanowire Systems for Tunable Superomniphobic Surfaces Enabled by Atomic Layer Deposition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bielinski, Ashley R.; Boban, Mathew; He, Yang

2017-01-24

A method for tunable control of geometry in hyperbranched ZnO nanowire (NW) systems is reported, which enables the rational design and fabrication of superomniphobic surfaces. Branched NWs with tunable density and orientation were grown via a sequential hydrothermal process, in which atomic layer deposition (ALD) was used for NW seeding, disruption of epitaxy, and selective blocking of NW nucleation. This approach allows for the rational design and optimization of three-level hierarchical structures, in which the geometric parameters of each level of hierarchy can be individually controlled. We demonstrate the coupled relationships between geometry and contact angle for a variety ofmore » liquids, which is supported by mathematical models of structural superomniphobicity. The highest performing superomniphobic surface was designed with three levels of hierarchy and achieved the following advancing/receding contact angles, water: 172°/170°, hexadecane: 166°/156°, octane: 162°/145°, and heptane: 160°/130°. Low surface tension liquids were shown to bounce off the surface from a height of 7 cm without breaking through and wetting. This approach demonstrates the power of ALD as an enabling technique for hierarchical materials by design, spanning the macro, micro, and nano length scales.« less

The Rational-Reality Based Approach to Treating the Criminal Child Abuser.

ERIC Educational Resources Information Center

Cox, Steven G.

1979-01-01

This appraoch to treating child abusers incorporates the philosophies of Rational Behavior Training and Reality Therapy into a therapeutic strategy that helps clients to learn skills in making rational decisions that can aid them in living harmoniously within the family structure. Five specific techniques are presented. (Author)

A "Mindful Rational Living" Approach for Addressing HIV in the School Setting

ERIC Educational Resources Information Center

Chenneville, Tiffany; St. John Walsh, Audra

2016-01-01

This paper describes a "mindful rational living" approach, which incorporates mindfulness techniques with rational emotive behavioral therapy strategies for addressing HIV in the school setting. The utility of this approach for attending to the physical, mental, and psychosocial aspects of school-based HIV prevention and treatment will…

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

PubMed Central

Jin, Ruifa; Wang, Kai

2015-01-01

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

Economic rationality and health and lifestyle choices for people with diabetes.

PubMed

Baker, Rachel Mairi

2006-11-01

Economic rationality is traditionally represented by goal-oriented, maximising behaviour, or 'instrumental rationality'. Such a consequentialist, instrumental model of choice is often implicit in a biomedical approach to health promotion and education. The research reported here assesses the relevance of a broader conceptual framework of rationality, which includes 'procedural' and 'expressive' rationality as complements to an instrumental model of rationality, in a health context. Q methodology was used to derive 'factors' underlying health and lifestyle choices, based on a factor analysis of the results of a card sorting procedure undertaken by 27 adult respondents with type 2 diabetes in Newcastle upon Tyne, UK. These factors were then compared with the rationality framework and the appropriateness of an extended model of economic rationality as a means of better understanding health and lifestyle choices was assessed. Taking a wider rational choice perspective, choices which are rendered irrational within a narrow-biomedical or strictly instrumental model, can be understood in terms of a coherent rationale, grounded in the accounts of respondents. The implications of these findings are discussed in terms of rational choice theory and diabetes management and research.

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

PubMed

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.

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

PubMed

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.

The NMatrix, a new method of presenting statistics, displays the characteristics of medicines with similar effects used in the treatment of lumbar spinal stenosis concisely and clearly, facilitating the selection of appropriate medications.

PubMed

Nakamura, Masao

2015-07-01

It is often difficult to compare the characteristics of a medicine with those of others based on common standards, whereas the application of rational standards would be expected to facilitate the comparison of medicines with similar effects. The present study was conducted to clarify the characteristics of individual medicines and to examine whether rational standards allow the most appropriate medicines to be chosen. Participants diagnosed with lumbar spinal stenosis (LSS) were assessed for QOL and ADL based on the Roland-Morris Disability Questionnaire, JOA score, VAS, and the presence of intermittent claudication (IC). Four medicines--beraprost sodium, ethyl icosapentate (EPA), sarpogrelate hydrochloride, and limaprost alfadex (PGE1)--were prescribed in a random manner. These four medicines were assessed independently in four studies using the same study design and size in each case. Using the NMatrix, the characteristics of the four medicines and the results of mutual comparisons could be displayed concisely and clearly in one matrix based on significance levels. This work involved analyzing pooled data from the four studies. All four medicines improved IC--one of the characteristic symptoms of LSS--by 12 weeks after administration. PGE1 required more time than the other medicines to affect IC. EPA appeared to almost significantly ameliorate some items at every point, though the evidence was insufficient. The NMatrix concisely and clearly displays the characteristics of "medicines with similar effects" for the treatment of lumbar spinal stenosis, and can help physicians to choose the optimal medicine based on rational criteria for individual patients, according to their symptoms and progress.

DNA rendering of polyhedral meshes at the nanoscale

NASA Astrophysics Data System (ADS)

Benson, Erik; Mohammed, Abdulmelik; Gardell, Johan; Masich, Sergej; Czeizler, Eugen; Orponen, Pekka; Högberg, Björn

2015-07-01

It was suggested more than thirty years ago that Watson-Crick base pairing might be used for the rational design of nanometre-scale structures from nucleic acids. Since then, and especially since the introduction of the origami technique, DNA nanotechnology has enabled increasingly more complex structures. But although general approaches for creating DNA origami polygonal meshes and design software are available, there are still important constraints arising from DNA geometry and sense/antisense pairing, necessitating some manual adjustment during the design process. Here we present a general method of folding arbitrary polygonal digital meshes in DNA that readily produces structures that would be very difficult to realize using previous approaches. The design process is highly automated, using a routeing algorithm based on graph theory and a relaxation simulation that traces scaffold strands through the target structures. Moreover, unlike conventional origami designs built from close-packed helices, our structures have a more open conformation with one helix per edge and are therefore stable under the ionic conditions usually used in biological assays.

DNA rendering of polyhedral meshes at the nanoscale.

PubMed

Benson, Erik; Mohammed, Abdulmelik; Gardell, Johan; Masich, Sergej; Czeizler, Eugen; Orponen, Pekka; Högberg, Björn

2015-07-23

It was suggested more than thirty years ago that Watson-Crick base pairing might be used for the rational design of nanometre-scale structures from nucleic acids. Since then, and especially since the introduction of the origami technique, DNA nanotechnology has enabled increasingly more complex structures. But although general approaches for creating DNA origami polygonal meshes and design software are available, there are still important constraints arising from DNA geometry and sense/antisense pairing, necessitating some manual adjustment during the design process. Here we present a general method of folding arbitrary polygonal digital meshes in DNA that readily produces structures that would be very difficult to realize using previous approaches. The design process is highly automated, using a routeing algorithm based on graph theory and a relaxation simulation that traces scaffold strands through the target structures. Moreover, unlike conventional origami designs built from close-packed helices, our structures have a more open conformation with one helix per edge and are therefore stable under the ionic conditions usually used in biological assays.

The Design of Case Products’ Shape Form Information Database Based on NURBS Surface

NASA Astrophysics Data System (ADS)

Liu, Xing; Liu, Guo-zhong; Xu, Nuo-qi; Zhang, Wei-she

2017-07-01

In order to improve the computer design of product shape design,applying the Non-uniform Rational B-splines(NURBS) of curves and surfaces surface to the representation of the product shape helps designers to design the product effectively.On the basis of the typical product image contour extraction and using Pro/Engineer(Pro/E) to extract the geometric feature of scanning mold,in order to structure the information data base system of value point,control point and node vector parameter information,this paper put forward a unified expression method of using NURBS curves and surfaces to describe products’ geometric shape and using matrix laboratory(MATLAB) to simulate when products have the same or similar function.A case study of electric vehicle’s front cover illustrates the access process of geometric shape information of case product in this paper.This method can not only greatly reduce the capacity of information debate,but also improve the effectiveness of computer aided geometric innovation modeling.

Simple triple-state polymer actuators with controllable folding characteristics

NASA Astrophysics Data System (ADS)

Chen, Shuyang; Li, Jing; Fang, Lichen; Zhu, Zeyu; Kang, Sung Hoon

2017-03-01

Driven by the interests in self-folding, there have been studies developing artificial self-folding structures at different length scales based on various polymer actuators that can realize dual-state actuation. However, their unidirectional nature limits the applicability of the actuators for a wide range of multi-state self-folding behaviors. In addition, complex fabrication and programming procedures hinder broad applications of existing polymer actuators. Moreover, few of the existing polymer actuators are able to show the self-folding behaviors with the precise control of curvature and force. To address these issues, we report an easy-to-fabricate triple-state actuator with controllable folding behaviors based on bilayer polymer composites with different glass transition temperatures. Initially, the fabricated actuator is in the flat state, and it can sequentially self-fold to angled folding states of opposite directions as it is heated up. Based on an analytical model and measured partial recovery behaviors of polymers, we can accurately control the folding characteristics (curvature and force) for the rational design. To demonstrate an application of our triple-state actuator, we have developed a self-folding transformer robot which self-folds from a two-dimensional sheet into a three-dimensional boat-like configuration and transforms from the boat shape to a car shape with the increase in the temperature applied to the actuator. Our findings offer a simple approach to generate multiple configurations from a single system by harnessing behaviors of polymers with the rational design.

A theoretical and experimental approach toward the development of affinity adsorbents for GFP and GFP-fusion proteins purification.

PubMed

Fernandes, Cláudia S M; Pina, Ana Sofia; Dias, Ana M G C; Branco, Ricardo J F; Roque, Ana Cecília Afonso

2014-09-30

The green fluorescent protein (GFP) is widely employed to report on a variety of molecular phenomena, but its selective recovery is hampered by the lack of a low-cost and robust purification alternative. This work reports an integrated approach combining rational design and experimental validation toward the optimization of a small fully-synthetic ligand for GFP purification. A total of 56 affinity ligands based on a first-generation lead structure were rationally designed through molecular modeling protocols. The library of ligands was further synthesized by solid-phase combinatorial methods based on the Ugi reaction and screened against Escherichia coli extracts containing GFP. Ligands A4C2, A5C5 and A5C6 emerged as the new lead structures based on the high estimated theoretical affinity constants and the high GFP binding percentages and enrichment factors. The elution of GFP from these adsorbents was further characterized, where the best compromise between mild elution conditions, yield and purity was found for ligands A5C5 and A5C6. These were tested for purifying a model GFP-fusion protein, where ligand A5C5 yielded higher protein recovery and purity. The molecular interactions between the lead ligands and GFP were further assessed by molecular dynamics simulations, showing a wide range of potential hydrophobic and hydrogen-bond interactions. Copyright © 2014 Elsevier B.V. All rights reserved.

Rational design of class I MHC ligands

NASA Astrophysics Data System (ADS)

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

1995-04-01

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

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

PubMed

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.

"Drug" Discovery with the Help of Organic Chemistry.

PubMed

Itoh, Yukihiro; Suzuki, Takayoshi

2017-01-01

The first step in "drug" discovery is to find compounds binding to a potential drug target. In modern medicinal chemistry, the screening of a chemical library, structure-based drug design, and ligand-based drug design, or a combination of these methods, are generally used for identifying the desired compounds. However, they do not necessarily lead to success and there is no infallible method for drug discovery. Therefore, it is important to explore medicinal chemistry based on not only the conventional methods but also new ideas. So far, we have found various compounds as drug candidates. In these studies, some strategies based on organic chemistry have allowed us to find drug candidates, through 1) construction of a focused library using organic reactions and 2) rational design of enzyme inhibitors based on chemical reactions catalyzed by the target enzyme. Medicinal chemistry based on organic chemical reactions could be expected to supplement the conventional methods. In this review, we present drug discovery with the help of organic chemistry showing examples of our explorative studies on histone deacetylase inhibitors and lysine-specific demethylase 1 inhibitors.

Rationality and drug use: an experimental approach.

PubMed

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.

Rational tuning of high-energy visible light absorption for panchromatic small molecules by a two-dimensional conjugation approach

DOE PAGES

He, B.; Zherebetskyy, D.; Wang, H.; ...

2016-02-29

We have demonstrated a rational two-dimensional (2D) conjugation approach towards achieving panchromatic absorption of small molecules. Furthermore, by extending the conjugation on two orthogonal axes of an electron acceptor, namely, bay-annulated indigo (BAI), the optical absorptions could be tuned independently in both high- and low-energy regions. The unconventional modulation of the high-energy absorption is rationalized by density functional theory (DFT) calculations. Finally, we determine that a 2D tuning strategy provides novel guidelines for the design of molecular materials with tailored optoelectronic properties.

Condensation on slippery asymmetric bumps

NASA Astrophysics Data System (ADS)

Park, Kyoo-Chul; Kim, Philseok; Grinthal, Alison; He, Neil; Fox, David; Weaver, James C.; Aizenberg, Joanna

2016-03-01

Controlling dropwise condensation is fundamental to water-harvesting systems, desalination, thermal power generation, air conditioning, distillation towers, and numerous other applications. For any of these, it is essential to design surfaces that enable droplets to grow rapidly and to be shed as quickly as possible. However, approaches based on microscale, nanoscale or molecular-scale textures suffer from intrinsic trade-offs that make it difficult to optimize both growth and transport at once. Here we present a conceptually different design approach—based on principles derived from Namib desert beetles, cacti, and pitcher plants—that synergistically combines these aspects of condensation and substantially outperforms other synthetic surfaces. Inspired by an unconventional interpretation of the role of the beetle’s bumpy surface geometry in promoting condensation, and using theoretical modelling, we show how to maximize vapour diffusion fluxat the apex of convex millimetric bumps by optimizing the radius of curvature and cross-sectional shape. Integrating this apex geometry with a widening slope, analogous to cactus spines, directly couples facilitated droplet growth with fast directional transport, by creating a free-energy profile that drives the droplet down the slope before its growth rate can decrease. This coupling is further enhanced by a slippery, pitcher-plant-inspired nanocoating that facilitates feedback between coalescence-driven growth and capillary-driven motion on the way down. Bumps that are rationally designed to integrate these mechanisms are able to grow and transport large droplets even against gravity and overcome the effect of an unfavourable temperature gradient. We further observe an unprecedented sixfold-higher exponent of growth rate, faster onset, higher steady-state turnover rate, and a greater volume of water collected compared to other surfaces. We envision that this fundamental understanding and rational design strategy can be applied to a wide range of water-harvesting and phase-change heat-transfer applications.

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

PubMed

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.

Promoter and Terminator Discovery and Engineering.

PubMed

Deaner, Matthew; Alper, Hal S

Control of gene expression is crucial to optimize metabolic pathways and synthetic gene networks. Promoters and terminators are stretches of DNA upstream and downstream (respectively) of genes that control both the rate at which the gene is transcribed and the rate at which mRNA is degraded. As a result, both of these elements control net protein expression from a synthetic construct. Thus, it is highly important to discover and engineer promoters and terminators with desired characteristics. This chapter highlights various approaches taken to catalogue these important synthetic elements. Specifically, early strategies have focused largely on semi-rational techniques such as saturation mutagenesis to diversify native promoters and terminators. Next, in an effort to reduce the length of the synthetic biology design cycle, efforts in the field have turned towards the rational design of synthetic promoters and terminators. In this vein, we cover recently developed methods such as hybrid engineering, high throughput characterization, and thermodynamic modeling which allow finer control in the rational design of novel promoters and terminators. Emphasis is placed on the methodologies used and this chapter showcases the utility of these methods across multiple host organisms.

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

PubMed Central

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

Dynamic pricing of network goods with boundedly rational consumers.

PubMed

Radner, Roy; Radunskaya, Ami; Sundararajan, Arun

2014-01-07

We present a model of dynamic monopoly pricing for a good that displays network effects. In contrast with the standard notion of a rational-expectations equilibrium, we model consumers as boundedly rational and unable either to pay immediate attention to each price change or to make accurate forecasts of the adoption of the network good. Our analysis shows that the seller's optimal price trajectory has the following structure: The price is low when the user base is below a target level, is high when the user base is above the target, and is set to keep the user base stationary once the target level has been attained. We show that this pricing policy is robust to a number of extensions, which include the product's user base evolving over time and consumers basing their choices on a mixture of a myopic and a "stubborn" expectation of adoption. Our results differ significantly from those that would be predicted by a model based on rational-expectations equilibrium and are more consistent with the pricing of network goods observed in practice.

Dynamic pricing of network goods with boundedly rational consumers

PubMed Central

Radner, Roy; Radunskaya, Ami; Sundararajan, Arun

2014-01-01

We present a model of dynamic monopoly pricing for a good that displays network effects. In contrast with the standard notion of a rational-expectations equilibrium, we model consumers as boundedly rational and unable either to pay immediate attention to each price change or to make accurate forecasts of the adoption of the network good. Our analysis shows that the seller’s optimal price trajectory has the following structure: The price is low when the user base is below a target level, is high when the user base is above the target, and is set to keep the user base stationary once the target level has been attained. We show that this pricing policy is robust to a number of extensions, which include the product’s user base evolving over time and consumers basing their choices on a mixture of a myopic and a “stubborn” expectation of adoption. Our results differ significantly from those that would be predicted by a model based on rational-expectations equilibrium and are more consistent with the pricing of network goods observed in practice. PMID:24367101

Metabolome analysis-based design and engineering of a metabolic pathway in Corynebacterium glutamicum to match rates of simultaneous utilization of D-glucose and L-arabinose.

PubMed

Kawaguchi, Hideo; Yoshihara, Kumiko; Hara, Kiyotaka Y; Hasunuma, Tomohisa; Ogino, Chiaki; Kondo, Akihiko

2018-05-17

L-Arabinose is the second most abundant component of hemicellulose in lignocellulosic biomass, next to D-xylose. However, few microorganisms are capable of utilizing pentoses, and catabolic genes and operons enabling bacterial utilization of pentoses are typically subject to carbon catabolite repression by more-preferred carbon sources, such as D-glucose, leading to a preferential utilization of D-glucose over pentoses. In order to simultaneously utilize both D-glucose and L-arabinose at the same rate, a modified metabolic pathway was rationally designed based on metabolome analysis. Corynebacterium glutamicum ATCC 31831 utilized D-glucose and L-arabinose simultaneously at a low concentration (3.6 g/L each) but preferentially utilized D-glucose over L-arabinose at a high concentration (15 g/L each), although L-arabinose and D-glucose were consumed at comparable rates in the absence of the second carbon source. Metabolome analysis revealed that phosphofructokinase and pyruvate kinase were major bottlenecks for D-glucose and L-arabinose metabolism, respectively. Based on the results of metabolome analysis, a metabolic pathway was engineered by overexpressing pyruvate kinase in combination with deletion of araR, which encodes a repressor of L-arabinose uptake and catabolism. The recombinant strain utilized high concentrations of D-glucose and L-arabinose (15 g/L each) at the same consumption rate. During simultaneous utilization of both carbon sources at high concentrations, intracellular levels of phosphoenolpyruvate declined and acetyl-CoA levels increased significantly as compared with the wild-type strain that preferentially utilized D-glucose. These results suggest that overexpression of pyruvate kinase in the araR deletion strain increased the specific consumption rate of L-arabinose and that citrate synthase activity becomes a new bottleneck in the engineered pathway during the simultaneous utilization of D-glucose and L-arabinose. Metabolome analysis identified potential bottlenecks in D-glucose and L-arabinose metabolism and was then applied to the following rational metabolic engineering. Manipulation of only two genes enabled simultaneous utilization of D-glucose and L-arabinose at the same rate in metabolically engineered C. glutamicum. This is the first report of rational metabolic design and engineering for simultaneous hexose and pentose utilization without inactivating the phosphotransferase system.

Rational assignment of key motifs for function guides in silico enzyme identification.

PubMed

Höhne, Matthias; Schätzle, Sebastian; Jochens, Helge; Robins, Karen; Bornscheuer, Uwe T

2010-11-01

Biocatalysis has emerged as a powerful alternative to traditional chemistry, especially for asymmetric synthesis. One key requirement during process development is the discovery of a biocatalyst with an appropriate enantiopreference and enantioselectivity, which can be achieved, for instance, by protein engineering or screening of metagenome libraries. We have developed an in silico strategy for a sequence-based prediction of substrate specificity and enantiopreference. First, we used rational protein design to predict key amino acid substitutions that indicate the desired activity. Then, we searched protein databases for proteins already carrying these mutations instead of constructing the corresponding mutants in the laboratory. This methodology exploits the fact that naturally evolved proteins have undergone selection over millions of years, which has resulted in highly optimized catalysts. Using this in silico approach, we have discovered 17 (R)-selective amine transaminases, which catalyzed the synthesis of several (R)-amines with excellent optical purity up to >99% enantiomeric excess.

Bacterial Transcription as a Target for Antibacterial Drug Development

PubMed Central

Ma, Cong; Yang, Xiao

2016-01-01

SUMMARY Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design. PMID:26764017

Resource Planning for Massive Number of Process Instances

NASA Astrophysics Data System (ADS)

Xu, Jiajie; Liu, Chengfei; Zhao, Xiaohui

Resource allocation has been recognised as an important topic for business process execution. In this paper, we focus on planning resources for a massive number of process instances to meet the process requirements and cater for rational utilisation of resources before execution. After a motivating example, we present a model for planning resources for process instances. Then we design a set of heuristic rules that take both optimised planning at build time and instance dependencies at run time into account. Based on these rules we propose two strategies, one is called holistic and the other is called batched, for resource planning. Both strategies target a lower cost, however, the holistic strategy can achieve an earlier deadline while the batched strategy aims at rational use of resources. We discuss how to find balance between them in the paper with a comprehensive experimental study on these two approaches.

Passionate Rationalism: The Role of Emotion in Decision Making

ERIC Educational Resources Information Center

Lakomski, Gabriele; Evers, Colin W.

2010-01-01

Purpose: The purpose of this paper is to argue that emotion has a central role to play in rational decision making based on recent research in the neuroanatomy of emotion. As a result, traditional rational decision-making theories, including Herbert Simon's modified model of satisficing that sharply demarcates emotions and values from rationality…

DNAzyme-Based Logic Gate-Mediated DNA Self-Assembly.

PubMed

Zhang, Cheng; Yang, Jing; Jiang, Shuoxing; Liu, Yan; Yan, Hao

2016-01-13

Controlling DNA self-assembly processes using rationally designed logic gates is a major goal of DNA-based nanotechnology and programming. Such controls could facilitate the hierarchical engineering of complex nanopatterns responding to various molecular triggers or inputs. Here, we demonstrate the use of a series of DNAzyme-based logic gates to control DNA tile self-assembly onto a prescribed DNA origami frame. Logic systems such as "YES," "OR," "AND," and "logic switch" are implemented based on DNAzyme-mediated tile recognition with the DNA origami frame. DNAzyme is designed to play two roles: (1) as an intermediate messenger to motivate downstream reactions and (2) as a final trigger to report fluorescent signals, enabling information relay between the DNA origami-framed tile assembly and fluorescent signaling. The results of this study demonstrate the plausibility of DNAzyme-mediated hierarchical self-assembly and provide new tools for generating dynamic and responsive self-assembly systems.

Design of virus-based nanomaterials for medicine, biotechnology, and energy.

PubMed

Wen, Amy M; Steinmetz, Nicole F

2016-07-25

This review provides an overview of recent developments in "chemical virology." Viruses, as materials, provide unique nanoscale scaffolds that have relevance in chemical biology and nanotechnology, with diverse areas of applications. Some fundamental advantages of viruses, compared to synthetically programmed materials, include the highly precise spatial arrangement of their subunits into a diverse array of shapes and sizes and many available avenues for easy and reproducible modification. Here, we will first survey the broad distribution of viruses and various methods for producing virus-based nanoparticles, as well as engineering principles used to impart new functionalities. We will then examine the broad range of applications and implications of virus-based materials, focusing on the medical, biotechnology, and energy sectors. We anticipate that this field will continue to evolve and grow, with exciting new possibilities stemming from advancements in the rational design of virus-based nanomaterials.

Mechanical Response Analysis of Long-life Asphalt Pavement Structure of Yunluo High-speed on the Semi-rigid Base

NASA Astrophysics Data System (ADS)

Liu, Feng; Wu, Chuanhai; Xu, Xinquan; Li, Hao; Wang, Zhixiang

2018-01-01

In order to grasp the rule of the strain change of the semi-rigid asphalt pavement structure under the FWD load and provide a reliable theoretical and practical basis for the design of the pavement structure, based on the test section of Guangdong Yunluo expressway, taking FWD as the loading tool, by using the finite element analysis software ANSYS, the internal variation rules of each pavement structural layer were obtained. Based on the results of the theoretical analysis, the measured strain sensor was set up in the corresponding layer of the pavement structure, and the strain test plan was determined. Based on the analysis of the strain data obtained from several structural layers and field monitoring, the rationality of the type pavement structure and the strain test scheme were verified, so as to provide useful help for the design and the maintenance of the pavement structure.

Rational and Experiential Decision-Making Preferences of Third-Year Student Pharmacists

PubMed Central

McLaughlin, Jacqueline E.; Cox, Wendy C.; Williams, Charlene R.

2014-01-01

Objective. To examine the rational (systematic and rule-based) and experiential (fast and intuitive) decision-making preferences of student pharmacists, and to compare these preferences to the preferences of other health professionals and student populations. Methods. The Rational-Experiential Inventory (REI-40), a validated psychometric tool, was administered electronically to 114 third-year (P3) student pharmacists. Student demographics and preadmission data were collected. The REI-40 results were compared with student demographics and admissions data to identify possible correlations between these factors. Results. Mean REI-40 rational scores were higher than experiential scores. Rational scores for younger students were significantly higher than students aged 30 years and older (p<0.05). No significant differences were found based on gender, race, or the presence of a prior degree. All correlations between REI-40 scores and incoming grade point average (GPA) and Pharmacy College Admission Test (PCAT) scores were weak. Conclusion. Student pharmacists favored rational decision making over experiential decision making, which was similar to results of studies done of other health professions. PMID:25147392

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

NASA Astrophysics Data System (ADS)

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

2016-08-01

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

Rational design of fiber forming supramolecular structures

PubMed Central

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

Porous SnO2-CuO nanotubes for highly reversible lithium storage

NASA Astrophysics Data System (ADS)

Cheong, Jun Young; Kim, Chanhoon; Jung, Ji-Won; Yoon, Ki Ro; Kim, Il-Doo

2018-01-01

Facile synthesis of rationally designed structures is critical to realize a high performance electrode for lithium-ion batteries (LIBs). Among different candidates, tin(IV) oxide (SnO2) is one of the most actively researched electrode materials due to its high theoretical capacity (1493 mAh g-1), abundance, inexpensive costs, and environmental friendliness. However, severe capacity decay from the volume expansion and low conductivity of SnO2 have hampered its use as a feasible electrode for LIBs. Rationally designed SnO2-based nanostructures with conductive materials can be an ideal solution to resolve such limitations. In this work, we have successfully fabricated porous SnO2-CuO composite nanotubes (SnO2-CuO p-NTs) by electrospinning and subsequent calcination step. The porous nanotubular structure is expected to mitigate the volume expansion of SnO2, while the as-formed Cu from CuO upon lithiation allows faster electron transport by improving the low conductivity of SnO2. With a synergistic effect of both Sn and Cu-based oxides, SnO2-CuO p-NTs deliver stable cycling performance (91.3% of capacity retention, ∼538 mAh g-1) even after 350 cycles at a current density of 500 mA g-1, along with enhanced rate capabilities compared with SnO2.

Regret and rationalization among smokers in Thailand and Malaysia: findings from the International Tobacco Control Southeast Asia Survey.

PubMed

Lee, Wonkyong B; Fong, Geoffrey T; Zanna, Mark P; Omar, Maizurah; Sirirassamee, Buppha; Borland, Ron

2009-07-01

To test whether differences of history and strength in tobacco control policies will influence social norms, which, in turn, will influence quit intentions, by influencing smokers' regret and rationalization. The data were from the International Tobacco Control (ITC) Policy Evaluation Southeast Asia Survey, a cohort survey of representative samples of adult smokers in Thailand (N = 2,000) and Malaysia (N = 2,006). The survey used a stratified multistage sampling design. Measures included regret, rationalization, social norms, and quit intention. Thai smokers were more likely to have quit intentions than Malaysian smokers. This difference in quit intentions was, in part, explained by the country differences in social norms, regret, and rationalization. Reflecting Thailand's history of stronger tobacco control policies, Thai smokers, compared with Malaysian smokers, perceived more negative social norms toward smoking, were more likely to regret, and less likely to rationalize smoking. Mediational analyses revealed that these differences in social norms, accounted, in part, for the country-quit intention relation and that regret and rationalization accounted, in part, for the social norm-quit intention relation. The results suggest that social norms toward smoking, which are shaped by tobacco control policies, and smokers' regret and rationalization influence quit intentions.

Oligoalanine helical callipers for cell penetration.

PubMed

Pazo, Marta; Juanes, Marisa; Lostalé-Seijo, Irene; Montenegro, Javier

2018-06-04

Even for short peptides that are enriched in basic amino acids, the large chemical space that can be spanned by combinations of natural amino acids hinders the rational design of cell penetrating peptides. We here report on short oligoalanine scaffolds for the fine-tuning of peptide helicity in different media and the study of cell penetrating properties. This strategy allowed the extraction of the structure/activity features required for maximal membrane interaction and cellular penetration at minimal toxicity. These results confirmed oligoalanine helical callipers as optimal scaffolds for the rational design and the identification of cell penetrating peptides.

Porphyrin-Based Nanostructures for Photocatalytic Applications

PubMed Central

Chen, Yingzhi; Li, Aoxiang; Huang, Zheng-Hong; Wang, Lu-Ning; Kang, Feiyu

2016-01-01

Well-defined organic nanostructures with controllable size and morphology are increasingly exploited in optoelectronic devices. As promising building blocks, porphyrins have demonstrated great potentials in visible-light photocatalytic applications, because of their electrical, optical and catalytic properties. From this perspective, we have summarized the recent significant advances on the design and photocatalytic applications of porphyrin-based nanostructures. The rational strategies, such as texture or crystal modification and interfacial heterostructuring, are described. The applications of the porphyrin-based nanostructures in photocatalytic pollutant degradation and hydrogen evolution are presented. Finally, the ongoing challenges and opportunities for the future development of porphyrin nanostructures in high-quality nanodevices are also proposed. PMID:28344308

Technology for the product and process data base

NASA Technical Reports Server (NTRS)

Barnes, R. D.

1984-01-01

The computerized product and process data base is increasingly recognized to be the cornerstone component of an overall system aimed at the integrated automation of the industrial processes of a given company or enterprise. The technology needed to support these more effective computer integrated design and manufacturing methods, especially the concept of 3-D computer-sensible product definitions rather than engineering drawings, is not fully available and rationalized. Progress is being made, however, in bridging this technology gap with concentration on the modeling of sophisticated information and data structures, high-performance interactive user interfaces and comprehensive tools for managing the resulting computerized product definition and process data base.

Rational design of gene-based vaccines.

PubMed

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.

In Silico Augmentation of the Drug Development Pipeline: Examples from the study of Acute Inflammation

PubMed Central

An, Gary; Bartels, John; Vodovotz, Yoram

2011-01-01

The clinical translation of promising basic biomedical findings, whether derived from reductionist studies in academic laboratories or as the product of extensive high-throughput and –content screens in the biotechnology and pharmaceutical industries, has reached a period of stagnation in which ever higher research and development costs are yielding ever fewer new drugs. Systems biology and computational modeling have been touted as potential avenues by which to break through this logjam. However, few mechanistic computational approaches are utilized in a manner that is fully cognizant of the inherent clinical realities in which the drugs developed through this ostensibly rational process will be ultimately used. In this article, we present a Translational Systems Biology approach to inflammation. This approach is based on the use of mechanistic computational modeling centered on inherent clinical applicability, namely that a unified suite of models can be applied to generate in silico clinical trials, individualized computational models as tools for personalized medicine, and rational drug and device design based on disease mechanism. PMID:21552346

Recommendations for rationalizing cleaning-in-place in the dairy industry: case study of an ultra-high temperature heat exchanger.

PubMed

Alvarez, N; Daufin, G; Gésan-Guiziou, G

2010-02-01

The objective of this work was to propose a new strategy, based on objective and rational arguments and calculations, that can be implemented by plant designers and operators in the dairy industry to reduce operating time and the volume and load of effluents. The strategy is based on the on-line and off-line use of sensors and tracers, the accuracy, relevance, and robustness of which were evaluated for each phase of the sequence used for cleaning an industrial sterilizer. The efficient duration of each phase of the cleaning sequence (management of the end of operation) and the sorting of the fluids (management of mixtures and destination of fluids) were determined in real time. As a result, significant reduction in total overall duration of the cleaning sequence, wastewater volume (waste volume was reduced by half), and detergent volume (caustic soda and acid was reduced by up to a few tens of kilograms per cleaning) was achievable. Copyright 2010 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Rational design of small molecules as vaccine adjuvants.

PubMed

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

2014-11-19

Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants. Copyright © 2014, American Association for the Advancement of Science.

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

PubMed

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.

Intrinsic disorder as a generalizable strategy for the rational design of highly responsive, allosterically cooperative receptors.

PubMed

Simon, Anna J; Vallée-Bélisle, Alexis; Ricci, Francesco; Plaxco, Kevin W

2014-10-21

Control over the sensitivity with which biomolecular receptors respond to small changes in the concentration of their target ligand is critical for the proper function of many cellular processes. Such control could likewise be of utility in artificial biotechnologies, such as biosensors, genetic logic gates, and "smart" materials, in which highly responsive behavior is of value. In nature, the control of molecular responsiveness is often achieved using "Hill-type" cooperativity, a mechanism in which sequential binding events on a multivalent receptor are coupled such that the first enhances the affinity of the next, producing a steep, higher-order dependence on target concentration. Here, we use an intrinsic-disorder-based mechanism that can be implemented without requiring detailed structural knowledge to rationally introduce this potentially useful property into several normally noncooperative biomolecules. To do so, we fabricate a tandem repeat of the receptor that is destabilized (unfolded) via the introduction of a long, unstructured loop. The first binding event requires the energetically unfavorable closing of this loop, reducing its affinity relative to that of the second binding event, which, in contrast occurs at a preformed site. Using this approach, we have rationally introduced cooperativity into three unrelated DNA aptamers, achieving in the best of these a Hill coefficient experimentally indistinguishable from the theoretically expected maximum. The extent of cooperativity and thus the steepness of the binding transition are, moreover, well modeled as simple functions of the energetic cost of binding-induced folding, speaking to the quantitative nature of this design strategy.

Linking patient satisfaction with nursing care: the case of care rationing - a correlational study.

PubMed

Papastavrou, Evridiki; Andreou, Panayiota; Tsangari, Haritini; Merkouris, Anastasios

2014-01-01

Implicit rationing of nursing care is the withholding of or failure to carry out all necessary nursing measures due to lack of resources. There is evidence supporting a link between rationing of nursing care, nurses' perceptions of their professional environment, negative patient outcomes, and placing patient safety at risk. The aims of the study were: a) To explore whether patient satisfaction is linked to nurse-reported rationing of nursing care and to nurses' perceptions of their practice environment while adjusting for patient and nurse characteristics. b) To identify the threshold score of rationing by comparing the level of patient satisfaction factors across rationing levels. A descriptive, correlational design was employed. Participants in this study included 352 patients and 318 nurses from ten medical and surgical units of five general hospitals. Three measurement instruments were used: the BERNCA scale for rationing of care, the RPPE scale to explore nurses' perceptions of their work environment and the Patient Satisfaction scale to assess the level of patient satisfaction with nursing care. The statistical analysis included the use of Kendall's correlation coefficient to explore a possible relationship between the variables and multiple regression analysis to assess the effects of implicit rationing of nursing care together with organizational characteristics on patient satisfaction. The mean score of implicit rationing of nursing care was 0.83 (SD = 0.52, range = 0-3), the overall mean of RPPE was 2.76 (SD = 0.32, range = 1.28 - 3.69) and the two scales were significantly correlated (τ = -0.234, p < 0.001). The regression analysis showed that care rationing and work environment were related to patient satisfaction, even after controlling for nurse and patient characteristics. The results from the adjusted regression models showed that even at the lowest level of rationing (i.e. 0.5) patients indicated low satisfaction. The results support the relationships between organizational and environmental variables, care rationing and patient satisfaction. The identification of thresholds at which rationing starts to influence patient outcomes in a negative way may allow nurse managers to introduce interventions so as to keep rationing at a level at which patient safety is not jeopardized.

Automatic illumination compensation device based on a photoelectrochemical biofuel cell driven by visible light

NASA Astrophysics Data System (ADS)

Yu, You; Han, Yanchao; Xu, Miao; Zhang, Lingling; Dong, Shaojun

2016-04-01

Inverted illumination compensation is important in energy-saving projects, artificial photosynthesis and some forms of agriculture, such as hydroponics. However, only a few illumination adjustments based on self-powered biodetectors that quantitatively detect the intensity of visible light have been reported. We constructed an automatic illumination compensation device based on a photoelectrochemical biofuel cell (PBFC) driven by visible light. The PBFC consisted of a glucose dehydrogenase modified bioanode and a p-type semiconductor cuprous oxide photocathode. The PBFC had a high power output of 161.4 μW cm-2 and an open circuit potential that responded rapidly to visible light. It adjusted the amount of illumination inversely irrespective of how the external illumination was changed. This rational design of utilizing PBFCs provides new insights into automatic light adjustable devices and may be of benefit to intelligent applications.Inverted illumination compensation is important in energy-saving projects, artificial photosynthesis and some forms of agriculture, such as hydroponics. However, only a few illumination adjustments based on self-powered biodetectors that quantitatively detect the intensity of visible light have been reported. We constructed an automatic illumination compensation device based on a photoelectrochemical biofuel cell (PBFC) driven by visible light. The PBFC consisted of a glucose dehydrogenase modified bioanode and a p-type semiconductor cuprous oxide photocathode. The PBFC had a high power output of 161.4 μW cm-2 and an open circuit potential that responded rapidly to visible light. It adjusted the amount of illumination inversely irrespective of how the external illumination was changed. This rational design of utilizing PBFCs provides new insights into automatic light adjustable devices and may be of benefit to intelligent applications. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr00759g

Influence of individual rationality on continuous double auction markets with networked traders

NASA Astrophysics Data System (ADS)

Zhang, Junhuan

2018-04-01

This paper investigates the influence of individual rationality of buyers and sellers on continuous double auction market outcomes in terms of the proportion of boundedly-rational buyers and sellers. The individual rationality is discussed in a social network artificial stock market model by embedding network formation and information set. Traders automatically select the most profitable trading strategy based on individual and social learning of the profits and trading strategies of themselves and their neighbors, and submit orders to markets. The results show that (i) a higher proportion of boundedly-rational sellers induces a higher market price, higher sellers' profits and a higher market efficiency; (ii) a higher proportion of boundedly-rational sellers induces a lower number of trades and lower buyers' profits; (iii) a higher proportion of boundedly-rational buyers induces a lower market price, a lower number of trades, and lower sellers' profits; (iv) a higher proportion of boundedly-rational buyers induces higher buyers' profits and a higher market efficiency.

Computational approaches for drug discovery.

PubMed

Hung, Che-Lun; Chen, Chi-Chun

2014-09-01

Cellular proteins are the mediators of multiple organism functions being involved in physiological mechanisms and disease. By discovering lead compounds that affect the function of target proteins, the target diseases or physiological mechanisms can be modulated. Based on knowledge of the ligand-receptor interaction, the chemical structures of leads can be modified to improve efficacy, selectivity and reduce side effects. One rational drug design technology, which enables drug discovery based on knowledge of target structures, functional properties and mechanisms, is computer-aided drug design (CADD). The application of CADD can be cost-effective using experiments to compare predicted and actual drug activity, the results from which can used iteratively to improve compound properties. The two major CADD-based approaches are structure-based drug design, where protein structures are required, and ligand-based drug design, where ligand and ligand activities can be used to design compounds interacting with the protein structure. Approaches in structure-based drug design include docking, de novo design, fragment-based drug discovery and structure-based pharmacophore modeling. Approaches in ligand-based drug design include quantitative structure-affinity relationship and pharmacophore modeling based on ligand properties. Based on whether the structure of the receptor and its interaction with the ligand are known, different design strategies can be seed. After lead compounds are generated, the rule of five can be used to assess whether these have drug-like properties. Several quality validation methods, such as cost function analysis, Fisher's cross-validation analysis and goodness of hit test, can be used to estimate the metrics of different drug design strategies. To further improve CADD performance, multi-computers and graphics processing units may be applied to reduce costs. © 2014 Wiley Periodicals, Inc.

Validation of mobile phone text messages for nicotine and tobacco risk communication among college students: A content analysis.

PubMed

Khalil, Georges E; Calabro, Karen S; Crook, Brittani; Machado, Tamara C; Perry, Cheryl L; Prokhorov, Alexander V

2018-02-01

In the United States, young adults have the highest prevalence of tobacco use. The dissemination of mobile phone text messages is a growing strategy for tobacco risk communication among young adults. However, little has been done concerning the design and validation of such text messages. The Texas Tobacco Center of Regulatory Science (Texas-TCORS) has developed a library of messages based on framing (gain- or loss-framed), depth (simple or complex) and appeal (emotional or rational). This study validated the library based on depth and appeal, identified text messages that may need improvement, and explored new themes. The library formed the study sample (N=976 messages). The Linguistic Inquiry and Word Count (LIWC) software of 2015 was used to code for word count, word length and frequency of emotional and cognitive words. Analyses of variance, logistic regression and scatter plots were conducted for validation. In all, 874 messages agreed with LIWC-coding. Several messages did not agree with LIWC. Ten messages designed to be complex indicated simplicity, while 51 messages designed to be rational exhibited no cognitive words. New relevant themes were identified, such as health (e.g. 'diagnosis', 'cancer'), death (e.g. 'dead', 'lethal') and social connotations (e.g. 'parents', 'friends'). Nicotine and tobacco researchers can safely use, for young adults, messages from the Texas-TCORS library to convey information in the intended style. Future work may expand upon the new themes. Findings will be utilized to develop new campaigns, so that risks of nicotine and tobacco products can be widely disseminated.

Rational Design and Evaluation of an Artificial Escherichia coli K1 Protein Vaccine Candidate Based on the Structure of OmpA

PubMed Central

Gu, Hao; Liao, Yaling; Zhang, Jin; Wang, Ying; Liu, Zhiyong; Cheng, Ping; Wang, Xingyong; Zou, Quanming; Gu, Jiang

2018-01-01

Escherichia coli (E. coli) K1 causes meningitis and remains an unsolved problem in neonates, despite the application of antibiotics and supportive care. The cross-reactivity of bacterial capsular polysaccharides with human antigens hinders their application as vaccine candidates. Thus, protein antigens could be an alternative strategy for the development of an E. coli K1 vaccine. Outer membrane protein A (OmpA) of E. coli K1 is a potential vaccine candidate because of its predominant contribution to bacterial pathogenesis and sub-cellular localization. However, little progress has been made regarding the use of OmpA for this purpose due to difficulties in OmpA production. In the present study, we first investigated the immunogenicity of the four extracellular loops of OmpA. Using the structure of OmpA, we rationally designed and successfully generated the artificial protein OmpAVac, composed of connected loops from OmpA. Recombinant OmpAVac was successfully produced in E. coli BL21 and behaved as a soluble homogenous monomer in the aqueous phase. Vaccination with OmpAVac induced Th1, Th2, and Th17 immune responses and conferred effective protection in mice. In addition, OmpAVac-specific antibodies were able to mediate opsonophagocytosis and inhibit bacterial invasion, thereby conferring prophylactic protection in E. coli K1-challenged adult mice and neonatal mice. These results suggest that OmpAVac could be a good vaccine candidate for the control of E. coli K1 infection and provide an additional example of structure-based vaccine design. PMID:29876324

Rational Design and Evaluation of an Artificial Escherichia coli K1 Protein Vaccine Candidate Based on the Structure of OmpA.

PubMed

Gu, Hao; Liao, Yaling; Zhang, Jin; Wang, Ying; Liu, Zhiyong; Cheng, Ping; Wang, Xingyong; Zou, Quanming; Gu, Jiang

2018-01-01

Escherichia coli ( E. coli ) K1 causes meningitis and remains an unsolved problem in neonates, despite the application of antibiotics and supportive care. The cross-reactivity of bacterial capsular polysaccharides with human antigens hinders their application as vaccine candidates. Thus, protein antigens could be an alternative strategy for the development of an E. coli K1 vaccine. Outer membrane protein A (OmpA) of E. coli K1 is a potential vaccine candidate because of its predominant contribution to bacterial pathogenesis and sub-cellular localization. However, little progress has been made regarding the use of OmpA for this purpose due to difficulties in OmpA production. In the present study, we first investigated the immunogenicity of the four extracellular loops of OmpA. Using the structure of OmpA, we rationally designed and successfully generated the artificial protein OmpAVac, composed of connected loops from OmpA. Recombinant OmpAVac was successfully produced in E. coli BL21 and behaved as a soluble homogenous monomer in the aqueous phase. Vaccination with OmpAVac induced Th1, Th2, and Th17 immune responses and conferred effective protection in mice. In addition, OmpAVac-specific antibodies were able to mediate opsonophagocytosis and inhibit bacterial invasion, thereby conferring prophylactic protection in E. coli K1-challenged adult mice and neonatal mice. These results suggest that OmpAVac could be a good vaccine candidate for the control of E. coli K1 infection and provide an additional example of structure-based vaccine design.

Segmented molecular design of self-healing proteinaceous materials

PubMed Central

Sariola, Veikko; Pena-Francesch, Abdon; Jung, Huihun; Çetinkaya, Murat; Pacheco, Carlos; Sitti, Metin; Demirel, Melik C.

2015-01-01

Hierarchical assembly of self-healing adhesive proteins creates strong and robust structural and interfacial materials, but understanding of the molecular design and structure–property relationships of structural proteins remains unclear. Elucidating this relationship would allow rational design of next generation genetically engineered self-healing structural proteins. Here we report a general self-healing and -assembly strategy based on a multiphase recombinant protein based material. Segmented structure of the protein shows soft glycine- and tyrosine-rich segments with self-healing capability and hard beta-sheet segments. The soft segments are strongly plasticized by water, lowering the self-healing temperature close to body temperature. The hard segments self-assemble into nanoconfined domains to reinforce the material. The healing strength scales sublinearly with contact time, which associates with diffusion and wetting of autohesion. The finding suggests that recombinant structural proteins from heterologous expression have potential as strong and repairable engineering materials. PMID:26323335

Probabilistic confidence for decisions based on uncertain reliability estimates

NASA Astrophysics Data System (ADS)

Reid, Stuart G.

2013-05-01

Reliability assessments are commonly carried out to provide a rational basis for risk-informed decisions concerning the design or maintenance of engineering systems and structures. However, calculated reliabilities and associated probabilities of failure often have significant uncertainties associated with the possible estimation errors relative to the 'true' failure probabilities. For uncertain probabilities of failure, a measure of 'probabilistic confidence' has been proposed to reflect the concern that uncertainty about the true probability of failure could result in a system or structure that is unsafe and could subsequently fail. The paper describes how the concept of probabilistic confidence can be applied to evaluate and appropriately limit the probabilities of failure attributable to particular uncertainties such as design errors that may critically affect the dependability of risk-acceptance decisions. This approach is illustrated with regard to the dependability of structural design processes based on prototype testing with uncertainties attributable to sampling variability.

[Design and Analysis of CT High-speed Data Transmission Rotating Connector Ring System Retaining Ring].

PubMed

Pan, Li; Cao, Jujiang; Liu, Min; Fu, Weiwei

2017-11-30

High speed data transmission rotating connector system for signal high-speed transmission used in the fixed end and rotating end, it is one of the core component in the CT system. This paper involves structure design and analysis of the retaining ring in the CT high speed data transmission rotating connector system based on the principle of off-axis free space optical transmission. According to the problem of the actual engineering application of space limitations, optical fiber fixed and collimator installation location, we designed the structure of the retaining ring. Using the static analysis function of ANSYS Workbench, it verifies rationality and safety of the strength of retaining ring structure. And based on modal analysis function of ANSYS Workbench, it evaluates the effect of the retaining ring on the stability of the system date transmission, and provides theoretical basis for the feasibility of the structure in practical application.

Segmented molecular design of self-healing proteinaceous materials

NASA Astrophysics Data System (ADS)

Sariola, Veikko; Pena-Francesch, Abdon; Jung, Huihun; Çetinkaya, Murat; Pacheco, Carlos; Sitti, Metin; Demirel, Melik C.

2015-09-01

Hierarchical assembly of self-healing adhesive proteins creates strong and robust structural and interfacial materials, but understanding of the molecular design and structure-property relationships of structural proteins remains unclear. Elucidating this relationship would allow rational design of next generation genetically engineered self-healing structural proteins. Here we report a general self-healing and -assembly strategy based on a multiphase recombinant protein based material. Segmented structure of the protein shows soft glycine- and tyrosine-rich segments with self-healing capability and hard beta-sheet segments. The soft segments are strongly plasticized by water, lowering the self-healing temperature close to body temperature. The hard segments self-assemble into nanoconfined domains to reinforce the material. The healing strength scales sublinearly with contact time, which associates with diffusion and wetting of autohesion. The finding suggests that recombinant structural proteins from heterologous expression have potential as strong and repairable engineering materials.

Design and development of the mobile game based on the J2ME technology

NASA Astrophysics Data System (ADS)

He, Junhua

2011-12-01

With the continuous improvement of mobile performance, mobile entertainment applications market trend has been increasingly clear, mobile entertainment applications will be after the PC entertainment applications is another important business growth. Through the full analysis of the current mobile entertainment applications market demand and trends, the author has accumulated a lot of theoretical knowledge and practical experience. Rational, using of some new technology for a mobile entertainment games design, and described the development of key technologies required for mobile game an analysis and design of the game, and to achieve a complete game development. Light of the specific mobile game project - "Battle City", detailed the development of a mobile game based on the J2ME platform, the basic steps and the various key elements, focusing on how to use object-oriented thinking on the role of mobile phones in the abstract and Game Animation package, the source code with specific instructions.

Design and development of the mobile game based on the J2ME technology

NASA Astrophysics Data System (ADS)

He, JunHua

2012-01-01

With the continuous improvement of mobile performance, mobile entertainment applications market trend has been increasingly clear, mobile entertainment applications will be after the PC entertainment applications is another important business growth. Through the full analysis of the current mobile entertainment applications market demand and trends, the author has accumulated a lot of theoretical knowledge and practical experience. Rational, using of some new technology for a mobile entertainment games design, and described the development of key technologies required for mobile game an analysis and design of the game, and to achieve a complete game development. Light of the specific mobile game project - "Battle City", detailed the development of a mobile game based on the J2ME platform, the basic steps and the various key elements, focusing on how to use object-oriented thinking on the role of mobile phones in the abstract and Game Animation package, the source code with specific instructions.

Segmented molecular design of self-healing proteinaceous materials.

PubMed

Sariola, Veikko; Pena-Francesch, Abdon; Jung, Huihun; Çetinkaya, Murat; Pacheco, Carlos; Sitti, Metin; Demirel, Melik C

2015-09-01

Hierarchical assembly of self-healing adhesive proteins creates strong and robust structural and interfacial materials, but understanding of the molecular design and structure-property relationships of structural proteins remains unclear. Elucidating this relationship would allow rational design of next generation genetically engineered self-healing structural proteins. Here we report a general self-healing and -assembly strategy based on a multiphase recombinant protein based material. Segmented structure of the protein shows soft glycine- and tyrosine-rich segments with self-healing capability and hard beta-sheet segments. The soft segments are strongly plasticized by water, lowering the self-healing temperature close to body temperature. The hard segments self-assemble into nanoconfined domains to reinforce the material. The healing strength scales sublinearly with contact time, which associates with diffusion and wetting of autohesion. The finding suggests that recombinant structural proteins from heterologous expression have potential as strong and repairable engineering materials.

Part I: Reverse-docking studies of a squaramide-catalyzed conjugate addition of a diketone to a nitro-olefin Part II: The development of ChemSort: an education game for organic chemistry

NASA Astrophysics Data System (ADS)

Granger, Jenna Christine

Part 1: Reverse-docking studies of a squaramide-catalyzed conjugate addition of a diketone to a nitro-olefin. Asymmetric organocatalysis, the catalysis of asymmetric reactions by small organic molecules, is a rapidly growing field within organic synthesis. The ability to rationally design organocatalysts is therefore of increasing interest to organic chemists. Computational chemistry is quickly proving to be an extremely successful method for understanding and predicting the roles of organocatalysts, and therefore is certain to be of use in the rational design of such catalysts. A methodology for reverse-docking flexible organocatalysts to rigid transition state models of asymmetric reactions has been previously developed by the Deslongchamps group. The investigation of Rawal's squaramide-based organocatalyst for the addition of a diketone to a nitro-olefin is described, and the results of the reverse docking of Rawal's catalyst to the geometry optimized transition state models of the uncatalyzed reaction for both the R and S-product enantiomers are presented. The results of this study indicate a preference for binding of the organocatalyst to the R-enantiomer transition state model with a predicted enantiomeric excess of 99%, which is consistent with the experimental results. A plausible geometric model of the transition state for the catalyzed reaction is also presented. The success of this study demonstrates the credibility of using reverse docking methods for the rational design of asymmetric organocatalysts. Part 2: The development of ChemSort: an educational game for organic chemistry. With the advent of the millennial learner, we need to rethink traditional classroom approaches to science learning in terms of goals, approaches, and assessments. Digital simulations and games hold much promise in support of this educational shift. Although the idea of using games for education is not a new one, well-designed computer-based "serious games" are only beginning to emerge as exceptional tools for helping learners understand concepts and processes. The use of computer games for learning college-level organic chemistry is still relatively unexplored and underrepresented within the realm of "serious gaming". In this section, ideas for games as a way for teaching and learning organic chemistry will be introduced and the development process of ChemSort, a web-based Flash game for learning college-level organic chemistry topics, will be outlined. ChemSort is a path-based game, in which the player, or in this case the learner, must match the chemical structures with their appropriate functional groups. At the end of this section a 4-level useable prototype of ChemSort will be unveiled.

Design for active and passive flutter suppression and gust alleviation. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Karpel, M.

1981-01-01

Analytical design techniques for active and passive control of aeroelastic systems are based on a rational approximation of the unsteady aerodynamic loads in the entire Laplace domain, which yields matrix equations of motion with constant coefficients. Some existing schemes are reviewed, the matrix Pade approximant is modified, and a technique which yields a minimal number of augmented states for a desired accuracy is presented. The state-space aeroelastic model is used to design an active control system for simultaneous flutter suppression and gust alleviation. The design target is for a continuous controller which transfers some measurements taken on the vehicle to a control command applied to a control surface. Structural modifications are formulated in a way which enables the treatment of passive flutter suppression system with the same procedures by which active control systems are designed.

Peer-Based Control in Self-Managing Teams: Linking Rational and Normative Influence with Individual and Group Performance

ERIC Educational Resources Information Center

Stewart, Greg L.; Courtright, Stephen H.; Barrick, Murray R.

2012-01-01

The authors use a multilevel framework to introduce peer-based control as a motivational state that emerges in self-managing teams. The authors specifically describe how "peer-based rational control", which is defined as team members perceiving the distribution of economic rewards as dependent on input from teammates, extends and…

Ethics and public health emergencies: rationing vaccines.

PubMed

Wynia, Matthew K

2006-01-01

There are three broad ethical issues related to handling public health emergencies. They are the three R's-rationing, restrictions and responsibilities. Recently, a severe shortage of annual influenza vaccine in the US, combined with the threat of pandemic flu, has provided an opportunity for policy makers to think about rationing in very concrete terms. Some lessons from annual flu vaccination likely will apply to pandemic vaccine distribution, but many preparatory decisions must be based on very rough estimates. What ethical principles should guide rationing decisions, what data should inform these decisions, how to revise decisions as new data emerge, and how to implement rationing decisions on the ground are all important considerations. In addition, ethicists might be able to help policy makers think through the importance of international cooperation in surmounting global rationing dilemmas and to accept the inevitable responsibilities of government in making and implementing rationing decisions.

New strategy for protein interactions and application to structure-based drug design

NASA Astrophysics Data System (ADS)

Zou, Xiaoqin

One of the greatest challenges in computational biophysics is to predict interactions between biological molecules, which play critical roles in biological processes and rational design of therapeutic drugs. Biomolecular interactions involve delicate interplay between multiple interactions, including electrostatic interactions, van der Waals interactions, solvent effect, and conformational entropic effect. Accurate determination of these complex and subtle interactions is challenging. Moreover, a biological molecule such as a protein usually consists of thousands of atoms, and thus occupies a huge conformational space. The large degrees of freedom pose further challenges for accurate prediction of biomolecular interactions. Here, I will present our development of physics-based theory and computational modeling on protein interactions with other molecules. The major strategy is to extract microscopic energetics from the information embedded in the experimentally-determined structures of protein complexes. I will also present applications of the methods to structure-based therapeutic design. Supported by NSF CAREER Award DBI-0953839, NIH R01GM109980, and the American Heart Association (Midwest Affiliate) [13GRNT16990076].

Aerosol Processing of Crumpled Graphene Oxide-based Nanocomposites for Drug Delivery.

PubMed

Wang, Wei-Ning; He, Xiang

2016-01-01

The flexibility of graphene oxide (GO) nanosheets and their unique properties enable them to be excellent two dimensional (2D) building blocks for designing functional materials. Aerosol routes are proved to be a rational approach to fold the 2D flat GO nanosheets into 3D crumpled spheres to mitigate the restacking issue for large-scale applications, such as for drug delivery. The fundamentals of graphene, GO, and the crumpling process of GO nanosheets are summarized. Various crumpled graphene oxide (CGO)-based nanocomposites have been synthesized by aerosol routes. This mini review focuses on the state-of-the-art in the design and fabrication of these nanocomposites for a specific application in drug delivery. Various techniques are demonstrated and discussed to control the release rates, tailor the morphology, and adjust the components inside the nanocomposites. Potential risks and possible trends are also pointed out. Aerosol processing of CGO-based nanocomposites provides a promising approach to design functional nanomaterials for drug delivery and other related applications.

Design and analysis of coherent OCDM en/decoder based on photonic crystal

NASA Astrophysics Data System (ADS)

Zhang, Chongfu; Qiu, Kun

2008-08-01

The design and performance analysis of a new coherent optical en/decoder based on photonic crystal (PhC) for optical code -division -multiple (OCDM) are presented in this paper. In this scheme, the optical pulse phase and time delay can be flexibly controlled by photonic crystal phase shifter and time delayer by using the appropriate design of fabrication. According to the PhC transmission matrix theorem, combination calculation of the impurity and normal period layers is applied, and performances of the PhC-based optical en/decoder are also analyzed. The reflection, transmission, time delay characteristic and optical spectrum of pulse en/decoded are studied for the waves tuned in the photonic band-gap by numerical calculation. Theoretical analysis and numerical results indicate that the optical pulse is achieved to properly phase modulation and time delay, and an auto-correlation of about 8 dB ration and cross-correlation is gained, which demonstrates the applicability of true pulse phase modulation in a number of applications.

Method for automation of tool preproduction

NASA Astrophysics Data System (ADS)

Rychkov, D. A.; Yanyushkin, A. S.; Lobanov, D. V.; Arkhipov, P. V.

2018-03-01

The primary objective of tool production is a creation or selection of such tool design which could make it possible to secure high process efficiency, tool availability as well as a quality of received surfaces with minimum means and resources spent on it. It takes much time of application people, being engaged in tool preparation, to make a correct selection of the appropriate tool among the set of variants. Program software has been developed to solve the problem, which helps to create, systematize and carry out a comparative analysis of tool design to identify the rational variant under given production conditions. The literature indicates that systematization and selection of the tool rational design has been carried out in accordance with the developed modeling technology and comparative design analysis. Software application makes it possible to reduce the period of design by 80....85% and obtain a significant annual saving.

Rational design of cyclopropane-based chiral PHOX ligands for intermolecular asymmetric Heck reaction

PubMed Central

Rubina, Marina; Sherrill, William M; Barkov, Alexey Yu

2014-01-01

Summary A novel class of chiral phosphanyl-oxazoline (PHOX) ligands with a conformationally rigid cyclopropyl backbone was synthesized and tested in the intermolecular asymmetric Heck reaction. Mechanistic modelling and crystallographic studies were used to predict the optimal ligand structure and helped to design a very efficient and highly selective catalytic system. Employment of the optimized ligands in the asymmetric arylation of cyclic olefins allowed for achieving high enantioselectivities and significantly suppressing product isomerization. Factors affecting the selectivity and the rate of the isomerization were identified. It was shown that the nature of this isomerization is different from that demonstrated previously using chiral diphosphine ligands. PMID:25161709

Structure-based receptor MIMICS targeted against bacterial superantigen toxins

DOEpatents

Gupta, Goutam [Santa Fe, NM; Hong-Geller, Elizabeth [Los Alamos, NM; Shiflett, Patrick R [Los Alamos, NM; Lehnert, Nancy M [Albuquerque, NM

2009-08-18

The invention provides therapeutic compositions useful in the treatment of bacterial superantigen mediated conditions, such as Toxic Shock Syndrome. The compositions comprise genetically engineered bifunctional polypeptides containing a specific T-cell receptor binding domain and a specific MHC class II receptor binding domain, each targeting non-overlapping epitopes on a superantigen molecule against which they are designed. The anti-superantigen "receptor mimetics" or "chimeras" are rationally designed to recreate the modality of superantigen binding directly to both the TCR and the MHC-II receptor, and are capable of acting as decoys for superantigen binding, effectively out-competing the host T-cell and MHC-II receptors, the natural host receptors.

Rational Rhymes for Addressing Common Childhood Issues

ERIC Educational Resources Information Center

Warren, Jeffrey M.

2011-01-01

Music-based interventions are valuable tools counselors can use when working with children. Specific types of music-based interventions, such as songs or rhymes, can be especially pertinent in addressing the thoughts, feelings, and behaviors of children. Rational-emotive behavior therapy (REBT) provides a therapeutic framework that encourages…

Physical and molecular bases of protein thermal stability and cold adaptation.

PubMed

Pucci, Fabrizio; Rooman, Marianne

2017-02-01

The molecular bases of thermal and cold stability and adaptation, which allow proteins to remain folded and functional in the temperature ranges in which their host organisms live and grow, are still only partially elucidated. Indeed, both experimental and computational studies fail to yield a fully precise and global physical picture, essentially because all effects are context-dependent and thus quite intricate to unravel. We present a snapshot of the current state of knowledge of this highly complex and challenging issue, whose resolution would enable large-scale rational protein design. Copyright © 2016 Elsevier Ltd. All rights reserved.

Kinetically Controlled Synthesis of Pt-Based One-Dimensional Hierarchically Porous Nanostructures with Large Mesopores as Highly Efficient ORR Catalysts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fu, Shaofang; Zhu, Chengzhou; Song, Junhua

2016-12-28

Rational design and construction of Pt-based porous nanostructures with large mesopores have triggered significant considerations because of their high surface area and more efficient mass transport. Hydrochloric acid-induced kinetic reduction of metal precursors in the presence of soft template F-127 and hard template tellurium nanowires has been successfully demonstrated to construct one-dimensional hierarchical porous PtCu alloy nanostructures with large mesopores. Moreover, the electrochemical experiments demonstrated that the resultant PtCu hierarchically porous nanostructures with optimized composition exhibit enhanced electrocatalytic performance for oxygen reduction reaction.

Vehicle/engine integration. [orbit transfer vehicles

NASA Technical Reports Server (NTRS)

Cooper, L. P.; Vinopal, T. J.; Florence, D. E.; Michel, R. W.; Brown, J. R.; Bergeron, R. P.; Weldon, V. A.

1984-01-01

VEHICLE/ENGINE Integration Issues are explored for orbit transfer vehicles (OTV's). The impact of space basing and aeroassist on VEHICLE/ENGINE integration is discussed. The AOTV structure and thermal protection subsystem weights were scaled as the vehicle length and surface was changed. It is concluded that for increased allowable payload lengths in a ground-based system, lower length-to-diameter (L/D) is as important as higher mixture ration (MR) in the range of mid L/D ATOV's. Scenario validity, geometry constraints, throttle levels, reliability, and servicing are discussed in the context of engine design and engine/vehicle integration.

Vascular stents with submicrometer-scale surface patterning realized via titanium deep reactive ion etching

NASA Astrophysics Data System (ADS)

Gott, Shannon C.; Jabola, Benjamin A.; Rao, Masaru P.

2015-08-01

Herein, we report progress towards realization of vascular stents that will eventually provide opportunity for evaluating cellular response to rationally-designed, submicrometer-scale surface patterning in physiologically-relevant contexts, i.e. those that provide exposure to the complex multicellular milieu, flow-induced shear, and tissue-device interactions present in vivo. Specifically, using our novel titanium deep reactive ion etching technique (Ti DRIE), we discuss recent advances that have enabled: (a) fabrication of precisely-defined, grating-based surface patterns on planar Ti foils with minimum feature sizes as small as 0.15 μm (b) creation of cylindrical stents from micromachined planar Ti foils; and (c) integration of these processes to produce the first submicrometer-scale surface-patterned Ti stents that are compatible with conventional balloon catheter deployment techniques. We also discuss results from elastoplastic finite element simulations and preliminary mechanical testing of these devices to assess their mechanical performance. These efforts represent key steps towards our long-term goal of developing a new paradigm in stenting, where rationally-designed surface patterning provides a physical means for facilitating healing, and thus, improving outcomes in vascular intervention applications.

Specific noncovalent interactions at protein-ligand interface: implications for rational drug design.

PubMed

Zhou, P; Huang, J; Tian, F

2012-01-01

Specific noncovalent interactions that are indicative of attractive, directional intermolecular forces have always been of key interest to medicinal chemists in their search for the "glue" that holds drugs and their targets together. With the rapid increase in the number of solved biomolecular structures as well as the performance enhancement of computer hardware and software in recent years, it is now possible to give more comprehensive insight into the geometrical characteristics and energetic landscape of certain sophisticated noncovalent interactions present at the binding interface of protein receptors and small ligands based on accumulated knowledge gaining from the combination of two quite disparate but complementary approaches: crystallographic data analysis and quantum-mechanical ab initio calculation. In this perspective, we survey massive body of published works relating to structural characterization and theoretical investigation of three kinds of strong, specific, direct, enthalpy-driven intermolecular forces, including hydrogen bond, halogen bond and salt bridge, involved in the formation of protein-ligand complex architecture in order to characterize their biological functions in conferring affinity and specificity for ligand recognition by host protein. In particular, the biomedical implications of raised knowledge are discussed with respect to potential applications in rational drug design.

Facile one-step construction of covalently networked, self-healable, and transparent superhydrophobic composite films

NASA Astrophysics Data System (ADS)

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

2018-07-01

Despite the considerable demand for bioinspired superhydrophobic surfaces with highly transparent, self-cleaning, and self-healable properties, a facile and scalable fabrication method for multifunctional superhydrophobic films with strong chemical networks has rarely been established. Here, we report a rationally designed facile one-step construction of covalently networked, transparent, self-cleaning, and self-healable superhydrophobic films via a one-step preparation and single-reaction process of multi-components. As coating materials for achieving the one-step fabrication of multifunctional superhydrophobic films, we included two different sizes of Al2O3 nanoparticles for hierarchical micro/nano dual-scale structures and transparent films, fluoroalkylsilane for both low surface energy and covalent binding functions, and aluminum nitrate for aluminum oxide networked films. On the basis of stability tests for the robust film composition, the optimized, covalently linked superhydrophobic composite films with a high water contact angle (>160°) and low sliding angle (<1°) showed excellent thermal stability (up to 400 °C), transparency (≈80%), self-healing, self-cleaning, and waterproof abilities. Therefore, the rationally designed, covalently networked superhydrophobic composite films, fabricated via a one-step solution-based process, can be further utilized for various optical and optoelectronic applications.

Discovery of a new class of ionotropic glutamate receptor antagonists by the rational design of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid.

PubMed

Larsen, Ann M; Venskutonytė, Raminta; Valadés, Elena Antón; Nielsen, Birgitte; Pickering, Darryl S; Bunch, Lennart

2011-02-16

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 Glu receptors were determined to be in the micromolar range (AMPA, 51 μM; KA, 22 μM; NMDA 6 μM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 μM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a K(b) of 11.4 μM.

Indirect Z-Scheme BiOI/g-C3N4 Photocatalysts with Enhanced Photoreduction CO2 Activity under Visible Light Irradiation.

PubMed

Wang, Ji-Chao; Yao, Hong-Chang; Fan, Ze-Yu; Zhang, Lin; Wang, Jian-She; Zang, Shuang-Quan; Li, Zhong-Jun

2016-02-17

Rational design and construction of Z-scheme photocatalysts has received much attention in the field of CO2 reduction because of its great potential to solve the current energy and environmental crises. In this study, a series of Z-scheme BiOI/g-C3N4 photocatalysts are synthesized and their photocatalytic performance for CO2 reduction to produce CO, H2 and/or CH4 is evaluated under visible light irradiation (λ > 400 nm). The results show that the as-synthesized composites exhibit more highly efficient photocatalytic activity than pure g-C3N4 and BiOI and that the product yields change remarkably depending on the reaction conditions such as irradiation light wavelength. Emphasis is placed on identifying how the charge transfers across the heterojunctions and an indirect Z-scheme charge transfer mechanism is verified by detecting the intermediate I3(-) ions. The reaction mechanism is further proposed based on the detection of the intermediate (•)OH and H2O2. This work may be useful for rationally designing of new types of Z-scheme photocatalyst and provide some illuminating insights into the Z-scheme transfer mechanism.

Electromagnetic field enhancement and spectrum shaping through plasmonically integrated optical vortices.

PubMed

Ahn, Wonmi; Boriskina, Svetlana V; Hong, Yan; Reinhard, Björn M

2012-01-11

We introduce a new design approach for surface-enhanced Raman spectroscopy (SERS) substrates that is based on molding the optical powerflow through a sequence of coupled nanoscale optical vortices "pinned" to rationally designed plasmonic nanostructures, referred to as Vortex Nanogear Transmissions (VNTs). We fabricated VNTs composed of Au nanodiscs by electron beam lithography on quartz substrates and characterized their near- and far-field responses through combination of computational electromagnetism, and elastic and inelastic scattering spectroscopy. Pronounced dips in the far-field scattering spectra of VNTs provide experimental evidence for an efficient light trapping and circulation within the nanostructures. Furthermore, we demonstrate that VNT integration into periodic arrays of Au nanoparticles facilitates the generation of high E-field enhancements in the VNTs at multiple defined wavelengths. We show that spectrum shaping in nested VNT structures is achieved through an electromagnetic feed-mechanism driven by the coherent multiple scattering in the plasmonic arrays and that this process can be rationally controlled by tuning the array period. The ability to generate high E-field enhancements at predefined locations and frequencies makes nested VNTs interesting substrates for challenging SERS applications. © 2011 American Chemical Society

Insights into the regioselectivity and RNA-binding affinity of HIV-1 nucleocapsid protein from linear-scaling quantum methods.

PubMed

Khandogin, Jana; Musier-Forsyth, Karin; York, Darrin M

2003-07-25

Human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein (NC) plays several important roles in the viral life-cycle and presents an attractive target for rational drug design. Here, the macromolecular reactivity of NC and its binding to RNA is characterized through determination of electrostatic and chemical descriptors derived from linear-scaling quantum calculations in solution. The computational results offer a rationale for the experimentally observed susceptibility of the Cys49 thiolate toward small-molecule electrophilic agents, and support the recently proposed stepwise protonation mechanism of the C-terminal Zn-coordination complex. The distinctive binding mode of NC to SL2 and SL3 stem-loops of the HIV-1 genomic RNA packaging signal is studied on the basis of protein side-chain contributions to the electrostatic binding energies. These results indicate the importance of several basic residues in the 3(10) helical region and the N-terminal zinc finger, and rationalize the presence of several evolutionarily conserved residues in NC. The combined reactivity and RNA-binding study provides new insights that may contribute toward the structure-based design of anti-HIV therapies.

Beyond directed evolution - semi-rational protein engineering and design

PubMed Central

Lutz, Stefan

2010-01-01

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

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

PubMed

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.

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

PubMed Central

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. PMID:28035082

Transitioning Rationally Designed Catalytic Materials to Real 'Working' Catalysts Produced at Commercial Scale: Nanoparticle Materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schaidle, Joshua A.; Habas, Susan E.; Baddour, Frederick G.

Catalyst design, from idea to commercialization, requires multi-disciplinary scientific and engineering research and development over 10-20 year time periods. Historically, the identification of new or improved catalyst materials has largely been an empirical trial-and-error process. However, advances in computational capabilities (new tools and increased processing power) coupled with new synthetic techniques have started to yield rationally-designed catalysts with controlled nano-structures and tailored properties. This technological advancement represents an opportunity to accelerate the catalyst development timeline and to deliver new materials that outperform existing industrial catalysts or enable new applications, once a number of unique challenges associated with the scale-up ofmore » nano-structured materials are overcome.« less

Design of a small molecule against an oncogenic noncoding RNA.

PubMed

Velagapudi, Sai Pradeep; Cameron, Michael D; Haga, Christopher L; Rosenberg, Laura H; Lafitte, Marie; Duckett, Derek R; Phinney, Donald G; Disney, Matthew D

2016-05-24

The design of precision, preclinical therapeutics from sequence is difficult, but advances in this area, particularly those focused on rational design, could quickly transform the sequence of disease-causing gene products into lead modalities. Herein, we describe the use of Inforna, a computational approach that enables the rational design of small molecules targeting RNA to quickly provide a potent modulator of oncogenic microRNA-96 (miR-96). We mined the secondary structure of primary microRNA-96 (pri-miR-96) hairpin precursor against a database of RNA motif-small molecule interactions, which identified modules that bound RNA motifs nearby and in the Drosha processing site. Precise linking of these modules together provided Targaprimir-96 (3), which selectively modulates miR-96 production in cancer cells and triggers apoptosis. Importantly, the compound is ineffective on healthy breast cells, and exogenous overexpression of pri-miR-96 reduced compound potency in breast cancer cells. Chemical Cross-Linking and Isolation by Pull-Down (Chem-CLIP), a small-molecule RNA target validation approach, shows that 3 directly engages pri-miR-96 in breast cancer cells. In vivo, 3 has a favorable pharmacokinetic profile and decreases tumor burden in a mouse model of triple-negative breast cancer. Thus, rational design can quickly produce precision, in vivo bioactive lead small molecules against hard-to-treat cancers by targeting oncogenic noncoding RNAs, advancing a disease-to-gene-to-drug paradigm.

Mass and Momentum Transport in Microcavities for Diffusion-Dominant Cell Culture Applications

NASA Technical Reports Server (NTRS)

Yew, Alvin G.; Pinero, Daniel; Hsieh, Adam H.; Atencia, Javier

2012-01-01

For the informed design of microfluidic devices, it is important to understand transport phenomena at the microscale. This letter outlines an analytically-driven approach to the design of rectangular microcavities extending perpendicular to a perfusion microchannel for microfluidic cell culture devices. We present equations to estimate the spatial transition from advection- to diffusion-dominant transport inside cavities as a function of the geometry and flow conditions. We also estimate the time required for molecules, such as nutrients or drugs to travel from the microchannel to a given depth into the cavity. These analytical predictions can facilitate the rational design of microfluidic devices to optimize and maintain long-term, physiologically-based culture conditions with low fluid shear stress.

Astronomy in the training of teachers and the role of practical rationality in sky observation

NASA Astrophysics Data System (ADS)

Bretones, P. S.; Compiani, M.

2006-08-01

This work analyses a program in the training of teachers that departs from the courses based on the technical rationality. An Astronomy course was offered to Science and Geography teachers of the four last years of high school education, comprising 46 hours, and organized in 2002 by the Instituto Superior de Ciências Aplicadas in Limeira, Brazil. Following the course a study group was established and held five meetings. The data was obtained through assessments, interviews, and accounts by the teachers and records from the classes and meetings. The actions and conceptual changes and the role of the Practical Rationality were then investigated. It was verified that for sky observation, the model of Practical Rationality within the reflective teacher theoretical framework and tutorial actions leads to knowledge acquisition, conceptual changes and extracurricular activities. Examples are: suggestions, personal actions of the teachers without their students, accounts of extracurricular activities and development of astronomical contents in class, actions in the pedagogical practices and reflections of the teachers with the teacher/ researcher towards the assessment of such changes are shown. It is important to stress that sky observation has specific features that lead to an equally specific school practice, in which the contents and procedures based on observations and their representation point towards a more practical rationality. Even in a training course for teachers based on technical rationality, the introduction of sky observation deepens the practical rationality and the development of principles that guide the acquisition and the teaching of knowledge about sky observation.

Analytic Procedures For Designing and Evaluating Decision Aids.

DTIC Science & Technology

1980-04-01

the taxonomy of decision charateristics . Chapter 5 applies the taxonomies to the information processing functions needed for AAW decisions, and...rationality emphasizes the extent to which organizations and other social institutions consist of individuals who pursue individual objectives by means of...adaptive rationality is always wrong or naive; most of us know persons that seem to be naturally good decision-makers. There is no logic that guarantees

Effect of supplementing orchardgrass herbage with a total mixed ration or flaxseed fermentation profile and bacterial protein synthesis in continuous culture

USDA-ARS?s Scientific Manuscript database

A 4-unit dual-flow continuous culture fermentor system was used to evaluate the effects of herbage, a total mixed ration (TMR) and flaxseed on nutrient digestibility and microbial N synthesis. Treatments were randomly assigned to fermentors in a 4 x 4 Latin square design. Each fermentor was fed a to...

Robust consensus algorithm for multi-agent systems with exogenous disturbances under convergence conditions

NASA Astrophysics Data System (ADS)

Jiang, Yulian; Liu, Jianchang; Tan, Shubin; Ming, Pingsong

2014-09-01

In this paper, a robust consensus algorithm is developed and sufficient conditions for convergence to consensus are proposed for a multi-agent system (MAS) with exogenous disturbances subject to partial information. By utilizing H∞ robust control, differential game theory and a design-based approach, the consensus problem of the MAS with exogenous bounded interference is resolved and the disturbances are restrained, simultaneously. Attention is focused on designing an H∞ robust controller (the robust consensus algorithm) based on minimisation of our proposed rational and individual cost functions according to goals of the MAS. Furthermore, sufficient conditions for convergence of the robust consensus algorithm are given. An example is employed to demonstrate that our results are effective and more capable to restrain exogenous disturbances than the existing literature.

Orientation-Dependent Exciton-Plasmon Coupling in Embedded Organic/Metal Nanowire Heterostructures.

PubMed

Li, Yong Jun; Hong, Yan; Peng, Qian; Yao, Jiannian; Zhao, Yong Sheng

2017-10-24

The excitation of surface plasmons by optical emitters based on exciton-plasmon coupling is important for plasmonic devices with active optical properties. It has been theoretically demonstrated that the orientation of exciton dipole can significantly influence the coupling strength, yet systematic study of the coupling process in nanostructures is still hindered by the lack of proper material systems. In this work, we have experimentally investigated the orientation-dependent exciton-plasmon coupling in a rationally designed organic/metal nanowire heterostructure system. The heterostructures were prepared by inserting silver nanowires into crystalline organic waveguides during the self-assembly of dye molecules. Structures with different exciton orientations exhibited varying coupling efficiencies. The near-field exciton-plasmon coupling facilitates the design of nanophotonic devices based on the directional surface plasmon polariton propagations.

Polymorphic design of DNA origami structures through mechanical control of modular components.

PubMed

Lee, Chanseok; Lee, Jae Young; Kim, Do-Nyun

2017-12-12

Scaffolded DNA origami enables the bottom-up fabrication of diverse DNA nanostructures by designing hundreds of staple strands, comprised of complementary sequences to the specific binding locations of a scaffold strand. Despite its exceptionally high design flexibility, poor reusability of staples has been one of the major hurdles to fabricate assorted DNA constructs in an effective way. Here we provide a rational module-based design approach to create distinct bent shapes with controllable geometries and flexibilities from a single, reference set of staples. By revising the staple connectivity within the desired module, we can control the location, stiffness, and included angle of hinges precisely, enabling the construction of dozens of single- or multiple-hinge structures with the replacement of staple strands up to 12.8% only. Our design approach, combined with computational shape prediction and analysis, can provide a versatile and cost-effective procedure in the design of DNA origami shapes with stiffness-tunable units.

Developments in the Tools and Methodologies of Synthetic Biology

PubMed Central

Kelwick, Richard; MacDonald, James T.; Webb, Alexander J.; Freemont, Paul

2014-01-01

Synthetic biology is principally concerned with the rational design and engineering of biologically based parts, devices, or systems. However, biological systems are generally complex and unpredictable, and are therefore, intrinsically difficult to engineer. In order to address these fundamental challenges, synthetic biology is aiming to unify a “body of knowledge” from several foundational scientific fields, within the context of a set of engineering principles. This shift in perspective is enabling synthetic biologists to address complexity, such that robust biological systems can be designed, assembled, and tested as part of a biological design cycle. The design cycle takes a forward-design approach in which a biological system is specified, modeled, analyzed, assembled, and its functionality tested. At each stage of the design cycle, an expanding repertoire of tools is being developed. In this review, we highlight several of these tools in terms of their applications and benefits to the synthetic biology community. PMID:25505788

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

NASA Astrophysics Data System (ADS)

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.

Estimation of parameters in rational reaction rates of molecular biological systems via weighted least squares

NASA Astrophysics Data System (ADS)

Wu, Fang-Xiang; Mu, Lei; Shi, Zhong-Ke

2010-01-01

The models of gene regulatory networks are often derived from statistical thermodynamics principle or Michaelis-Menten kinetics equation. As a result, the models contain rational reaction rates which are nonlinear in both parameters and states. It is challenging to estimate parameters nonlinear in a model although there have been many traditional nonlinear parameter estimation methods such as Gauss-Newton iteration method and its variants. In this article, we develop a two-step method to estimate the parameters in rational reaction rates of gene regulatory networks via weighted linear least squares. This method takes the special structure of rational reaction rates into consideration. That is, in the rational reaction rates, the numerator and the denominator are linear in parameters. By designing a special weight matrix for the linear least squares, parameters in the numerator and the denominator can be estimated by solving two linear least squares problems. The main advantage of the developed method is that it can produce the analytical solutions to the estimation of parameters in rational reaction rates which originally is nonlinear parameter estimation problem. The developed method is applied to a couple of gene regulatory networks. The simulation results show the superior performance over Gauss-Newton method.

Starlings uphold principles of economic rationality for delay and probability of reward.

PubMed

Monteiro, Tiago; Vasconcelos, Marco; Kacelnik, Alex

2013-04-07

Rationality principles are the bedrock of normative theories of decision-making in biology and microeconomics, but whereas in microeconomics, consistent choice underlies the notion of utility; in biology, the assumption of consistent selective pressures justifies modelling decision mechanisms as if they were designed to maximize fitness. In either case, violations of consistency contradict expectations and attract theoretical interest. Reported violations of rationality in non-humans include intransitivity (i.e. circular preferences) and lack of independence of irrelevant alternatives (changes in relative preference between options when embedded in different choice sets), but the extent to which these observations truly represent breaches of rationality is debatable. We tested both principles with starlings (Sturnus vulgaris), training subjects either with five options differing in food delay (exp. 1) or with six options differing in reward probability (exp. 2), before letting them choose repeatedly one option out of several binary and trinary sets of options. The starlings conformed to economic rationality on both tests, showing strong stochastic transitivity and no violation of the independence principle. These results endorse the rational choice and optimality approaches used in behavioural ecology, and highlight the need for functional and mechanistic enquiring when apparent violations of such principles are observed.

Starlings uphold principles of economic rationality for delay and probability of reward

PubMed Central

Monteiro, Tiago; Vasconcelos, Marco; Kacelnik, Alex

2013-01-01

Rationality principles are the bedrock of normative theories of decision-making in biology and microeconomics, but whereas in microeconomics, consistent choice underlies the notion of utility; in biology, the assumption of consistent selective pressures justifies modelling decision mechanisms as if they were designed to maximize fitness. In either case, violations of consistency contradict expectations and attract theoretical interest. Reported violations of rationality in non-humans include intransitivity (i.e. circular preferences) and lack of independence of irrelevant alternatives (changes in relative preference between options when embedded in different choice sets), but the extent to which these observations truly represent breaches of rationality is debatable. We tested both principles with starlings (Sturnus vulgaris), training subjects either with five options differing in food delay (exp. 1) or with six options differing in reward probability (exp. 2), before letting them choose repeatedly one option out of several binary and trinary sets of options. The starlings conformed to economic rationality on both tests, showing strong stochastic transitivity and no violation of the independence principle. These results endorse the rational choice and optimality approaches used in behavioural ecology, and highlight the need for functional and mechanistic enquiring when apparent violations of such principles are observed. PMID:23390098

Model-theoretic framework for sensor data fusion

NASA Astrophysics Data System (ADS)

Zavoleas, Kyriakos P.; Kokar, Mieczyslaw M.

1993-09-01

The main goal of our research in sensory data fusion (SDF) is the development of a systematic approach (a methodology) to designing systems for interpreting sensory information and for reasoning about the situation based upon this information and upon available data bases and knowledge bases. To achieve such a goal, two kinds of subgoals have been set: (1) develop a theoretical framework in which rational design/implementation decisions can be made, and (2) design a prototype SDF system along the lines of the framework. Our initial design of the framework has been described in our previous papers. In this paper we concentrate on the model-theoretic aspects of this framework. We postulate that data are embedded in data models, and information processing mechanisms are embedded in model operators. The paper is devoted to analyzing the classes of model operators and their significance in SDF. We investigate transformation abstraction and fusion operators. A prototype SDF system, fusing data from range and intensity sensors, is presented, exemplifying the structures introduced. Our framework is justified by the fact that it provides modularity, traceability of information flow, and a basis for a specification language for SDF.

Appendix G : end region design models.

DOT National Transportation Integrated Search

2013-03-01

The 2007 AASHTO LRFD Bridge Design Specifications contain prescriptive : requirements for the quantity and placement of confinement reinforcement located in the bottom : flange of pretensioned concrete I-girders. This chapter proposes a rational mode...

Design, Synthesis and Affinity Properties of Biologically Active Peptide and Protein Conjugates of Cotton Cellulose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Edwards, J. V.; Goheen, Steven C.

The formation of peptide and protein conjugates of cellulose on cotton fabrics provides promising leads for the development of wound healing, antibacterial, and decontaminating textiles. An approach to the design, synthesis, and analysis of bioconjugates containing cellulose peptide and protein conjugates includes: 1) computer graphic modeling for a rationally designed structure; 2) attachment of the peptide or protein to cotton cellulose through a linker amino acid, and 3) characterization of the resulting bioconjugate. Computer graphic simulation of protein and peptide cellulose conjugates gives a rationally designed biopolymer to target synthetic modifications to the cotton cellulose. Techniques for preparing these typesmore » of conjugates involve both sequential assembly of the peptide on the fabric and direct crosslinking of the peptide or protein as cellulose bound esters or carboxymethylcellulose amides.« less

Supracolloidal fullerene-like cages: design principles and formation mechanisms.

PubMed

Li, Zhan-Wei; Zhu, You-Liang; Lu, Zhong-Yuan; Sun, Zhao-Yan

2016-11-30

How to create novel desired structures by rational design of building blocks represents a significant challenge in materials science. Here we report a conceptually new design principle for creating supracolloidal fullerene-like cages through the self-assembly of soft patchy particles interacting via directional nonbonded interactions by mimicking non-planar sp 2 hybridized carbon atoms in C 60 . Our numerical investigations demonstrate that the rational design of patch configuration, size, and interaction can drive soft three-patch particles to reversibly self-assemble into a vast collection of supracolloidal fullerene-like cages. We further elucidate the formation mechanisms of supracolloidal fullerene-like cages by analyzing the structural characteristics and the formation process. Our results provide conceptual and practical guidance towards the experimental realization of supracolloidal fullerene-like cages, as well as a new perspective on understanding the fullerene formation mechanisms.

Resonant Spin-Transfer-Torque Nano-Oscillators

NASA Astrophysics Data System (ADS)

Sharma, Abhishek; Tulapurkar, Ashwin A.; Muralidharan, Bhaskaran

2017-12-01

Spin-transfer-torque nano-oscillators are potential candidates for replacing the traditional inductor-based voltage-controlled oscillators in modern communication devices. Typical oscillator designs are based on trilayer magnetic tunnel junctions, which have the disadvantages of low power outputs and poor conversion efficiencies. We theoretically propose using resonant spin filtering in pentalayer magnetic tunnel junctions as a possible route to alleviate these issues and present viable device designs geared toward a high microwave output power and an efficient conversion of the dc input power. We attribute these robust qualities to the resulting nontrivial spin-current profiles and the ultrahigh tunnel magnetoresistance, both of which arise from resonant spin filtering. The device designs are based on the nonequilibrium Green's-function spin-transport formalism self-consistently coupled with the stochastic Landau-Lifshitz-Gilbert-Slonczewski equation and Poisson's equation. We demonstrate that the proposed structures facilitate oscillator designs featuring a large enhancement in microwave power of around 1150% and an efficiency enhancement of over 1100% compared to typical trilayer designs. We rationalize the optimum operating regions via an analysis of the dynamic and static device resistances. We also demonstrate the robustness of our structures against device design fluctuations and elastic dephasing. This work sets the stage for pentalyer spin-transfer-torque nano-oscillator device designs that ameliorate major issues associated with typical trilayer designs.

Predictive modelling-based design and experiments for synthesis and spinning of bioinspired silk fibres

PubMed Central

Gronau, Greta; Jacobsen, Matthew M.; Huang, Wenwen; Rizzo, Daniel J.; Li, David; Staii, Cristian; Pugno, Nicola M.; Wong, Joyce Y.; Kaplan, David L.; Buehler, Markus J.

2016-01-01

Scalable computational modelling tools are required to guide the rational design of complex hierarchical materials with predictable functions. Here, we utilize mesoscopic modelling, integrated with genetic block copolymer synthesis and bioinspired spinning process, to demonstrate de novo materials design that incorporates chemistry, processing and material characterization. We find that intermediate hydrophobic/hydrophilic block ratios observed in natural spider silks and longer chain lengths lead to outstanding silk fibre formation. This design by nature is based on the optimal combination of protein solubility, self-assembled aggregate size and polymer network topology. The original homogeneous network structure becomes heterogeneous after spinning, enhancing the anisotropic network connectivity along the shear flow direction. Extending beyond the classical polymer theory, with insights from the percolation network model, we illustrate the direct proportionality between network conductance and fibre Young's modulus. This integrated approach provides a general path towards de novo functional network materials with enhanced mechanical properties and beyond (optical, electrical or thermal) as we have experimentally verified. PMID:26017575

Predictive modelling-based design and experiments for synthesis and spinning of bioinspired silk fibres.

PubMed

Lin, Shangchao; Ryu, Seunghwa; Tokareva, Olena; Gronau, Greta; Jacobsen, Matthew M; Huang, Wenwen; Rizzo, Daniel J; Li, David; Staii, Cristian; Pugno, Nicola M; Wong, Joyce Y; Kaplan, David L; Buehler, Markus J

2015-05-28

Scalable computational modelling tools are required to guide the rational design of complex hierarchical materials with predictable functions. Here, we utilize mesoscopic modelling, integrated with genetic block copolymer synthesis and bioinspired spinning process, to demonstrate de novo materials design that incorporates chemistry, processing and material characterization. We find that intermediate hydrophobic/hydrophilic block ratios observed in natural spider silks and longer chain lengths lead to outstanding silk fibre formation. This design by nature is based on the optimal combination of protein solubility, self-assembled aggregate size and polymer network topology. The original homogeneous network structure becomes heterogeneous after spinning, enhancing the anisotropic network connectivity along the shear flow direction. Extending beyond the classical polymer theory, with insights from the percolation network model, we illustrate the direct proportionality between network conductance and fibre Young's modulus. This integrated approach provides a general path towards de novo functional network materials with enhanced mechanical properties and beyond (optical, electrical or thermal) as we have experimentally verified.

Semantics and technologies in modern design of interior stairs

NASA Astrophysics Data System (ADS)

Kukhta, M.; Sokolov, A.; Pelevin, E.

2015-10-01

Use of metal in the design of interior stairs presents new features for shaping, and can be implemented using different technologies. The article discusses the features of design and production technologies of forged metal spiral staircase considering the image semantics based on the historical and cultural heritage. To achieve the objective was applied structural- semantic method (to identify the organization of structure and semantic features of the artistic image), engineering methods (to justify the construction of the object), anthropometry method and ergonomics (to provide usability), methods of comparative analysis (to reveale the features of the way the ladder in different periods of culture). According to the research results are as follows. Was revealed the semantics influence on the design of interior staircase that is based on the World Tree image. Also was suggested rational calculation of steps to ensure the required strength. And finally was presented technology, providing the realization of the artistic image. In the practical part of the work is presented version of forged staircase.

Urban permeable pavement system design based on “sponge city” concept

NASA Astrophysics Data System (ADS)

Yu, M. M.; Zhu, J. W.; Gao, W. F.; Xu, D. P.; Zhao, M.

2017-08-01

Based on the “sponge city” concept, to implement the goal of building a city within the city to solve the sponge waterlogging, rational utilization of water resources, reduce water pollution this paper, combined with the city planning level in China, establishes the design system of city road flooding from the macro, medium and micro level, explore the design method of city water permeable pavement system, and has a practical significance the lower flood risk water ecological problems. On the macro level, we established an urban pavement sponge system under the regional ecological pattern by “spot permeable open space - low impact developing rain water road system - catchment area and catchment wetland”. On a medium level, this paper proposed the permeable suitability of pavement and the planning control indicators when combined with urban functional districts to conduct permeable pavement roads plans and controls. On micro level, the paper studied sponge technology design of permeable pavement from road structure, surface material, and other aspects aimed at the pavement permeability requirements.

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

NASA Astrophysics Data System (ADS)

Enzenhöfer, R.; Geiges, A.; Nowak, W.

2011-12-01

Advection-based well-head protection zones are commonly used to manage the contamination risk of drinking water wells. Considering the insufficient knowledge about hazards and transport properties within the catchment, current Water Safety Plans recommend that catchment managers and stakeholders know, control and monitor all possible hazards within the catchments and perform rational risk-based decisions. Our goal is to supply catchment managers with the required probabilistic risk information, and to generate tools that allow for optimal and rational allocation of resources between improved monitoring versus extended safety margins and risk mitigation measures. To support risk managers with the indispensable information, we address the epistemic uncertainty of advective-dispersive solute transport and well vulnerability (Enzenhoefer et al., 2011) within a stochastic simulation framework. Our framework can separate between uncertainty of contaminant location and actual dilution of peak concentrations by resolving heterogeneity with high-resolution Monte-Carlo simulation. To keep computational costs low, we solve the reverse temporal moment transport equation. Only in post-processing, we recover the time-dependent solute breakthrough curves and the deduced well vulnerability criteria from temporal moments by non-linear optimization. Our first step towards optimal risk management is optimal positioning of sampling locations and optimal choice of data types to reduce best the epistemic prediction uncertainty for well-head delineation, using the cross-bred Likelihood Uncertainty Estimator (CLUE, Leube et al., 2011) for optimal sampling design. Better monitoring leads to more reliable and realistic protection zones and thus helps catchment managers to better justify smaller, yet conservative safety margins. In order to allow an optimal choice in sampling strategies, we compare the trade-off in monitoring versus the delineation costs by accounting for ill-delineated fractions of protection zones. Within an illustrative simplified 2D synthetic test case, we demonstrate our concept, involving synthetic transmissivity and head measurements for conditioning. We demonstrate the worth of optimally collected data in the context of protection zone delineation by assessing the reduced areal demand of delineated area at user-specified risk acceptance level. Results indicate that, thanks to optimally collected data, risk-aware delineation can be made at low to moderate additional costs compared to conventional delineation strategies.

Rational construction of a stable Zn4O-based MOF for highly efficient CO2 capture and conversion.

PubMed

Zhou, Hui-Fang; Liu, Bo; Hou, Lei; Zhang, Wen-Yan; Wang, Yao-Yu

2018-01-11

By employing a carboxylate ligand derived from benzene-1,4-dicarboxylate, a chemically stable Zn 4 O-based self-penetrating metal-organic framework has been rationally synthesized, which exhibits high CO 2 adsorption and efficient catalytic conversion for CO 2 cycloaddition.

Academic Procrastinators: Their Rationalizations and Web-Course Performance.

ERIC Educational Resources Information Center

Tuckman, Bruce W.

This study compared high, moderate, and low procrastinators on their (1) frequency and nature of rationalizations to justify procrastination, (2) reported degree of self-regulation, and (3) grades in a web-based course with 216 performances, all with deadlines. One hundred and sixteen college students enrolled in a web-based "study…

A Rational Analysis of Rule-Based Concept Learning

ERIC Educational Resources Information Center

Goodman, Noah D.; Tenenbaum, Joshua B.; Feldman, Jacob; Griffiths, Thomas L.

2008-01-01

This article proposes a new model of human concept learning that provides a rational analysis of learning feature-based concepts. This model is built upon Bayesian inference for a grammatically structured hypothesis space--a concept language of logical rules. This article compares the model predictions to human generalization judgments in several…

PROCESS DESIGN MANUAL: LAND TREATMENT OF MUNICIPAL WASTEWATER

EPA Science Inventory

The manual presents a rational procedure for the design of land treatment systems. Slow rate, rapid infiltration, and overland flow processes for the treatment of municipal wastewaters are discussed in detail, and the design concepts and criteria are presented. A two-phased plann...

Mapping networks of light-dark transition in LOV photoreceptors.

PubMed

Kaur Grewal, Rajdeep; Mitra, Devrani; Roy, Soumen

2015-11-15

In optogenetics, designing modules of long or short signaling state lifetime is necessary for control over precise cellular events. A critical parameter for designing artificial or synthetic photoreceptors is the signaling state lifetime of photosensor modules. Design and engineering of biologically relevant artificial photoreceptors is based on signaling mechanisms characteristic of naturally occurring photoreceptors. Therefore identifying residues important for light-dark transition is a definite first step towards rational design of synthetic photoreceptors. A thorough grasp of detailed mechanisms of photo induced signaling process would be immensely helpful in understanding the behaviour of organisms. Herein, we introduce the technique of differential networks. We identify key biological interactions, using light-oxygen-voltage domains of all organisms whose dark and light state crystal structures are simultaneously available. Even though structural differences between dark and light states are subtle (other than the covalent bond formation between flavin chromophore and active site Cysteine), our results successfully capture functionally relevant residues and are in complete agreement with experimental findings from literature. Additionally, using sequence-structure alignments, we predict functional significance of interactions found to be important from network perspective yet awaiting experimental validation. Our approach would not only help in minimizing extensive photo-cycle kinetics procedure but is also helpful in providing first-hand information on the fundamentals of photo-adaptation and rational design of synthetic photoreceptors in optogenetics. devrani.dbs@presiuniv.ac.in or soumen@jcbose.ac.in Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Design of experiments (DoE) in pharmaceutical development.

PubMed

N Politis, Stavros; Colombo, Paolo; Colombo, Gaia; M Rekkas, Dimitrios

2017-06-01

At the beginning of the twentieth century, Sir Ronald Fisher introduced the concept of applying statistical analysis during the planning stages of research rather than at the end of experimentation. When statistical thinking is applied from the design phase, it enables to build quality into the product, by adopting Deming's profound knowledge approach, comprising system thinking, variation understanding, theory of knowledge, and psychology. The pharmaceutical industry was late in adopting these paradigms, compared to other sectors. It heavily focused on blockbuster drugs, while formulation development was mainly performed by One Factor At a Time (OFAT) studies, rather than implementing Quality by Design (QbD) and modern engineering-based manufacturing methodologies. Among various mathematical modeling approaches, Design of Experiments (DoE) is extensively used for the implementation of QbD in both research and industrial settings. In QbD, product and process understanding is the key enabler of assuring quality in the final product. Knowledge is achieved by establishing models correlating the inputs with the outputs of the process. The mathematical relationships of the Critical Process Parameters (CPPs) and Material Attributes (CMAs) with the Critical Quality Attributes (CQAs) define the design space. Consequently, process understanding is well assured and rationally leads to a final product meeting the Quality Target Product Profile (QTPP). This review illustrates the principles of quality theory through the work of major contributors, the evolution of the QbD approach and the statistical toolset for its implementation. As such, DoE is presented in detail since it represents the first choice for rational pharmaceutical development.