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.

Navigation-based tibial rotation at 90° of flexion is associated with better range of motion in navigated total knee arthroplasty.

PubMed

Ishida, Kazunari; Shibanuma, Nao; Matsumoto, Tomoyuki; Sasaki, Hiroshi; Takayama, Koji; Hiroshima, Yuji; Kuroda, Ryosuke; Kurosaka, Masahiro

2016-08-01

In clinical practice, people with better femorotibial rotation in the flexed position often achieve a favourable postoperative maximum flexion angle (MFA). However, no objective data have been reported to support this clinical observation. In the present study, we aimed to investigate the correlation between the amount of intraoperative rotation and the pre- and postoperative flexion angles. Fifty-five patients with varus osteoarthritis undergoing computer-assisted posterior-stabilized total knee arthroplasty (TKA) were enrolled. After registration, rotational stress was applied towards the knee joint, and the rotational angles were recorded by using a navigation system at maximum extension and 90° of flexion. After implantation, rotational stress was applied for a second time, and the angles were recorded once more. The MFA was measured before surgery and 1 month after surgery, and the correlation between the amount of femorotibial rotation during surgery and the MFA was statistically evaluated. Although the amount of tibial rotation at maximum extension was not correlated with the MFA, the amount of tibial rotation at 90° of flexion after registration was positively correlated with the pre- and postoperative MFA (both p < 0.005). However, no significant relationship was observed between the amount of tibial rotation after implantation and the postoperative MFA (n.s.). The results showed that better femorotibial rotation at 90° of flexion is associated with a favourable postoperative MFA, suggesting that the flexibility of the surrounding soft tissues is an important factor for obtaining a better MFA, which has important clinical relevance. Hence, further evaluation of navigation-based kinematics during TKA may provide useful information on MFA. Diagnostic studies, development of diagnostic criteria in a consecutive series of patients, and a universally applied "gold" standard, Level II.

Isotopically Nonstationary Metabolic Flux Analysis (INST-MFA) of Photosynthesis and Photorespiration in Plants.

PubMed

Ma, Fangfang; Jazmin, Lara J; Young, Jamey D; Allen, Doug K

2017-01-01

Photorespiration is a central component of photosynthesis; however to better understand its role it should be viewed in the context of an integrated metabolic network rather than a series of individual reactions that operate independently. Isotopically nonstationary 13 C metabolic flux analysis (INST-MFA), which is based on transient labeling studies at metabolic steady state, offers a comprehensive platform to quantify plant central metabolism. In this chapter, we describe the application of INST-MFA to investigate metabolism in leaves. Leaves are an autotrophic tissue, assimilating CO 2 over a diurnal period implying that the metabolic steady state is limited to less than 12 h and thus requiring an INST-MFA approach. This strategy results in a comprehensive unified description of photorespiration, Calvin cycle, sucrose and starch synthesis, tricarboxylic acid (TCA) cycle, and amino acid biosynthetic fluxes. We present protocols of the experimental aspects for labeling studies: transient 13 CO 2 labeling of leaf tissue, sample quenching and extraction, mass spectrometry (MS) analysis of isotopic labeling data, measurement of sucrose and amino acids in vascular exudates, and provide details on the computational flux estimation using INST-MFA.

Customization of ¹³C-MFA strategy according to cell culture system.

PubMed

Quek, Lake-Ee; Nielsen, Lars K

2014-01-01

(13)C-MFA is far from being a simple assay for quantifying metabolic activity. It requires considerable up-front experimental planning and familiarity with the cell culture system in question, as well as optimized analytics and adequate computation frameworks. The success of a (13)C-MFA experiment is ultimately rated by the ability to accurately quantify the flux of one or more reactions of interest. In this chapter, we describe the different (13)C-MFA strategies that have been developed for the various fermentation or cell culture systems, as well as the limitations of the respective strategies. The strategies are affected by many factors and the (13)C-MFA modeling and experimental strategy must be tailored to conditions. The prevailing philosophy in the computation process is that any metabolic processes that produce significant systematic bias in the labeling pattern of the metabolites being measured must be described in the model. It is equally important to plan a labeling strategy by analytical screening or by heuristics.

Morphological characteristics and genetic diversity of Burmese long-tailed Macaques (Macaca fascicularis aurea).

PubMed

Bunlungsup, Srichan; Imai, Hiroo; Hamada, Yuzuru; Gumert, Michael D; San, Aye Mi; Malaivijitnond, Suchinda

2015-12-15

Macaca fascicularis aurea (Mfa) is the only macaque which has been recorded to use stone tools to access encased foods. They live in close contact with M. fascicularis fascicularis (Mff) in southwestern Thailand and the hybrids were reported [Fooden, 1995]. Although Mff and Mfa can be seen in the same habitat types, tool-use behavior has never been reported in Mff. Thus, comparing the morphological characteristics and genetics between Mfa and Mff should help elucidate not only the morphological differences and genetic divergence between these subspecies but also potentially the relationship between genetics and their tool use behavior. We surveyed Mfa and Mff in Myanmar and Thailand, ranging from 16° 58' to 7° 12' N. Fecal or blood samples were collected from eight, five, and four populations of Mfa, Mff, and Mff × Mfa morphological hybrids along with three individuals of captive Chinese M. mulatta (Mm), respectively, for mtDNA and Y-chromosome (TSPY and SRY genes) DNA sequence analyses. In addition, eight populations were captured and measured for 38 somatometric dimensions. Comparison of the somatic measurements revealed that Mfa had a statistically significantly shorter tail than Mff (P < 0.05). Based on the mtDNA sequences, Mfa was separated from the Mm/Mff clade. Within the Mfa clade, the mainland Myanmar population was separate from the Mergui Archipelago and Thailand Andaman seacoast populations. All the morphological hybrids had the Mff mtDNA haplotype. Based on the Y-chromosome sequences, the three major clades of Mm/Indochinese Mff, Sundaic Mff, and Mfa were constructed. The hybrid populations grouped either with the Mm/Indochinese Mff or with the Mfa. Regarding the genetic analysis, one subspecies hybrid population in Thailand (KRI) elicited tool use behavior, thus the potential role of genetics in tool use behavior is raised in addition to the environmental force, morphological suitability, and cognitive capability. Am. J. Primatol. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

3D-QSAR analysis of MCD inhibitors by CoMFA and CoMSIA.

PubMed

Pourbasheer, Eslam; Aalizadeh, Reza; Ebadi, Amin; Ganjali, Mohammad Reza

2015-01-01

Three-dimensional quantitative structure-activity relationship was developed for the series of compounds as malonyl-CoA decarboxylase antagonists (MCD) using the CoMFA and CoMSIA methods. The statistical parameters for CoMFA (q(2)=0.558, r(2)=0.841) and CoMSIA (q(2)= 0.615, r(2) = 0.870) models were derived based on 38 compounds as training set in the basis of the selected alignment. The external predictive abilities of the built models were evaluated by using the test set of nine compounds. From obtained results, the CoMSIA method was found to have highly predictive capability in comparison with CoMFA method. Based on the given results by CoMSIA and CoMFA contour maps, some features that can enhance the activity of compounds as MCD antagonists were introduced and used to design new compounds with better inhibition activity.

Three-dimensional quantitative structure-activity relationship studies on UGT1A9-mediated 3-O-glucuronidation of natural flavonols using a pharmacophore-based comparative molecular field analysis model.

PubMed

Wu, Baojian; Morrow, John Kenneth; Singh, Rashim; Zhang, Shuxing; Hu, Ming

2011-02-01

Glucuronidation is often recognized as one of the rate-determining factors that limit the bioavailability of flavonols. Hence, design and synthesis of more bioavailable flavonols would benefit from the establishment of predictive models of glucuronidation using kinetic parameters [e.g., K(m), V(max), intrinsic clearance (CL(int)) = V(max)/K(m)] derived for flavonols. This article aims to construct position (3-OH)-specific comparative molecular field analysis (CoMFA) models to describe UDP-glucuronosyltransferase (UGT) 1A9-mediated glucuronidation of flavonols, which can be used to design poor UGT1A9 substrates. The kinetics of recombinant UGT1A9-mediated 3-O-glucuronidation of 30 flavonols was characterized, and kinetic parameters (K(m), V(max), CL(int)) were obtained. The observed K(m), V(max), and CL(int) values of 3-O-glucuronidation ranged from 0.04 to 0.68 μM, 0.04 to 12.95 nmol/mg/min, and 0.06 to 109.60 ml/mg/min, respectively. To model UGT1A9-mediated glucuronidation, 30 flavonols were split into the training (23 compounds) and test (7 compounds) sets. These flavonols were then aligned by mapping the flavonols to specific common feature pharmacophores, which were used to construct CoMFA models of V(max) and CL(int), respectively. The derived CoMFA models possessed good internal and external consistency and showed statistical significance and substantive predictive abilities (V(max) model: q(2) = 0.738, r(2) = 0.976, r(pred)(2) = 0.735; CL(int) model: q(2) = 0.561, r(2) = 0.938, r(pred)(2) = 0.630). The contour maps derived from CoMFA modeling clearly indicate structural characteristics associated with rapid or slow 3-O-glucuronidation. In conclusion, the approach of coupling CoMFA analysis with a pharmacophore-based structural alignment is viable for constructing a predictive model for regiospecific glucuronidation rates of flavonols by UGT1A9.

Comparative 3D QSAR study on β1-, β2-, and β3-adrenoceptor agonists

PubMed Central

Senthil Kumar, P.

2009-01-01

A quantitative structure–activity relationship study of tryptamine-based derivatives of β1-, β2-, and β3-adrenoceptor agonists was conducted using comparative molecular field analysis (CoMFA). Correlation coefficients (cross-validated r2) of 0.578, 0.595, and 0.558 were obtained for the three subtypes, respectively, in three different CoMFA models. All three CoMFA models have different steric and electrostatic contributions, implying different requirements inside the binding cavity. The CoMFA coefficient contour plots of the three models and comparisons among these plots provide clues regarding the main chemical features responsible for the biological activity variations and also result in predictions which correlate very well with the observed biological activity. Based on the analysis, a summary regeospecific description of the requirements for improving β-adrenoceptor subtype selectivity is given. PMID:21170122

Multiple receptor conformation docking and dock pose clustering as tool for CoMFA and CoMSIA analysis - a case study on HIV-1 protease inhibitors.

PubMed

Sivan, Sree Kanth; Manga, Vijjulatha

2012-02-01

Multiple receptors conformation docking (MRCD) and clustering of dock poses allows seamless incorporation of receptor binding conformation of the molecules on wide range of ligands with varied structural scaffold. The accuracy of the approach was tested on a set of 120 cyclic urea molecules having HIV-1 protease inhibitory activity using 12 high resolution X-ray crystal structures and one NMR resolved conformation of HIV-1 protease extracted from protein data bank. A cross validation was performed on 25 non-cyclic urea HIV-1 protease inhibitor having varied structures. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were generated using 60 molecules in the training set by applying leave one out cross validation method, r (loo) (2) values of 0.598 and 0.674 for CoMFA and CoMSIA respectively and non-cross validated regression coefficient r(2) values of 0.983 and 0.985 were obtained for CoMFA and CoMSIA respectively. The predictive ability of these models was determined using a test set of 60 cyclic urea molecules that gave predictive correlation (r (pred) (2) ) of 0.684 and 0.64 respectively for CoMFA and CoMSIA indicating good internal predictive ability. Based on this information 25 non-cyclic urea molecules were taken as a test set to check the external predictive ability of these models. This gave remarkable out come with r (pred) (2) of 0.61 and 0.53 for CoMFA and CoMSIA respectively. The results invariably show that this method is useful for performing 3D QSAR analysis on molecules having different structural motifs.

War trauma and maternal-fetal attachment predicting maternal mental health, infant development, and dyadic interaction in Palestinian families.

PubMed

Punamäki, Raija-Leena; Isosävi, Sanna; Qouta, Samir R; Kuittinen, Saija; Diab, Safwat Y

2017-10-01

Optimal maternal-fetal attachment (MFA) is believed to be beneficial for infant well-being and dyadic interaction, but research is scarce in general and among risk populations. Our study involved dyads living in war conditions and examined how traumatic war trauma associates with MFA and which factors mediate that association. It also modeled the role of MFA in predicting newborn health, infant development, mother-infant interaction, and maternal postpartum mental health. Palestinian women from the Gaza Strip (N = 511) participated during their second trimester (T1), and when their infants were 4 (T2) and 12 (T3) months. Mothers reported MFA (interaction with, attributions to, and fantasies about the fetus), social support, and prenatal mental health (post-traumatic stress disorder, depression, and anxiety) at T1, newborn health at T2, and the postpartum mental health, infant's sensorimotor and language development, and mother-infant interaction (emotional availability) at T3. Results revealed, first, that war trauma was not directly associated with MFA but that it was mediated through a low level of social support and high level of maternal prenatal mental health problems. Second, intensive MFA predicted optimal mother-reported infant's sensorimotor and language development and mother-infant emotional availability but not newborn health or maternal postpartum mental health.

How to Deal with Low-Resolution Target Structures: Using SAR, Ensemble Docking, Hydropathic Analysis, and 3D-QSAR to Definitively Map the αβ-Tubulin Colchicine Site

PubMed Central

Da, Chenxiao; Mooberry, Susan L.; Gupton, John T.; Kellogg, Glen E.

2013-01-01

αβ-tubulin colchicine site inhibitors (CSIs) from four scaffolds that we previously tested for antiproliferative activity were modeled to better understand their effect on microtubules. Docking models, constructed by exploiting the SAR of a pyrrole subset and HINT scoring, guided ensemble docking of all 59 compounds. This conformation set and two variants having progressively less structure knowledge were subjected to CoMFA, CoMFA+HINT, and CoMSIA 3D-QSAR analyses. The CoMFA+HINT model (docked alignment) showed the best statistics: leave-one-out q2 of 0.616, r2 of 0.949 and r2pred (internal test set) of 0.755. An external (tested in other laboratories) collection of 24 CSIs from eight scaffolds were evaluated with the 3D-QSAR models, which correctly ranked their activity trends in 7/8 scaffolds for CoMFA+HINT (8/8 for CoMFA). The combination of SAR, ensemble docking, hydropathic analysis and 3D-QSAR provides an atomic-scale colchicine site model more consistent with a target structure resolution much higher than the ~3.6 Å available for αβ-tubulin. PMID:23961916

3D TOCSY-HSQC NMR for metabolic flux analysis using non-uniform sampling

DOE PAGES

Reardon, Patrick N.; Marean-Reardon, Carrie L.; Bukovec, Melanie A.; ...

2016-02-05

13C-Metabolic Flux Analysis ( 13C-MFA) is rapidly being recognized as the authoritative method for determining fluxes through metabolic networks. Site-specific 13C enrichment information obtained using NMR spectroscopy is a valuable input for 13C-MFA experiments. Chemical shift overlaps in the 1D or 2D NMR experiments typically used for 13C-MFA frequently hinder assignment and quantitation of site-specific 13C enrichment. Here we propose the use of a 3D TOCSY-HSQC experiment for 13C-MFA. We employ Non-Uniform Sampling (NUS) to reduce the acquisition time of the experiment to a few hours, making it practical for use in 13C-MFA experiments. Our data show that the NUSmore » experiment is linear and quantitative. Identification of metabolites in complex mixtures, such as a biomass hydrolysate, is simplified by virtue of the 13C chemical shift obtained in the experiment. In addition, the experiment reports 13C-labeling information that reveals the position specific labeling of subsets of isotopomers. As a result, the information provided by this technique will enable more accurate estimation of metabolic fluxes in larger metabolic networks.« less

A scientific workflow framework for (13)C metabolic flux analysis.

PubMed

Dalman, Tolga; Wiechert, Wolfgang; Nöh, Katharina

2016-08-20

Metabolic flux analysis (MFA) with (13)C labeling data is a high-precision technique to quantify intracellular reaction rates (fluxes). One of the major challenges of (13)C MFA is the interactivity of the computational workflow according to which the fluxes are determined from the input data (metabolic network model, labeling data, and physiological rates). Here, the workflow assembly is inevitably determined by the scientist who has to consider interacting biological, experimental, and computational aspects. Decision-making is context dependent and requires expertise, rendering an automated evaluation process hardly possible. Here, we present a scientific workflow framework (SWF) for creating, executing, and controlling on demand (13)C MFA workflows. (13)C MFA-specific tools and libraries, such as the high-performance simulation toolbox 13CFLUX2, are wrapped as web services and thereby integrated into a service-oriented architecture. Besides workflow steering, the SWF features transparent provenance collection and enables full flexibility for ad hoc scripting solutions. To handle compute-intensive tasks, cloud computing is supported. We demonstrate how the challenges posed by (13)C MFA workflows can be solved with our approach on the basis of two proof-of-concept use cases. Copyright © 2015 Elsevier B.V. All rights reserved.

Irradiation data for the MFA-1 and MFA-2 tests in the FFTF

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

Nelson, J.V.

This report provides key information on the irradiation environment of the MONJU fuel tests MFA-1 and MFA-2 in the Fast Flux Test Facility (FFTF). This information includes the fission powers, neutron fluxes, sodium temperatures and sodium flow rates in MFA-I, MFA-2 and adjacent assemblies. It also includes MFA-1 and MFA-2 compositions as a function of exposure. The work was performed at the request of Power Reactor and Nuclear Fuels Corporation (PNC) of Japan.

Combined HQSAR, topomer CoMFA, homology modeling and docking studies on triazole derivatives as SGLT2 inhibitors.

PubMed

Yu, Shuling; Yuan, Jintao; Zhang, Yi; Gao, Shufang; Gan, Ying; Han, Meng; Chen, Yuewen; Zhou, Qiaoqiao; Shi, Jiahua

2017-06-01

Sodium-glucose cotransporter 2 (SGLT2) is a promising target for diabetes therapy. We aimed to develop computational approaches to identify structural features for more potential SGLT2 inhibitors. In this work, 46 triazole derivatives as SGLT2 inhibitors were studied using a combination of several approaches, including hologram quantitative structure-activity relationships (HQSAR), topomer comparative molecular field analysis (CoMFA), homology modeling, and molecular docking. HQSAR and topomer CoMFA were used to construct models. Molecular docking was conducted to investigate the interaction of triazole derivatives and homology modeling of SGLT2, as well as to validate the results of the HQSAR and topomer CoMFA models. The most effective HQSAR and topomer CoMFA models exhibited noncross-validated correlation coefficients of 0.928 and 0.891 for the training set, respectively. External predictions were made successfully on a test set and then compared with previously reported models. The graphical results of HQSAR and topomer CoMFA were proven to be consistent with the binding mode of the inhibitors and SGLT2 from molecular docking. The models and docking provided important insights into the design of potent inhibitors for SGLT2.

Assessing the Reliability of Material Flow Analysis Results: The Cases of Rhenium, Gallium, and Germanium in the United States Economy.

PubMed

Meylan, Grégoire; Reck, Barbara K; Rechberger, Helmut; Graedel, Thomas E; Schwab, Oliver

2017-10-17

Decision-makers traditionally expect "hard facts" from scientific inquiry, an expectation that the results of material flow analyses (MFAs) can hardly meet. MFA limitations are attributable to incompleteness of flowcharts, limited data quality, and model assumptions. Moreover, MFA results are, for the most part, based less on empirical observation but rather on social knowledge construction processes. Developing, applying, and improving the means of evaluating and communicating the reliability of MFA results is imperative. We apply two recently proposed approaches for making quantitative statements on MFA reliability to national minor metals systems: rhenium, gallium, and germanium in the United States in 2012. We discuss the reliability of results in policy and management contexts. The first approach consists of assessing data quality based on systematic characterization of MFA data and the associated meta-information and quantifying the "information content" of MFAs. The second is a quantification of data inconsistencies indicated by the "degree of data reconciliation" between the data and the model. A high information content and a low degree of reconciliation indicate reliable or certain MFA results. This article contributes to reliability and uncertainty discourses in MFA, exemplifying the usefulness of the approaches in policy and management, and to raw material supply discussions by providing country-level information on three important minor metals often considered critical.

Synergy between (13)C-metabolic flux analysis and flux balance analysis for understanding metabolic adaptation to anaerobiosis in E. coli.

PubMed

Chen, Xuewen; Alonso, Ana P; Allen, Doug K; Reed, Jennifer L; Shachar-Hill, Yair

2011-01-01

Genome-based Flux Balance Analysis (FBA) and steady-state isotopic-labeling-based Metabolic Flux Analysis (MFA) are complimentary approaches to predicting and measuring the operation and regulation of metabolic networks. Here, genome-derived models of Escherichia coli (E. coli) metabolism were used for FBA and ¹³C-MFA analyses of aerobic and anaerobic growths of wild-type E. coli (K-12 MG1655) cells. Validated MFA flux maps reveal that the fraction of maintenance ATP consumption in total ATP production is about 14% higher under anaerobic (51.1%) than aerobic conditions (37.2%). FBA revealed that an increased ATP utilization is consumed by ATP synthase to secrete protons from fermentation. The TCA cycle is shown to be incomplete in aerobically growing cells and submaximal growth is due to limited oxidative phosphorylation. An FBA was successful in predicting product secretion rates in aerobic culture if both glucose and oxygen uptake measurement were constrained, but the most-frequently predicted values of internal fluxes yielded from sampling the feasible space differ substantially from MFA-derived fluxes. © 2010 Elsevier Inc. All rights reserved.

Metabolic Flux Analysis in Isotope Labeling Experiments Using the Adjoint Approach.

PubMed

Mottelet, Stephane; Gaullier, Gil; Sadaka, Georges

2017-01-01

Comprehension of metabolic pathways is considerably enhanced by metabolic flux analysis (MFA-ILE) in isotope labeling experiments. The balance equations are given by hundreds of algebraic (stationary MFA) or ordinary differential equations (nonstationary MFA), and reducing the number of operations is therefore a crucial part of reducing the computation cost. The main bottleneck for deterministic algorithms is the computation of derivatives, particularly for nonstationary MFA. In this article, we explain how the overall identification process may be speeded up by using the adjoint approach to compute the gradient of the residual sum of squares. The proposed approach shows significant improvements in terms of complexity and computation time when it is compared with the usual (direct) approach. Numerical results are obtained for the central metabolic pathways of Escherichia coli and are validated against reference software in the stationary case. The methods and algorithms described in this paper are included in the sysmetab software package distributed under an Open Source license at http://forge.scilab.org/index.php/p/sysmetab/.

Synergizing 13C Metabolic Flux Analysis and Metabolic Engineering for Biochemical Production.

PubMed

Guo, Weihua; Sheng, Jiayuan; Feng, Xueyang

Metabolic engineering of industrial microorganisms to produce chemicals, fuels, and drugs has attracted increasing interest as it provides an environment-friendly and renewable route that does not depend on depleting petroleum sources. However, the microbial metabolism is so complex that metabolic engineering efforts often have difficulty in achieving a satisfactory yield, titer, or productivity of the target chemical. To overcome this challenge, 13 C Metabolic Flux Analysis ( 13 C-MFA) has been developed to investigate rigorously the cell metabolism and quantify the carbon flux distribution in central metabolic pathways. In the past decade, 13 C-MFA has been widely used in academic labs and the biotechnology industry to pinpoint the key issues related to microbial-based chemical production and to guide the development of the appropriate metabolic engineering strategies for improving the biochemical production. In this chapter we introduce the basics of 13 C-MFA and illustrate how 13 C-MFA has been applied to synergize with metabolic engineering to identify and tackle the rate-limiting steps in biochemical production.

Combined 3D-QSAR modeling and molecular docking study on azacycles CCR5 antagonists

NASA Astrophysics Data System (ADS)

Ji, Yongjun; Shu, Mao; Lin, Yong; Wang, Yuanqiang; Wang, Rui; Hu, Yong; Lin, Zhihua

2013-08-01

The beta chemokine receptor 5 (CCR5) is an attractive target for pharmaceutical industry in the HIV-1, inflammation and cancer therapeutic areas. In this study, we have developed quantitative structure activity relationship (QSAR) models for a series of 41 azacycles CCR5 antagonists using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA methods. The cross-validated coefficient q2 values of 3D-QASR (CoMFA, CoMSIA, and Topomer CoMFA) methods were 0.630, 0.758, and 0.852, respectively, the non-cross-validated R2 values were 0.979, 0.978, and 0.990, respectively. Docking studies were also employed to determine the most probable binding mode. 3D contour maps and docking results suggested that bulky groups and electron-withdrawing groups on the core part would decrease antiviral activity. Furthermore, docking results indicated that H-bonds and π bonds were favorable for antiviral activities. Finally, a set of novel derivatives with predicted activities were designed.

Rapid Prediction of Bacterial Heterotrophic Fluxomics Using Machine Learning and Constraint Programming.

PubMed

Wu, Stephen Gang; Wang, Yuxuan; Jiang, Wu; Oyetunde, Tolutola; Yao, Ruilian; Zhang, Xuehong; Shimizu, Kazuyuki; Tang, Yinjie J; Bao, Forrest Sheng

2016-04-01

13C metabolic flux analysis (13C-MFA) has been widely used to measure in vivo enzyme reaction rates (i.e., metabolic flux) in microorganisms. Mining the relationship between environmental and genetic factors and metabolic fluxes hidden in existing fluxomic data will lead to predictive models that can significantly accelerate flux quantification. In this paper, we present a web-based platform MFlux (http://mflux.org) that predicts the bacterial central metabolism via machine learning, leveraging data from approximately 100 13C-MFA papers on heterotrophic bacterial metabolisms. Three machine learning methods, namely Support Vector Machine (SVM), k-Nearest Neighbors (k-NN), and Decision Tree, were employed to study the sophisticated relationship between influential factors and metabolic fluxes. We performed a grid search of the best parameter set for each algorithm and verified their performance through 10-fold cross validations. SVM yields the highest accuracy among all three algorithms. Further, we employed quadratic programming to adjust flux profiles to satisfy stoichiometric constraints. Multiple case studies have shown that MFlux can reasonably predict fluxomes as a function of bacterial species, substrate types, growth rate, oxygen conditions, and cultivation methods. Due to the interest of studying model organism under particular carbon sources, bias of fluxome in the dataset may limit the applicability of machine learning models. This problem can be resolved after more papers on 13C-MFA are published for non-model species.

Rapid Prediction of Bacterial Heterotrophic Fluxomics Using Machine Learning and Constraint Programming

PubMed Central

Wu, Stephen Gang; Wang, Yuxuan; Jiang, Wu; Oyetunde, Tolutola; Yao, Ruilian; Zhang, Xuehong; Shimizu, Kazuyuki; Tang, Yinjie J.; Bao, Forrest Sheng

2016-01-01

13C metabolic flux analysis (13C-MFA) has been widely used to measure in vivo enzyme reaction rates (i.e., metabolic flux) in microorganisms. Mining the relationship between environmental and genetic factors and metabolic fluxes hidden in existing fluxomic data will lead to predictive models that can significantly accelerate flux quantification. In this paper, we present a web-based platform MFlux (http://mflux.org) that predicts the bacterial central metabolism via machine learning, leveraging data from approximately 100 13C-MFA papers on heterotrophic bacterial metabolisms. Three machine learning methods, namely Support Vector Machine (SVM), k-Nearest Neighbors (k-NN), and Decision Tree, were employed to study the sophisticated relationship between influential factors and metabolic fluxes. We performed a grid search of the best parameter set for each algorithm and verified their performance through 10-fold cross validations. SVM yields the highest accuracy among all three algorithms. Further, we employed quadratic programming to adjust flux profiles to satisfy stoichiometric constraints. Multiple case studies have shown that MFlux can reasonably predict fluxomes as a function of bacterial species, substrate types, growth rate, oxygen conditions, and cultivation methods. Due to the interest of studying model organism under particular carbon sources, bias of fluxome in the dataset may limit the applicability of machine learning models. This problem can be resolved after more papers on 13C-MFA are published for non-model species. PMID:27092947

IO-MFA and Thermodynamic Approach for Metal Recycling

NASA Astrophysics Data System (ADS)

Nakajima, Kenichi; Matsubae, Kazuyo; Kondo, Yasushi; Nakamura, Shinichiro; Nagasaka, Tetsuya

Recently, the issue of sustainable resource management has been increasingly recognized. In order to increase resource efficiency, Castro et al. (2004) pointed out an importance to understand the interconnections between the materials' processing routes and their thermodynamic constraints, and discussed losses due to contaminations during recycling. One of the dominant solutions to avoid such losses or contaminants is knowledge about the substance flows in material cycles. Material flow analysis (MFA) is a powerful tool to understand the resource consumption and material cycle in the national economy. Some advanced MFA studies discussed the complex web of metal flows and their linkages (Nakamura et al. 2007, 2008). Discussions on the limitations of impurity removal and the recoverability of elements in the recycling of EoL metal products, however, have been insufficient even in conventional MFA studies.

QSAR studies on triazole derivatives as sglt inhibitors via CoMFA and CoMSIA

NASA Astrophysics Data System (ADS)

Zhi, Hui; Zheng, Junxia; Chang, Yiqun; Li, Qingguo; Liao, Guochao; Wang, Qi; Sun, Pinghua

2015-10-01

Forty-six sodium-dependent glucose cotransporters-2 (SGLT-2) inhibitors with hypoglycemic activity were selected to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. A training set of 39 compounds were used to build up the models, which were then evaluated by a series of internal and external cross-validation techniques. A test set of 7 compounds was used for the external validation. The CoMFA model predicted a q2 value of 0.792 and an r2 value of 0.985. The best CoMSIA model predicted a q2 value of 0.633 and an r2 value of 0.895 based on a combination of steric, electrostatic, hydrophobic and hydrogen-bond acceptor effects. The predictive correlation coefficients (rpred2) of CoMFA and CoMSIA models were 0.872 and 0.839, respectively. The analysis of the contour maps from each model provided insight into the structural requirements for the development of more active sglt inhibitors, and on the basis of the models 8 new sglt inhibitors were designed and predicted.

CoMFA and CoMSIA 3D-QSAR studies on S(6)-(4-nitrobenzyl)mercaptopurine riboside (NBMPR) analogs as inhibitors of human equilibrative nucleoside transporter 1 (hENT1).

PubMed

Gupte, Amol; Buolamwini, John K

2009-01-15

3D-QSAR (CoMFA and CoMSIA) studies were performed on human equlibrative nucleoside transporter (hENT1) inhibitors displaying K(i) values ranging from 10,000 to 0.7nM. Both CoMFA and CoMSIA analysis gave reliable models with q2 values >0.50 and r2 values >0.92. The models have been validated for their stability and robustness using group validation and bootstrapping techniques and for their predictive abilities using an external test set of nine compounds. The high predictive r2 values of the test set (0.72 for CoMFA model and 0.74 for CoMSIA model) reveals that the models can prove to be a useful tool for activity prediction of newly designed nucleoside transporter inhibitors. The CoMFA and CoMSIA contour maps identify features important for exhibiting good binding affinities at the transporter, and can thus serve as a useful guide for the design of potential equilibrative nucleoside transporter inhibitors.

UPIOM: a new tool of MFA and its application to the flow of iron and steel associated with car production.

PubMed

Nakamura, Shinichiro; Kondo, Yasushi; Matsubae, Kazuyo; Nakajima, Kenichi; Nagasaka, Tetsuya

2011-02-01

Identification of the flow of materials and substances associated with a product system provides useful information for Life Cycle Analysis (LCA), and contributes to extending the scope of complementarity between LCA and Materials Flow Analysis/Substances Flow Analysis (MFA/SFA), the two major tools of industrial ecology. This paper proposes a new methodology based on input-output analysis for identifying the physical input-output flow of individual materials that is associated with the production of a unit of given product, the unit physical input-output by materials (UPIOM). While the Sankey diagram has been a standard tool for the visualization of MFA/SFA, with an increase in the complexity of the flows under consideration, which will be the case when economy-wide intersectoral flows of materials are involved, the Sankey diagram may become too complex for effective visualization. An alternative way to visually represent material flows is proposed which makes use of triangulation of the flow matrix based on degrees of fabrication. The proposed methodology is applied to the flow of pig iron and iron and steel scrap that are associated with the production of a passenger car in Japan. Its usefulness to identify a specific MFA pattern from the original IO table is demonstrated.

Meclofenamic acid blocks the gap junction communication between the retinal pigment epithelial cells.

PubMed

Ning, N; Wen, Y; Li, Y; Li, J

2013-11-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage the pain and inflammation. NSAIDs can cause serious side effects, including vision problems. However, the underlying mechanisms are still unclear. Therefore, we aimed to investigate the effect of meclofenamic acid (MFA) on retinal pigment epithelium (RPE). In our study, we applied image analysis and whole-cell patch clamp recording to directly measure the effect of MFA on the gap junctional coupling between RPE cells. Analysis of Lucifer yellow (LY) transfer revealed that the gap junction communication existed between RPE cells. Functional experiments using the whole-cell configuration of the patch clamp technique showed that a gap junction conductance also existed between this kind of cells. Importantly, MFA largely inhibited the gap junction conductance and induced the uncoupling of RPE cells. Other NSAIDs, like aspirin and flufenamic acid (FFA), had the same effect. The gap junction functionally existed in RPE cells, which can be blocked by MFA. These findings may explain, at least partially, the vision problems with certain clinically used NSAIDs.

A ligand-based comparative molecular field analysis (CoMFA) and homology model based molecular docking studies on 3', 4'-dihydroxyflavones as rat 5-lipoxygenase inhibitors: Design of new inhibitors.

PubMed

Ahamed, T K Shameera; Muraleedharan, K

2017-12-01

In this study, ligand based comparative molecular field analysis (CoMFA) with five principal components was performed on class of 3', 4'-dihydroxyflavone derivatives for potent rat 5-LOX inhibitors. The percentage contributions in building of CoMFA model were 91.36% for steric field and 8.6% for electrostatic field. R 2 values for training and test sets were found to be 0.9320 and 0.8259, respectively. In case of LOO, LTO and LMO cross validation test, q 2 values were 0.6587, 0.6479 and 0.5547, respectively. These results indicate that the model has high statistical reliability and good predictive power. The extracted contour maps were used to identify the important regions where the modification was necessary to design a new molecule with improved activity. The study has developed a homology model for rat 5-LOX and recognized the key residues at the binding site. Docking of most active molecule to the binding site of 5-LOX confirmed the stability and rationality of CoMFA model. Based on molecular docking results and CoMFA contour plots, new inhibitors with higher activity with respect to the most active compound in data set were designed. Copyright © 2017 Elsevier Ltd. All rights reserved.

3D-QSAR and docking studies of 3-Pyridine heterocyclic derivatives as potent PI3K/mTOR inhibitors

NASA Astrophysics Data System (ADS)

Yang, Wenjuan; Shu, Mao; Wang, Yuanqiang; Wang, Rui; Hu, Yong; Meng, Lingxin; Lin, Zhihua

2013-12-01

Phosphoinosmde-3-kinase/ mammalian target of rapamycin (PI3K/mTOR) dual inhibitors have attracted a great deal of interest as antitumor drugs research. In order to design and optimize these dual inhibitors, two types of 3D-quantitative structure-activity relationship (3D-QSAR) studies based on the ligand alignment and receptor alignment were applied using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). In the study based on ligands alignment, models of PI3K (CoMFA with r2, 0.770; q2, 0.622; CoMSIA with r2, 0.945; q2, 0.748) and mTOR (CoMFA with r2, 0.850; q2, 0.654; CoMSIA with r2, 0.983; q2, 0.676) have good predictability. And in the study based on receptor alignment, models of PI3K (CoMFA with r2, 0.745; q2, 0.538; CoMSIA with r2, 0.938; q2, 0.630) and mTOR (CoMFA with r2, 0.977; q2, 0.825; CoMSIA with r2, 0.985; q2, 0.728) also have good predictability. 3D contour maps and docking results suggested different groups on the core parts of the compounds could enhance the biological activities. Finally, ten derivatives as potential candidates of PI3K/mTOR inhibitors with good predicted activities were designed.

3D-QSAR modeling and molecular docking studies on a series of 2,5 disubstituted 1,3,4-oxadiazoles

NASA Astrophysics Data System (ADS)

Ghaleb, Adib; Aouidate, Adnane; Ghamali, Mounir; Sbai, Abdelouahid; Bouachrine, Mohammed; Lakhlifi, Tahar

2017-10-01

3D-QSAR (comparative molecular field analysis (CoMFA)) and comparative molecular similarity indices analysis (CoMSIA) were performed on novel 2,5 disubstituted 1,3,4-oxadiazoles analogues as anti-fungal agents. The CoMFA and CoMSIA models using 13 compounds in the training set gives Q2 values of 0.52 and 0.51 respectively, while R2 values of 0.92. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to determine a three-dimensional quantitative structure-activity relationship. Based on this study a set of new molecules with high predicted activities were designed. Surflex-docking confirmed the stability of predicted molecules in the receptor.

Three-dimensional quantitative structure-activity relationship (3D QSAR) and pharmacophore elucidation of tetrahydropyran derivatives as serotonin and norepinephrine transporter inhibitors

NASA Astrophysics Data System (ADS)

Kharkar, Prashant S.; Reith, Maarten E. A.; Dutta, Aloke K.

2008-01-01

Three-dimensional quantitative structure-activity relationship (3D QSAR) using comparative molecular field analysis (CoMFA) was performed on a series of substituted tetrahydropyran (THP) derivatives possessing serotonin (SERT) and norepinephrine (NET) transporter inhibitory activities. The study aimed to rationalize the potency of these inhibitors for SERT and NET as well as the observed selectivity differences for NET over SERT. The dataset consisted of 29 molecules, of which 23 molecules were used as the training set for deriving CoMFA models for SERT and NET uptake inhibitory activities. Superimpositions were performed using atom-based fitting and 3-point pharmacophore-based alignment. Two charge calculation methods, Gasteiger-Hückel and semiempirical PM3, were tried. Both alignment methods were analyzed in terms of their predictive abilities and produced comparable results with high internal and external predictivities. The models obtained using the 3-point pharmacophore-based alignment outperformed the models with atom-based fitting in terms of relevant statistics and interpretability of the generated contour maps. Steric fields dominated electrostatic fields in terms of contribution. The selectivity analysis (NET over SERT), though yielded models with good internal predictivity, showed very poor external test set predictions. The analysis was repeated with 24 molecules after systematically excluding so-called outliers (5 out of 29) from the model derivation process. The resulting CoMFA model using the atom-based fitting exhibited good statistics and was able to explain most of the selectivity (NET over SERT)-discriminating factors. The presence of -OH substituent on the THP ring was found to be one of the most important factors governing the NET selectivity over SERT. Thus, a 4-point NET-selective pharmacophore, after introducing this newly found H-bond donor/acceptor feature in addition to the initial 3-point pharmacophore, was proposed.

A gas chromatography-mass spectrometry (GC-MS) method for the detection and quantitation of monofluoroacetate in plants toxic to livestock

USDA-ARS?s Scientific Manuscript database

Monofluoroacetate (MFA) is a potent toxin that occurs in over 50 plant species in Africa, Australia, and South America and is responsible for significant livestock deaths in these regions. A gas chromatography–mass spectrometry (GC-MS) method for the analysis of MFA in plants based on the derivatiza...

A gas chromatography-mass spectrometry (GC-MS) method for the detection and quantitation of monofluoroacetate in plants toxic to livestock

USDA-ARS?s Scientific Manuscript database

Monofluoroacetate (MFA) is a potent toxin that occurs in over 50 plant species in Africa, Australia, and South America and is responsible for significant livestock deaths in these regions. A gas chromatography–mass spectrometry (GC-MS) method for the analysis of MFA in plants based on the derivatiz...

Defining a Closed-Loop U.S. Aluminum Can Supply Chain Through Technical Design and Supply Chain Innovation

NASA Astrophysics Data System (ADS)

Buffington, Jack; Peterson, Ray

2013-08-01

The purpose of this study is to conduct a supply chain material flow analysis (MFA) for the U.S. aluminum can market, consistent with studies conducted for the overall worldwide aluminum industry. A technical definition of the use of alloys 5182 and 3104 is conducted by metallurgists for use in the "aluminum can" MFA. Four propositions are created: technical, economic, and supply chain factors are as important to secondary aluminum recycling in an aluminum can as higher recycling rates (P1); the development of a unialloy aluminum can will increase reuse rates, but recycling rates must increase for this to happen (P2); a closed-loop aluminum can supply chain is not able to be fully realized in today's environment but is very useful for understanding improvement through both supply and demand (P3); and UBC supply can improve through a "voluntary deposit-refund system" approach (P4).

13C-Metabolic Flux Analysis: An Accurate Approach to Demystify Microbial Metabolism for Biochemical Production

PubMed Central

Guo, Weihua; Sheng, Jiayuan; Feng, Xueyang

2015-01-01

Metabolic engineering of various industrial microorganisms to produce chemicals, fuels, and drugs has raised interest since it is environmentally friendly, sustainable, and independent of nonrenewable resources. However, microbial metabolism is so complex that only a few metabolic engineering efforts have been able to achieve a satisfactory yield, titer or productivity of the target chemicals for industrial commercialization. In order to overcome this challenge, 13C Metabolic Flux Analysis (13C-MFA) has been continuously developed and widely applied to rigorously investigate cell metabolism and quantify the carbon flux distribution in central metabolic pathways. In the past decade, many 13C-MFA studies have been performed in academic labs and biotechnology industries to pinpoint key issues related to microbe-based chemical production. Insightful information about the metabolic rewiring has been provided to guide the development of the appropriate metabolic engineering strategies for improving the biochemical production. In this review, we will introduce the basics of 13C-MFA and illustrate how 13C-MFA has been applied via integration with metabolic engineering to identify and tackle the rate-limiting steps in biochemical production for various host microorganisms PMID:28952565

The 3D Structure of the Binding Pocket of the Human Oxytocin Receptor for Benzoxazine Antagonists, Determined by Molecular Docking, Scoring Functions and 3D-QSAR Methods

NASA Astrophysics Data System (ADS)

Jójárt, Balázs; Martinek, Tamás A.; Márki, Árpád

2005-05-01

Molecular docking and 3D-QSAR studies were performed to determine the binding mode for a series of benzoxazine oxytocin antagonists taken from the literature. Structural hypotheses were generated by docking the most active molecule to the rigid receptor by means of AutoDock 3.05. The cluster analysis yielded seven possible binding conformations. These structures were refined by using constrained simulated annealing, and the further ligands were aligned in the refined receptor by molecular docking. A good correlation was found between the estimated Δ G bind and the p K i values for complex F. The Connolly-surface analysis, CoMFA and CoMSIA models q CoMFA 2 = 0.653, q CoMSA 2 = 0.630 and r pred,CoMFA 2 = 0.852 , r pred,CoMSIA 2 = 0.815) confirmed the scoring function results. The structural features of the receptor-ligand complex and the CoMFA and CoMSIA fields are in closely connected. These results suggest that receptor-ligand complex F is the most likely binding hypothesis for the studied benzoxazine analogs.

Adsorption and fractionation of a muck fulvic acid on kaolinite and goethite at pH 3.7,6, and 8

USGS Publications Warehouse

Namjesnik-Dejanovic, K.; Maurice, P.A.; Aiken, G.R.; Cabaniss, S.; Chin, Y.-P.; Pullin, M.J.

2000-01-01

Molecular weight (MW) of humic materials is a key factor controlling proton and metal binding and organic pollutant partitioning. Several studies have suggested preferential adsorption of higher MW, more aromatic moieties to mineral surfaces; quantification of such processes is fundamental to development of predictive models. We used high pressure size exclusion chromatography (HPSEC) to quantify MW changes upon adsorption of a muck fulvic acid (MFA) extracted from a peat deposit to kaolinite and goethite, at pH 3.7,6, and 8 at 22 ??C, I = 0.01 (NaC1), 24-h reaction time. MFA adsorption affinity was greater for goethite than for kaolinite. At concentrations less than the adsorption maximum (A(max)) for both adsorbents, the weight-average MW (M(w)) of MFA remaining in solution decreased by as much as several hundred Daltons relative to control samples, indicating preferential adsorption of the higher MW components. At concentrations more than A(max), M(w) of MFA in solution did not change appreciably. Although total adsorption decreased significantly as pH increased, fractionation as measured by change in M(w) remained similar, perhaps indicating greater selectivity for higher MW components at higher pH. Absorptivities at ?? = 280 nm normalized to mg C L-1 (??) suggested preferential adsorption of more aromatic moieties to kaolinite. ?? could not be used for goethite-reacted samples because high Fe concentrations in the aqueous phase brought about by goethite dissolution interfered with the spectroscopic analysis. Preliminary kinetic experiments suggested that smaller molecules adsorbed first and were replaced by larger molecules whose adsorption was thermodynamically favored.

Prediction of octanol-air partition coefficients for polychlorinated biphenyls (PCBs) using 3D-QSAR models.

PubMed

Chen, Ying; Cai, Xiaoyu; Jiang, Long; Li, Yu

2016-02-01

Based on the experimental data of octanol-air partition coefficients (KOA) for 19 polychlorinated biphenyl (PCB) congeners, two types of QSAR methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), are used to establish 3D-QSAR models using the structural parameters as independent variables and using logKOA values as the dependent variable with the Sybyl software to predict the KOA values of the remaining 190 PCB congeners. The whole data set (19 compounds) was divided into a training set (15 compounds) for model generation and a test set (4 compounds) for model validation. As a result, the cross-validation correlation coefficient (q(2)) obtained by the CoMFA and CoMSIA models (shuffled 12 times) was in the range of 0.825-0.969 (>0.5), the correlation coefficient (r(2)) obtained was in the range of 0.957-1.000 (>0.9), and the SEP (standard error of prediction) of test set was within the range of 0.070-0.617, indicating that the models were robust and predictive. Randomly selected from a set of models, CoMFA analysis revealed that the corresponding percentages of the variance explained by steric and electrostatic fields were 23.9% and 76.1%, respectively, while CoMSIA analysis by steric, electrostatic and hydrophobic fields were 0.6%, 92.6%, and 6.8%, respectively. The electrostatic field was determined as a primary factor governing the logKOA. The correlation analysis of the relationship between the number of Cl atoms and the average logKOA values of PCBs indicated that logKOA values gradually increased as the number of Cl atoms increased. Simultaneously, related studies on PCB detection in the Arctic and Antarctic areas revealed that higher logKOA values indicate a stronger PCB migration ability. From CoMFA and CoMSIA contour maps, logKOA decreased when substituents possessed electropositive groups at the 2-, 3-, 3'-, 5- and 6- positions, which could reduce the PCB migration ability. These results are expected to be beneficial in predicting logKOA values of PCB homologues and derivatives and in providing a theoretical foundation for further elucidation of the global migration behaviour of PCBs. Copyright © 2015 Elsevier Inc. All rights reserved.

Exploring multifunctional agriculture. A review of conceptual approaches and prospects for an integrative transitional framework.

PubMed

Renting, H; Rossing, W A H; Groot, J C J; Van der Ploeg, J D; Laurent, C; Perraud, D; Stobbelaar, D J; Van Ittersum, M K

2009-05-01

In the last decade the multifunctional agriculture (MFA) concept has emerged as a key notion in scientific and policy debates on the future of agriculture and rural development. Broadly speaking, MFA refers to the fact that agricultural activity beyond its role of producing food and fibre may also have several other functions such as renewable natural resources management, landscape and biodiversity conservation and contribution to the socio-economic viability of rural areas. The use of the concept can be traced to a number of wider societal and political transformation processes, which have influenced scientific and policy approaches in different ways amongst countries and disciplines. This paper critically discusses various existing research approaches to MFA, both from natural and social sciences. To this aim different strands of literature are classified according to their focus on specific governance mechanisms and levels of analysis into four main categories of research approaches (market regulation, land-use approaches, actor-oriented and public regulation approaches). For each category an overview of the state-of-the-art of research is given and an assessment is made of its strengths and weaknesses. The review demonstrates that the multifunctionality concept has attracted a wealth of scientific contributions, which have considerably improved our understanding of key aspects of MFA. At the same time approaches in the four categories have remained fragmented and each has limitations to understand MFA in all its complexity due to inherent constraints of applied conceptualizations and associated disciplinary backgrounds. To go beyond these limitations, we contend, new meta-level frameworks of analysis are to be developed that enable a more integrated approach. The paper concludes by presenting the main lines of an integrative, transitional framework for the study of MFA, which analyses multifunctional agriculture against the background of wider societal change processes towards sustainability and identifies a number of key elements and research challenges for this.

Fluxes through plant metabolic networks: measurements, predictions, insights and challenges.

PubMed

Kruger, Nicholas J; Ratcliffe, R George

2015-01-01

Although the flows of material through metabolic networks are central to cell function, they are not easy to measure other than at the level of inputs and outputs. This is particularly true in plant cells, where the network spans multiple subcellular compartments and where the network may function either heterotrophically or photoautotrophically. For many years, kinetic modelling of pathways provided the only method for describing the operation of fragments of the network. However, more recently, it has become possible to map the fluxes in central carbon metabolism using the stable isotope labelling techniques of metabolic flux analysis (MFA), and to predict intracellular fluxes using constraints-based modelling procedures such as flux balance analysis (FBA). These approaches were originally developed for the analysis of microbial metabolism, but over the last decade, they have been adapted for the more demanding analysis of plant metabolic networks. Here, the principal features of MFA and FBA as applied to plants are outlined, followed by a discussion of the insights that have been gained into plant metabolic networks through the application of these time-consuming and non-trivial methods. The discussion focuses on how a system-wide view of plant metabolism has increased our understanding of network structure, metabolic perturbations and the provision of reducing power and energy for cell function. Current methodological challenges that limit the scope of plant MFA are discussed and particular emphasis is placed on the importance of developing methods for cell-specific MFA.

Combination of Analytical and Chemometric Methods as a Useful Tool for the Characterization of Extra Virgin Argan Oil and Other Edible Virgin Oils. Role of Polyphenols and Tocopherols.

PubMed

Rueda, Ascensión; Samaniego-Sánchez, Cristina; Olalla, Manuel; Giménez, Rafael; Cabrera-Vique, Carmen; Seiquer, Isabel; Lara, Luis

2016-01-01

Analysis of phenolic profile and tocopherol fractions in conjunction with chemometrics techniques were used for the accurate characterization of extra virgin argan oil and eight other edible vegetable virgin oils (olive, soybean, wheat germ, walnut, almond, sesame, avocado, and linseed) and to establish similarities among them. Phenolic profile and tocopherols were determined by HPLC coupled with diode-array and fluorescence detectors, respectively. Multivariate factor analysis (MFA) and linear correlations were applied. Significant negative correlations were found between tocopherols and some of the polyphenols identified, but more intensely (P < 0.001) between the γ-tocopherol and oleuropein, pinoresinol, and luteolin. MFA revealed that tocopherols, especially γ-fraction, most strongly influenced the oil characterization. Among the phenolic compounds, syringic acid, dihydroxybenzoic acid, oleuropein, pinoresinol, and luteolin also contributed to the discrimination of the oils. According to the variables analyzed in the present study, argan oil presented the greatest similarity with walnut oil, followed by sesame and linseed oils. Olive, avocado, and almond oils showed close similarities.

IsoDesign: a software for optimizing the design of 13C-metabolic flux analysis experiments.

PubMed

Millard, Pierre; Sokol, Serguei; Letisse, Fabien; Portais, Jean-Charles

2014-01-01

The growing demand for (13) C-metabolic flux analysis ((13) C-MFA) in the field of metabolic engineering and systems biology is driving the need to rationalize expensive and time-consuming (13) C-labeling experiments. Experimental design is a key step in improving both the number of fluxes that can be calculated from a set of isotopic data and the precision of flux values. We present IsoDesign, a software that enables these parameters to be maximized by optimizing the isotopic composition of the label input. It can be applied to (13) C-MFA investigations using a broad panel of analytical tools (MS, MS/MS, (1) H NMR, (13) C NMR, etc.) individually or in combination. It includes a visualization module to intuitively select the optimal label input depending on the biological question to be addressed. Applications of IsoDesign are described, with an example of the entire (13) C-MFA workflow from the experimental design to the flux map including important practical considerations. IsoDesign makes the experimental design of (13) C-MFA experiments more accessible to a wider biological community. IsoDesign is distributed under an open source license at http://metasys.insa-toulouse.fr/software/isodes/ © 2013 Wiley Periodicals, Inc.

13C-Labeled Gluconate Tracing as a Direct and Accurate Method for Determining the Pentose Phosphate Pathway Split Ratio in Penicillium chrysogenum

PubMed Central

Kleijn, Roelco J.; van Winden, Wouter A.; Ras, Cor; van Gulik, Walter M.; Schipper, Dick; Heijnen, Joseph J.

2006-01-01

In this study we developed a new method for accurately determining the pentose phosphate pathway (PPP) split ratio, an important metabolic parameter in the primary metabolism of a cell. This method is based on simultaneous feeding of unlabeled glucose and trace amounts of [U-13C]gluconate, followed by measurement of the mass isotopomers of the intracellular metabolites surrounding the 6-phosphogluconate node. The gluconate tracer method was used with a penicillin G-producing chemostat culture of the filamentous fungus Penicillium chrysogenum. For comparison, a 13C-labeling-based metabolic flux analysis (MFA) was performed for glycolysis and the PPP of P. chrysogenum. For the first time mass isotopomer measurements of 13C-labeled primary metabolites are reported for P. chrysogenum and used for a 13C-based MFA. Estimation of the PPP split ratio of P. chrysogenum at a growth rate of 0.02 h−1 yielded comparable values for the gluconate tracer method and the 13C-based MFA method, 51.8% and 51.1%, respectively. A sensitivity analysis of the estimated PPP split ratios showed that the 95% confidence interval was almost threefold smaller for the gluconate tracer method than for the 13C-based MFA method (40.0 to 63.5% and 46.0 to 56.5%, respectively). From these results we concluded that the gluconate tracer method permits accurate determination of the PPP split ratio but provides no information about the remaining cellular metabolism, while the 13C-based MFA method permits estimation of multiple fluxes but provides a less accurate estimate of the PPP split ratio. PMID:16820467

I-mfa domain proteins specifically interact with HTLV-1 Tax and repress its transactivating functions

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

Kusano, Shuichi, E-mail: skusano@m2.kufm.kagoshima-u.ac.jp; Yoshimitsu, Makoto; Hachiman, Miho

The I-mfa domain proteins HIC (also known as MDFIC) and I-mfa (also known as MDFI) are candidate tumor suppressor genes that are involved in cellular and viral transcriptional regulation. Here, we show that HIC and I-mfa directly interact with human T-cell leukemia virus type-1 (HTLV-1) Tax protein in vitro. In addition, HIC and I-mfa repress Tax-dependent transactivation of an HTLV-1 long terminal repeat (LTR) reporter construct in COS-1, Jurkat and high-Tax-producing HTLV-1-infected T cells. HIC also interacts with Tax through its I-mfa domain in vivo and represses Tax-dependent transactivation of HTLV-1 LTR and NF-κB reporter constructs in an interaction-dependent manner.more » Furthermore, we show that HIC decreases the nuclear distribution and stimulates the proteasomal degradation of Tax. These data reveal that HIC specifically interacts with HTLV-1 Tax and negatively regulates Tax transactivational activity by altering its subcellular distribution and stability. - Highlights: • I-mfa domain proteins, HIC and I-mfa, specifically interact with HTLV-1 Tax. • HIC and I-mfa repress the Tax-dependent transactivation of HTLV-1 LTR. • HIC represses the Tax-dependent transactivation of NF-κΒ. • HIC decreases the nuclear distribution of Tax. • HIC stimulates the proteasomal degradation of Tax.« less

Doing more with less (data): complexities of resource flow analysis in the Gauteng City-Region

NASA Astrophysics Data System (ADS)

Culwick, Christina; Götz, Graeme; Butcher, Siân; Harber, Jesse; Maree, Gillian; Mushongera, Darlington

2017-12-01

Urban metabolism is a growing field of study into resource flows through cities, and how these could be managed more sustainably. There are two main schools of thought on urban metabolism—metabolic flow analysis (MFA) and urban political ecology (UPE). The two schools remain siloed despite common foundations. This paper reflects on recent research by the Gauteng City-Region Observatory (GCRO) into urban sustainability transitions in South Africa’s Gauteng City-Region, a large and sprawling urban formation that faces a host of sustainability challenges including water deficits, erratic electricity supply, stretched infrastructure networks and increasingly carbon-intensive settlement patterns. Three GCRO research projects are reviewed. Each project began with the assumption that data collection on the region’s metabolism could enable an MFA or MFA-like analysis to highlight where possible resource efficiency and sustainability gains might be achieved. However, in each case we confronted severe data-limitations, and ended up asking UPE-style questions on the reasons for and implications of the chronic paucity of urban metabolism data. We have been led to conclude that urban metabolism research will require much more than just assembling and modelling flows data, although these efforts should not be abandoned. A synthesis of MFA and UPE is needed, which simultaneously builds a deeper understanding of resource flows and the systems that govern these flows. We support the emerging approach in political-industrial ecology literature which values both material data on and socio-political insight into urban metabolism, and emphasises the importance of multi-disciplinary and multi-dimensional analysis to inform decision-making in urban sustainability transitions.

Identifying model error in metabolic flux analysis - a generalized least squares approach.

PubMed

Sokolenko, Stanislav; Quattrociocchi, Marco; Aucoin, Marc G

2016-09-13

The estimation of intracellular flux through traditional metabolic flux analysis (MFA) using an overdetermined system of equations is a well established practice in metabolic engineering. Despite the continued evolution of the methodology since its introduction, there has been little focus on validation and identification of poor model fit outside of identifying "gross measurement error". The growing complexity of metabolic models, which are increasingly generated from genome-level data, has necessitated robust validation that can directly assess model fit. In this work, MFA calculation is framed as a generalized least squares (GLS) problem, highlighting the applicability of the common t-test for model validation. To differentiate between measurement and model error, we simulate ideal flux profiles directly from the model, perturb them with estimated measurement error, and compare their validation to real data. Application of this strategy to an established Chinese Hamster Ovary (CHO) cell model shows how fluxes validated by traditional means may be largely non-significant due to a lack of model fit. With further simulation, we explore how t-test significance relates to calculation error and show that fluxes found to be non-significant have 2-4 fold larger error (if measurement uncertainty is in the 5-10 % range). The proposed validation method goes beyond traditional detection of "gross measurement error" to identify lack of fit between model and data. Although the focus of this work is on t-test validation and traditional MFA, the presented framework is readily applicable to other regression analysis methods and MFA formulations.

Quantitative evaluation of dual-flip-angle T1 mapping on DCE-MRI kinetic parameter estimation in head and neck

PubMed Central

Chow, Steven Kwok Keung; Yeung, David Ka Wai; Ahuja, Anil T; King, Ann D

2012-01-01

Purpose To quantitatively evaluate the kinetic parameter estimation for head and neck (HN) dynamic contrast-enhanced (DCE) MRI with dual-flip-angle (DFA) T1 mapping. Materials and methods Clinical DCE-MRI datasets of 23 patients with HN tumors were included in this study. T1 maps were generated based on multiple-flip-angle (MFA) method and different DFA combinations. Tofts model parameter maps of kep, Ktrans and vp based on MFA and DFAs were calculated and compared. Fitted parameter by MFA and DFAs were quantitatively evaluated in primary tumor, salivary gland and muscle. Results T1 mapping deviations by DFAs produced remarkable kinetic parameter estimation deviations in head and neck tissues. In particular, the DFA of [2º, 7º] overestimated, while [7º, 12º] and [7º, 15º] underestimated Ktrans and vp, significantly (P<0.01). [2º, 15º] achieved the smallest but still statistically significant overestimation for Ktrans and vp in primary tumors, 32.1% and 16.2% respectively. kep fitting results by DFAs were relatively close to the MFA reference compared to Ktrans and vp. Conclusions T1 deviations induced by DFA could result in significant errors in kinetic parameter estimation, particularly Ktrans and vp, through Tofts model fitting. MFA method should be more reliable and robust for accurate quantitative pharmacokinetic analysis in head and neck. PMID:23289084

Three-dimensional quantitative structure-activity relationship CoMSIA/CoMFA and LeapFrog studies on novel series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists.

PubMed

Morales-Bayuelo, Alejandro; Ayazo, Hernan; Vivas-Reyes, Ricardo

2010-10-01

Comparative molecular similarity indices analysis (CoMSIA) and comparative molecular field analysis (CoMFA) were performed on a series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists (MCHR1 antagonists). Molecular superimposition of antagonists on the template structure was performed by database alignment method. The statistically significant model was established on sixty five molecules, which were validated by a test set of ten molecules. The CoMSIA model yielded the best predictive model with a q(2) = 0.639, non cross-validated R(2) of 0.953, F value of 92.802, bootstrapped R(2) of 0.971, standard error of prediction = 0.402, and standard error of estimate = 0.146 while the CoMFA model yielded a q(2) = 0.680, non cross-validated R(2) of 0.922, F value of 114.351, bootstrapped R(2) of 0.925, standard error of prediction = 0.364, and standard error of estimate = 0.180. CoMFA analysis maps were employed for generating a pseudo cavity for LeapFrog calculation. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. The results show the variability of steric and electrostatic contributions that determine the activity of the MCHR1 antagonist, with these results we proposed new antagonists that may be more potent than previously reported, these novel antagonists were designed from the addition of highly electronegative groups in the substituent di(i-C(3)H(7))N- of the bicycle [4.1.0] heptanes, using the model CoMFA which also was used for the molecular design using the technique LeapFrog. The data generated from the present study will further help to design novel, potent, and selective MCHR1 antagonists. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Reducing Recon 2 for steady-state flux analysis of HEK cell culture.

PubMed

Quek, Lake-Ee; Dietmair, Stefanie; Hanscho, Michael; Martínez, Verónica S; Borth, Nicole; Nielsen, Lars K

2014-08-20

A representative stoichiometric model is essential to perform metabolic flux analysis (MFA) using experimentally measured consumption (or production) rates as constraints. For Human Embryonic Kidney (HEK) cell culture, there is the opportunity to use an extremely well-curated and annotated human genome-scale model Recon 2 for MFA. Performing MFA using Recon 2 without any modification would have implied that cells have access to all functionality encoded by the genome, which is not realistic. The majority of intracellular fluxes are poorly determined as only extracellular exchange rates are measured. This is compounded by the fact that there is no suitable metabolic objective function to suppress non-specific fluxes. We devised a heuristic to systematically reduce Recon 2 to emphasize flux through core metabolic reactions. This implies that cells would engage these dominant metabolic pathways to grow, and any significant changes in gross metabolic phenotypes would have invoked changes in these pathways. The reduced metabolic model becomes a functionalized version of Recon 2 used for identifying significant metabolic changes in cells by flux analysis. Copyright © 2014 Elsevier B.V. All rights reserved.

Exploring Hydrophobic Binding Surfaces Using Comfa and Flexible Hydrophobic Ligands

NASA Astrophysics Data System (ADS)

Thakkar, Shraddha; Sanchez, Rosa. I.; Bhuveneswaran, Chidambaram; Compadre, Cesar M.

2011-06-01

Cysteine proteinases are a very important group of enzymes involved in a variety of physiological and pathological processes including cancer metastasis and rheumatoid arthritis. In this investigation we used 3D-Quantitative Structure Activity Relationships (3D-QSAR) techniques to model the binding of a variety of substrates to two cysteine proteinases, papain, and cathepsin B. The analysis was performed using Comparative Molecular Field Analysis (CoMFA). The molecules were constructed using standard bond angles and lengths, minimized and aligned. Charges were calculated using the PM3 method in MOPAC. The CoMFA models derived for the binding of the studied substrates to the two proteinases were compared with the expected results from the experimental X-ray crystal structures of the same proteinases. The results showed the value of CoMFA modeling of flexible hydrophobic ligands to analyze ligand binding to protein receptors, and could also serve as the basis to design specific inhibitors of cysteine proteinases with potential therapeutic value.

PFA toolbox: a MATLAB tool for Metabolic Flux Analysis.

PubMed

Morales, Yeimy; Bosque, Gabriel; Vehí, Josep; Picó, Jesús; Llaneras, Francisco

2016-07-11

Metabolic Flux Analysis (MFA) is a methodology that has been successfully applied to estimate metabolic fluxes in living cells. However, traditional frameworks based on this approach have some limitations, particularly when measurements are scarce and imprecise. This is very common in industrial environments. The PFA Toolbox can be used to face those scenarios. Here we present the PFA (Possibilistic Flux Analysis) Toolbox for MATLAB, which simplifies the use of Interval and Possibilistic Metabolic Flux Analysis. The main features of the PFA Toolbox are the following: (a) It provides reliable MFA estimations in scenarios where only a few fluxes can be measured or those available are imprecise. (b) It provides tools to easily plot the results as interval estimates or flux distributions. (c) It is composed of simple functions that MATLAB users can apply in flexible ways. (d) It includes a Graphical User Interface (GUI), which provides a visual representation of the measurements and their uncertainty. (e) It can use stoichiometric models in COBRA format. In addition, the PFA Toolbox includes a User's Guide with a thorough description of its functions and several examples. The PFA Toolbox for MATLAB is a freely available Toolbox that is able to perform Interval and Possibilistic MFA estimations.

Stabilization of a supersaturated solution of mefenamic acid from a solid dispersion with EUDRAGIT(®) EPO.

PubMed

Kojima, Taro; Higashi, Kenjirou; Suzuki, Toyofumi; Tomono, Kazuo; Moribe, Kunikazu; Yamamoto, Keiji

2012-10-01

The stabilization mechanism of a supersaturated solution of mefenamic acid (MFA) from a solid dispersion with EUDRAGIT(®) EPO (EPO) was investigated. The solid dispersions were prepared by cryogenic grinding method. Powder X-ray diffractometry, in vitro dissolution test, in vivo oral absorption study, infrared spectroscopy, and solid- and solution-state NMR spectroscopies were used to characterize the solid dispersions. Dissolution tests in acetate buffer (pH 5.5) revealed that solid dispersion showed > 200-fold higher concentration of MFA. Supersaturated solution was stable over 1 month and exhibited improved oral bioavailability of MFA in rats, with a 7.8-fold higher area under the plasma concentration-versus-time curve. Solid-state (1)H spin-lattice relaxation time (T(1)) measurement showed that MFA was almost monomolecularly dispersed in the EPO polymer matrix. Intermolecular interaction between MFA and EPO was indicated by solid-state infrared and (13)C-T(1) measurements. Solution-state (1)H-NMR measurement demonstrated that MFA existed in monomolecular state in supersaturated solution. (1)H-T(1) and difference nuclear Overhauser effect measurements indicated that cross relaxation occurred between MFA and EPO due to the small distance between them. The formation and high stability of the supersaturated solution were attributable to the specifically formed intermolecular interactions between MFA and EPO.

Advancing biopharmaceutical process development by system-level data analysis and integration of omics data.

PubMed

Schaub, Jochen; Clemens, Christoph; Kaufmann, Hitto; Schulz, Torsten W

2012-01-01

Development of efficient bioprocesses is essential for cost-effective manufacturing of recombinant therapeutic proteins. To achieve further process improvement and process rationalization comprehensive data analysis of both process data and phenotypic cell-level data is essential. Here, we present a framework for advanced bioprocess data analysis consisting of multivariate data analysis (MVDA), metabolic flux analysis (MFA), and pathway analysis for mapping of large-scale gene expression data sets. This data analysis platform was applied in a process development project with an IgG-producing Chinese hamster ovary (CHO) cell line in which the maximal product titer could be increased from about 5 to 8 g/L.Principal component analysis (PCA), k-means clustering, and partial least-squares (PLS) models were applied to analyze the macroscopic bioprocess data. MFA and gene expression analysis revealed intracellular information on the characteristics of high-performance cell cultivations. By MVDA, for example, correlations between several essential amino acids and the product concentration were observed. Also, a grouping into rather cell specific productivity-driven and process control-driven processes could be unraveled. By MFA, phenotypic characteristics in glycolysis, glutaminolysis, pentose phosphate pathway, citrate cycle, coupling of amino acid metabolism to citrate cycle, and in the energy yield could be identified. By gene expression analysis 247 deregulated metabolic genes were identified which are involved, inter alia, in amino acid metabolism, transport, and protein synthesis.

Effect of monofluoroacetate on renal H+ excretion in the rat.

PubMed

Simonnet, H; Gauthier, C; Pellet, M V

1979-05-01

In order to investigate the effect of monofluoroacetate (MFA) on renal H+ excretion, anesthetized rats under mannitol diuresis were given intraperitoneally MFA and some of the acido-basic status parameters were determined. Urinary pH and pCO2 did not change after MFA administration, while urinary flow rate increased. MFA induced a decrease in H+ net excretion and in ammonia excretion. Titratable acidity did not change significantly within the experiment.

Amino Acid and Peptide Utilization Profiles of the Fluoroacetate-Degrading Bacterium Synergistetes Strain MFA1 Under Varying Conditions.

PubMed

Leong, Lex E X; Denman, Stuart E; Hugenholtz, Philip; McSweeney, Christopher S

2016-02-01

Synergistetes strain MFA1 is an asaccharolytic ruminal bacterium isolated based on its ability to degrade fluoroacetate, a plant toxin. The amino acid and peptide requirements of the bacterium were investigated under different culturing conditions. The growth of strain MFA1 and its fluoroacetate degradation rate were enhanced by peptide-rich protein hydrolysates (tryptone and yeast extract) compared to casamino acid, an amino acid-rich protein hydrolysate. Complete utilization and preference for arginine, asparagine, glutamate, glycine, and histidine as free amino acids from yeast extract were observed, while the utilization of serine, threonine, and lysine in free form and peptide-bound glutamate was stimulated during growth on fluoroacetate. A predominant peptide in yeast extract preferentially utilized by strain MFA1 was partially characterized by high-liquid performance chromatography-mass spectrometry as a hepta-glutamate oligopeptide. Similar utilization profiles of amino acids were observed between the co-culture of strain MFA1 with Methanobrevibacter smithii without fluoroacetate and pure strain MFA1 culture with fluoroacetate. This suggests that growth of strain MFA1 could be enhanced by a reduction of hydrogen partial pressure as a result of hydrogen removal by a methanogen or reduction of fluoroacetate.

3D-QSAR studies on the inhibitory activity of trimethoprim analogues against Escherichia coli dihydrofolate reductase.

PubMed

Vijayaraj, Ramadoss; Devi, Mekapothula Lakshmi Vasavi; Subramanian, Venkatesan; Chattaraj, Pratim Kumar

2012-06-01

Three-dimensional quantitative structure activity relationship (3D-QSAR) study has been carried out on the Escherichia coli DHFR inhibitors 2,4-diamino-5-(substituted-benzyl)pyrimidine derivatives to understand the structural features responsible for the improved potency. To construct highly predictive 3D-QSAR models, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used. The predicted models show statistically significant cross-validated and non-cross-validated correlation coefficient of r2 CV and r2 nCV, respectively. The final 3D-QSAR models were validated using structurally diverse test set compounds. Analysis of the contour maps generated from CoMFA and CoMSIA methods reveals that the substitution of electronegative groups at the first and second position along with electropositive group at the third position of R2 substitution significantly increases the potency of the derivatives. The results obtained from the CoMFA and CoMSIA study delineate the substituents on the trimethoprim analogues responsible for the enhanced potency and also provide valuable directions for the design of new trimethoprim analogues with improved affinity. © 2012 John Wiley & Sons A/S.

3D-QSAR and molecular docking study on bisarylmaleimide series as glycogen synthase kinase 3, cyclin dependent kinase 2 and cyclin dependent kinase 4 inhibitors: an insight into the criteria for selectivity.

PubMed

Dessalew, Nigus; Bharatam, Prasad V

2007-07-01

Selective glycogen synthase kinase 3 (GSK3) inhibition over cyclin dependent kinases such as cyclin dependent kinase 2 (CDK2) and cyclin dependent kinase 4 (CDK4) is an important requirement for improved therapeutic profile of GSK3 inhibitors. The concepts of selectivity and additivity fields have been employed in developing selective CoMFA models for these related kinases. Initially, sets of three individual CoMFA models were developed, using 36 compounds of bisarylmaleimide series to correlate with the GSK3, CDK2 and CDK4 inhibitory potencies. These models showed a satisfactory statistical significance: CoMFA-GSK3 (r(2)(con), r(2)(cv): 0.931, 0.519), CoMFA-CDK2 (0.937, 0.563), and CoMFA-CDK4 (0.892, 0.725). Three different selective CoMFA models were then developed using differences in pIC(50) values. These three models showed a superior statistical significance: (i) CoMFA-Selective1 (r(2)(con), r(2)(cv): 0.969, 0.768), (ii) CoMFA-Selective 2 (0.974, 0.835) and (iii) CoMFA-Selective3 (0.963, 0.776). The selective models were found to outperform the individual models in terms of the quality of correlation and were found to be more informative in pinpointing the structural basis for the observed quantitative differences of kinase inhibition. An in-depth comparative investigation was carried out between the individual and selective models to gain an insight into the selectivity criterion. To further validate this approach, a set of new compounds were designed which show selectivity and were docked into the active site of GSK3, using FlexX based incremental construction algorithm.

Molecular Modeling Studies of 4,5-Dihydro-1H-pyrazolo[4,3-h] quinazoline Derivatives as Potent CDK2/Cyclin A Inhibitors Using 3D-QSAR and Docking

PubMed Central

Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

2010-01-01

CDK2/cyclin A has appeared as an attractive drug targets over the years with diverse therapeutic potentials. A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) followed by molecular docking studies were performed on a series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent CDK2/cyclin A inhibitors. The CoMFA and CoMSIA models, using 38 molecules in the training set, gave r2cv values of 0.747 and 0.518 and r2 values of 0.970 and 0.934, respectively. 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. Molecular docking was applied to explore the binding mode between the ligands and the receptor. The information obtained from molecular modeling studies may be helpful to design novel inhibitors of CDK2/cyclin A with desired activity. PMID:21152296

Molecular modeling studies of 4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline derivatives as potent CDK2/Cyclin a inhibitors using 3D-QSAR and docking.

PubMed

Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

2010-09-28

CDK2/cyclin A has appeared as an attractive drug targets over the years with diverse therapeutic potentials. A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) followed by molecular docking studies were performed on a series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent CDK2/cyclin A inhibitors. The CoMFA and CoMSIA models, using 38 molecules in the training set, gave r(2) (cv) values of 0.747 and 0.518 and r(2) values of 0.970 and 0.934, respectively. 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. Molecular docking was applied to explore the binding mode between the ligands and the receptor. The information obtained from molecular modeling studies may be helpful to design novel inhibitors of CDK2/cyclin A with desired activity.

Human I-mfa domain proteins specifically interact with KSHV LANA and affect its regulation of Wnt signaling-dependent transcription

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

Kusano, Shuichi, E-mail: skusano@m2.kufm.kagoshima-u.ac.jp; Eizuru, Yoshito

2010-06-04

Kaposi's sarcoma-associated herpes virus (KSHV)-encoded latency-associated nuclear antigen (LANA) protein has been reported to interact with glycogen synthase kinase 3{beta} (GSK-3{beta}) and to negatively regulate its activity, leading to stimulation of GSK-3{beta}-dependent {beta}-catenin degradation. We show here that the I-mfa domain proteins, HIC (human I-mfa domain-containing protein) and I-mfa (inhibitor of MyoD family a), interacted in vivo with LANA through their C-terminal I-mfa domains. This interaction affected the intracellular localization of HIC, inhibited the LANA-dependent transactivation of a {beta}-catenin-regulated reporter construct, and decreased the level of the LANA.GSK-3{beta} complex. These data reveal for the first time that I-mfa domain proteinsmore » interact with LANA and negatively regulate LANA-mediated activation of Wnt signaling-dependent transcription by inhibiting the formation of the LANA.GSK-3{beta} complex.« less

I-mfa domain proteins specifically interact with HTLV-1 Tax and repress its transactivating functions.

PubMed

Kusano, Shuichi; Yoshimitsu, Makoto; Hachiman, Miho; Ikeda, Masanori

2015-12-01

The I-mfa domain proteins HIC (also known as MDFIC) and I-mfa (also known as MDFI) are candidate tumor suppressor genes that are involved in cellular and viral transcriptional regulation. Here, we show that HIC and I-mfa directly interact with human T-cell leukemia virus type-1 (HTLV-1) Tax protein in vitro. In addition, HIC and I-mfa repress Tax-dependent transactivation of an HTLV-1 long terminal repeat (LTR) reporter construct in COS-1, Jurkat and high-Tax-producing HTLV-1-infected T cells. HIC also interacts with Tax through its I-mfa domain in vivo and represses Tax-dependent transactivation of HTLV-1 LTR and NF-κB reporter constructs in an interaction-dependent manner. Furthermore, we show that HIC decreases the nuclear distribution and stimulates the proteasomal degradation of Tax. These data reveal that HIC specifically interacts with HTLV-1 Tax and negatively regulates Tax transactivational activity by altering its subcellular distribution and stability. Copyright © 2015 Elsevier Inc. All rights reserved.

CoMFA analyses of C-2 position salvinorin A analogs at the kappa-opioid receptor provides insights into epimer selectivity.

PubMed

McGovern, Donna L; Mosier, Philip D; Roth, Bryan L; Westkaemper, Richard B

2010-04-01

The highly potent and kappa-opioid (KOP) receptor-selective hallucinogen Salvinorin A and selected analogs have been analyzed using the 3D quantitative structure-affinity relationship technique Comparative Molecular Field Analysis (CoMFA) in an effort to derive a statistically significant and predictive model of salvinorin affinity at the KOP receptor and to provide additional statistical support for the validity of previously proposed structure-based interaction models. Two CoMFA models of Salvinorin A analogs substituted at the C-2 position are presented. Separate models were developed based on the radioligand used in the kappa-opioid binding assay, [(3)H]diprenorphine or [(125)I]6 beta-iodo-3,14-dihydroxy-17-cyclopropylmethyl-4,5 alpha-epoxymorphinan ([(125)I]IOXY). For each dataset, three methods of alignment were employed: a receptor-docked alignment derived from the structure-based docking algorithm GOLD, another from the ligand-based alignment algorithm FlexS, and a rigid realignment of the poses from the receptor-docked alignment. The receptor-docked alignment produced statistically superior results compared to either the FlexS alignment or the realignment in both datasets. The [(125)I]IOXY set (Model 1) and [(3)H]diprenorphine set (Model 2) gave q(2) values of 0.592 and 0.620, respectively, using the receptor-docked alignment, and both models produced similar CoMFA contour maps that reflected the stereoelectronic features of the receptor model from which they were derived. Each model gave significantly predictive CoMFA statistics (Model 1 PSET r(2)=0.833; Model 2 PSET r(2)=0.813). Based on the CoMFA contour maps, a binding mode was proposed for amine-containing Salvinorin A analogs that provides a rationale for the observation that the beta-epimers (R-configuration) of protonated amines at the C-2 position have a higher affinity than the corresponding alpha-epimers (S-configuration). (c) 2010. Published by Elsevier Inc.

MFA Writers' Relationships with Writing

ERIC Educational Resources Information Center

Olthouse, Jill M.

2013-01-01

Through a qualitative research design, I explored how eight talented masters in fine arts (MFA) writers related to their craft. The phenomenon "relationship with writing" includes writers' goals, values, identity, and emotions as these relate to writing. I found that that these MFA writers experience compatibilities and conflicts…

Non-stationary (13)C-metabolic flux ratio analysis.

PubMed

Hörl, Manuel; Schnidder, Julian; Sauer, Uwe; Zamboni, Nicola

2013-12-01

(13)C-metabolic flux analysis ((13)C-MFA) has become a key method for metabolic engineering and systems biology. In the most common methodology, fluxes are calculated by global isotopomer balancing and iterative fitting to stationary (13)C-labeling data. This approach requires a closed carbon balance, long-lasting metabolic steady state, and the detection of (13)C-patterns in a large number of metabolites. These restrictions mostly reduced the application of (13)C-MFA to the central carbon metabolism of well-studied model organisms grown in minimal media with a single carbon source. Here we introduce non-stationary (13)C-metabolic flux ratio analysis as a novel method for (13)C-MFA to allow estimating local, relative fluxes from ultra-short (13)C-labeling experiments and without the need for global isotopomer balancing. The approach relies on the acquisition of non-stationary (13)C-labeling data exclusively for metabolites in the proximity of a node of converging fluxes and a local parameter estimation with a system of ordinary differential equations. We developed a generalized workflow that takes into account reaction types and the availability of mass spectrometric data on molecular ions or fragments for data processing, modeling, parameter and error estimation. We demonstrated the approach by analyzing three key nodes of converging fluxes in central metabolism of Bacillus subtilis. We obtained flux estimates that are in agreement with published results obtained from steady state experiments, but reduced the duration of the necessary (13)C-labeling experiment to less than a minute. These results show that our strategy enables to formally estimate relative pathway fluxes on extremely short time scale, neglecting cellular carbon balancing. Hence this approach paves the road to targeted (13)C-MFA in dynamic systems with multiple carbon sources and towards rich media. © 2013 Wiley Periodicals, Inc.

Effects of acute ingestion of different fats on oxidative stress and inflammation in overweight and obese adults.

PubMed

Peairs, Abigail D; Rankin, Janet W; Lee, Yong Woo

2011-11-07

Studies show that obese individuals have prolonged elevations in postprandial lipemia and an exacerbated inflammatory response to high fat meals, which can increase risk for cardiovascular diseases. As epidemiological studies indicate an association between type of fat and circulating inflammatory markers, the purpose of this study was to investigate the acute effect of different fat sources on inflammation and oxidative stress in overweight and obese individuals. Eleven overweight and obese subjects consumed three high fat milkshakes rich in monounsaturated fat (MFA), saturated fat (SFA), or long-chain omega 3 polyunsaturated fat (O3FA) in random order. Blood samples collected at baseline, 1, 2, 4, and 6 hours postprandial were analyzed for markers of inflammation (soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tumor necrosis factor- α (TNF-α), and C-reactive protein (CRP)), oxidative stress (8-epi-prostaglandin-F2α (8-epi) and nuclear factor-κB (NF-κB)), and metabolic factors (glucose, insulin, non-esterified free fatty acids, and triglycerides (TG)). O3FA enhanced NF-kB activation compared to SFA, but did not increase any inflammatory factors measured. Conversely, SFA led to higher ICAM-1 levels than MFA (p = 0.051), while MFA increased TG more than SFA (p < 0.05). CRP increased while TNF-α and 8-epi decreased with no difference between treatments. While most of the inflammatory factors measured had modest or no change following the meal, ICAM-1 and NF-κB responded differently by meal type. These results are provocative and suggest that type of fat in meals may differentially influence postprandial inflammation and endothelial activation. © 2011 Peairs et al; licensee BioMed Central Ltd.

Efficacy and immunological actions of FAHF-2 in a murine model of multiple food allergies.

PubMed

Srivastava, Kamal D; Bardina, Ludmilla; Sampson, Hugh A; Li, Xiu-Min

2012-05-01

Food Allergy Herbal Formula-2 (FAHF-2) prevents anaphylaxis in a murine model of peanut allergy. Multiple food allergies (MFA) are common and associated with a higher risk of anaphylaxis. No well-characterized murine model of sensitization to multiple food allergens exists, and no satisfactory therapy for MFA is currently available. To determine the effect of FAHF-2 in a murine model of MFA. C3H/HeJ mice were orally sensitized to peanut, codfish, and egg concurrently. Oral FAHF-2 treatment commenced 1 day after completing sensitization and continued daily for 7 weeks. Mice were subsequently orally challenged with each allergen. Antibodies in sera from mice simultaneously sensitized with peanut, codfish, and egg recognized major allergens of all 3 foods, demonstrating sensitization to multiple unrelated food allergens (MFA mice). Sham-treated MFA mice exhibited anaphylactic symptoms accompanied by elevation of plasma histamine and hypothermia. In contrast, FAHF-2-treated MFA mice showed no anaphylactic symptoms, normal body temperature, and histamine levels after challenge with each allergen. Protection was accompanied by reduction in allergen-specific immunoglobulin E levels. Allergen-stimulated Th2 cytokine interleukin-4 and interleukin-13 production levels decreased, whereas the Th1 cytokine interferon-γ levels were elevated in cultured splenocytes and mesenteric lymph node cells in FAHF-2-treated mice. We established the first murine model of MFA. FAHF-2 prevents peanut, egg, and fish-induced anaphylactic reactions in this model, suggesting that FAHF-2 may have potential for treating human MFA. Copyright © 2012 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

QSAR and 3D QSAR of inhibitors of the epidermal growth factor receptor

NASA Astrophysics Data System (ADS)

Pinto-Bazurco, Mariano; Tsakovska, Ivanka; Pajeva, Ilza

This article reports quantitative structure-activity relationships (QSAR) and 3D QSAR models of 134 structurally diverse inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase. Free-Wilson analysis was used to derive the QSAR model. It identified the substituents in aniline, the polycyclic system, and the substituents at the 6- and 7-positions of the polycyclic system as the most important structural features. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used in the 3D QSAR modeling. The steric and electrostatic interactions proved the most important for the inhibitory effect. Both QSAR and 3D QSAR models led to consistent results. On the basis of the statistically significant models, new structures were proposed and their inhibitory activities were predicted.

Community phylogenetics at the biogeographical scale: cold tolerance, niche conservatism and the structure of North American forests.

PubMed

Hawkins, Bradford A; Rueda, Marta; Rangel, Thiago F; Field, Richard; Diniz-Filho, José Alexandre F; Linder, Peter

2014-01-01

Aim The fossil record has led to a historical explanation for forest diversity gradients within the cool parts of the Northern Hemisphere, founded on a limited ability of woody angiosperm clades to adapt to mid-Tertiary cooling. We tested four predictions of how this should be manifested in the phylogenetic structure of 91,340 communities: (1) forests to the north should comprise species from younger clades (families) than forests to the south; (2) average cold tolerance at a local site should be associated with the mean family age (MFA) of species; (3) minimum temperature should account for MFA better than alternative environmental variables; and (4) traits associated with survival in cold climates should evolve under a niche conservatism constraint. Location The contiguous United States. Methods We extracted angiosperms from the US Forest Service's Forest Inventory and Analysis database. MFA was calculated by assigning age of the family to which each species belongs and averaging across the species in each community. We developed a phylogeny to identify phylogenetic signal in five traits: realized cold tolerance, seed size, seed dispersal mode, leaf phenology and height. Phylogenetic signal representation curves and phylogenetic generalized least squares were used to compare patterns of trait evolution against Brownian motion. Eleven predictors structured at broad or local scales were generated to explore relationships between environment and MFA using random forest and general linear models. Results Consistent with predictions, (1) southern communities comprise angiosperm species from older families than northern communities, (2) cold tolerance is the trait most strongly associated with local MFA, (3) minimum temperature in the coldest month is the environmental variable that best describes MFA, broad-scale variables being much stronger correlates than local-scale variables, and (4) the phylogenetic structures of cold tolerance and at least one other trait associated with survivorship in cold climates indicate niche conservatism. Main conclusions Tropical niche conservatism in the face of long-term climate change, probably initiated in the Late Cretaceous associated with the rise of the Rocky Mountains, is a strong driver of the phylogenetic structure of the angiosperm component of forest communities across the USA. However, local deterministic and/or stochastic processes account for perhaps a quarter of the variation in the MFA of local communities.

Model experiment of magnetic field amplification in laser-produced plasmas via the Richtmyer-Meshkov instability

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

Kuramitsu, Y., E-mail: yasu@ncu.edu.tw; Moritaka, T.; Ohnishi, N.

2016-03-15

A model experiment of magnetic field amplification (MFA) via the Richtmyer-Meshkov instability (RMI) in supernova remnants (SNRs) was performed using a high-power laser. In order to account for very-fast acceleration of cosmic rays observed in SNRs, it is considered that the magnetic field has to be amplified by orders of magnitude from its background level. A possible mechanism for the MFA in SNRs is stretching and mixing of the magnetic field via the RMI when shock waves pass through dense molecular clouds in interstellar media. In order to model the astrophysical phenomenon in laboratories, there are three necessary factors formore » the RMI to be operative: a shock wave, an external magnetic field, and density inhomogeneity. By irradiating a double-foil target with several laser beams with focal spot displacement under influence of an external magnetic field, shock waves were excited and passed through the density inhomogeneity. Radiative hydrodynamic simulations show that the RMI evolves as the density inhomogeneity is shocked, resulting in higher MFA.« less

Structure-Activity Relationships Based on 3D-QSAR CoMFA/CoMSIA and Design of Aryloxypropanol-Amine Agonists with Selectivity for the Human β3-Adrenergic Receptor and Anti-Obesity and Anti-Diabetic Profiles.

PubMed

Lorca, Marcos; Morales-Verdejo, Cesar; Vásquez-Velásquez, David; Andrades-Lagos, Juan; Campanini-Salinas, Javier; Soto-Delgado, Jorge; Recabarren-Gajardo, Gonzalo; Mella, Jaime

2018-05-16

The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r ² ncv = 0.993 and 0.984 and values of r ² test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation ( q ², r ², r ² m , etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC 50 = 8.561).

Genetic variation in the microfibril angle of loblolly pine from two test sites

Treesearch

Jennifer H. Myszewski; Floyd E. Bridgwater; William J. Lowe; Thomas D. Byram; Robert A. Megraw

2004-01-01

In recent years, several studies have examined the effect of microfibril angle (MFA) on wood quality. However, little research has been conducted upon the genetic mechanisms controlling MFA. In this study, we examined the heritability of MFA in loblolly pine, Pinus taeda L., and its genetic relationships with height, diameter, volume, and specific...

"The Writing Writes Itself": Deleuzian Desire and the Creative Writing MFA Degree

ERIC Educational Resources Information Center

Walker, Ginger Marie

2017-01-01

This post-qualitative inquiry project investigated subjectivity (sense of self) among graduates of creative writing Master of Fine Arts (MFA) programs. The project asked how subjectivity is involved in the creative writing process and how that process fuels further writing after a creative piece (such as the MFA thesis) is completed. A…

Detection and analysis of microseismic events using a Matched Filtering Algorithm (MFA)

NASA Astrophysics Data System (ADS)

Caffagni, Enrico; Eaton, David W.; Jones, Joshua P.; van der Baan, Mirko

2016-07-01

A new Matched Filtering Algorithm (MFA) is proposed for detecting and analysing microseismic events recorded by downhole monitoring of hydraulic fracturing. This method requires a set of well-located template (`parent') events, which are obtained using conventional microseismic processing and selected on the basis of high signal-to-noise (S/N) ratio and representative spatial distribution of the recorded microseismicity. Detection and extraction of `child' events are based on stacked, multichannel cross-correlation of the continuous waveform data, using the parent events as reference signals. The location of a child event relative to its parent is determined using an automated process, by rotation of the multicomponent waveforms into the ray-centred co-ordinates of the parent and maximizing the energy of the stacked amplitude envelope within a search volume around the parent's hypocentre. After correction for geometrical spreading and attenuation, the relative magnitude of the child event is obtained automatically using the ratio of stacked envelope peak with respect to its parent. Since only a small number of parent events require interactive analysis such as picking P- and S-wave arrivals, the MFA approach offers the potential for significant reduction in effort for downhole microseismic processing. Our algorithm also facilitates the analysis of single-phase child events, that is, microseismic events for which only one of the S- or P-wave arrivals is evident due to unfavourable S/N conditions. A real-data example using microseismic monitoring data from four stages of an open-hole slickwater hydraulic fracture treatment in western Canada demonstrates that a sparse set of parents (in this case, 4.6 per cent of the originally located events) yields a significant (more than fourfold increase) in the number of located events compared with the original catalogue. Moreover, analysis of the new MFA catalogue suggests that this approach leads to more robust interpretation of the induced microseismicity and novel insights into dynamic rupture processes based on the average temporal (foreshock-aftershock) relationship of child events to parents.

The Global Flows of Metals and Minerals

USGS Publications Warehouse

Rogich, Donald G.; Matos, Grecia R.

2008-01-01

This paper provides a preliminary review of the trends in worldwide metals and industrial minerals production and consumption based on newly developed global metals and minerals Material Flow Accounts (MFA). The MFA developed encompass data on extraction and consumption for 25 metal and mineral commodities, on a country-by-country and year-by-year basis, for the period 1970 to 2004. The data-base, jointly developed by the authors, resides with the U.S. Geological Survey (USGS) as individual commodity Excel workbooks and within a Filemaker data management system for use in analysis. Numerous national MFA have been developed to provide information on the industrial metabolism of individual countries. These MFA include material flows associated with the four commodity categories of goods that are inputs to a country's economy, agriculture, forestry, metals and minerals, and nonrenewable organic material. In some cases, the material flows associated with the creation and maintenance of the built infrastructure (such as houses, buildings, roads, airports, dams, and so forth) were also examined. The creation of global metals and industrial minerals flows is viewed as a first step in the creation of comprehensive global MFA documenting the historical and current flows of all of the four categories of physical goods that support world economies. Metals and minerals represent a major category of nonrenewable resources that humans extract from and return to the natural ecosystem. As human populations and economies have increased, metals and industrial minerals use has increased concomitantly. This dramatic growth in metals and minerals use has serious implications for both the availability of future resources and the health of the environment, which is affected by the outputs associated with their use. This paper provides an overview of a number of the trends observed by examining the database and suggests areas for future study.

Decrease of energy spilling in Escherichia coli continuous cultures with rising specific growth rate and carbon wasting

PubMed Central

2011-01-01

Background Growth substrates, aerobic/anaerobic conditions, specific growth rate (μ) etc. strongly influence Escherichia coli cell physiology in terms of cell size, biomass composition, gene and protein expression. To understand the regulation behind these different phenotype properties, it is useful to know carbon flux patterns in the metabolic network which are generally calculated by metabolic flux analysis (MFA). However, rarely is biomass composition determined and carbon balance carefully measured in the same experiments which could possibly lead to distorted MFA results and questionable conclusions. Therefore, we carried out both detailed carbon balance and biomass composition analysis in the same experiments for more accurate quantitative analysis of metabolism and MFA. Results We applied advanced continuous cultivation methods (A-stat and D-stat) to continuously monitor E. coli K-12 MG1655 flux and energy metabolism dynamic responses to change of μ and glucose-acetate co-utilisation. Surprisingly, a 36% reduction of ATP spilling was detected with increasing μ and carbon wasting to non-CO2 by-products under constant biomass yield. The apparent discrepancy between constant biomass yield and decline of ATP spilling could be explained by the rise of carbon wasting from 3 to 11% in the carbon balance which was revealed by the discovered novel excretion profile of E. coli pyrimidine pathway intermediates carbamoyl-phosphate, dihydroorotate and orotate. We found that carbon wasting patterns are dependent not only on μ, but also on glucose-acetate co-utilisation capability. Accumulation of these compounds was coupled to the two-phase acetate accumulation profile. Acetate overflow was observed in parallel with the reduction of TCA cycle and glycolysis fluxes, and induction of pentose phosphate pathway. Conclusions It can be concluded that acetate metabolism is one of the major regulating factors of central carbon metabolism. More importantly, our model calculations with actual biomass composition and detailed carbon balance analysis in steady state conditions with -omics data comparison demonstrate the importance of a comprehensive systems biology approach for more advanced understanding of metabolism and carbon re-routing mechanisms potentially leading to more successful metabolic engineering. PMID:21726468

Combined 3D-QSAR Modeling and Molecular Docking Studies on Pyrrole-Indolin-2-ones as Aurora A Kinase Inhibitors

PubMed Central

Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

2011-01-01

Aurora kinases have emerged as attractive targets for the design of anticancer drugs. 3D-QSAR (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) and Surflex-docking studies were performed on a series of pyrrole-indoline-2-ones as Aurora A inhibitors. The CoMFA and CoMSIA models using 25 inhibitors in the training set gave r2cv values of 0.726 and 0.566, and r2 values of 0.972 and 0.984, respectively. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to rationalize the key structural requirements responsible for the activity. Surflex-docking studies revealed that the sulfo group, secondary amine group on indolin-2-one, and carbonyl of 6,7-dihydro-1H-indol-4(5H)-one groups were significant for binding to the receptor, and some essential features were also identified. Based on the 3D-QSAR and docking results, a set of new molecules with high predicted activities were designed. PMID:21673910

Combined 3D-QSAR modeling and molecular docking studies on pyrrole-indolin-2-ones as Aurora A kinase inhibitors.

PubMed

Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

2011-01-01

Aurora kinases have emerged as attractive targets for the design of anticancer drugs. 3D-QSAR (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) and Surflex-docking studies were performed on a series of pyrrole-indoline-2-ones as Aurora A inhibitors. The CoMFA and CoMSIA models using 25 inhibitors in the training set gave r(2) (cv) values of 0.726 and 0.566, and r(2) values of 0.972 and 0.984, respectively. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to rationalize the key structural requirements responsible for the activity. Surflex-docking studies revealed that the sulfo group, secondary amine group on indolin-2-one, and carbonyl of 6,7-dihydro-1H-indol-4(5H)-one groups were significant for binding to the receptor, and some essential features were also identified. Based on the 3D-QSAR and docking results, a set of new molecules with high predicted activities were designed.

Integrated Analysis of Environment, Cattle and Human Serological Data: Risks and Mechanisms of Transmission of Rift Valley Fever in Madagascar

PubMed Central

Olive, Marie-Marie; Chevalier, Véronique; Grosbois, Vladimir; Tran, Annelise; Andriamandimby, Soa-Fy; Durand, Benoit; Ravalohery, Jean-Pierre; Andriamamonjy, Seta; Rakotomanana, Fanjasoa; Rogier, Christophe; Heraud, Jean-Michel

2016-01-01

Background Rift Valley fever (RVF) is a vector-borne disease affecting ruminants and humans. Madagascar was heavily affected by RVF in 2008–2009, with evidence of a large and heterogeneous spread of the disease. The identification of at-risk environments is essential to optimize the available resources by targeting RVF surveillance in Madagascar. Herein, the objectives of our study were: (i) to identify the environmental factors and areas favorable to RVF transmission to both cattle and human and (ii) to identify human behaviors favoring human infections in Malagasy contexts. Methodology/Principal Findings First, we characterized the environments of Malagasy communes using a Multiple Factor Analysis (MFA). Then, we analyzed cattle and human serological data collected at national level using Generalized Linear Mixed Models, with the individual serological status (cattle or human) as the response, and MFA factors, as well as other potential risk factors (cattle density, human behavior) as explanatory variables. Cattle and human seroprevalence rates were positively associated to humid environments (p<0.001). Areas with high cattle density were at risk (p<0.01; OR = 2.6). Furthermore, our analysis showed that frequent contact with raw milk contributed to explain human infection (OR = 1.6). Finally, our study highlighted the eastern-coast, western and north-western parts as high-risk areas for RVF transmission in cattle. Conclusions/Significance Our integrated approach analyzing environmental, cattle and human datasets allow us to bring new insight on RVF transmission patterns in Madagascar. The association between cattle seroprevalence, humid environments and high cattle density suggests that concomitant vectorial and direct transmissions are critical to maintain RVF enzootic transmission. Additionally, in the at-risk humid environment of the western, north-western and the eastern-coast areas, suitable to Culex and Anopheles mosquitoes, vectorial transmission probably occurs in both cattle and human. The relative contribution of vectorial or direct transmissions could be further assessed by mathematic modelling. PMID:27415438

Integrated Analysis of Environment, Cattle and Human Serological Data: Risks and Mechanisms of Transmission of Rift Valley Fever in Madagascar.

PubMed

Olive, Marie-Marie; Chevalier, Véronique; Grosbois, Vladimir; Tran, Annelise; Andriamandimby, Soa-Fy; Durand, Benoit; Ravalohery, Jean-Pierre; Andriamamonjy, Seta; Rakotomanana, Fanjasoa; Rogier, Christophe; Heraud, Jean-Michel

2016-07-01

Rift Valley fever (RVF) is a vector-borne disease affecting ruminants and humans. Madagascar was heavily affected by RVF in 2008-2009, with evidence of a large and heterogeneous spread of the disease. The identification of at-risk environments is essential to optimize the available resources by targeting RVF surveillance in Madagascar. Herein, the objectives of our study were: (i) to identify the environmental factors and areas favorable to RVF transmission to both cattle and human and (ii) to identify human behaviors favoring human infections in Malagasy contexts. First, we characterized the environments of Malagasy communes using a Multiple Factor Analysis (MFA). Then, we analyzed cattle and human serological data collected at national level using Generalized Linear Mixed Models, with the individual serological status (cattle or human) as the response, and MFA factors, as well as other potential risk factors (cattle density, human behavior) as explanatory variables. Cattle and human seroprevalence rates were positively associated to humid environments (p<0.001). Areas with high cattle density were at risk (p<0.01; OR = 2.6). Furthermore, our analysis showed that frequent contact with raw milk contributed to explain human infection (OR = 1.6). Finally, our study highlighted the eastern-coast, western and north-western parts as high-risk areas for RVF transmission in cattle. Our integrated approach analyzing environmental, cattle and human datasets allow us to bring new insight on RVF transmission patterns in Madagascar. The association between cattle seroprevalence, humid environments and high cattle density suggests that concomitant vectorial and direct transmissions are critical to maintain RVF enzootic transmission. Additionally, in the at-risk humid environment of the western, north-western and the eastern-coast areas, suitable to Culex and Anopheles mosquitoes, vectorial transmission probably occurs in both cattle and human. The relative contribution of vectorial or direct transmissions could be further assessed by mathematic modelling.

Quantitative insights for the design of substrate-based SIRT1 inhibitors.

PubMed

Kokkonen, Piia; Mellini, Paolo; Nyrhilä, Olli; Rahnasto-Rilla, Minna; Suuronen, Tiina; Kiviranta, Päivi; Huhtiniemi, Tero; Poso, Antti; Jarho, Elina; Lahtela-Kakkonen, Maija

2014-08-01

Sirtuin 1 (SIRT1) is the most studied human sirtuin and it catalyzes the deacetylation reaction of acetylated lysine residues of its target proteins, for example histones. It is a promising drug target in the treatment of age-related diseases, such as neurodegenerative diseases and cancer. In this study, a series of known substrate-based sirtuin inhibitors was analyzed with comparative molecular field analysis (CoMFA), which is a three-dimensional quantitative structure-activity relationships (3D-QSAR) technique. The CoMFA model was validated both internally and externally, producing the statistical values concordance correlation coefficient (CCC) of 0.88, the mean value r(2)m of 0.66 and Q(2)F3 of 0.89. Based on the CoMFA interaction contours, 13 new potential inhibitors with high predicted activity were designed, and the activities were verified by in vitro measurements. This work proposes an effective approach for the design and activity prediction of new potential substrate-based SIRT1 inhibitors. Copyright © 2014 Elsevier B.V. All rights reserved.

Substituent effects on the enantioselective retention of anti-HIV 5-aryl-delta 2-1,2,4-oxadiazolines on R,R-DACH-DNB chiral stationary phase.

PubMed

Altomare, C; Cellamare, S; Carotti, A; Barreca, M L; Chimirri, A; Monforte, A M; Gasparrini, F; Villani, C; Cirilli, M; Mazza, F

1996-01-01

A series of racemic 3-phenyl-4-(1-adamantyl)-5-X-phenyl- delta 2-1,2,4-oxadiazo lines (PAdOx) were directly resolved by HPLC using a Pirkle-type stationary phase containing N,N'-(3,5-dinitrobenzoyl)-1(R),2(R)-diaminocyclohexane as chiral selector. The more retained enantiomers have S configuration, as demonstrated by X-ray crystallography and circular dichroism measurements. The influence of aromatic ring substituents on enantioselective retention was quantitatively assessed by traditional linear free energy-related (LFER) equations and comparative molecular field analysis (CoMFA). In good agreement with previous findings, the results from this study indicate that the increase in retention (k') is favoured mainly by the phi-basicity and the hydrophilicity of solute, whereas enantioselectivity (alpha) can be satisfactorily modeled by electronic and bulk parameters or CoMFA descriptors. The LFER equations and CoMFA models gave helpful insights into chiral recognition mechanisms.

Three-dimensional quantitative structure-property relationship (3D-QSPR) models for prediction of thermodynamic properties of polychlorinated biphenyls (PCBs): enthalpy of vaporization.

PubMed

Puri, Swati; Chickos, James S; Welsh, William J

2002-01-01

Three-dimensional Quantitative Structure-Property Relationship (QSPR) models have been derived using Comparative Molecular Field Analysis (CoMFA) to correlate the vaporization enthalpies of a representative set of polychlorinated biphenyls (PCBs) at 298.15 K with their CoMFA-calculated physicochemical properties. Various alignment schemes, such as inertial, as is, and atom fit, were employed in this study. The CoMFA models were also developed using different partial charge formalisms, namely, electrostatic potential (ESP) charges and Gasteiger-Marsili (GM) charges. The most predictive model for vaporization enthalpy (Delta(vap)H(m)(298.15 K)), with atom fit alignment and Gasteiger-Marsili charges, yielded r2 values 0.852 (cross-validated) and 0.996 (conventional). The vaporization enthalpies of PCBs increased with the number of chlorine atoms and were found to be larger for the meta- and para-substituted isomers. This model was used to predict Delta(vap)H(m)(298.15 K) of the entire set of 209 PCB congeners.

77 FR 66074 - Regulation of Fuel and Fuel Additives: Modification to Octamix Waiver (TOLAD MFA-10A)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-01

... Texas Methanol's gasoline-alcohol fuel, OCTAMIX. This correction notice explains that TOLAD MFA-10A is... inhibitor, TOLAD TM MFA-10A, at a concentration of 42 mg/l, in the OCTAMIX gasoline-alcohol fuel blend which... corrosion inhibitor in Texas Methanol's gasoline- alcohol fuel, OCTAMIX.\\2\\ \\1\\ EPA-HQ-OAR-2011-0894-0001...

Comparative molecular field analysis to derive pharmacophore maps for induction doses of intravenous anaesthetic agents.

PubMed

Sear, J W

2011-03-01

The present study examines the molecular basis of induction of anaesthesia by i.v. hypnotic agents using comparative molecular field analysis (CoMFA). ED(50) induction doses for 14 i.v. anaesthetics in human subjects (expressed as molar dose per kilogram body weight) were obtained from the literature. Immobilizing potency data for the same 14 agents (expressed as the EC(50) plasma free drug concentrations that abolish movement in response to a noxious stimulus in 50% patients) were taken from our previous publication. These data were used to form CoMFA models for the two aspects of anaesthetic activity. Molecular alignment was achieved by field-fit minimization techniques. The lead structure for both models was eltanolone. The final CoMFA model for the ED(50) induction dose was based on two latent variables, and explained 99.3% of the variance in observed activities. It showed good intrinsic predictability (cross-validated q(2)=0.849). The equivalent model for immobilizing activity was also based on two latent variables, with r(2)=0.988 and q(2)=0.852. Although there was a correlation between -log ED(50) and -log EC(50) (r(2)=0.779), comparison of the pharmacophore maps showed poor correlation for both electrostatic and steric regions when isocontours were constructed by linking lattice grid points, making the greatest 40% contributions; the relative contributions of electrostatic and steric interactions differing between the models (induction dose: 2.5:1; immobilizing activity 1.8:1). Comparison of two CoMFA activity models shows only small elements of commonality, suggesting that different molecular features may be responsible for these two properties of i.v. anaesthetics.

A systematic quantitative approach to rational drug design and discovery of novel human carbonic anhydrase IX inhibitors.

PubMed

Sethi, Kalyan K; Verma, Saurabh M

2014-08-01

Drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed for a series of carbonic anhydrase IX inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques with the help of SYBYL 7.1 software. The large set of 36 different aromatic/heterocyclic sulfamates carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, such as hCA IX, was chosen for this study. The conventional ligand-based 3D-QSAR studies were performed based on the low energy conformations employing database alignment rule. The ligand-based model gave q(2) values 0.802 and 0.829 and r(2) values 1.000 and 0.994 for CoMFA and CoMSIA, respectively, and the predictive ability of the model was validated. The predicted r(2) values are 0.999 and 0.502 for CoMFA and CoMSIA, respectively. SEA (steric, electrostatic, hydrogen bond acceptor) of CoMSIA has the significant contribution for the model development. The docking of inhibitors into hCA IX active site using Glide XP (Schrödinger) software revealed the vital interactions and binding conformation of the inhibitors. The CoMFA and CoMSIA field contour maps are well in agreement with the structural characteristics of the binding pocket of hCA IX active site, which suggests that the information rendered by 3D-QSAR models and the docking interactions can provide guidelines for the development of improved hCA IX inhibitors as leads for various types of metastatic cancers including those of cervical, renal, breast and head and neck origin.

Parallel labeling experiments for pathway elucidation and (13)C metabolic flux analysis.

PubMed

Antoniewicz, Maciek R

2015-12-01

Metabolic pathway models provide the foundation for quantitative studies of cellular physiology through the measurement of intracellular metabolic fluxes. For model organisms metabolic models are well established, with many manually curated genome-scale model reconstructions, gene knockout studies and stable-isotope tracing studies. However, for non-model organisms a similar level of knowledge is often lacking. Compartmentation of cellular metabolism in eukaryotic systems also presents significant challenges for quantitative (13)C-metabolic flux analysis ((13)C-MFA). Recently, innovative (13)C-MFA approaches have been developed based on parallel labeling experiments, the use of multiple isotopic tracers and integrated data analysis, that allow more rigorous validation of pathway models and improved quantification of metabolic fluxes. Applications of these approaches open new research directions in metabolic engineering, biotechnology and medicine. Copyright © 2015 Elsevier Ltd. All rights reserved.

Test Review: Reynolds, C. R., Voress, J. V., Kamphaus, R. W. (2015), "Mathematics Fluency and Calculation Tests (MFaCTs) review." PRO-ED

ERIC Educational Resources Information Center

Marbach, Joshua

2017-01-01

The Mathematics Fluency and Calculation Tests (MFaCTs) are a series of measures designed to assess for arithmetic calculation skills and calculation fluency in children ages 6 through 18. There are five main purposes of the MFaCTs: (1) identifying students who are behind in basic math fact automaticity; (2) evaluating possible delays in arithmetic…

Molecular description of α-keto-based inhibitors of cruzain with activity against Chagas disease combining 3D-QSAR studies and molecular dynamics.

PubMed

Saraiva, Ádria P B; Miranda, Ricardo M; Valente, Renan P P; Araújo, Jéssica O; Souza, Rutelene N B; Costa, Clauber H S; Oliveira, Amanda R S; Almeida, Michell O; Figueiredo, Antonio F; Ferreira, João E V; Alves, Cláudio Nahum; Honorio, Kathia M

2018-04-22

In this work, a group of α-keto-based inhibitors of the cruzain enzyme with anti-chagas activity was selected for a three-dimensional quantitative structure-activity relationship study (3D-QSAR) combined with molecular dynamics (MD). Firstly, statistical models based on Partial Least Square (PLS) regression were developed employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) descriptors. Validation parameters (q 2 and r 2 )for the models were, respectively, 0.910 and 0.997 (CoMFA) and 0.913 and 0.992 (CoMSIA). In addition, external validation for the models using a test group revealed r 2 pred  = 0.728 (CoMFA) and 0.971 (CoMSIA). The most relevant aspect in this study was the generation of molecular fields in both favorable and unfavorable regions based on the models developed. These fields are important to interpret modifications necessary to enhance the biological activities of the inhibitors. This analysis was restricted considering the inhibitors in a fixed conformation, not interacting with their target, the cruzain enzyme. Then, MD was employed taking into account important variables such as time and temperature. MD helped describe the behavior of the inhibitors and their properties showed similar results as those generated by QSAR-3D study. © 2018 John Wiley & Sons A/S.

Molecular docking and 3D-QSAR studies on triazolinone and pyridazinone, non-nucleoside inhibitor of HIV-1 reverse transcriptase.

PubMed

Sivan, Sree Kanth; Manga, Vijjulatha

2010-06-01

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV-1 reverse transcriptase. Recently a series of Triazolinone and Pyridazinone were reported as potent inhibitors of HIV-1 wild type reverse transcriptase. In the present study, docking and 3D quantitative structure activity relationship (3D QSAR) studies involving comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 31 molecules. Ligands were built and minimized using Tripos force field and applying Gasteiger-Hückel charges. These ligands were docked into protein active site using GLIDE 4.0. The docked poses were analyzed; the best docked poses were selected and aligned. CoMFA and CoMSIA fields were calculated using SYBYL6.9. The molecules were divided into training set and test set, a PLS analysis was performed and QSAR models were generated. The model showed good statistical reliability which is evident from the r2 nv, q2 loo and r2 pred values. The CoMFA model provides the most significant correlation of steric and electrostatic fields with biological activities. The CoMSIA model provides a correlation of steric, electrostatic, acceptor and hydrophobic fields with biological activities. The information rendered by 3D QSAR model initiated us to optimize the lead and design new potential inhibitors.

Investigation of Antigen-Antibody Interactions of Sulfonamides with a Monoclonal Antibody in a Fluorescence Polarization Immunoassay Using 3D-QSAR Models

PubMed Central

Wang, Zhanhui; Kai, Zhenpeng; Beier, Ross C.; Shen, Jianzhong; Yang, Xinling

2012-01-01

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs binding a monoclonal antibody (MAbSMR) produced against sulfamerazine was carried out by Distance Comparison (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA). The affinities of the MAbSMR, expressed as Log10IC50, for 17 sulfonamide analogs were determined by competitive fluorescence polarization immunoassay (FPIA). The results demonstrated that the proposed pharmacophore model containing two hydrogen-bond acceptors, two hydrogen-bond donors and two hydrophobic centers characterized the structural features of the sulfonamides necessary for MAbSMR binding. Removal of two outliers from the initial set of 17 sulfonamide analogs improved the predictability of the models. The 3D-QSAR models of 15 sulfonamides based on CoMFA and CoMSIA resulted in q2 cv values of 0.600 and 0.523, and r2 values of 0.995 and 0.994, respectively, which indicates that both methods have significant predictive capability. Connolly surface analysis, which mainly focused on steric force fields, was performed to complement the results from CoMFA and CoMSIA. This novel study combining FPIA with pharmacophore modeling demonstrates that multidisciplinary research is useful for investigating antigen-antibody interactions and also may provide information required for the design of new haptens. PMID:22754368

Inferring genetic parameters on latent variables underlying milk yield and quality, protein composition, curd firmness and cheese-making traits in dairy cattle.

PubMed

Dadousis, C; Cipolat-Gotet, C; Bittante, G; Cecchinato, A

2018-02-01

We studied the genetics of cheese-related latent variables (factors; Fs) for application in dairy cattle breeding. In total, 26 traits, recorded in 1264 Brown Swiss cows, were analyzed through multivariate factor analysis (MFA). Traits analyzed were descriptors of milk quality and yield (including protein fractions) and measures of coagulation, curd firmness (CF), cheese yields (%CY) and nutrient recoveries in the curd (REC). A total of 10 Fs (mutual orthogonal with a varimax rotation) were obtained. To assess the practical use of the Fs into breeding, we inferred their genetic parameters using single and bivariate animal models under a Bayesian framework. Heritability estimates (intra-herd) varied between 0.11 and 0.72 (F3: Yield and F7: κ-β-CN, respectively). The Fs underlined basic characteristics of the cheese-making process, milk components and udder health, while retaining 74% of the original variability. The first two Fs were indicators of the CY percentage (F1: %CY) and the CF process (F2: CF t ), and presented similar heritability estimates: 0.268 and 0.295, respectively. The third factor was associated with the yield of milk and solids (F3: Yield) characterized by a low heritability (0.108) and the fourth with the cheese nitrogen (N) (F4: Cheese N) that conversely appeared to be characterized by a high heritability (0.618). Three Fs were associated with the proportion of the basic milk caseins on total milk protein (F5: as1-β-CN, F7: κ-β-CN, F8: as2-CN), also highly heritable (0.565, 0.723 and 0.397, respectively) and 1 factor with the phosphorylated form of the as1-CN (F9: as1-CN-Ph; 0.318). Moreover, 1 factor was linked to the whey protein α-LA (F10: α-LA; 0.147). An indicator factor of a cow's udder health (F6: Udder health) was also obtained and showed a moderate heritability (0.204). Although the Fs were phenotypically uncorrelated, considerable additive genetic correlations existed among them, with highest values observed between F10: α-LA and F6: Udder health (-0.67) as well as between F9: as1-CN-Ph and F3: Yield (-0.60). Our results show the usefulness of MFA in dairy cattle breeding. The ability to replace a large number of variables with a few latent indicators of the same biological meaning marks MFA as a valuable tool for developing breeding strategies to improve cow's cheese-related traits.

Constraining Genome-Scale Models to Represent the Bow Tie Structure of Metabolism for 13C Metabolic Flux Analysis

PubMed Central

Ando, David; Singh, Jahnavi; Keasling, Jay D.; García Martín, Héctor

2018-01-01

Determination of internal metabolic fluxes is crucial for fundamental and applied biology because they map how carbon and electrons flow through metabolism to enable cell function. 13C Metabolic Flux Analysis (13C MFA) and Two-Scale 13C Metabolic Flux Analysis (2S-13C MFA) are two techniques used to determine such fluxes. Both operate on the simplifying approximation that metabolic flux from peripheral metabolism into central “core” carbon metabolism is minimal, and can be omitted when modeling isotopic labeling in core metabolism. The validity of this “two-scale” or “bow tie” approximation is supported both by the ability to accurately model experimental isotopic labeling data, and by experimentally verified metabolic engineering predictions using these methods. However, the boundaries of core metabolism that satisfy this approximation can vary across species, and across cell culture conditions. Here, we present a set of algorithms that (1) systematically calculate flux bounds for any specified “core” of a genome-scale model so as to satisfy the bow tie approximation and (2) automatically identify an updated set of core reactions that can satisfy this approximation more efficiently. First, we leverage linear programming to simultaneously identify the lowest fluxes from peripheral metabolism into core metabolism compatible with the observed growth rate and extracellular metabolite exchange fluxes. Second, we use Simulated Annealing to identify an updated set of core reactions that allow for a minimum of fluxes into core metabolism to satisfy these experimental constraints. Together, these methods accelerate and automate the identification of a biologically reasonable set of core reactions for use with 13C MFA or 2S-13C MFA, as well as provide for a substantially lower set of flux bounds for fluxes into the core as compared with previous methods. We provide an open source Python implementation of these algorithms at https://github.com/JBEI/limitfluxtocore. PMID:29300340

MetaFluxNet: the management of metabolic reaction information and quantitative metabolic flux analysis.

PubMed

Lee, Dong-Yup; Yun, Hongsoek; Park, Sunwon; Lee, Sang Yup

2003-11-01

MetaFluxNet is a program package for managing information on the metabolic reaction network and for quantitatively analyzing metabolic fluxes in an interactive and customized way. It allows users to interpret and examine metabolic behavior in response to genetic and/or environmental modifications. As a result, quantitative in silico simulations of metabolic pathways can be carried out to understand the metabolic status and to design the metabolic engineering strategies. The main features of the program include a well-developed model construction environment, user-friendly interface for metabolic flux analysis (MFA), comparative MFA of strains having different genotypes under various environmental conditions, and automated pathway layout creation. http://mbel.kaist.ac.kr/ A manual for MetaFluxNet is available as PDF file.

Concerns about a variance approach to X-ray diffractometric estimation of microfibril angle in wood

Treesearch

Steve P. Verrill; David E. Kretschmann; Victoria L. Herian; Michael C. Wiemann; Harry A. Alden

2011-01-01

In this article, we raise three technical concerns about Evans’ 1999 Appita Journal “variance approach” to estimating microfibril angle (MFA). The first concern is associated with the approximation of the variance of an X-ray intensity half-profile by a function of the MFA and the natural variability of the MFA. The second concern is associated with the approximation...

Structural safety analysis based on seismic service conditions for butterfly valves in a nuclear power plant.

PubMed

Han, Sang-Uk; Ahn, Dae-Gyun; Lee, Myeong-Gon; Lee, Kwon-Hee; Han, Seung-Ho

2014-01-01

The structural integrity of valves that are used to control cooling waters in the primary coolant loop that prevents boiling within the reactor in a nuclear power plant must be capable of withstanding earthquakes or other dangerous situations. In this study, numerical analyses using a finite element method, that is, static and dynamic analyses according to the rigid or flexible characteristics of the dynamic properties of a 200A butterfly valve, were performed according to the KEPIC MFA. An experimental vibration test was also carried out in order to verify the results from the modal analysis, in which a validated finite element model was obtained via a model-updating method that considers changes in the in situ experimental data. By using a validated finite element model, the equivalent static load under SSE conditions stipulated by the KEPIC MFA gave a stress of 135 MPa that occurred at the connections of the stem and body. A larger stress of 183 MPa was induced when we used a CQC method with a design response spectrum that uses 2% damping ratio. These values were lower than the allowable strength of the materials used for manufacturing the butterfly valve, and, therefore, its structural safety met the KEPIC MFA requirements.

Toward the identification of a reliable 3D-QSAR model for the protein tyrosine phosphatase 1B inhibitors

NASA Astrophysics Data System (ADS)

Wang, Fangfang; Zhou, Bo

2018-04-01

Protein tyrosine phosphatase 1B (PTP1B) is an intracellular non-receptor phosphatase that is implicated in signal transduction of insulin and leptin pathways, thus PTP1B is considered as potential target for treating type II diabetes and obesity. The present article is an attempt to formulate the three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling of a series of compounds possessing PTP1B inhibitory activities using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The optimum template ligand-based models are statistically significant with great CoMFA (R2cv = 0.600, R2pred = 0.6760) and CoMSIA (R2cv = 0.624, R2pred = 0.8068) values. Molecular docking was employed to elucidate the inhibitory mechanisms of this series of compounds against PTP1B. In addition, the CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of PTP1B active site. The knowledge of structure-activity relationship and ligand-receptor interactions from 3D-QSAR model and molecular docking will be useful for better understanding the mechanism of ligand-receptor interaction and facilitating development of novel compounds as potent PTP1B inhibitors.

3D-QSAR (CoMFA, CoMSIA), molecular docking and molecular dynamics simulations study of 6-aryl-5-cyano-pyrimidine derivatives to explore the structure requirements of LSD1 inhibitors.

PubMed

Ding, Lina; Wang, Zhi-Zheng; Sun, Xu-Dong; Yang, Jing; Ma, Chao-Ya; Li, Wen; Liu, Hong-Min

2017-08-01

Recently, Histone Lysine Specific Demethylase 1 (LSD1) was regarded as a promising anticancer target for the novel drug discovery. And several small molecules as LSD1 inhibitors in different structures have been reported. In this work, we carried out a molecular modeling study on the 6-aryl-5-cyano-pyrimidine fragment LSD1 inhibitors using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics simulations. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models. The results show that the best CoMFA model has q 2 =0.802, r 2 ncv =0.979, and the best CoMSIA model has q 2 =0.799, r 2 ncv =0.982. The electrostatic, hydrophobic and H-bond donor fields play important roles in the models. Molecular docking studies predict the binding mode and the interactions between the ligand and the receptor protein. Molecular dynamics simulations results reveal that the complex of the ligand and the receptor protein are stable at 300K. All the results can provide us more useful information for our further drug design. Copyright © 2017. Published by Elsevier Ltd.

Structure-based CoMFA as a predictive model - CYP2C9 inhibitors as a test case.

PubMed

Yasuo, Kazuya; Yamaotsu, Noriyuki; Gouda, Hiroaki; Tsujishita, Hideki; Hirono, Shuichi

2009-04-01

In this study, we tried to establish a general scheme to create a model that could predict the affinity of small compounds to their target proteins. This scheme consists of a search for ligand-binding sites on a protein, a generation of bound conformations (poses) of ligands in each of the sites by docking, identifications of the correct poses of each ligand by consensus scoring and MM-PBSA analysis, and a construction of a CoMFA model with the obtained poses to predict the affinity of the ligands. By using a crystal structure of CYP 2C9 and the twenty known CYP inhibitors as a test case, we obtained a CoMFA model with a good statistics, which suggested that the classification of the binding sites as well as the predicted bound poses of the ligands should be reasonable enough. The scheme described here would give a method to predict the affinity of small compounds with a reasonable accuracy, which is expected to heighten the value of computational chemistry in the drug design process.

Ligand-based 3D QSAR analysis of reactivation potency of mono- and bis-pyridinium aldoximes toward VX-inhibited rat acetylcholinesterase.

PubMed

Dolezal, Rafael; Korabecny, Jan; Malinak, David; Honegr, Jan; Musilek, Kamil; Kuca, Kamil

2015-03-01

To predict unknown reactivation potencies of 12 mono- and bis-pyridinium aldoximes for VX-inhibited rat acetylcholinesterase (rAChE), three-dimensional quantitative structure-activity relationship (3D QSAR) analysis has been carried out. Utilizing molecular interaction fields (MIFs) calculated by molecular mechanical (MMFF94) and quantum chemical (B3LYP/6-31G*) methods, two satisfactory ligand-based CoMFA models have been developed: 1. R(2)=0.9989, Q(LOO)(2)=0.9090, Q(LTO)(2)=0.8921, Q(LMO(20%))(2)=0.8853, R(ext)(2)=0.9259, SDEP(ext)=6.8938; 2. R(2)=0.9962, Q(LOO)(2)=0.9368, Q(LTO)(2)=0.9298, Q(LMO(20%))(2)=0.9248, R(ext)(2)=0.8905, SDEP(ext)=6.6756. High statistical significance of the 3D QSAR models has been achieved through the application of several data noise reduction techniques (i.e. smart region definition SRD, fractional factor design FFD, uninformative/iterative variable elimination UVE/IVE) on the original MIFs. Besides the ligand-based CoMFA models, an alignment molecular set constructed by flexible molecular docking has been also studied. The contour maps as well as the predicted reactivation potencies resulting from 3D QSAR analyses help better understand which structural features are associated with increased reactivation potency of studied compounds. Copyright © 2014 Elsevier Inc. All rights reserved.

Exploring the Effects of Geographical Origin on the Chemical Composition and Quality Grading of Vitis vinifera L. cv. Chardonnay Grapes.

PubMed

Gambetta, Joanna M; Cozzolino, Daniel; Bastian, Susan E P; Jeffery, David W

2017-01-31

The relationship between berry chemical composition, region of origin and quality grade was investigated for Chardonnay grapes sourced from vineyards located in seven South Australian Geographical Indications (GI). Measurements of basic chemical parameters, amino acids, elements, and free and bound volatiles were conducted for grapes collected during 2015 and 2016. Multiple factor analysis (MFA) was used to determine the sets of data that best discriminated each GI and quality grade. Important components for the discrimination of grapes based on GI were 2-phenylethanol, benzyl alcohol and C6 compounds, as well as Cu, Zn, and Mg, titratable acidity (TA), total soluble solids (TSS), and pH. Discriminant analysis (DA) based on MFA results correctly classified 100% of the samples into GI in 2015 and 2016. Classification according to grade was achieved based on the results for elements such as Cu, Na, Fe, volatiles including C6 and aryl alcohols, hydrolytically-released volatiles such as (Z)-linalool oxide and vitispirane, pH, TSS, alanine and proline. Correct classification through DA according to grade was 100% for both vintages. Significant correlations were observed between climate, GI, grade, and berry composition. Climate influenced the synthesis of free and bound volatiles as well as amino acids, sugars, and acids, as a result of higher temperatures and precipitation.

Modular life cycle assessment of municipal solid waste management.

PubMed

Haupt, M; Kägi, T; Hellweg, S

2018-05-31

Life cycle assessment (LCA) is commonly applied to examine the environmental performance of waste management systems. The system boundaries are, however, often limited to either one tonne of material or to specific waste treatments and are, therefore, lacking a systems perspective. Here, a framework is proposed to assess complete waste management systems based on actual waste flows, assessed with a detailed material flow analysis (MFA) in a modular MFA/LCA approach. The transformation of the MFA into a product-process-matrix facilitates a direct link between MFA and LCA, therefore allowing for the assessment of variations in flows. To allow for an up-to-date and geographically specific assessment, 190 LCA modules were set up based on primary industrial data and the ecoinvent database. The LCA modules show where there have been improvements in different recycling processes over the past years (e.g. for paper recycling) and highlight that, from an environmental perspective, closed-loop recycling is not always preferable to open-loop recycling. In a case study, the Swiss municipal solid waste management system, of which there is already a detailed MFA, was modeled using the new LCA modules and applying the modular MFA/LCA approach. Five different mass flow distribution scenarios for the Swiss municipal solid waste management system were assessed to show the environmental impact of political measures and to test the sensitivity of the results to key parameters. The results of the case study highlight the importance of the dominant fractions in the overall environmental impacts assessment; while the metal fraction has the highest impact on a per kilogram basis, paper, cardboard, glass and mixed municipal solid waste were found to dominate the environmental impacts of the Swiss waste management system due to their mass. The scenarios also highlight the importance of the energy efficiency of municipal solid waste incineration plants and the credits from material substitution as key variables. In countries with advanced waste management systems such as Switzerland, there is limited improvement potential with further increases in recycling rates. In these cases, the focus of political measures should be laid on (i) the utilization of secondary materials in applications where they replace high-impact primary production, and (ii) an increased recovery of energy in waste-to-energy plants. Copyright © 2018. Published by Elsevier Ltd.

The Role of Shevardnadze and the Ministry of Foreign Affairs in the Making of Soviet Defense and Arms Control Policy

DTIC Science & Technology

1990-07-01

changes either in the MFA or in Soviet foreign and defense policy. This situation began to change in May 1986, when Gorbachev gave an unusual speech to the...MFA in which he demanded better performance from Soviet diplomats. Although it was later reported that Gorbachev’s speech contained strong criticism...July 1988 with a sweeping critique of Soviet strategy and ,military policy since World War II. Subsequent speeches and articles in MFA-controlled

The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs.

PubMed

Helgren, Travis R; Sciotti, Richard J; Lee, Patricia; Duffy, Sandra; Avery, Vicky M; Igbinoba, Osayawemwen; Akoto, Matthew; Hagen, Timothy J

2015-01-15

A series of novel aminoalkylated quercetin analogs, prepared via the Mannich reaction of various primary and secondary amines with formaldehyde, were tested for antimalarial activity. The compounds were screened against three drug resistant malarial strains (D6, C235 and W2) and were found to exhibit sub-micromolar activity across all three strains (0.065-13.0μM). The structure-activity relationship determined from the antimalarial activity data suggests the inclusion of phenethyl amine sidechains on the quercetin scaffolding is necessary for potent activity. Additionally, the most active compounds ((5) and (6)) were tested for both early and late stage anti-gametocytocidal activity. Finally, the antimalarial activity data were utilized to construct comparative molecular field analysis (CoMFA) models to be used for further compound refinement. Copyright © 2014 Elqsevier Ltd. All rights reserved.

Design and prediction of new acetylcholinesterase inhibitor via quantitative structure activity relationship of huprines derivatives.

PubMed

Zhang, Shuqun; Hou, Bo; Yang, Huaiyu; Zuo, Zhili

2016-05-01

Acetylcholinesterase (AChE) is an important enzyme in the pathogenesis of Alzheimer's disease (AD). Comparative quantitative structure-activity relationship (QSAR) analyses on some huprines inhibitors against AChE were carried out using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR) methods. Three highly predictive QSAR models were constructed successfully based on the training set. The CoMFA, CoMSIA, and HQSAR models have values of r (2) = 0.988, q (2) = 0.757, ONC = 6; r (2) = 0.966, q (2) = 0.645, ONC = 5; and r (2) = 0.957, q (2) = 0.736, ONC = 6. The predictabilities were validated using an external test sets, and the predictive r (2) values obtained by the three models were 0.984, 0.973, and 0.783, respectively. The analysis was performed by combining the CoMFA and CoMSIA field distributions with the active sites of the AChE to further understand the vital interactions between huprines and the protease. On the basis of the QSAR study, 14 new potent molecules have been designed and six of them are predicted to be more active than the best active compound 24 described in the literature. The final QSAR models could be helpful in design and development of novel active AChE inhibitors.

Culling from the herd's perspective-Exploring herd-level management factors and culling rates in Québec dairy herds.

PubMed

Haine, Denis; Delgado, Hector; Cue, Roger; Sewalem, Asheber; Wade, Kevin; Lacroix, René; Lefebvre, Daniel; Arsenault, Julie; Bouchard, Émile; Dubuc, Jocelyn

2017-11-01

The relationship between cows' health, reproductive performance or disorders and their longevity is well demonstrated in the literature. However these associations at the cow level might not hold true at the herd level, and herd-level variables can modify cow-level outcomes independently of the cows' characteristics. The interaction between cow-level and herd-level variables is a relevant issue for understanding the culling of dairy cows. However it requires the appropriate group-level variables to assess any contextual effect. Based on 10 years of health and production data, the objectives of this paper are:(a) to quantify the culling rates of dairy herds in Québec; (b) to determine the profiles of the herds based on herd-level factors, such as demographics, reproduction, production and health indicators, and whether these profiles can be related to herd culling rates for use as potential contextual variables in multilevel modelling of culling risk. A retrospective longitudinal study was conducted on data from dairy herds in Québec, Canada, by extracting health information events from the dairy herd health management software used by most Québec producers and their veterinarians. Data were extracted for all lactations taking place between January 1st, 2001 and December 31st, 2010. A total of 432,733 lactations from 156,409 cows out of 763 herds were available for analysis. Thirty cow-level variables were aggregated for each herd and years of follow-up, and their relationship was investigated by Multiple Factor Analysis (MFA). The overall annual culling rate was 32%, with a 95% confidence interval (CI) of [31.6%,32.5%]. The dairy sale rate by 60 days in milk (DIM) was 3.2% [2.8%,3.6%]. The annual culling rate within 60 DIM was 8.2% [7.9%,8.4%]. The explained variance for each axis from the MFA was very low: 14.8% for the first axis and 13.1% for the second. From the MFA results, we conclude there is no relationship between the groups of herd-level indicators, demonstrating the heterogeneity among herds for their demographics, reproduction and production performance, and health status. However, based on Principal Component Analysis (PCA), the profiles of herds could be determined according to specific, single, herd-level indicators independently. The relationships between culling rates and specific herd-level variables within factors were limited to livestock sales, proportion of first lactation cows, herd size, proportion of calvings occurring in the fall, longer calving intervals and reduced 21-day pregnancy rates, increased days to first service, average age at first calving, and reduced milk fever incidence. The indicators found could be considered as contextual variables in multilevel model-building strategies to investigate cow culling risk. Copyright © 2017 Elsevier B.V. All rights reserved.

Optimal tracers for parallel labeling experiments and 13C metabolic flux analysis: A new precision and synergy scoring system.

PubMed

Crown, Scott B; Long, Christopher P; Antoniewicz, Maciek R

2016-11-01

13 C-Metabolic flux analysis ( 13 C-MFA) is a widely used approach in metabolic engineering for quantifying intracellular metabolic fluxes. The precision of fluxes determined by 13 C-MFA depends largely on the choice of isotopic tracers and the specific set of labeling measurements. A recent advance in the field is the use of parallel labeling experiments for improved flux precision and accuracy. However, as of today, no systemic methods exist for identifying optimal tracers for parallel labeling experiments. In this contribution, we have addressed this problem by introducing a new scoring system and evaluating thousands of different isotopic tracer schemes. Based on this extensive analysis we have identified optimal tracers for 13 C-MFA. The best single tracers were doubly 13 C-labeled glucose tracers, including [1,6- 13 C]glucose, [5,6- 13 C]glucose and [1,2- 13 C]glucose, which consistently produced the highest flux precision independent of the metabolic flux map (here, 100 random flux maps were evaluated). Moreover, we demonstrate that pure glucose tracers perform better overall than mixtures of glucose tracers. For parallel labeling experiments the optimal isotopic tracers were [1,6- 13 C]glucose and [1,2- 13 C]glucose. Combined analysis of [1,6- 13 C]glucose and [1,2- 13 C]glucose labeling data improved the flux precision score by nearly 20-fold compared to widely use tracer mixture 80% [1- 13 C]glucose +20% [U- 13 C]glucose. Copyright © 2016 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Metabolic flux analysis of Cyanothece sp. ATCC 51142 under mixotrophic conditions.

PubMed

Alagesan, Swathi; Gaudana, Sandeep B; Sinha, Avinash; Wangikar, Pramod P

2013-11-01

Cyanobacteria are a group of photosynthetic prokaryotes capable of utilizing solar energy to fix atmospheric carbon dioxide to biomass. Despite several "proof of principle" studies, low product yield is an impediment in commercialization of cyanobacteria-derived biofuels. Estimation of intracellular reaction rates by (13)C metabolic flux analysis ((13)C-MFA) would be a step toward enhancing biofuel yield via metabolic engineering. We report (13)C-MFA for Cyanothece sp. ATCC 51142, a unicellular nitrogen-fixing cyanobacterium, known for enhanced hydrogen yield under mixotrophic conditions. Rates of reactions in the central carbon metabolism under nitrogen-fixing and -non-fixing conditions were estimated by monitoring the competitive incorporation of (12)C and (13)C from unlabeled CO2 and uniformly labeled glycerol, respectively, into terminal metabolites such as amino acids. The observed labeling patterns suggest mixotrophic growth under both the conditions, with a larger fraction of unlabeled carbon in nitrate-sufficient cultures asserting a greater contribution of carbon fixation by photosynthesis and an anaplerotic pathway. Indeed, flux analysis complements the higher growth observed under nitrate-sufficient conditions. On the other hand, the flux through the oxidative pentose phosphate pathway and tricarboxylic acid cycle was greater in nitrate-deficient conditions, possibly to supply the precursors and reducing equivalents needed for nitrogen fixation. In addition, an enhanced flux through fructose-6-phosphate phosphoketolase possibly suggests the organism's preferred mode under nitrogen-fixing conditions. The (13)C-MFA results complement the reported predictions by flux balance analysis and provide quantitative insight into the organism's distinct metabolic features under nitrogen-fixing and -non-fixing conditions.

Mixed Micelle System Produced by Interaction Between Transglycosylated Stevia and an Ionic Surfactant Improves Dissolution Profile of Mefenamic Acid.

PubMed

Fujimori, Miki; Kadota, Kazunori; Tozuka, Yuichi

2017-04-01

Transglycosylated stevia (stevia-G) can effectively improve the dissolution and bioavailability of poorly water-soluble drugs. Furthermore, addition of an ionic surfactant to stevia-G solution has been shown to enhance the dissolution effect of stevia-G on flurbiprofen. Herein, 4 surfactants, namely sodium dodecyl sulfate, sodium N-dodecanoylsarcosinate, sodium monododecyl phosphate, and lauryltrimethylammonium chloride (LTAC) were screened to investigate their synergistic effect with stevia-G in enhancing the solubility of mefenamic acid (MFA). The ternary formulation containing LTAC produced the highest increase in solubility, whereas the binary MFA/LTAC formulation did not increase the solubility of MFA. Surface tension was evaluated to analyze the interaction between stevia-G and each ionic surfactant, wherein the Rubingh model was applied to predict mixed micelle formation between stevia-G and LTAC. Interaction parameters calculated by the Rubingh model reflected mixed micelle formation between stevia-G and LTAC relative to the self-interactions of the 2 individual surfactants. All interaction parameters in this system showed negative values, indicating a favorable interaction (e.g., hydrogen bond or electrostatic and dipole) between binary components in the mixed micelles. Spray-dried particles of ternary formulations (MFA/stevia-G/LTAC) were prepared to evaluate the dissolution profile and physicochemical properties. Dissolution profiling showed that the concentration of MFA released from spray-dried particles was significantly higher than untreated MFA. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

CLUSTERING SOUTH AFRICAN HOUSEHOLDS BASED ON THEIR ASSET STATUS USING LATENT VARIABLE MODELS

PubMed Central

McParland, Damien; Gormley, Isobel Claire; McCormick, Tyler H.; Clark, Samuel J.; Kabudula, Chodziwadziwa Whiteson; Collinson, Mark A.

2014-01-01

The Agincourt Health and Demographic Surveillance System has since 2001 conducted a biannual household asset survey in order to quantify household socio-economic status (SES) in a rural population living in northeast South Africa. The survey contains binary, ordinal and nominal items. In the absence of income or expenditure data, the SES landscape in the study population is explored and described by clustering the households into homogeneous groups based on their asset status. A model-based approach to clustering the Agincourt households, based on latent variable models, is proposed. In the case of modeling binary or ordinal items, item response theory models are employed. For nominal survey items, a factor analysis model, similar in nature to a multinomial probit model, is used. Both model types have an underlying latent variable structure—this similarity is exploited and the models are combined to produce a hybrid model capable of handling mixed data types. Further, a mixture of the hybrid models is considered to provide clustering capabilities within the context of mixed binary, ordinal and nominal response data. The proposed model is termed a mixture of factor analyzers for mixed data (MFA-MD). The MFA-MD model is applied to the survey data to cluster the Agincourt households into homogeneous groups. The model is estimated within the Bayesian paradigm, using a Markov chain Monte Carlo algorithm. Intuitive groupings result, providing insight to the different socio-economic strata within the Agincourt region. PMID:25485026

The topology of metabolic isotope labeling networks.

PubMed

Weitzel, Michael; Wiechert, Wolfgang; Nöh, Katharina

2007-08-29

Metabolic Flux Analysis (MFA) based on isotope labeling experiments (ILEs) is a widely established tool for determining fluxes in metabolic pathways. Isotope labeling networks (ILNs) contain all essential information required to describe the flow of labeled material in an ILE. Whereas recent experimental progress paves the way for high-throughput MFA, large network investigations and exact statistical methods, these developments are still limited by the poor performance of computational routines used for the evaluation and design of ILEs. In this context, the global analysis of ILN topology turns out to be a clue for realizing large speedup factors in all required computational procedures. With a strong focus on the speedup of algorithms the topology of ILNs is investigated using graph theoretic concepts and algorithms. A rigorous determination of all cyclic and isomorphic subnetworks, accompanied by the global analysis of ILN connectivity is performed. Particularly, it is proven that ILNs always brake up into a large number of small strongly connected components (SCCs) and, moreover, there are natural isomorphisms between many of these SCCs. All presented techniques are universal, i.e. they do not require special assumptions on the network structure, bidirectionality of fluxes, measurement configuration, or label input. The general results are exemplified with a practically relevant metabolic network which describes the central metabolism of E. coli comprising 10390 isotopomer pools. Exploiting the topological features of ILNs leads to a significant speedup of all universal algorithms for ILE evaluation. It is proven in theory and exemplified with the E. coli example that a speedup factor of about 1000 compared to standard algorithms is achieved. This widely opens the door for new high performance algorithms suitable for high throughput applications and large ILNs. Moreover, for the first time the global topological analysis of ILNs allows to comprehensively describe and understand the general patterns of label flow in complex networks. This is an invaluable tool for the structural design of new experiments and the interpretation of measured data.

CoMFA and CoMSIA studies on C-aryl glucoside SGLT2 inhibitors as potential anti-diabetic agents.

PubMed

Vyas, V K; Bhatt, H G; Patel, P K; Jalu, J; Chintha, C; Gupta, N; Ghate, M

2013-01-01

SGLT2 has become a target of therapeutic interest in diabetes research. CoMFA and CoMSIA studies were performed on C-aryl glucoside SGLT2 inhibitors (180 analogues) as potential anti-diabetic agents. Three different alignment strategies were used for the compounds. The best CoMFA and CoMSIA models were obtained by means of Distill rigid body alignment of training and test sets, and found statistically significant with cross-validated coefficients (q²) of 0.602 and 0.618, respectively, and conventional coefficients (r²) of 0.905 and 0.902, respectively. Both models were validated by a test set of 36 compounds giving satisfactory predicted correlation coefficients (r² pred) of 0.622 and 0.584 for CoMFA and CoMSIA models, respectively. A comparison was made with earlier 3D QSAR study on SGLT2 inhibitors, which shows that our 3D QSAR models are better than earlier models to predict good inhibitory activity. CoMFA and CoMSIA models generated in this work can provide useful information to design new compounds and helped in prediction of activity prior to synthesis.

Single-Cell-Based Platform for Copy Number Variation Profiling through Digital Counting of Amplified Genomic DNA Fragments.

PubMed

Li, Chunmei; Yu, Zhilong; Fu, Yusi; Pang, Yuhong; Huang, Yanyi

2017-04-26

We develop a novel single-cell-based platform through digital counting of amplified genomic DNA fragments, named multifraction amplification (mfA), to detect the copy number variations (CNVs) in a single cell. Amplification is required to acquire genomic information from a single cell, while introducing unavoidable bias. Unlike prevalent methods that directly infer CNV profiles from the pattern of sequencing depth, our mfA platform denatures and separates the DNA molecules from a single cell into multiple fractions of a reaction mix before amplification. By examining the sequencing result of each fraction for a specific fragment and applying a segment-merge maximum likelihood algorithm to the calculation of copy number, we digitize the sequencing-depth-based CNV identification and thus provide a method that is less sensitive to the amplification bias. In this paper, we demonstrate a mfA platform through multiple displacement amplification (MDA) chemistry. When performing the mfA platform, the noise of MDA is reduced; therefore, the resolution of single-cell CNV identification can be improved to 100 kb. We can also determine the genomic region free of allelic drop-out with mfA platform, which is impossible for conventional single-cell amplification methods.

Combined 3D-QSAR and molecular docking study on 7,8-dialkyl-1,3-diaminopyrrolo-[3,2-f] Quinazoline series compounds to understand the binding mechanism of DHFR inhibitors

NASA Astrophysics Data System (ADS)

Aouidate, Adnane; Ghaleb, Adib; Ghamali, Mounir; Chtita, Samir; Choukrad, M'barek; Sbai, Abdelouahid; Bouachrine, Mohammed; Lakhlifi, Tahar

2017-07-01

A series of nineteen DHFR inhibitors was studied based on the combination of two computational techniques namely, three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular docking. The comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) were developed using 19 molecules having pIC50 ranging from 9.244 to 5.839. The best CoMFA and CoMSIA models show conventional determination coefficients R2 of 0.96 and 0.93 as well as the Leave One Out cross-validation determination coefficients Q2 of 0.64 and 0.72, respectively. The predictive ability of those models was evaluated by the external validation using a test set of five compounds with predicted determination coefficients R2test of 0.92 and 0.94, respectively. The binding mode between this kind of compounds and the DHFR enzyme in addition to the key amino acid residues were explored by molecular docking simulation. Contour maps and molecular docking identified that the R1 and R2 natures at the pyrazole moiety are the important features for the optimization of the binding affinity to the DHFR receptor. According to the good concordance between the CoMFA/CoMSIA contour maps and docking results, the obtained information was explored to design novel molecules.

3D-QSAR and docking studies of flavonoids as potent Escherichia coli inhibitors

PubMed Central

Fang, Yajing; Lu, Yulin; Zang, Xixi; Wu, Ting; Qi, XiaoJuan; Pan, Siyi; Xu, Xiaoyun

2016-01-01

Flavonoids are potential antibacterial agents. However, key substituents and mechanism for their antibacterial activity have not been fully investigated. The quantitative structure-activity relationship (QSAR) and molecular docking of flavonoids relating to potent anti-Escherichia coli agents were investigated. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were developed by using the pIC50 values of flavonoids. The cross-validated coefficient (q2) values for CoMFA (0.743) and for CoMSIA (0.708) were achieved, illustrating high predictive capabilities. Selected descriptors for the CoMFA model were ClogP (logarithm of the octanol/water partition coefficient), steric and electrostatic fields, while, ClogP, electrostatic and hydrogen bond donor fields were used for the CoMSIA model. Molecular docking results confirmed that half of the tested flavonoids inhibited DNA gyrase B (GyrB) by interacting with adenosine-triphosphate (ATP) pocket in a same orientation. Polymethoxyl flavones, flavonoid glycosides, isoflavonoids changed their orientation, resulting in a decrease of inhibitory activity. Moreover, docking results showed that 3-hydroxyl, 5-hydroxyl, 7-hydroxyl and 4-carbonyl groups were found to be crucial active substituents of flavonoids by interacting with key residues of GyrB, which were in agreement with the QSAR study results. These results provide valuable information for structure requirements of flavonoids as antibacterial agents. PMID:27049530

A Peptide-Based Method for 13C Metabolic Flux Analysis in Microbial Communities

PubMed Central

Ghosh, Amit; Nilmeier, Jerome; Weaver, Daniel; Adams, Paul D.; Keasling, Jay D.; Mukhopadhyay, Aindrila; Petzold, Christopher J.; Martín, Héctor García

2014-01-01

The study of intracellular metabolic fluxes and inter-species metabolite exchange for microbial communities is of crucial importance to understand and predict their behaviour. The most authoritative method of measuring intracellular fluxes, 13C Metabolic Flux Analysis (13C MFA), uses the labeling pattern obtained from metabolites (typically amino acids) during 13C labeling experiments to derive intracellular fluxes. However, these metabolite labeling patterns cannot easily be obtained for each of the members of the community. Here we propose a new type of 13C MFA that infers fluxes based on peptide labeling, instead of amino acid labeling. The advantage of this method resides in the fact that the peptide sequence can be used to identify the microbial species it originates from and, simultaneously, the peptide labeling can be used to infer intracellular metabolic fluxes. Peptide identity and labeling patterns can be obtained in a high-throughput manner from modern proteomics techniques. We show that, using this method, it is theoretically possible to recover intracellular metabolic fluxes in the same way as through the standard amino acid based 13C MFA, and quantify the amount of information lost as a consequence of using peptides instead of amino acids. We show that by using a relatively small number of peptides we can counter this information loss. We computationally tested this method with a well-characterized simple microbial community consisting of two species. PMID:25188426

3D-QSAR CoMFA of a series of DABO derivatives as HIV-1 reverse transcriptase non-nucleoside inhibitors.

PubMed

de Brito, Monique Araújo; Rodrigues, Carlos Rangel; Cirino, José Jair Vianna; de Alencastro, Ricardo Bicca; Castro, Helena Carla; Albuquerque, Magaly Girão

2008-08-01

A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was retrieved from the literature and studied by comparative molecular field analysis (CoMFA) in order to derive three-dimensional quantitative structure-activity relationship (3D-QSAR) models. The CoMFA study has been performed with a training set of 59 compounds, testing three alignments and four charge schemes (DFT, HF, AM1, and PM3) and using defaults probe atom (Csp (3), +1 charge), cutoffs (30 kcal.mol (-1) for both steric and electrostatic fields), and grid distance (2.0 A). The best model ( N = 59), derived from Alignment 1 and PM3 charges, shows q (2) = 0.691, SE cv = 0.475, optimum number of components = 6, r (2) = 0.930, SEE = 0.226, and F-value = 115.544. The steric and electrostatic contributions for the best model were 43.2% and 56.8%, respectively. The external predictive ability (r (2) pred = 0.918) of the resultant best model was evaluated using a test set of 15 compounds. In order to design more potent DABO analogues as anti-HIV/AIDS agents, attention should be taken in order to select a substituent for the 4-oxopyrimidine ring, since, as revealed by the best CoMFA model, there are a steric restriction at the C2-position, a electron-rich group restriction at the C6-position ( para-substituent of the 6-benzyl group), and a steric allowed region at the C5-position.

New potent and selective cytochrome P450 2B6 (CYP2B6) inhibitors based on three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis

PubMed Central

Korhonen, L E; Turpeinen, M; Rahnasto, M; Wittekindt, C; Poso, A; Pelkonen, O; Raunio, H; Juvonen, R O

2007-01-01

Background and purpose: The cytochrome P450 2B6 (CYP2B6) enzyme metabolises a number of clinically important drugs. Drug-drug interactions resulting from inhibition or induction of CYP2B6 activity may cause serious adverse effects. The aims of this study were to construct a three-dimensional structure-activity relationship (3D-QSAR) model of the CYP2B6 protein and to identify novel potent and selective inhibitors of CYP2B6 for in vitro research purposes. Experimental approach: The inhibition potencies (IC50 values) of structurally diverse chemicals were determined with recombinant human CYP2B6 enzyme. Two successive models were constructed using Comparative Molecular Field Analysis (CoMFA). Key results: Three compounds proved to be very potent and selective competitive inhibitors of CYP2B6 in vitro (IC50<1 μM): 4-(4-chlorobenzyl)pyridine (CBP), 4-(4-nitrobenzyl)pyridine (NBP), and 4-benzylpyridine (BP). A complete inhibition of CYP2B6 activity was achieved with 0.1 μM CBP, whereas other CYP-related activities were not affected. Forty-one compounds were selected for further testing and construction of the final CoMFA model. The created CoMFA model was of high quality and predicted accurately the inhibition potency of a test set (n=7) of structurally diverse compounds. Conclusions and implications: Two CoMFA models were created which revealed the key molecular characteristics of inhibitors of the CYP2B6 enzyme. The final model accurately predicted the inhibitory potencies of several structurally unrelated compounds. CBP, BP and NBP were identified as novel potent and selective inhibitors of CYP2B6 and CBP especially is a suitable inhibitor for in vitro screening studies. PMID:17325652

Inhibition of the de novo synthesis of PCDD/Fs on model fly ash by sludge drying gases.

PubMed

Chen, Tong; Zhan, Ming-Xiu; Lin, Xiao-Qing; Li, Xiao-Dong; Lu, Sheng-Yong; Yan, Jian-Hua; Buekens, Alfons; Cen, Ke-Fa

2014-11-01

Sludge drying gases (SDG), evolving from drying and mild thermal decomposition (<300°C) of raw sewage sludge contain NH3 and SO2 as well as other N- and S-compounds. All of these are potential PCDD/Fs suppressants. It is indeed observed that these SDG suppress 2,3,7,8-substitued PCDD/Fs formation on Model Fly Ash (MFA) with an efficiency up to 97.6% in wt. units and 96% in I-TEQ, respectively. This suppression is strong for (the bulk of) PCDD/Fs, adsorbed on the model fly ash; conversely, sludge drying gases enhance PCDD/Fs desorption from MFA. Moreover, TCDD/Fs are suppressed least, possibly following stepwise dechlorination of higher chlorinated PCDD/Fs. Characteristics, such as the type, origins and amount of sludge, its moisture-, nitrogen- and sulfur content and the nature of the thermal treatment applied are all expected to influence upon the suppression capabilities. In this study three types of dry sludge are tested and applied as suppressant in four different amounts or modes. The quality of the sludge drying gases is continuously monitored: the Gasmet results reveal that NH3 and SO2 are the most important components of SDG. The MFA reaction residue is scrutinized by Scanning Electron Microscope (SEM) and Energy Dispersive Spectrometer (EDS) analysis. A large number of particles attaching to the surface of model fly ash are observed by SEM. Moreover, EDS analysis reveals that part of the chlorine in MFA is carried away with the SDG and replaced by sulfur, so that eliminating chlorine may be part of the inhibition mechanism. However, further research is still needed to establish the optimum operating modes and to confirm the role of both inorganic and organic nitrogen and sulfur compounds in the suppression of PCDD/Fs formation on model fly ash. Copyright © 2014 Elsevier Ltd. All rights reserved.

Advanced Stoichiometric Analysis of Metabolic Networks of Mammalian Systems

PubMed Central

Orman, Mehmet A.; Berthiaume, Francois; Androulakis, Ioannis P.; Ierapetritou, Marianthi G.

2013-01-01

Metabolic engineering tools have been widely applied to living organisms to gain a comprehensive understanding about cellular networks and to improve cellular properties. Metabolic flux analysis (MFA), flux balance analysis (FBA), and metabolic pathway analysis (MPA) are among the most popular tools in stoichiometric network analysis. Although application of these tools into well-known microbial systems is extensive in the literature, various barriers prevent them from being utilized in mammalian cells. Limited experimental data, complex regulatory mechanisms, and the requirement of more complex nutrient media are some major obstacles in mammalian cell systems. However, mammalian cells have been used to produce therapeutic proteins, to characterize disease states or related abnormal metabolic conditions, and to analyze the toxicological effects of some medicinally important drugs. Therefore, there is a growing need for extending metabolic engineering principles to mammalian cells in order to understand their underlying metabolic functions. In this review article, advanced metabolic engineering tools developed for stoichiometric analysis including MFA, FBA, and MPA are described. Applications of these tools in mammalian cells are discussed in detail, and the challenges and opportunities are highlighted. PMID:22196224

Transcriptome profiling of Pinus radiata juvenile wood with contrasting stiffness identifies putative candidate genes involved in microfibril orientation and cell wall mechanics

PubMed Central

2011-01-01

Background The mechanical properties of wood are largely determined by the orientation of cellulose microfibrils in secondary cell walls. Several genes and their allelic variants have previously been found to affect microfibril angle (MFA) and wood stiffness; however, the molecular mechanisms controlling microfibril orientation and mechanical strength are largely uncharacterised. In the present study, cDNA microarrays were used to compare gene expression in developing xylem with contrasting stiffness and MFA in juvenile Pinus radiata trees in order to gain further insights into the molecular mechanisms underlying microfibril orientation and cell wall mechanics. Results Juvenile radiata pine trees with higher stiffness (HS) had lower MFA in the earlywood and latewood of each ring compared to low stiffness (LS) trees. Approximately 3.4 to 14.5% out of 3, 320 xylem unigenes on cDNA microarrays were differentially regulated in juvenile wood with contrasting stiffness and MFA. Greater variation in MFA and stiffness was observed in earlywood compared to latewood, suggesting earlywood contributes most to differences in stiffness; however, 3-4 times more genes were differentially regulated in latewood than in earlywood. A total of 108 xylem unigenes were differentially regulated in juvenile wood with HS and LS in at least two seasons, including 43 unigenes with unknown functions. Many genes involved in cytoskeleton development and secondary wall formation (cellulose and lignin biosynthesis) were preferentially transcribed in wood with HS and low MFA. In contrast, several genes involved in cell division and primary wall synthesis were more abundantly transcribed in LS wood with high MFA. Conclusions Microarray expression profiles in Pinus radiata juvenile wood with contrasting stiffness has shed more light on the transcriptional control of microfibril orientation and the mechanical properties of wood. The identified candidate genes provide an invaluable resource for further gene function and association genetics studies aimed at deepening our understanding of cell wall biomechanics with a view to improving the mechanical properties of wood. PMID:21962175

MFA Oil Company

EPA Pesticide Factsheets

The EPA is providing notice of a proposed Administrative Penalty Assessment against MFA Oil Company, a business located at One Ray Young Dr, Columbia, MO 65201, for alleged violations at five of the Company’s facilities located at: 624 Ashcroft Rd, Poplar

Structure-activity relationships of cannabinoids: A joint CoMFA and pseudoreceptor modelling study

NASA Astrophysics Data System (ADS)

Schmetzer, Silke; Greenidge, Paulette; Kovar, Karl-Artur; Schulze-Alexandru, Meike; Folkers, Gerd

1997-05-01

A cannabinoid pseudoreceptor model for the CB1-receptor has been constructed for 31 cannabinoids using the molecular modelling software YAK. Additionally, two CoMFA studies were performed on these ligands, the first of which was conducted prior to the building of the pseudoreceptor. Its pharmacophore is identical with the initial superposition of ligands used for pseudoreceptor construction. In contrast, the ligand alignment for the second CoMFA study was taken directly from the final cannabinoid pseudoreceptor model. This altered alignment gives markedly improved cross-validated r2 values as compared to those obtained from the original alignment with{{r}}_{{{cross}}}^2 values of 0.79 and 0.63, respectively, for five components. However, the pharmacophore alignment has the better predictive ability. Both the CoMFA and pseudoreceptor methods predict the free energy of binding of test ligands well.

Leaching characteristics of rare metal elements and chlorine in fly ash from ash melting plants for metal recovery.

PubMed

Jung, Chang-Hwan; Osako, Masahiro

2009-05-01

In terms of resource recovery and environmental impact, melting furnace fly ash (MFA) is attracting much attention in Japan due to its high metal content. The study aims to obtain fundamental information on using a water extraction method not only to concentrate valuable rare metals but also to remove undesirable substances such as chlorine for their recovery from MFA. The composition and leaching characteristics of MFA was investigated. The results revealed that the metal content in MFA is nearly equal to raw ore quality. The content of Ag, In, Pd, Pb, and Zn is, in fact, higher than the content of raw ore. As for leaching behavior, Ag, Bi, In, Ga, Ge, Sb, Sn, and Te showed the lowest release at a neutral pH range. Pd was leached constantly regardless of pH, but its concentration was quite low. On the other hand, most of the Tl was easily leached, revealing that water extraction is not appropriate for Tl recovery from MFA. Major elements Cl, Ca, Na, and K, occupying about 70% of MFA, were mostly leached regardless of pH. Base metal elements Cu, Pb, and Zn showed minimum solubility at a neutral pH. The leaching ratio of target rare metal elements and base metal elements suggests that the optimal pH for water extraction is 8-10, at which the leaching concentration is minimized. The water extraction process removed most of the Cl, Ca, Na, and K, and the concentration of rare metals and base metals increased by four or five times.

Isotopically nonstationary metabolic flux analysis (INST-MFA) of photosynthesis and photorespiration in plants

USDA-ARS?s Scientific Manuscript database

Photorespiration is a central component of photosynthesis; however to better understand its role it should be viewed in the context of an integrated metabolic network rather than a series of individual reactions that operate independently. Isotopically nonstationary 13C metabolic flux analysis (INST...

MicroFilament Analyzer, an image analysis tool for quantifying fibrillar orientation, reveals changes in microtubule organization during gravitropism.

PubMed

Jacques, Eveline; Buytaert, Jan; Wells, Darren M; Lewandowski, Michal; Bennett, Malcolm J; Dirckx, Joris; Verbelen, Jean-Pierre; Vissenberg, Kris

2013-06-01

Image acquisition is an important step in the study of cytoskeleton organization. As visual interpretations and manual measurements of digital images are prone to errors and require a great amount of time, a freely available software package named MicroFilament Analyzer (MFA) was developed. The goal was to provide a tool that facilitates high-throughput analysis to determine the orientation of filamentous structures on digital images in a more standardized, objective and repeatable way. Here, the rationale and applicability of the program is demonstrated by analyzing the microtubule patterns in epidermal cells of control and gravi-stimulated Arabidopsis thaliana roots. Differential expansion of cells on either side of the root results in downward bending of the root tip. As cell expansion depends on the properties of the cell wall, this may imply a differential orientation of cellulose microfibrils. As cellulose deposition is orchestrated by cortical microtubules, the microtubule patterns were analyzed. The MFA program detects the filamentous structures on the image and identifies the main orientation(s) within individual cells. This revealed four distinguishable microtubule patterns in root epidermal cells. The analysis indicated that gravitropic stimulation and developmental age are both significant factors that determine microtubule orientation. Moreover, the data show that an altered microtubule pattern does not precede differential expansion. Other possible applications are also illustrated, including field emission scanning electron micrographs of cellulose microfibrils in plant cell walls and images of fluorescent actin. © 2013 The Authors The Plant Journal © 2013 John Wiley & Sons Ltd.

Social health assistance schemes: the case of Medical Financial Assistance for the rural poor in four counties of China

PubMed Central

2011-01-01

Background Economic transition which took place in China over the last three decades, has led to a rapid marketization of the health care sector. Today inequity in health and poverty resulting from major illness has become a serious problem in rural areas of China. Medical Financial Assistance (MFA) is a health assistance scheme that helps rural poor people cope with major illness and alleviate their financial burden from major illness, which will definitely play a significant role in the process of rebuilding Chinese new rural health system. It mainly provides assistance to cover medical expenditure for inpatient services or the treatment of major illnesses, with joint funding from the central and local government. The purpose of this paper is to review the design, funding, implementation and to explore the preliminary effects of four counties' MFA in Hubei and Sichuan province of China. Methods We used an analytical framework built around the main objective of any social assistance scheme. The framework contains six 'targeting' procedural 'steps' which may explain why a specific group does not receive the assistance it ought to receive. More specifically, we explored to what extent the targeting, a key component of social assistance programs, is successful, based on the qualitative and quantitative data collected from four representative counties in central and western China. Results In the study sites, the budget of MFA ranged from 0.8 million Yuan to 1.646 million Yuan in each county and the budget per eligible person ranged from 32.67 Yuan to 149.09 Yuan. The preliminary effects of MFA were quite modest because of the scarcity of funds dedicated to the scheme. The coverage rate of MFA ranged from 17.8% to 24.1% among the four counties. MFA in the four counties used several ways to ration a restricted budget and provided only limited assistance. Substantial problems remained in terms of eligibility and identification of the beneficiaries, utilization and management of funds. Conclusions MFA needs to be improved further although it evidences the concern of the government for the poor rural people with major illness. Some ideas on how to improve MFA are put forward for future policy making. PMID:22011478

4D-LQTA-QSAR and docking study on potent Gram-negative specific LpxC inhibitors: a comparison to CoMFA modeling.

PubMed

Ghasemi, Jahan B; Safavi-Sohi, Reihaneh; Barbosa, Euzébio G

2012-02-01

A quasi 4D-QSAR has been carried out on a series of potent Gram-negative LpxC inhibitors. This approach makes use of the molecular dynamics (MD) trajectories and topology information retrieved from the GROMACS package. This new methodology is based on the generation of a conformational ensemble profile, CEP, for each compound instead of only one conformation, followed by the calculation intermolecular interaction energies at each grid point considering probes and all aligned conformations resulting from MD simulations. These interaction energies are independent variables employed in a QSAR analysis. The comparison of the proposed methodology to comparative molecular field analysis (CoMFA) formalism was performed. This methodology explores jointly the main features of CoMFA and 4D-QSAR models. Step-wise multiple linear regression was used for the selection of the most informative variables. After variable selection, multiple linear regression (MLR) and partial least squares (PLS) methods used for building the regression models. Leave-N-out cross-validation (LNO), and Y-randomization were performed in order to confirm the robustness of the model in addition to analysis of the independent test set. Best models provided the following statistics: [Formula in text] (PLS) and [Formula in text] (MLR). Docking study was applied to investigate the major interactions in protein-ligand complex with CDOCKER algorithm. Visualization of the descriptors of the best model helps us to interpret the model from the chemical point of view, supporting the applicability of this new approach in rational drug design.

Isotopically nonstationary 13C flux analysis of changes in Arabidopsis thaliana leaf metabolism due to high light acclimation

PubMed Central

Ma, Fangfang; Jazmin, Lara J.; Young, Jamey D.; Allen, Doug K.

2014-01-01

Improving plant productivity is an important aim for metabolic engineering. There are few comprehensive methods that quantitatively describe leaf metabolism, although such information would be valuable for increasing photosynthetic capacity, enhancing biomass production, and rerouting carbon flux toward desirable end products. Isotopically nonstationary metabolic flux analysis (INST-MFA) has been previously applied to map carbon fluxes in photoautotrophic bacteria, which involves model-based regression of transient 13C-labeling patterns of intracellular metabolites. However, experimental and computational difficulties have hindered its application to terrestrial plant systems. We performed in vivo isotopic labeling of Arabidopsis thaliana rosettes with 13CO2 and estimated fluxes throughout leaf photosynthetic metabolism by INST-MFA. Plants grown at 200 µmol m-2s−1 light were compared with plants acclimated for 9 d at an irradiance of 500 µmol⋅m−2⋅s−1. Approximately 1,400 independent mass isotopomer measurements obtained from analysis of 37 metabolite fragment ions were regressed to estimate 136 total fluxes (54 free fluxes) under each condition. The results provide a comprehensive description of changes in carbon partitioning and overall photosynthetic flux after long-term developmental acclimation of leaves to high light. Despite a doubling in the carboxylation rate, the photorespiratory flux increased from 17 to 28% of net CO2 assimilation with high-light acclimation (Vc/Vo: 3.5:1 vs. 2.3:1, respectively). This study highlights the potential of 13C INST-MFA to describe emergent flux phenotypes that respond to environmental conditions or plant physiology and cannot be obtained by other complementary approaches. PMID:25368168

Design of Novel Chemotherapeutic Agents Targeting Checkpoint Kinase 1 Using 3D-QSAR Modeling and Molecular Docking Methods.

PubMed

Balupuri, Anand; Balasubramanian, Pavithra K; Cho, Seung J

2016-01-01

Checkpoint kinase 1 (Chk1) has emerged as a potential therapeutic target for design and development of novel anticancer drugs. Herein, we have performed three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking analyses on a series of diazacarbazoles to design potent Chk1 inhibitors. 3D-QSAR models were developed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Docking studies were performed using AutoDock. The best CoMFA and CoMSIA models exhibited cross-validated correlation coefficient (q2) values of 0.631 and 0.585, and non-cross-validated correlation coefficient (r2) values of 0.933 and 0.900, respectively. CoMFA and CoMSIA models showed reasonable external predictabilities (r2 pred) of 0.672 and 0.513, respectively. A satisfactory performance in the various internal and external validation techniques indicated the reliability and robustness of the best model. Docking studies were performed to explore the binding mode of inhibitors inside the active site of Chk1. Molecular docking revealed that hydrogen bond interactions with Lys38, Glu85 and Cys87 are essential for Chk1 inhibitory activity. The binding interaction patterns observed during docking studies were complementary to 3D-QSAR results. Information obtained from the contour map analysis was utilized to design novel potent Chk1 inhibitors. Their activities and binding affinities were predicted using the derived model and docking studies. Designed inhibitors were proposed as potential candidates for experimental synthesis.

Model-free adaptive control of advanced power plants

DOEpatents

Cheng, George Shu-Xing; Mulkey, Steven L.; Wang, Qiang

2015-08-18

A novel 3-Input-3-Output (3.times.3) Model-Free Adaptive (MFA) controller with a set of artificial neural networks as part of the controller is introduced. A 3.times.3 MFA control system using the inventive 3.times.3 MFA controller is described to control key process variables including Power, Steam Throttle Pressure, and Steam Temperature of boiler-turbine-generator (BTG) units in conventional and advanced power plants. Those advanced power plants may comprise Once-Through Supercritical (OTSC) Boilers, Circulating Fluidized-Bed (CFB) Boilers, and Once-Through Supercritical Circulating Fluidized-Bed (OTSC CFB) Boilers.

Structural and physicochemical characterization of pyridine derivative salts of anti-inflammatory drugs

NASA Astrophysics Data System (ADS)

Nechipadappu, Sunil Kumar; Trivedi, Darshak R.

2017-08-01

Salts of common anti-inflammatory drugs mefenamic acid (MFA), tolfenamic acid (TFA) and naproxen (NPX) with various pyridine derivatives (4-amino pyridine (4AP), 4-dimethylaminopyridine (DMAP) and 2-amino pyridine (2AP)) were synthesized by crystal engineering approach based on the pKa values of API's and the salt former. All the salts were characterized systematically by various spectroscopic methods including FT-IR and 1H NMR and the crystal structure was determined by single-crystal X-ray diffraction techniques (SCXRD). DMAP salt of NPX and 2AP salts of MFA and TFA were not obtained in the salt screening experiments. All the molecular salts exhibited 1:1 molecular stoichiometry in the asymmetric unit and except NPX-2AP salt, all the molecular salts included a water molecule in the crystal lattice. Physicochemical and structural properties between drug-drug molecular salts of MFA-4AP, TFA-4AP and NPX-4AP have been evaluated and it was found that these molecular salts were found to be stable for a time period of six months at ambient condition and further hydration of molecular salts were not observed even at accelerated humid conditions (∼75% RH). It was found that 4AP salts of MFA and TFA and DMAP salts of MFA and TFA are isostructural.

Assessment of parameter uncertainty in hydrological model using a Markov-Chain-Monte-Carlo-based multilevel-factorial-analysis method

NASA Astrophysics Data System (ADS)

Zhang, Junlong; Li, Yongping; Huang, Guohe; Chen, Xi; Bao, Anming

2016-07-01

Without a realistic assessment of parameter uncertainty, decision makers may encounter difficulties in accurately describing hydrologic processes and assessing relationships between model parameters and watershed characteristics. In this study, a Markov-Chain-Monte-Carlo-based multilevel-factorial-analysis (MCMC-MFA) method is developed, which can not only generate samples of parameters from a well constructed Markov chain and assess parameter uncertainties with straightforward Bayesian inference, but also investigate the individual and interactive effects of multiple parameters on model output through measuring the specific variations of hydrological responses. A case study is conducted for addressing parameter uncertainties in the Kaidu watershed of northwest China. Effects of multiple parameters and their interactions are quantitatively investigated using the MCMC-MFA with a three-level factorial experiment (totally 81 runs). A variance-based sensitivity analysis method is used to validate the results of parameters' effects. Results disclose that (i) soil conservation service runoff curve number for moisture condition II (CN2) and fraction of snow volume corresponding to 50% snow cover (SNO50COV) are the most significant factors to hydrological responses, implying that infiltration-excess overland flow and snow water equivalent represent important water input to the hydrological system of the Kaidu watershed; (ii) saturate hydraulic conductivity (SOL_K) and soil evaporation compensation factor (ESCO) have obvious effects on hydrological responses; this implies that the processes of percolation and evaporation would impact hydrological process in this watershed; (iii) the interactions of ESCO and SNO50COV as well as CN2 and SNO50COV have an obvious effect, implying that snow cover can impact the generation of runoff on land surface and the extraction of soil evaporative demand in lower soil layers. These findings can help enhance the hydrological model's capability for simulating/predicting water resources.

MFA Oil Company - Clean Water Act Public Notice

EPA Pesticide Factsheets

The EPA is providing notice of a proposed Administrative Penalty Assessment against MFA Oil Company, a business located at One Ray Young Dr, Columbia, MO 65201, for alleged violations at five of the Company’s facilities located at: 624 Ashcroft Rd, Poplar

Maturation Stress Generation in Poplar Tension Wood Studied by Synchrotron Radiation Microdiffraction[C][W][OA

PubMed Central

Clair, Bruno; Alméras, Tancrède; Pilate, Gilles; Jullien, Delphine; Sugiyama, Junji; Riekel, Christian

2011-01-01

Tension wood is widespread in the organs of woody plants. During its formation, it generates a large tensile mechanical stress called maturation stress. Maturation stress performs essential biomechanical functions such as optimizing the mechanical resistance of the stem, performing adaptive movements, and ensuring the long-term stability of growing plants. Although various hypotheses have recently been proposed, the mechanism generating maturation stress is not yet fully understood. In order to discriminate between these hypotheses, we investigated structural changes in cellulose microfibrils along sequences of xylem cell differentiation in tension and normal wood of poplar (Populus deltoides × Populus trichocarpa ‘I45-51’). Synchrotron radiation microdiffraction was used to measure the evolution of the angle and lattice spacing of crystalline cellulose associated with the deposition of successive cell wall layers. Profiles of normal and tension wood were very similar in early development stages corresponding to the formation of the S1 layer and the outer part of the S2 layer. Subsequent layers were found with a lower microfibril angle (MFA), corresponding to the inner part of the S2 layer of normal wood (MFA approximately 10°) and the G layer of tension wood (MFA approximately 0°). In tension wood only, this steep decrease in MFA occurred together with an increase in cellulose lattice spacing. The relative increase in lattice spacing was found close to the usual value of maturation strains. Analysis showed that this increase in lattice spacing is at least partly due to mechanical stress induced in cellulose microfibrils soon after their deposition, suggesting that the G layer directly generates and supports the tensile maturation stress in poplar tension wood. PMID:21068364

3D QSAR based design of novel oxindole derivative as 5HT7 inhibitors.

PubMed

Chitta, Aparna; Sivan, Sree Kanth; Manga, Vijjulatha

2014-06-01

To understand the structural requirements of 5-hydroxytryptamine (5HT7) receptor inhibitors and to design new ligands against 5HT7 receptor with enhanced inhibitory potency, a three-dimensional quantitative structure-activity relationship study with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a data set of 56 molecules consisting of oxindole, tetrahydronaphthalene, aryl ketone substituted arylpiperazinealkylamide derivatives was performed. Derived model showed good statistical reliability in terms of predicting 5HT7 inhibitory activity of the molecules, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like conventional r2 and a cross validated (q2) values of 0.985, 0.743 for CoMFA and 0.970, 0.608 for CoMSIA, respectively. Predictive ability of the models to determine 5HT7 antagonistic activity is validated using a test set of 16 molecules that were not included in the training set. Predictive r2 obtained for the test set was 0.560 and 0.619 for CoMFA and CoMSIA, respectively. Steric, electrostatic fields majorly contributed toward activity which forms the basis for design of new molecules. Absorption, distribution, metabolism and elimination (ADME) calculation using QikProp 2.5 (Schrodinger 2010, Portland, OR) reveals that the molecules confer to Lipinski's rule of five in majority of the cases.

Parallel labeling experiments and metabolic flux analysis: Past, present and future methodologies.

PubMed

Crown, Scott B; Antoniewicz, Maciek R

2013-03-01

Radioactive and stable isotopes have been applied for decades to elucidate metabolic pathways and quantify carbon flow in cellular systems using mass and isotope balancing approaches. Isotope-labeling experiments can be conducted as a single tracer experiment, or as parallel labeling experiments. In the latter case, several experiments are performed under identical conditions except for the choice of substrate labeling. In this review, we highlight robust approaches for probing metabolism and addressing metabolically related questions though parallel labeling experiments. In the first part, we provide a brief historical perspective on parallel labeling experiments, from the early metabolic studies when radioisotopes were predominant to present-day applications based on stable-isotopes. We also elaborate on important technical and theoretical advances that have facilitated the transition from radioisotopes to stable-isotopes. In the second part of the review, we focus on parallel labeling experiments for (13)C-metabolic flux analysis ((13)C-MFA). Parallel experiments offer several advantages that include: tailoring experiments to resolve specific fluxes with high precision; reducing the length of labeling experiments by introducing multiple entry-points of isotopes; validating biochemical network models; and improving the performance of (13)C-MFA in systems where the number of measurements is limited. We conclude by discussing some challenges facing the use of parallel labeling experiments for (13)C-MFA and highlight the need to address issues related to biological variability, data integration, and rational tracer selection. Copyright © 2012 Elsevier Inc. All rights reserved.

Molecular docking and 3D-QSAR studies on inhibitors of DNA damage signaling enzyme human PARP-1.

PubMed

Fatima, Sabiha; Bathini, Raju; Sivan, Sree Kanth; Manga, Vijjulatha

2012-08-01

Poly (ADP-ribose) polymerase-1 (PARP-1) operates in a DNA damage signaling network. Molecular docking and three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on human PARP-1 inhibitors. Docked conformation obtained for each molecule was used as such for 3D-QSAR analysis. Molecules were divided into a training set and a test set randomly in four different ways, partial least square analysis was performed to obtain QSAR models using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Derived models showed good statistical reliability that is evident from their r², q²(loo) and r²(pred) values. To obtain a consensus for predictive ability from all the models, average regression coefficient r²(avg) was calculated. CoMFA and CoMSIA models showed a value of 0.930 and 0.936, respectively. Information obtained from the best 3D-QSAR model was applied for optimization of lead molecule and design of novel potential inhibitors.

A preliminary study on effects of increment of loads to lower extremity joints during kettlebell swing activity

NASA Astrophysics Data System (ADS)

Zin, Muhammad Athif Mat; Rambely, Azmin Sham; Ariff, Noratiqah Mohd

2018-04-01

The purpose of the study was to determine the effects of increment of loads to lower extremity joints during the two-hand kettlebell swing (KS) activity with loads of 4 kg, 6 kg and 8 kg. Three male adults participated in this study. Subjects were required to perform a two-hand KS with three different loads which were 4 kg, 6 kg and 8 kg. A Vicon Nexus system (v1.5.2) with three infrared cameras adjusted with 100 Hz speed were used to capture KS motion to produce kinematics data for lower extremity joints which were ankle, knee and hip joints. The results showed that mean maximum flexion angle (MFA) of ankle, knee and hip joints decreased as load increased. Mean MFA of knee joint was the highest while mean MFA of ankle joint was the smallest recorded. Mean MFA of ipsilateral leg was higher than that of contralateral leg for a right-dominant subject.

Magnetic Field Apparatus (MFA) Hardware Test

NASA Technical Reports Server (NTRS)

Anderson, Ken; Boody, April; Reed, Dave; Wang, Chung; Stuckey, Bob; Cox, Dave

1999-01-01

The objectives of this study are threefold: (1) Provide insight into water delivery in microgravity and determine optimal germination paper wetting for subsequent seed germination in microgravity; (2) Observe the behavior of water exposed to a strong localized magnetic field in microgravity; and (3) Simulate the flow of fixative (using water) through the hardware. The Magnetic Field Apparatus (MFA) is a new piece of hardware slated to fly on the Space Shuttle in early 2001. MFA is designed to expose plant tissue to magnets in a microgravity environment, deliver water to the plant tissue, record photographic images of plant tissue, and deliver fixative to the plant tissue.

Complications of the Middle Cranial Fossa Approach for Acoustic Neuroma Removal.

PubMed

Scheich, Matthias; Ginzkey, Christian; Ehrmann Müller, Desiree; Shehata Dieler, Wafaa; Hagen, Rudolf

2017-08-01

To analyze postoperative complications after microsurgery for acoustic neuroma (AN) via the middle fossa approach (MFA). In total, 203 consecutive patients of a tertiary skull base referral center at a university hospital were included in this retrospective chart and database analysis. All patients had undergone primary microsurgery at the Otorhinolaryngology department via MFA between December 2005 and October 2014. Postoperative complications were documented during the inpatient stay and outpatient follow-up. Overall, 41 complications were registered in 35 patients. The most common was cerebrospinal fluid (CSF) leakage in 13% of the patients. Bleeding complications were documented in seven patients: two cerebellar bleedings, one subdural and one epidural hematoma, two hematomas of the skin, and one bleeding through the closed wound. Two patients experienced meningitis and one patient had a transient ischemic attack. Furthermore, three cases of deep vein thrombosis occurred, which led to a lethal pulmonary embolism in one case. One patient sustained temporary palsy of the vocal fold and another reported antibiotic-associated diarrhea. Acoustic neuroma surgery via the MFA can be conducted with low morbidity and mortality. The most common complication is CSF leakage, which can be treated in most cases in a stepwise conservative manner. Severe adverse events that may require revision surgery are very scarce (1%).

Isotopically nonstationary 13C flux analysis of changes in Arabidopsis thaliana leaf metabolism due to high light acclimation

DOE PAGES

Ma, Fangfang; Jazmin, Lara J.; Young, Jamey D.; ...

2014-11-03

Improving plant productivity is an important aim for metabolic engineering. There are few comprehensive methods that quantitatively describe leaf metabolism, although such information would be valuable for increasing photosynthetic capacity, enhancing biomass production, and rerouting carbon flux toward desirable end products. Isotopically nonstationary metabolic flux analysis (INST-MFA) has been previously applied to map carbon fluxes in photoautotrophic bacteria, which involves model-based regression of transient 13C-labeling patterns of intracellular metabolites. However, experimental and computational difficulties have hindered its application to terrestrial plant systems. Here, we performed in vivo isotopic labeling of Arabidopsis thaliana rosettes with 13CO 2 and estimated fluxes throughoutmore » leaf photosynthetic metabolism by INST-MFA. Plants grown at 200 µmol m $-$2s $-$1 light were compared with plants acclimated for 9 d at an irradiance of 500 µmol∙m $-$2∙s $-$1. Approximately 1,400 independent mass isotopomer measurements obtained from analysis of 37 metabolite fragment ions were regressed to estimate 136 total fluxes (54 free fluxes) under each condition. The results provide a comprehensive description of changes in carbon partitioning and overall photosynthetic flux after long-term developmental acclimation of leaves to high light. Despite a doubling in the carboxylation rate, the photorespiratory flux increased from 17 to 28% of net CO 2 assimilation with high-light acclimation (Vc/Vo: 3.5:1 vs. 2.3:1, respectively). In conclusion, this study highlights the potential of 13C INST-MFA to describe emergent flux phenotypes that respond to environmental conditions or plant physiology and cannot be obtained by other complementary approaches.« less

Comprehensive metabolic modeling of multiple 13C-isotopomer data sets to study metabolism in perfused working hearts.

PubMed

Crown, Scott B; Kelleher, Joanne K; Rouf, Rosanne; Muoio, Deborah M; Antoniewicz, Maciek R

2016-10-01

In many forms of cardiomyopathy, alterations in energy substrate metabolism play a key role in disease pathogenesis. Stable isotope tracing in rodent heart perfusion systems can be used to determine cardiac metabolic fluxes, namely those relative fluxes that contribute to pyruvate, the acetyl-CoA pool, and pyruvate anaplerosis, which are critical to cardiac homeostasis. Methods have previously been developed to interrogate these relative fluxes using isotopomer enrichments of measured metabolites and algebraic equations to determine a predefined metabolic flux model. However, this approach is exquisitely sensitive to measurement error, thus precluding accurate relative flux parameter determination. In this study, we applied a novel mathematical approach to determine relative cardiac metabolic fluxes using 13 C-metabolic flux analysis ( 13 C-MFA) aided by multiple tracer experiments and integrated data analysis. Using 13 C-MFA, we validated a metabolic network model to explain myocardial energy substrate metabolism. Four different 13 C-labeled substrates were queried (i.e., glucose, lactate, pyruvate, and oleate) based on a previously published study. We integrated the analysis of the complete set of isotopomer data gathered from these mouse heart perfusion experiments into a single comprehensive network model that delineates substrate contributions to both pyruvate and acetyl-CoA pools at a greater resolution than that offered by traditional methods using algebraic equations. To our knowledge, this is the first rigorous application of 13 C-MFA to interrogate data from multiple tracer experiments in the perfused heart. We anticipate that this approach can be used widely to study energy substrate metabolism in this and other similar biological systems. Copyright © 2016 the American Physiological Society.

Comprehensive metabolic modeling of multiple 13C-isotopomer data sets to study metabolism in perfused working hearts

PubMed Central

Kelleher, Joanne K.; Rouf, Rosanne; Muoio, Deborah M.; Antoniewicz, Maciek R.

2016-01-01

In many forms of cardiomyopathy, alterations in energy substrate metabolism play a key role in disease pathogenesis. Stable isotope tracing in rodent heart perfusion systems can be used to determine cardiac metabolic fluxes, namely those relative fluxes that contribute to pyruvate, the acetyl-CoA pool, and pyruvate anaplerosis, which are critical to cardiac homeostasis. Methods have previously been developed to interrogate these relative fluxes using isotopomer enrichments of measured metabolites and algebraic equations to determine a predefined metabolic flux model. However, this approach is exquisitely sensitive to measurement error, thus precluding accurate relative flux parameter determination. In this study, we applied a novel mathematical approach to determine relative cardiac metabolic fluxes using 13C-metabolic flux analysis (13C-MFA) aided by multiple tracer experiments and integrated data analysis. Using 13C-MFA, we validated a metabolic network model to explain myocardial energy substrate metabolism. Four different 13C-labeled substrates were queried (i.e., glucose, lactate, pyruvate, and oleate) based on a previously published study. We integrated the analysis of the complete set of isotopomer data gathered from these mouse heart perfusion experiments into a single comprehensive network model that delineates substrate contributions to both pyruvate and acetyl-CoA pools at a greater resolution than that offered by traditional methods using algebraic equations. To our knowledge, this is the first rigorous application of 13C-MFA to interrogate data from multiple tracer experiments in the perfused heart. We anticipate that this approach can be used widely to study energy substrate metabolism in this and other similar biological systems. PMID:27496880

Predicting enteric methane emission of dairy cows with milk Fourier-transform infrared spectra and gas chromatography-based milk fatty acid profiles.

PubMed

van Gastelen, S; Mollenhorst, H; Antunes-Fernandes, E C; Hettinga, K A; van Burgsteden, G G; Dijkstra, J; Rademaker, J L W

2018-06-01

The objective of the present study was to compare the prediction potential of milk Fourier-transform infrared spectroscopy (FTIR) for CH 4 emissions of dairy cows with that of gas chromatography (GC)-based milk fatty acids (MFA). Data from 9 experiments with lactating Holstein-Friesian cows, with a total of 30 dietary treatments and 218 observations, were used. Methane emissions were measured for 3 consecutive days in climate respiration chambers and expressed as production (g/d), yield (g/kg of dry matter intake; DMI), and intensity (g/kg of fat- and protein-corrected milk; FPCM). Dry matter intake was 16.3 ± 2.18 kg/d (mean ± standard deviation), FPCM yield was 25.9 ± 5.06 kg/d, CH 4 production was 366 ± 53.9 g/d, CH 4 yield was 22.5 ± 2.10 g/kg of DMI, and CH 4 intensity was 14.4 ± 2.58 g/kg of FPCM. Milk was sampled during the same days and analyzed by GC and by FTIR. Multivariate GC-determined MFA-based and FTIR-based CH 4 prediction models were developed, and subsequently, the final CH 4 prediction models were evaluated with root mean squared error of prediction and concordance correlation coefficient analysis. Further, we performed a random 10-fold cross validation to calculate the performance parameters of the models (e.g., the coefficient of determination of cross validation). The final GC-determined MFA-based CH 4 prediction models estimate CH 4 production, yield, and intensity with a root mean squared error of prediction of 35.7 g/d, 1.6 g/kg of DMI, and 1.6 g/kg of FPCM and with a concordance correlation coefficient of 0.72, 0.59, and 0.77, respectively. The final FTIR-based CH 4 prediction models estimate CH 4 production, yield, and intensity with a root mean squared error of prediction of 43.2 g/d, 1.9 g/kg of DMI, and 1.7 g/kg of FPCM and with a concordance correlation coefficient of 0.52, 0.40, and 0.72, respectively. The GC-determined MFA-based prediction models described a greater part of the observed variation in CH 4 emission than did the FTIR-based models. The cross validation results indicate that all CH 4 prediction models (both GC-determined MFA-based and FTIR-based models) are robust; the difference between the coefficient of determination and the coefficient of determination of cross validation ranged from 0.01 to 0.07. The results indicate that GC-determined MFA have a greater potential than FTIR spectra to estimate CH 4 production, yield, and intensity. Both techniques hold potential but may not yet be ready to predict CH 4 emission of dairy cows in practice. Additional CH 4 measurements are needed to improve the accuracy and robustness of GC-determined MFA and FTIR spectra for CH 4 prediction. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Subspace K-means clustering.

PubMed

Timmerman, Marieke E; Ceulemans, Eva; De Roover, Kim; Van Leeuwen, Karla

2013-12-01

To achieve an insightful clustering of multivariate data, we propose subspace K-means. Its central idea is to model the centroids and cluster residuals in reduced spaces, which allows for dealing with a wide range of cluster types and yields rich interpretations of the clusters. We review the existing related clustering methods, including deterministic, stochastic, and unsupervised learning approaches. To evaluate subspace K-means, we performed a comparative simulation study, in which we manipulated the overlap of subspaces, the between-cluster variance, and the error variance. The study shows that the subspace K-means algorithm is sensitive to local minima but that the problem can be reasonably dealt with by using partitions of various cluster procedures as a starting point for the algorithm. Subspace K-means performs very well in recovering the true clustering across all conditions considered and appears to be superior to its competitor methods: K-means, reduced K-means, factorial K-means, mixtures of factor analyzers (MFA), and MCLUST. The best competitor method, MFA, showed a performance similar to that of subspace K-means in easy conditions but deteriorated in more difficult ones. Using data from a study on parental behavior, we show that subspace K-means analysis provides a rich insight into the cluster characteristics, in terms of both the relative positions of the clusters (via the centroids) and the shape of the clusters (via the within-cluster residuals).

13 C Flux Analysis Reveals that Rebalancing Medium Amino Acid Composition can Reduce Ammonia Production while Preserving Central Carbon Metabolism of CHO Cell Cultures.

PubMed

McAtee Pereira, Allison G; Walther, Jason L; Hollenbach, Myles; Young, Jamey D

2018-02-06

13 C metabolic flux analysis (MFA) provides a rigorous approach to quantify intracellular metabolism of industrial cell lines. In this study, 13 C MFA was used to characterize the metabolic response of Chinese hamster ovary (CHO) cells to a novel medium variant designed to reduce ammonia production. Ammonia inhibits growth and viability of CHO cell cultures, alters glycosylation of recombinant proteins, and enhances product degradation. Ammonia production was reduced by manipulating the amino acid composition of the culture medium; specifically, glutamine, glutamate, asparagine, aspartate, and serine levels were adjusted. Parallel 13 C flux analysis experiments determined that, while ammonia production decreased by roughly 40%, CHO cell metabolic phenotype, growth, viability, and monoclonal antibody (mAb) titer were not significantly altered by the changes in media composition. This study illustrates how 13 C flux analysis can be applied to assess the metabolic effects of media manipulations on mammalian cell cultures. The analysis revealed that adjusting the amino acid composition of CHO cell culture media can effectively reduce ammonia production while preserving fluxes throughout central carbon metabolism. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

78 FR 37537 - CHS Inc., Federal Express Corporation, GROWMARK, Inc., HWRT Oil Company LLC, MFA Oil Company...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-21

... will no longer accept nominations for the transportation of jet fuel or distillates, violates the...., United Airlines, Inc., UPS Fuel Services, Inc. v. Enterprise TE Products Pipeline Company, LLC; Notice of... LLC; MFA Oil Company; Southwest Airline Co.; United Airlines, Inc.; and UPS Fuel Services, Inc...

76 FR 19741 - Draft Environmental Assessment; Giant Miscanthus in Arkansas, Missouri, Ohio, and Pennsylvania

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-08

... Aloterra Energy and MFA Oil Biomass Company (project sponsors) proposed project areas in Arkansas, Missouri, Ohio, and Pennsylvania as part of the Biomass Crop Assistance Program (BCAP). This notice provides a... Energy and MFA Oil Biomass Company submitted a proposal to FSA to establish BCAP project areas in...

Current utilization, interpretation, and recommendations: the musculoskeletal function assessments (MFA/SMFA).

PubMed

Barei, David P; Agel, Julie; Swiontkowski, Marc F

2007-01-01

The development of patient-oriented health status measurements has resulted in the emergence of several generic condition-specific and anatomic-specific instruments. These instruments are generally designed to measure the function of the individual as a whole from the individual's own point of view. They are not intended to replace traditional physician-oriented clinical outcome measures, such as complication rates, ranges of motion, or time to fracture union; instead, they are an attempt to measure the results of a treatment or condition from the patient's perspective. Over the past decade, the Musculoskeletal Function Assessment (MFA) instrument has been developed and used as one of the primary generic musculoskeletal functional assessment tools, in part because of its validity, reliability, and responsiveness. Despite the numerous publications reporting the MFA/SMFA, we are unaware of any publications that have used those results to subsequently affect patient care. We hope that this special interest article highlights the current underutilization of the available data and encourages the orthopedic community to maximize the clinical and research potential of the MFA/SMFA (Short Musculoskeletal Function Assessment).

Hologram quantitative structure-activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1 integrase inhibitors.

PubMed

Magalhães, Uiaran de Oliveira; Souza, Alessandra Mendonça Teles de; Albuquerque, Magaly Girão; Brito, Monique Araújo de; Bello, Murilo Lamim; Cabral, Lucio Mendes; Rodrigues, Carlos Rangel

2013-01-01

Acquired immunodeficiency syndrome is a public health problem worldwide caused by the Human immunodeficiency virus (HIV). Treatment with antiretroviral drugs is the best option for viral suppression, reducing morbidity and mortality. However, viral resistance in HIV-1 therapy has been reported. HIV-1 integrase (IN) is an essential enzyme for effective viral replication and an attractive target for the development of new inhibitors. In the study reported here, two- and three-dimensional quantitative structure-activity relationship (2D/3D-QSAR) studies, applying hologram quantitative structure-activity relationship (HQSAR) and comparative molecular field analysis (CoMFA) methods, respectively, were performed on a series of tricyclic phthalimide HIV-1 IN inhibitors. The best HQSAR model (q (2) = 0.802, r (2) = 0.972) was obtained using atoms, bonds, and connectivity as the fragment distinction, a fragment size of 2-5 atoms, hologram length of 61 bins, and six components. The best CoMFA model (q (2) = 0.748, r (2) = 0.974) was obtained with alignment of all atoms of the tricyclic phthalimide moiety (alignment II). The HQSAR contribution map identified that the carbonyl-hydroxy-aromatic nitrogen motif made a positive contribution to the activity of the compounds. Furthermore, CoMFA contour maps suggested that bulky groups in meta and para positions in the phenyl ring would increase the biological activity of this class. The conclusions of this work may lead to a better understanding of HIV-1 IN inhibition and contribute to the design of new and more potent derivatives.

Three-dimensional quantitative structure-activity relationship studies on novel series of benzotriazine based compounds acting as Src inhibitors using CoMFA and CoMSIA.

PubMed

Gueto, Carlos; Ruiz, José L; Torres, Juan E; Méndez, Jefferson; Vivas-Reyes, Ricardo

2008-03-01

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of benzotriazine derivatives, as Src inhibitors. Ligand molecular superimposition on the template structure was performed by database alignment method. The statistically significant model was established of 72 molecules, which were validated by a test set of six compounds. The CoMFA model yielded a q(2)=0.526, non cross-validated R(2) of 0.781, F value of 88.132, bootstrapped R(2) of 0.831, standard error of prediction=0.587, and standard error of estimate=0.351 while the CoMSIA model yielded the best predictive model with a q(2)=0.647, non cross-validated R(2) of 0.895, F value of 115.906, bootstrapped R(2) of 0.953, standard error of prediction=0.519, and standard error of estimate=0.178. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. Results indicate that small steric volumes in the hydrophobic region, electron-withdrawing groups next to the aryl linker region, and atoms close to the solvent accessible region increase the Src inhibitory activity of the compounds. In fact, adding substituents at positions 5, 6, and 8 of the benzotriazine nucleus were generated new compounds having a higher predicted activity. The data generated from the present study will further help to design novel, potent, and selective Src inhibitors as anticancer therapeutic agents.

Hologram quantitative structure–activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1 integrase inhibitors

PubMed Central

de Oliveira Magalhães, Uiaran; de Souza, Alessandra Mendonça Teles; Albuquerque, Magaly Girão; de Brito, Monique Araújo; Bello, Murilo Lamim; Cabral, Lucio Mendes; Rodrigues, Carlos Rangel

2013-01-01

Acquired immunodeficiency syndrome is a public health problem worldwide caused by the Human immunodeficiency virus (HIV). Treatment with antiretroviral drugs is the best option for viral suppression, reducing morbidity and mortality. However, viral resistance in HIV-1 therapy has been reported. HIV-1 integrase (IN) is an essential enzyme for effective viral replication and an attractive target for the development of new inhibitors. In the study reported here, two- and three-dimensional quantitative structure–activity relationship (2D/3D-QSAR) studies, applying hologram quantitative structure–activity relationship (HQSAR) and comparative molecular field analysis (CoMFA) methods, respectively, were performed on a series of tricyclic phthalimide HIV-1 IN inhibitors. The best HQSAR model (q2 = 0.802, r2 = 0.972) was obtained using atoms, bonds, and connectivity as the fragment distinction, a fragment size of 2–5 atoms, hologram length of 61 bins, and six components. The best CoMFA model (q2 = 0.748, r2 = 0.974) was obtained with alignment of all atoms of the tricyclic phthalimide moiety (alignment II). The HQSAR contribution map identified that the carbonyl-hydroxy-aromatic nitrogen motif made a positive contribution to the activity of the compounds. Furthermore, CoMFA contour maps suggested that bulky groups in meta and para positions in the phenyl ring would increase the biological activity of this class. The conclusions of this work may lead to a better understanding of HIV-1 IN inhibition and contribute to the design of new and more potent derivatives. PMID:24039405

Antitumor evaluation and 3D-QSAR studies of a new series of the spiropyrroloquinoline isoindolinone/aza-isoindolinone derivatives by comparative molecular field analysis (CoMFA).

PubMed

Sadeghzadeh, Masoud; Salahinejad, Maryam; Zarezadeh, Nahid; Ghandi, Mehdi; Baghery, Maryam Keshavarz

2017-11-01

In current study, antitumor activity of two series of the newly synthesized spiropyrroloquinoline isoindolinone and spiropyrroloquinoline aza-isoindolinone scaffolds was evaluated against three human breast normal and cancer cell lines (MCF-10A, MCF-7 and SK-BR-3) and compared with cytotoxicity values of doxorubicin and colchicine as the standard drugs. It was found that several compounds were endowed with cytotoxicity in the low micromolar range. Among these two series, compounds 6i, 6j, 6k and 7l, 7m, 7n, 7o containing 3-ethyl-1H-indole moiety were found to be highly effective against both cancer cell lines ranging from [Formula: see text] to [Formula: see text] in comparison with the corresponding analogs. Compared with human cancer cells, the most potent compounds did not show high cytotoxicity against human breast normal MCF-10A cells. Generally, most of the evaluated compounds 6a-l and 7a-o series showed more antitumor activity against SK-BR-3 than MCF-7 cells. Moreover, comparative molecular field analysis (CoMFA) as a popular tools of three-dimensional quantitative structure-activity relationship (3D-QSAR) studies was carried out on 27 spiropyrroloquinolineisoindolinone and spiropyrroloquinolineaza-isoindolinone derivatives with antitumor activity against on SK-BR-3 cells. The obtained CoMFA models showed statistically excellent performance, which also possessed good predictive ability for an external test set. The results confirm the important effect of molecular steric and electrostatic interactions of these compounds on in vitro cytotoxicity against SK-BR-3.

Physical context for theoretical approaches to sediment transport magnitude-frequency analysis in alluvial channels

NASA Astrophysics Data System (ADS)

Sholtes, Joel; Werbylo, Kevin; Bledsoe, Brian

2014-10-01

Theoretical approaches to magnitude-frequency analysis (MFA) of sediment transport in channels couple continuous flow probability density functions (PDFs) with power law flow-sediment transport relations (rating curves) to produce closed-form equations relating MFA metrics such as the effective discharge, Qeff, and fraction of sediment transported by discharges greater than Qeff, f+, to statistical moments of the flow PDF and rating curve parameters. These approaches have proven useful in understanding the theoretical drivers behind the magnitude and frequency of sediment transport. However, some of their basic assumptions and findings may not apply to natural rivers and streams with more complex flow-sediment transport relationships or management and design scenarios, which have finite time horizons. We use simple numerical experiments to test the validity of theoretical MFA approaches in predicting the magnitude and frequency of sediment transport. Median values of Qeff and f+ generated from repeated, synthetic, finite flow series diverge from those produced with theoretical approaches using the same underlying flow PDF. The closed-form relation for f+ is a monotonically increasing function of flow variance. However, using finite flow series, we find that f+ increases with flow variance to a threshold that increases with flow record length. By introducing a sediment entrainment threshold, we present a physical mechanism for the observed diverging relationship between Qeff and flow variance in fine and coarse-bed channels. Our work shows that through complex and threshold-driven relationships sediment transport mode, channel morphology, flow variance, and flow record length all interact to influence estimates of what flow frequencies are most responsible for transporting sediment in alluvial channels.

Comparative molecular field analysis of fenoterol derivatives: A platform towards highly selective and effective beta(2)-adrenergic receptor agonists.

PubMed

Jozwiak, Krzysztof; Woo, Anthony Yiu-Ho; Tanga, Mary J; Toll, Lawrence; Jimenez, Lucita; Kozocas, Joseph A; Plazinska, Anita; Xiao, Rui-Ping; Wainer, Irving W

2010-01-15

To use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the beta(2)-adrenergic receptor. Out of 21 computationally designed structures 6 compounds were synthesized and characterized for beta(2)-AR binding affinities, subtype selectivities and functional activities. the best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with K(i)beta(2)-AR=0.28microm, K(i)beta(1)-AR/K(i)beta(2)-AR=573, EC(50cAMP)=3.9nm, EC(50cardio)=16nm. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure. Copyright 2009 Elsevier Ltd. All rights reserved.

A mean-field theory for self-propelled particles interacting by velocity alignment mechanisms

NASA Astrophysics Data System (ADS)

Peruani, F.; Deutsch, A.; Bär, M.

2008-04-01

A mean-field approach (MFA) is proposed for the analysis of orientational order in a two-dimensional system of stochastic self-propelled particles interacting by local velocity alignment mechanism. The treatment is applied to the cases of ferromagnetic (F) and liquid-crystal (LC) alignment. In both cases, MFA yields a second order phase transition for a critical noise strength and a scaling exponent of 1/2 for the respective order parameters. We find that the critical noise amplitude ηc at which orientational order emerges in the LC case is smaller than in the F-alignment case, i.e. ηLC C<ηF C. A comparison with simulations of individual-based models with F- resp. LC-alignment shows that the predictions about the critical behavior and the qualitative relation between the respective critical noise amplitudes are correct.

Three-dimensional quantitative structure-activity relationship studies on c-Src inhibitors based on different docking methods.

PubMed

Bairy, Santhosh Kumar; Suneel Kumar, B V S; Bhalla, Joseph Uday Tej; Pramod, A B; Ravikumar, Muttineni

2009-04-01

c-Src kinase play an important role in cell growth and differentiation and its inhibitors can be useful for the treatment of various diseases, including cancer, osteoporosis, and metastatic bone disease. Three dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out on quinazolin derivatives inhibiting c-Src kinase. Molecular field analysis (MFA) models with four different alignment techniques, namely, GLIDE, GOLD, LIGANDFIT and Least squares based methods were developed. glide based MFA model showed better results (Leave one out cross validation correlation coefficient r(2)(cv) = 0.923 and non-cross validation correlation coefficient r(2)= 0.958) when compared with other models. These results help us to understand the nature of descriptors required for activity of these compounds and thereby provide guidelines to design novel and potent c-Src kinase inhibitors.

Transitioning from School to Career: I've Got My MFA… Now What?

ERIC Educational Resources Information Center

Moffett, Ann-Thomas; Sorensen, Gina Bolles; Ifill, Valerie

2015-01-01

The Master of Fine Arts (MFA) is a terminal, practice-oriented degree in dance. Approximately 30 institutions in the United States offer MFA degrees in dance (National Association of Schools of Dance 2014). The degree was "designed historically to offer a broad education with a content specialization, 'without the latter overpowering the…

Supporting Museums--Serving Communities: An Evaluation of the Museums for America Program. Executive Summary

ERIC Educational Resources Information Center

Institute of Museum and Library Services, 2011

2011-01-01

Museums for America (MFA) is the largest IMLS grant program for museums; it supports institutions by investing in high-priority, high-value activities that are clearly linked to the institution's strategic plan and enhance its value to its community. MFA grants situate projects within a framework of meeting three strategic goals: engaging…

The Master of Fine Arts (MFA) in Creative Writing in the United States: Teaching the "Unteachable"

ERIC Educational Resources Information Center

Caglioti, Carla

2010-01-01

The Master of Fine Arts (MFA) in Creative Writing, usually housed within the English Department, has become a progressively more popular field of study among students and budget conscious administrators. But for all its popularity, it is a field that has been left generally unexamined by scholars. While there have been numerous scholarly studies…

Constrained Fisher Scoring for a Mixture of Factor Analyzers

DTIC Science & Technology

2016-09-01

expectation -maximization algorithm with similar computational requirements. Lastly, we demonstrate the efficacy of the proposed method for learning a... expectation maximization 44 Gene T Whipps 301 394 2372Unclassified Unclassified Unclassified UU ii Approved for public release; distribution is unlimited...14 3.6 Relationship with Expectation -Maximization 16 4. Simulation Examples 16 4.1 Synthetic MFA Example 17 4.2 Manifold Learning Example 22 5

Rapid analysis of the microfibril angle of loblolly pine from two test sites using near-infrared analysis

Treesearch

ChiLeung So; Jennifer Myszewski; Thomas Elder; Les Groom

2013-01-01

Abstract There have been several recent studies employing near infrared (NIR) spectroscopy for the rapid determination of microfibril angle (MFA). However, only a few have utilized samples cut from individual rings of increment cores, and none have been as large as this present study, sampling over 600 trees from two test sites producing over 3000 individual ring...

Design, synthesis, pharmacological evaluation and in silico ADMET prediction of novel substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonists based on predictive 3D QSAR models.

PubMed

Vyas, V K; Gupta, N; Ghate, M; Patel, S

2014-01-01

In this study we designed novel substituted benzimidazole derivatives and predicted their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, based on a predictive 3D QSAR study on 132 substituted benzimidazoles as AngII-AT1 receptor antagonists. The two best predicted compounds were synthesized and evaluated for AngII-AT1 receptor antagonism. Three different alignment tools for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used. The best 3D QSAR models were obtained using the rigid body (Distill) alignment method. CoMFA and CoMSIA models were found to be statistically significant with leave-one-out correlation coefficients (q(2)) of 0.630 and 0.623, respectively, cross-validated coefficients (r(2)cv) of 0.651 and 0.630, respectively, and conventional coefficients of determination (r(2)) of 0.848 and 0.843, respectively. 3D QSAR models were validated using a test set of 24 compounds, giving satisfactory predicted results (r(2)pred) of 0.727 and 0.689 for the CoMFA and CoMSIA models, respectively. We have identified some key features in substituted benzimidazole derivatives, such as lipophilicity and H-bonding at the 2- and 5-positions of the benzimidazole nucleus, respectively, for AT1 receptor antagonistic activity. We designed 20 novel substituted benzimidazole derivatives and predicted their activity. In silico ADMET properties were also predicted for these designed molecules. Finally, the compounds with best predicted activity were synthesized and evaluated for in vitro angiotensin II-AT1 receptor antagonism.

3D QSAR studies on binding affinities of coumarin natural products for glycosomal GAPDH of Trypanosoma cruzi

NASA Astrophysics Data System (ADS)

Menezes, Irwin R. A.; Lopes, Julio C. D.; Montanari, Carlos A.; Oliva, Glaucius; Pavão, Fernando; Castilho, Marcelo S.; Vieira, Paulo C.; Pupo, M.^onica T.

2003-05-01

Drug design strategies based on Comparative Molecular Field Analysis (CoMFA) have been used to predict the activity of new compounds. The major advantage of this approach is that it permits the analysis of a large number of quantitative descriptors and uses chemometric methods such as partial least squares (PLS) to correlate changes in bioactivity with changes in chemical structure. Because it is often difficult to rationalize all variables affecting the binding affinity of compounds using CoMFA solely, the program GRID was used to describe ligands in terms of their molecular interaction fields, MIFs. The program VolSurf that is able to compress the relevant information present in 3D maps into a few descriptors can treat these GRID fields. The binding affinities of a new set of compounds consisting of 13 coumarins, for one of which the three-dimensional ligand-enzyme bound structure is known, were studied. A final model based on the mentioned programs was independently validated by synthesizing and testing new coumarin derivatives. By relying on our knowledge of the real physical data (i.e., combining crystallographic and binding affinity results), it is also shown that ligand-based design agrees with structure-based design. The compound with the highest binding affinity was the coumarin chalepin, isolated from Rutaceae species, with an IC50 value of 55.5 μM towards the enzyme glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) from glycosomes of the parasite Trypanosoma cruzi, the causative agent of Chagas' disease. The proposed models from GRID MIFs have revealed the importance of lipophilic interactions in modulating the inhibition, but without excluding the dependence on stereo-electronic properties as found from CoMFA fields.

Shaping the role of 'fast' and 'slow' drivers of change in forest-shrubland socio-ecological systems.

PubMed

Ferrara, Agostino; Kelly, Claire; Wilson, Geoff A; Nolè, Angelo; Mancino, Giuseppe; Bajocco, Sofia; Salvati, Luca

2016-03-15

The temporal speeds and spatial scales at which ecosystem processes operate are often at odds with the scale and speed at which natural resources such as soil, water and vegetation are managed those. Scale mismatches often occur as a result of the time-lag between policy development, implementation and observable changes in natural capital in particular. In this study, we analyse some of the transformations that can occur in complex forest-shrubland socio-ecological systems undergoing biophysical and socioeconomic change. We use a Multiway Factor Analysis (MFA) applied to a representative set of variables to assess changes in components of natural, economic and social capitals over time. Our results indicate similarities among variables and spatial units (i.e. municipalities) which allows us to rank the variables used to describe the SES according to their rapidity of change. The novelty of the proposed framework lies in the fact that the assessment of rapidity-to-change, based on the MFA, takes into account the multivariate relationships among the system's variables, identifying the net rate of change for the whole system, and the relative impact that individual variables exert on the system itself. The aim of this study was to assess the influence of fast and slow variables on the evolution of socio-economic systems based on simplified multivariate procedures applicable to vastly different socio-economic contexts and conditions. This study also contributes to quantitative analysis methods for long-established socio-ecological systems, which may help in designing more effective, and sustainable land management strategies in environmentally sensitive areas. Copyright © 2015 Elsevier Ltd. All rights reserved.

Wood properties and trunk allometry of co-occurring rainforest canopy trees in a cyclone-prone environment.

PubMed

Read, Jennifer; Evans, Robert; Sanson, Gordon D; Kerr, Stuart; Jaffré, Tanguy

2011-11-01

New Caledonia commonly experiences cyclones, so trees there are expected to have enhanced wood traits and trunk allometry that confer resistance to wind damage. We ask whether there is evidence of a trade-off between these traits and growth rate among species. Wood traits, including density, microfibril angle (MFA), and modulus of elasticity (MOE), ratio of tree height to stem diameter, and growth rate were investigated in mature trees of 15 co-occurring canopy species in a New Caledonian rainforest. In contrast to some studies, wood density did not correlate negatively with growth increment. Among angiosperms, wood density and MOE correlated positively with diameter-adjusted tree height, and MOE correlated positively with stem-diameter growth increment. Tall slender trees achieved high stiffness with high efficiency with respect to wood density, in part by low MFA, and with a higher diameter growth increment but a lower buckling safety factor. However, some tree species of a similar niche differed in whole-tree resistance to wind damage and achieved wood stiffness in different ways. There was no evidence of a growth-safety trade-off in these trees. In forests that regularly experience cyclones, there may be stronger selection for high wood density and/or stiffness in fast-growing trees of the upper canopy, with the potential growth trade-off amortized by access to the upper canopy and by other plant traits. Furthermore, decreasing wood density does not necessarily decrease resistance to wind damage, resistance being influenced by other characteristics including cell-level traits (e.g., MFA) and whole-plant architecture.

A Contactless Capacitance Detection System for Microchip Capillary Electrophoresis

NASA Astrophysics Data System (ADS)

Wu, Peter

2008-05-01

The design, construction and operation of a simple, inexpensive and compact high voltage power supply for use in conjunction with a simple cross, capillary electrophoresis microchip is presented. The detection system utilizes a single high voltage power supply (15 kV), a voltage divider network for obtaining the required voltages for enabling a gated injection valve, and two high voltage relays for switching between the open and closed gate sequences of the injection. The system is used to determine sodium monofluoroacetate (MFA) concentration in diluted fruit juices and tap water. A separation buffer consisting of 20 mM citric acid and histidine at pH 3.5 enabled the detection of the anion in diluted apple juice, cranberry juice, and orange juice without lengthy sample pretreatments. Limit of detection in diluted juices and tap water were determined to be 125, 167, 138, and 173 mg/L for tap water, apple juice, cranberry juice, and orange juice, respectively, based upon an S/N of 3:1. The total analysis time for detecting the MFA anion in fruit juices was less than 5 min, which represents a considerable reduction in analysis time compared to other analytical methods currently used in food analysis.

Dynamic modeling of lactic acid fermentation metabolism with Lactococcus lactis.

PubMed

Oh, Euhlim; Lu, Mingshou; Park, Changhun; Park, Changhun; Oh, Han Bin; Lee, Sang Yup; Lee, Jinwon

2011-02-01

A dynamic model of lactic acid fermentation using Lactococcus lactis was constructed, and a metabolic flux analysis (MFA) and metabolic control analysis (MCA) were performed to reveal an intensive metabolic understanding of lactic acid bacteria (LAB). The parameter estimation was conducted with COPASI software to construct a more accurate metabolic model. The experimental data used in the parameter estimation were obtained from an LC-MS/ MS analysis and time-course simulation study. The MFA results were a reasonable explanation of the experimental data. Through the parameter estimation, the metabolic system of lactic acid bacteria can be thoroughly understood through comparisons with the original parameters. The coefficients derived from the MCA indicated that the reaction rate of L-lactate dehydrogenase was activated by fructose 1,6-bisphosphate and pyruvate, and pyruvate appeared to be a stronger activator of L-lactate dehydrogenase than fructose 1,6-bisphosphate. Additionally, pyruvate acted as an inhibitor to pyruvate kinase and the phosphotransferase system. Glucose 6-phosphate and phosphoenolpyruvate showed activation effects on pyruvate kinase. Hexose transporter was the strongest effector on the flux through L-lactate dehydrogenase. The concentration control coefficient (CCC) showed similar results to the flux control coefficient (FCC).

(13)C-metabolic flux analysis in S-adenosyl-L-methionine production by Saccharomyces cerevisiae.

PubMed

Hayakawa, Kenshi; Kajihata, Shuichi; Matsuda, Fumio; Shimizu, Hiroshi

2015-11-01

S-Adenosyl-L-methionine (SAM) is a major biological methyl group donor, and is used as a nutritional supplement and prescription drug. Yeast is used for the industrial production of SAM owing to its high intracellular SAM concentrations. To determine the regulation mechanisms responsible for such high SAM production, (13)C-metabolic flux analysis ((13)C-MFA) was conducted to compare the flux distributions in the central metabolism between Kyokai no. 6 (high SAM-producing) and S288C (control) strains. (13)C-MFA showed that the levels of tricarboxylic acid (TCA) cycle flux in SAM-overproducing strain were considerably increased compared to those in the S228C strain. Analysis of ATP balance also showed that a larger amount of excess ATP was produced in the Kyokai 6 strain because of increased oxidative phosphorylation. These results suggest that high SAM production in Kyokai 6 strains could be attributed to enhanced ATP regeneration with high TCA cycle fluxes and respiration activity. Thus, maintaining high respiration efficiency during cultivation is important for improving SAM production. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Establishing Empirical Bases for Sustainability Objectives

Treesearch

Lawrence Martin

2006-01-01

The argument is made that sustainability should be construed as measurable environmental conditions, and that sustainable development strategies should be considered in terms of how well they contribute to the sustainable condition target. A case study of the Chesapeake Bay is presented to illustrate how use of Material Flow Analysis (MFA) as a basic component in the...

Investigation of antigen-antibody interactions of sulfonamides with a monoclonal antibody in a fluorescence polarization immunoassay using 3D-QSAR models

USDA-ARS?s Scientific Manuscript database

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs binding a monoclonal antibody (MAbSMR) produced against sulfamerazine was carried out by Distance Comparison (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular si...

Material flow analysis of fossil fuels in China during 2000-2010.

PubMed

Wang, Sheng; Dai, Jing; Su, Meirong

2012-01-01

Since the relationship between the supply and demand of fossil fuels is on edge in the long run, the contradiction between the economic growth and limited resources will hinder the sustainable development of the Chinese society. This paper aims to analyze the input of fossil fuels in China during 2000-2010 via the material flow analysis (MFA) that takes hidden flows into account. With coal, oil, and natural gas quantified by MFA, three indexes, consumption and supply ratio (C/S ratio), resource consumption intensity (RCI), and fossil fuels productivity (FFP), are proposed to reflect the interactions between population, GDP, and fossil fuels. The results indicated that in the past 11 years, China's requirement for fossil fuels has been increasing continuously because of the growing mine productivity in domestic areas, which also leads to a single energy consumption structure as well as excessive dependence on the domestic exploitation. It is advisable to control the fossil fuels consumption by energy recycling and new energy facilities' popularization in order to lead a sustainable access to nonrenewable resources and decrease the soaring carbon emissions.

Material Flow Analysis of Fossil Fuels in China during 2000–2010

PubMed Central

Wang, Sheng; Dai, Jing; Su, Meirong

2012-01-01

Since the relationship between the supply and demand of fossil fuels is on edge in the long run, the contradiction between the economic growth and limited resources will hinder the sustainable development of the Chinese society. This paper aims to analyze the input of fossil fuels in China during 2000–2010 via the material flow analysis (MFA) that takes hidden flows into account. With coal, oil, and natural gas quantified by MFA, three indexes, consumption and supply ratio (C/S ratio), resource consumption intensity (RCI), and fossil fuels productivity (FFP), are proposed to reflect the interactions between population, GDP, and fossil fuels. The results indicated that in the past 11 years, China's requirement for fossil fuels has been increasing continuously because of the growing mine productivity in domestic areas, which also leads to a single energy consumption structure as well as excessive dependence on the domestic exploitation. It is advisable to control the fossil fuels consumption by energy recycling and new energy facilities' popularization in order to lead a sustainable access to nonrenewable resources and decrease the soaring carbon emissions. PMID:23365525

Comparative molecular field analysis of artemisinin derivatives: Ab initio versus semiempirical optimized structures

NASA Astrophysics Data System (ADS)

Tonmunphean, Somsak; Kokpol, Sirirat; Parasuk, Vudhichai; Wolschann, Peter; Winger, Rudolf H.; Liedl, Klaus R.; Rode, Bernd M.

1998-07-01

Based on the belief that structural optimization methods, producing structures more closely to the experimental ones, should give better, i.e. more relevant, steric fields and hence more predictive CoMFA models, comparative molecular field analyses of artemisinin derivatives were performed based on semiempirical AM1 and HF/3-21G optimized geometries. Using these optimized geometries, the CoMFA results derived from the HF/3-21G method are found to be usually but not drastically better than those from AM1. Additional calculations were performed to investigate the electrostatic field difference using the Gasteiger and Marsili charges, the electrostatic potential fit charges at the AM1 level, and the natural population analysis charges at the HF/3-21G level of theory. For the HF/3-21G optimized structures no difference in predictability was observed, whereas for AM1 optimized structures such differences were found. Interestingly, if ionic compounds are omitted, differences between the various HF/3-21G optimized structure models using these electrostatic fields were found.

Variation in loblolly pine ring microfibril angle in the southeastern United States

Treesearch

Lewis Jordan; Rechun He; Daniel B. Hall; Alexander III Clark; Richard F. Daniels

2007-01-01

The effect of physiographic region on microfibril angle (MFA) in loblolly pine (Pinus taeda L.) in the southern United States was evaluated. MFA was determined at 1.4, 4.6, 7.6, 10.7, and 13.7 m up the stem of 59 trees, representing five physiographic regions. A nonlinear mixed-effects model was developed to test for regional differences in the...

Art and Delusion: Unreality in Art School

ERIC Educational Resources Information Center

Neher, Ross

2010-01-01

The author teaches painting in a Master of Fine Arts (MFA) program at Pratt Institute in Brooklyn, New York. Each fall semester he asks his students why they have come to Pratt and what they want to do when they graduate. The common answer is to develop as artists and find a commercial gallery to show and sell their work. Some want the MFA degree…

Effects of the P2 M-band flux asymmetry of laser-driven gold Hohlraums on the implosion of ICF ignition capsule

NASA Astrophysics Data System (ADS)

Li, Yongsheng; Gu, Jianfa; Wu, Changshu; Song, Peng; Dai, Zhensheng; Li, Shuanggui; Li, Xin; Kang, Dongguo; Gu, Peijun; Zheng, Wudi; Zou, Shiyang; Ding, Yongkun; Lan, Ke; Ye, Wenhua; Zhang, Weiyan

2016-07-01

Low-mode asymmetries in the laser-indirect-drive inertial confinement fusion implosion experiments conducted on the National Ignition Facility [G. H. Miller et al., Nucl. Fusion 44, S228 (2004)] are deemed the main obstacles hindering further improvement of the nuclear performance of deuterium-tritium-layered capsules. The dominant seeds of these asymmetries include the P2 and P4 asymmetries of x-ray drives and P2 asymmetry introduced by the supporting "tent." Here, we explore the effects of another possible seed that can lead to low-mode asymmetric implosions, i.e., the M-band flux asymmetry (MFA) in laser-driven cylindrical gold Hohlraums. It is shown that the M-band flux facilitates the ablation and acceleration of the shell, and that positive P2 MFAs can result in negative P2 asymmetries of hot spots and positive P2 asymmetries of shell's ρR. An oblate or toroidal hot spot, depending on the P2 amplitude of MFA, forms at stagnation. The energy loss of such a hot spot via electron thermal conduction is seriously aggravated not only due to the enlarged hot spot surface but also due to the vortices that develop and help transferring thermal energy from the hotter center to the colder margin of such a hot spot. The cliffs of nuclear performance for the two methodologies of applying MFA (i.e., symmetric flux in the presence of MFA and MFA added for symmetric soft x-ray flux) are obtained locating at 9.5% and 5.0% of P2/P0 amplitudes, respectively.

Porphyromonas gingivalis evasion of autophagy and intracellular killing by human myeloid dendritic cells involves DC-SIGN-TLR2 crosstalk.

PubMed

El-Awady, Ahmed R; Miles, Brodie; Scisci, Elizabeth; Kurago, Zoya B; Palani, Chithra D; Arce, Roger M; Waller, Jennifer L; Genco, Caroline A; Slocum, Connie; Manning, Matthew; Schoenlein, Patricia V; Cutler, Christopher W

2015-02-01

Signaling via pattern recognition receptors (PRRs) expressed on professional antigen presenting cells, such as dendritic cells (DCs), is crucial to the fate of engulfed microbes. Among the many PRRs expressed by DCs are Toll-like receptors (TLRs) and C-type lectins such as DC-SIGN. DC-SIGN is targeted by several major human pathogens for immune-evasion, although its role in intracellular routing of pathogens to autophagosomes is poorly understood. Here we examined the role of DC-SIGN and TLRs in evasion of autophagy and survival of Porphyromonas gingivalis in human monocyte-derived DCs (MoDCs). We employed a panel of P. gingivalis isogenic fimbriae deficient strains with defined defects in Mfa-1 fimbriae, a DC-SIGN ligand, and FimA fimbriae, a TLR2 agonist. Our results show that DC-SIGN dependent uptake of Mfa1+P. gingivalis strains by MoDCs resulted in lower intracellular killing and higher intracellular content of P. gingivalis. Moreover, Mfa1+P. gingivalis was mostly contained within single membrane vesicles, where it survived intracellularly. Survival was decreased by activation of TLR2 and/or autophagy. Mfa1+P. gingivalis strain did not induce significant levels of Rab5, LC3-II, and LAMP1. In contrast, P. gingivalis uptake through a DC-SIGN independent manner was associated with early endosomal routing through Rab5, increased LC3-II and LAMP-1, as well as the formation of double membrane intracellular phagophores, a characteristic feature of autophagy. These results suggest that selective engagement of DC-SIGN by Mfa-1+P. gingivalis promotes evasion of antibacterial autophagy and lysosome fusion, resulting in intracellular persistence in myeloid DCs; however TLR2 activation can overcome autophagy evasion and pathogen persistence in DCs.

Effects of the P2 M-band flux asymmetry of laser-driven gold Hohlraums on the implosion of ICF ignition capsule

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

Li, Yongsheng; Graduate School, China Academy of Engineering Physics, Beijing 100088; Gu, Jianfa

Low-mode asymmetries in the laser-indirect-drive inertial confinement fusion implosion experiments conducted on the National Ignition Facility [G. H. Miller et al., Nucl. Fusion 44, S228 (2004)] are deemed the main obstacles hindering further improvement of the nuclear performance of deuterium-tritium-layered capsules. The dominant seeds of these asymmetries include the P2 and P4 asymmetries of x-ray drives and P2 asymmetry introduced by the supporting “tent.” Here, we explore the effects of another possible seed that can lead to low-mode asymmetric implosions, i.e., the M-band flux asymmetry (MFA) in laser-driven cylindrical gold Hohlraums. It is shown that the M-band flux facilitates themore » ablation and acceleration of the shell, and that positive P2 MFAs can result in negative P2 asymmetries of hot spots and positive P2 asymmetries of shell's ρR. An oblate or toroidal hot spot, depending on the P2 amplitude of MFA, forms at stagnation. The energy loss of such a hot spot via electron thermal conduction is seriously aggravated not only due to the enlarged hot spot surface but also due to the vortices that develop and help transferring thermal energy from the hotter center to the colder margin of such a hot spot. The cliffs of nuclear performance for the two methodologies of applying MFA (i.e., symmetric flux in the presence of MFA and MFA added for symmetric soft x-ray flux) are obtained locating at 9.5% and 5.0% of P2/P0 amplitudes, respectively.« less

Effect of the Initial State of a Steel 38KhN3MFA Billet on the Microstructure and the Mechanical Properties of Seamless Pipes

NASA Astrophysics Data System (ADS)

Vorob'ev, R. A.; Dubinskii, V. N.; Sorokina, S. A.

2017-11-01

The effect of the initial structure of 38KhN3MFA steel on the mechanical properties of heattreated seamless pipes is studied. It is found that satisfactory macrostructure, strength, and plastic characteristics are insufficient to achieve the required set of service properties of the end product in the presence of a structural heterogeneity in tubular billets. A banded structure can cause a substantial scatter of the mechanical properties of the end product and a decrease in the impact toughness of the steel. It is shown that, in the presence of a banded structure, the required mechanical properties of the end product made of 38KhN3MFA steel can be achieved by correcting the final heat treatment conditions.

Bridging the gap between fluxomics and industrial biotechnology.

PubMed

Feng, Xueyang; Page, Lawrence; Rubens, Jacob; Chircus, Lauren; Colletti, Peter; Pakrasi, Himadri B; Tang, Yinjie J

2010-01-01

Metabolic flux analysis is a vital tool used to determine the ultimate output of cellular metabolism and thus detect biotechnologically relevant bottlenecks in productivity. ¹³C-based metabolic flux analysis (¹³C-MFA) and flux balance analysis (FBA) have many potential applications in biotechnology. However, noteworthy hurdles in fluxomics study are still present. First, several technical difficulties in both ¹³C-MFA and FBA severely limit the scope of fluxomics findings and the applicability of obtained metabolic information. Second, the complexity of metabolic regulation poses a great challenge for precise prediction and analysis of metabolic networks, as there are gaps between fluxomics results and other omics studies. Third, despite identified metabolic bottlenecks or sources of host stress from product synthesis, it remains difficult to overcome inherent metabolic robustness or to efficiently import and express nonnative pathways. Fourth, product yields often decrease as the number of enzymatic steps increases. Such decrease in yield may not be caused by rate-limiting enzymes, but rather is accumulated through each enzymatic reaction. Fifth, a high-throughput fluxomics tool hasnot been developed for characterizing nonmodel microorganisms and maximizing their application in industrial biotechnology. Refining fluxomics tools and understanding these obstacles will improve our ability to engineer highly efficient metabolic pathways in microbial hosts.

Urban water metabolism efficiency assessment: integrated analysis of available and virtual water.

PubMed

Huang, Chu-Long; Vause, Jonathan; Ma, Hwong-Wen; Yu, Chang-Ping

2013-05-01

Resolving the complex environmental problems of water pollution and shortage which occur during urbanization requires the systematic assessment of urban water metabolism efficiency (WME). While previous research has tended to focus on either available or virtual water metabolism, here we argue that the systematic problems arising during urbanization require an integrated assessment of available and virtual WME, using an indicator system based on material flow analysis (MFA) results. Future research should focus on the following areas: 1) analysis of available and virtual water flow patterns and processes through urban districts in different urbanization phases in years with varying amounts of rainfall, and their environmental effects; 2) based on the optimization of social, economic and environmental benefits, establishment of an indicator system for urban WME assessment using MFA results; 3) integrated assessment of available and virtual WME in districts with different urbanization levels, to facilitate study of the interactions between the natural and social water cycles; 4) analysis of mechanisms driving differences in WME between districts with different urbanization levels, and the selection of dominant social and economic driving indicators, especially those impacting water resource consumption. Combinations of these driving indicators could then be used to design efficient water resource metabolism solutions, and integrated management policies for reduced water consumption. Copyright © 2013 Elsevier B.V. All rights reserved.

Study on the activity of non-purine xanthine oxidase inhibitor by 3D-QSAR modeling and molecular docking

NASA Astrophysics Data System (ADS)

Li, Peizhen; Tian, Yueli; Zhai, Honglin; Deng, Fangfang; Xie, Meihong; Zhang, Xiaoyun

2013-11-01

Non-purine derivatives have been shown to be promising novel drug candidates as xanthine oxidase inhibitors. Based on three-dimensional quantitative structure-activity relationship (3D-QSAR) methods including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), two 3D-QSAR models for a series of non-purine xanthine oxidase (XO) inhibitors were established, and their reliability was supported by statistical parameters. Combined 3D-QSAR modeling and the results of molecular docking between non-purine xanthine oxidase inhibitors and XO, the main factors that influenced activity of inhibitors were investigated, and the obtained results could explain known experimental facts. Furthermore, several new potential inhibitors with higher activity predicted were designed, which based on our analyses, and were supported by the simulation of molecular docking. This study provided some useful information for the development of non-purine xanthine oxidase inhibitors with novel structures.

The potential of acoustics to determine family differences for wood quality in a loblolly pine (Pinus taeda L.) trial

Treesearch

E M Raley; Jennifer H Myszewski; T D Byram

2007-01-01

Acoustics have been used to determine wood quality attributes in both standing timber and sawn lumber. Sonic transmission data are collected non-destructively and can act as a surrogate for stiffness, they are directly related to modulus of elasticity (MOE) and closely related to differences in microfibril angle (MFA). Together with wood density, MFA and MOE are the...

Game of Life on the Equal Degree Random Lattice

NASA Astrophysics Data System (ADS)

Shao, Zhi-Gang; Chen, Tao

2010-12-01

An effective matrix method is performed to build the equal degree random (EDR) lattice, and then a cellular automaton game of life on the EDR lattice is studied by Monte Carlo (MC) simulation. The standard mean field approximation (MFA) is applied, and then the density of live cells is given ρ=0.37017 by MFA, which is consistent with the result ρ=0.37±0.003 by MC simulation.

Delphinid behavioral responses to incidental mid-frequency active sonar.

PubMed

Henderson, E Elizabeth; Smith, Michael H; Gassmann, Martin; Wiggins, Sean M; Douglas, Annie B; Hildebrand, John A

2014-10-01

Opportunistic observations of behavioral responses by delphinids to incidental mid-frequency active (MFA) sonar were recorded in the Southern California Bight from 2004 through 2008 using visual focal follows, static hydrophones, and autonomous recorders. Sound pressure levels were calculated between 2 and 8 kHz. Surface behavioral responses were observed in 26 groups from at least three species of 46 groups out of five species encountered during MFA sonar incidents. Responses included changes in behavioral state or direction of travel, changes in vocalization rates and call intensity, or a lack of vocalizations while MFA sonar occurred. However, 46% of focal groups not exposed to sonar also changed their behavior, and 43% of focal groups exposed to sonar did not change their behavior. Mean peak sound pressure levels when a behavioral response occurred were around 122 dB re: 1 μPa. Acoustic localizations of dolphin groups exhibiting a response gave insight into nighttime movement patterns and provided evidence that impacts of sonar may be mediated by behavioral state. The lack of response in some cases may indicate a tolerance of or habituation to MFA sonar by local populations; however, the responses that occur at lower received levels may point to some sensitization as well.

DFT and 3D-QSAR Studies of Anti-Cancer Agents m-(4-Morpholinoquinazolin-2-yl) Benzamide Derivatives for Novel Compounds Design

NASA Astrophysics Data System (ADS)

Zhao, Siqi; Zhang, Guanglong; Xia, Shuwei; Yu, Liangmin

2018-06-01

As a group of diversified frameworks, quinazolin derivatives displayed a broad field of biological functions, especially as anticancer. To investigate the quantitative structure-activity relationship, 3D-QSAR models were generated with 24 quinazolin scaffold molecules. The experimental and predicted pIC50 values for both training and test set compounds showed good correlation, which proved the robustness and reliability of the generated QSAR models. The most effective CoMFA and CoMSIA were obtained with correlation coefficient r 2 ncv of 1.00 (both) and leave-one-out coefficient q 2 of 0.61 and 0.59, respectively. The predictive abilities of CoMFA and CoMSIA were quite good with the predictive correlation coefficients ( r 2 pred ) of 0.97 and 0.91. In addition, the statistic results of CoMFA and CoMSIA were used to design new quinazolin molecules.

[Eco-efficiency change and its driving factors in Tongling City of Anhui Province].

PubMed

Wang, Yi-Chen; Wang, Yuan; Zhu, Xiao-Dong; Wu, Xiao-Qing; Wang, Ke; Ren, Ke-Xiu; Lu, Gen-Fa

2011-02-01

This paper first applied material flow analysis (MFA) to construct three levels of regional eco-efficiency indicators, i.e., regional direct eco-efficiency (RDE), regional total eco-efficiency (RTE), and holistic eco-efficiency (HE), and adopted the newly developed data envelopment analysis (DEA) to evaluate the eco-efficiency of Tongling City during the period of 1990-2008. We also applied Malmquist productivity index (MPI) to explore the eco-efficiency change between two following years and its driving factors. The main results were summarized as 1) though the RDE of Tongling City in 1990-2008 kept an increasing trend, its mean eco-efficiency was not high (close to 0.8 in 80% of the years), being lower than that of the RTE and HE, and 2) the RDE change was closely relevant to the improvement in resource management and the technical input in environmental protection in recent years. In order to further improve the RDE of the City, it would be necessary to raise its eco-efficiency via expanding raw material input, reducing domestic extraction, promoting resources productivity, and taking more measures on environmental protection facilities construction.

Modeling the effect of social networks on adoption of multifunctional agriculture.

PubMed

Manson, Steven M; Jordan, Nicholas R; Nelson, Kristen C; Brummel, Rachel F

2016-01-01

Rotational grazing (RG) has attracted much attention as a cornerstone of multifunctional agriculture (MFA) in animal systems, potentially capable of producing a range of goods and services of value to diverse stakeholders in agricultural landscapes and rural communities, as well as broader societal benefits. Despite these benefits, global adoption of MFA has been uneven, with some places seeing active participation, while others have seen limited growth. Recent conceptual models of MFA emphasize the potential for bottom-up processes and linkages among social and environmental systems to promote multifunctionality. Social networks are critical to these explanations but how and why these networks matter is unclear. We investigated fifty-three farms in three states in the United States (New York, Wisconsin, Pennsylvania) and developed a stylized model of social networks and systemic change in the dairy farming system. We found that social networks are important to RG adoption but their impact is contingent on social and spatial factors. Effects of networks on farmer decision making differ according to whether they comprise weak-tie relationships, which bridge across disparate people and organizations, or strong-tie relationships, which are shared by groups in which members are well known to one another. RG adoption is also dependent on features of the social landscape including the number of dairy households, the probability of neighboring farmers sharing strong ties, and the role of space in how networks are formed. The model replicates features of real-world adoption of RG practices in the Eastern US and illustrates pathways toward greater multifunctionality in the dairy landscape. Such models are likely to be of heuristic value in network-focused strategies for agricultural development.

Modeling the effect of social networks on adoption of multifunctional agriculture

PubMed Central

Manson, Steven M.; Jordan, Nicholas R.; Nelson, Kristen C.; Brummel, Rachel F.

2014-01-01

Rotational grazing (RG) has attracted much attention as a cornerstone of multifunctional agriculture (MFA) in animal systems, potentially capable of producing a range of goods and services of value to diverse stakeholders in agricultural landscapes and rural communities, as well as broader societal benefits. Despite these benefits, global adoption of MFA has been uneven, with some places seeing active participation, while others have seen limited growth. Recent conceptual models of MFA emphasize the potential for bottom-up processes and linkages among social and environmental systems to promote multifunctionality. Social networks are critical to these explanations but how and why these networks matter is unclear. We investigated fifty-three farms in three states in the United States (New York, Wisconsin, Pennsylvania) and developed a stylized model of social networks and systemic change in the dairy farming system. We found that social networks are important to RG adoption but their impact is contingent on social and spatial factors. Effects of networks on farmer decision making differ according to whether they comprise weak-tie relationships, which bridge across disparate people and organizations, or strong-tie relationships, which are shared by groups in which members are well known to one another. RG adoption is also dependent on features of the social landscape including the number of dairy households, the probability of neighboring farmers sharing strong ties, and the role of space in how networks are formed. The model replicates features of real-world adoption of RG practices in the Eastern US and illustrates pathways toward greater multifunctionality in the dairy landscape. Such models are likely to be of heuristic value in network-focused strategies for agricultural development. PMID:26744579

Template CoMFA Generates Single 3D-QSAR Models that, for Twelve of Twelve Biological Targets, Predict All ChEMBL-Tabulated Affinities

PubMed Central

Cramer, Richard D.

2015-01-01

The possible applicability of the new template CoMFA methodology to the prediction of unknown biological affinities was explored. For twelve selected targets, all ChEMBL binding affinities were used as training and/or prediction sets, making these 3D-QSAR models the most structurally diverse and among the largest ever. For six of the targets, X-ray crystallographic structures provided the aligned templates required as input (BACE, cdk1, chk2, carbonic anhydrase-II, factor Xa, PTP1B). For all targets including the other six (hERG, cyp3A4 binding, endocrine receptor, COX2, D2, and GABAa), six modeling protocols applied to only three familiar ligands provided six alternate sets of aligned templates. The statistical qualities of the six or seven models thus resulting for each individual target were remarkably similar. Also, perhaps unexpectedly, the standard deviations of the errors of cross-validation predictions accompanying model derivations were indistinguishable from the standard deviations of the errors of truly prospective predictions. These standard deviations of prediction ranged from 0.70 to 1.14 log units and averaged 0.89 (8x in concentration units) over the twelve targets, representing an average reduction of almost 50% in uncertainty, compared to the null hypothesis of “predicting” an unknown affinity to be the average of known affinities. These errors of prediction are similar to those from Tanimoto coefficients of fragment occurrence frequencies, the predominant approach to side effect prediction, which template CoMFA can augment by identifying additional active structural classes, by improving Tanimoto-only predictions, by yielding quantitative predictions of potency, and by providing interpretable guidance for avoiding or enhancing any specific target response. PMID:26065424

QSAR and molecular modelling studies on B-DNA recognition of minor groove binders.

PubMed

de Oliveira, André Mauricio; Custódio, Flávia Beatriz; Donnici, Cláudio Luis; Montanari, Carlos Alberto

2003-02-01

Aromatic bisamidines have been proved to be efficient compounds against Leishmania spp. and Pneumocystis carinii. Although the mode of action is still not known, these molecules are supposed to be DNA minor groove binders (MGBs). This paper describes a molecular modelling study for a set of MGBs in order to rank them through their complementarity to the Dickerson Drew Dodecamer (DDD) according to their interaction energies with B-DNA. A comparative molecular field analysis (CoMFA) has shown the importance of relatively bulky positively charged groups attached to the MGB aromatic rings, and small and negatively charged substituents into the middle chain. Models were obtained for DNA denaturation related to H-bonding processes of binding modes. Validation of the model demonstrated the robustness of CoMFA in terms of independent test set of similar MGBs. GRID results allotted bioisosteric substitution of z.sbnd;Oz.sbnd; by z.sbnd;NHz.sbnd; in furan ring of furamidine and related compounds as being capable to enhance the binding to DDD.

CoMFA, LeapFrog and blind docking studies on sulfonanilide derivatives acting as selective aromatase expression regulators.

PubMed

Gueto, Carlos; Torres, Juan; Vivas-Reyes, Ricardo

2009-09-01

Aromatase, the enzyme responsible for estrogen biosynthesis, is an attractive target in the treatment of hormone-dependent breast cancer. In this manuscript, the structure-based drug design approach of sulfonanilide analogues as potential selective aromatase expression regulators (SAERs) is described. Receptor-independent CoMFA (Comparative Molecular Field Analysis) maps were employed for generating a pseudocavity for LeapFrog calculation. A robust model, using 45 and 10 molecules in the training and test sets, respectively, was developed producing statistically significant results with cross-validated and conventional correlation coefficients of 0.656 and 0.956, respectively. This model was used to predict the activity of newly proposed molecules as SAERs candidates being two magnitude orders more potent than the previously reported compounds. Also in the present study, the computational blind docking method using eHiTS is tested on molecules study group and COX-2 enzyme. Future perspectives of the method in the screening of SAERs candidates with no COX-2 inhibitory activity are discussed.

MicroFilament Analyzer identifies actin network organizations in epidermal cells of Arabidopsis thaliana roots

PubMed Central

Jacques, Eveline; Lewandowski, Michal; Buytaert, Jan; Fierens, Yves; Verbelen, Jean-Pierre; Vissenberg, Kris

2013-01-01

The plant cytoskeleton plays a crucial role in the cells’ growth and development during different developmental stages and it undergoes many rearrangements. In order to describe the arrangements of the F-actin cytoskeleton in root epidermal cells of Arabidopsis thaliana, the recently developed software MicroFilament Analyzer (MFA) was exploited. This software enables high-throughput identification and quantification of the orientation of filamentous structures on digital images in a highly standardized and fast way. Using confocal microscopy and transgenic GFP-FABD2-GFP plants the actin cytoskeleton was visualized in the root epidermis. MFA analysis revealed that during the early stages of cell development F-actin is organized in a mainly random pattern. As the cells grow, they preferentially adopt a longitudinal organization, a pattern that is also preserved in the largest cells. In the evolution from young to old cells, an approximately even distribution of transverse, oblique or combined orientations is always present besides the switch from random to a longitudinal oriented actin cytoskeleton. PMID:23656865

Dream controller

DOEpatents

Cheng, George Shu-Xing; Mulkey, Steven L; Wang, Qiang; Chow, Andrew J

2013-11-26

A method and apparatus for intelligently controlling continuous process variables. A Dream Controller comprises an Intelligent Engine mechanism and a number of Model-Free Adaptive (MFA) controllers, each of which is suitable to control a process with specific behaviors. The Intelligent Engine can automatically select the appropriate MFA controller and its parameters so that the Dream Controller can be easily used by people with limited control experience and those who do not have the time to commission, tune, and maintain automatic controllers.

Material Flow Analysis as a Tool to improve Waste Management Systems: The Case of Austria.

PubMed

Allesch, Astrid; Brunner, Paul H

2017-01-03

This paper demonstrates the power of material flow analysis (MFA) for designing waste management (WM) systems and for supporting decisions with regards to given environmental and resource goals. Based on a comprehensive case study of a nationwide WM-system, advantages and drawbacks of a mass balance approach are discussed. Using the software STAN, a material flow system comprising all relevant inputs, stocks and outputs of wastes, products, residues, and emissions is established and quantified. Material balances on the level of goods and selected substances (C, Cd, Cr, Cu, Fe, Hg, N, Ni, P, Pb, Zn) are developed to characterize this WM-system. The MFA results serve well as a base for further assessments. Based on given goals, stakeholders engaged in this study selected the following seven criteria for evaluating their WM-system: (i) waste input into the system, (ii) export of waste (iii) gaseous emissions from waste treatment plants, (iv) long-term gaseous and liquid emissions from landfills, (v) waste being recycled, (vi) waste for energy recovery, (vii) total waste landfilled. By scenario analysis, strengths and weaknesses of different measures were identified. The results reveal the benefits of a mass balance approach due to redundancy, data consistency, and transparency for optimization, design, and decision making in WM.

Three-dimensional quantitative structure-activity relationship analysis for human pregnane X receptor for the prediction of CYP3A4 induction in human hepatocytes: structure-based comparative molecular field analysis.

PubMed

Handa, Koichi; Nakagome, Izumi; Yamaotsu, Noriyuki; Gouda, Hiroaki; Hirono, Shuichi

2015-01-01

The pregnane X receptor [PXR (NR1I2)] induces the expression of xenobiotic metabolic genes and transporter genes. In this study, we aimed to establish a computational method for quantifying the enzyme-inducing potencies of different compounds via their ability to activate PXR, for the application in drug discovery and development. To achieve this purpose, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) for predicting enzyme-inducing potencies, based on computer-ligand docking to multiple PXR protein structures sampled from the trajectory of a molecular dynamics simulation. Molecular mechanics-generalized born/surface area scores representing the ligand-protein-binding free energies were calculated for each ligand. As a result, the predicted enzyme-inducing potencies for compounds generated by the CoMFA model were in good agreement with the experimental values. Finally, we concluded that this 3D-QSAR model has the potential to predict the enzyme-inducing potencies of novel compounds with high precision and therefore has valuable applications in the early stages of the drug discovery process. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Metabolic flux analysis of heterotrophic growth in Chlamydomonas reinhardtii.

PubMed

Boyle, Nanette R; Sengupta, Neelanjan; Morgan, John A

2017-01-01

Despite the wealth of knowledge available for C. reinhardtii, the central metabolic fluxes of growth on acetate have not yet been determined. In this study, 13C-metabolic flux analysis (13C-MFA) was used to determine and quantify the metabolic pathways of primary metabolism in C. reinhardtii cells grown under heterotrophic conditions with acetate as the sole carbon source. Isotopic labeling patterns of compartment specific biomass derived metabolites were used to calculate the fluxes. It was found that acetate is ligated with coenzyme A in the three subcellular compartments (cytosol, mitochondria and plastid) included in the model. Two citrate synthases were found to potentially be involved in acetyl-coA metabolism; one localized in the mitochondria and the other acting outside the mitochondria. Labeling patterns demonstrate that Acetyl-coA synthesized in the plastid is directly incorporated in synthesis of fatty acids. Despite having a complete TCA cycle in the mitochondria, it was also found that a majority of the malate flux is shuttled to the cytosol and plastid where it is converted to oxaloacetate providing reducing equivalents to these compartments. When compared to predictions by flux balance analysis, fluxes measured with 13C-MFA were found to be suboptimal with respect to biomass yield; C. reinhardtii sacrifices biomass yield to produce ATP and reducing equivalents.

Outlook of the world steel cycle based on the stock and flow dynamics.

PubMed

Hatayama, Hiroki; Daigo, Ichiro; Matsuno, Yasunari; Adachi, Yoshihiro

2010-08-15

We present a comprehensive analysis of steel use in the future compiled using dynamic material flow analysis (MFA). A dynamic MFA for 42 countries depicted the global in-use stock and flow up to the end of 2005. On the basis of the transition of steel stock for 2005, the growth of future steel stock was then estimated considering the economic growth for every country. Future steel demand was estimated using dynamic analysis under the new concept of "stocks drive flows". The significant results follow. World steel stock reached 12.7 billion t in 2005, and has doubled in the last 25 years. The world stock in 2005 mainly consisted of construction (60%) and vehicles (10%). Stock in these end uses will reach 55 billion t in 2050, driven by a 10-fold increase in Asia. Steel demand will reach 1.8 billion t in 2025, then slightly decrease, and rise again by replacement of buildings. The forecast of demand clearly represents the industrial shift; at first the increase is dominated by construction, and then, after 2025, demand for construction decreases and demand for vehicles increases instead. This study thus provides the dynamic mechanism of steel stock and flow toward the future, which contributes to the design of sustainable steel use.

The influence of the rural health security schemes on health utilization and household impoverishment in rural China: data from a household survey of western and central China

PubMed Central

2010-01-01

Background The New Rural Cooperative Medical Scheme (NRCMS, voluntary health insurance) and the Medical Financial Assistance (MFA, financial relief program) were established in 2003 for rural China. The aim of this study was to document their coverage, assess their effectiveness on access to in-patient care and protection against financial catastrophe and household impoverishment due to health spending, and identify the factors predicting impoverishment with and without these schemes. Methods A cross-sectional household survey was conducted in 2008 in Hebei and Shaanxi provinces and the Inner Mongolia Autonomous Region using a multi-stage sampling technique. Information on personal demographic characteristics, chronic illness status, health care use, household expenditure, and household health spending were collected by interview. Results NRCMS covered 90.8% of the studied individuals and among the designated poor, 7.6% had their premiums paid by MFA. Of those referred for hospitalization in the year prior to the interview, 34.3% failed to comply, mostly (80.2%) owing to financial constraints. There was no significant difference in the unmet need for admission between the insured with NRCMS and the uninsured. Before reimbursement, the incidence of catastrophic health payment (household health spending more than 40% of household's capacity to pay) and medical impoverishment (household per capita income falling below the poverty line due to medical expense) was 14.3% and 8.2%, respectively. NRCMS prevented 9.9% of the households from financial catastrophe and 7.7% from impoverishment, whereas MFA kept just one household from impoverishment and had no effect on financial catastrophe. Household per capita expenditure and household chronic disease proportion (proportion of members of a household with chronic illness) were the most important determinants of the unmet need for admission, risk of being impoverished and the chance of not being saved from impoverishment. Conclusion The coverage of NRCMS among the rural population was high but not adequate to improve access to in-patient care and protect against financial catastrophe and household impoverishment due to health payment, especially for the poor and the chronically ill. Furthermore, MFA played almost no such role; therefore, the current schemes need to be improved. PMID:20178565

Mapping the global journey of anthropogenic aluminum: a trade-linked multilevel material flow analysis.

PubMed

Liu, Gang; Müller, Daniel B

2013-10-15

Material cycles have become increasingly coupled and interconnected in a globalizing era. While material flow analysis (MFA) has been widely used to characterize stocks and flows along technological life cycle within a specific geographical area, trade networks among individual cycles have remained largely unexplored. Here we developed a trade-linked multilevel MFA model to map the contemporary global journey of anthropogenic aluminum. We demonstrate that the anthropogenic aluminum cycle depends substantially on international trade of aluminum in all forms and becomes highly interconnected in nature. While the Southern hemisphere is the main primary resource supplier, aluminum production and consumption concentrate in the Northern hemisphere, where we also find the largest potential for recycling. The more developed countries tend to have a substantial and increasing presence throughout the stages after bauxite refining and possess highly consumption-based cycles, thus maintaining advantages both economically and environmentally. A small group of countries plays a key role in the global redistribution of aluminum and in the connectivity of the network, which may render some countries vulnerable to supply disruption. The model provides potential insights to inform government and industry policies in resource criticality, supply chain security, value chain management, and cross-boundary environmental impacts mitigation.

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

PubMed

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

2018-04-01

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

Effect of Masking on Subjective Responses to Daily Disposable Contact Lenses.

PubMed

Keir, Nancy; Luensmann, Doerte; Woods, Craig A; Bergenske, Peter; Fahmy, Mary; Fonn, Desmond

2016-08-01

To explore the effect of masking on subjective responses when wearing daily disposable (DD) contact lenses. In an adaptation phase, habitual wearers of Manufacturer-A (MFA) (n = 43) and Manufacturer-B (MFB) (n = 53) wore MFA-brand 1 or MFB-brand 1 DDs, respectively, for 30 days, open-label. Subjects were then randomly assigned to one of two experiments. Each experiment included two, 3-day crossover phases. An enhanced version of MFA and MFB lenses (MFA-brand 2 and MFB-brand 2) were worn contralaterally to evaluate potential differences in masking result between manufacturers. Experiment 1: subjects were fully masked to lens and packaging (FM) then unmasked (UM). Experiment 2: subjects were FM then partially masked using an over-label (PM). Comfort ratings (0-100) were recorded for each lens daily and preference between lenses was recorded on day 3 for each crossover phase. The mean difference between 0-100 ratings or preference when FM or PM versus UM for the same lens was considered a measurement of the effect associated with masking. The purpose of the study was withheld from subjects to minimize bias. The effect associated with masking for habitual wearers of MFA and MFB lenses was less than 1 out of 100 (0 ± 2.5) in both experiments. Fifty-eight subjects (60%) expressed no preference when FM. This decreased to 29 (30%) when UM or PM (proportion test, p < 0.001). Approximately half the subjects had a change in lens preference when they were UM or PM, primarily in favor of their habitual lens manufacturer. Masking did not have a measurable impact on 0-100 ratings with the DD lenses used in this study but did have an impact on lens preference. Subjects were more likely to express a preference when they handled the lenses and were exposed to the lens packaging and, in some cases, able to read the lens brand and lens manufacturer.

Quantitative structure-activity relationship studies of threo-methylphenidate analogs.

PubMed

Misra, Milind; Shi, Qing; Ye, Xiaocong; Gruszecka-Kowalik, Ewa; Bu, Wei; Liu, Zhanzhu; Schweri, Margaret M; Deutsch, Howard M; Venanzi, Carol A

2010-10-15

Complementary two-dimensional (2D) and three-dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity of 80 racemic threo-methylphenidate (MP) analogs. A novel approach based on using the atom-level E-state indices of the 14 common scaffold atoms in a sphere exclusion protocol was used to identify a test set for 2D- and 3D-QSAR model validation. Comparative Molecular Field Analysis (CoMFA) contour maps based on the structure-activity data of the training set indicate that the 2' position of the phenyl ring cannot tolerate much steric bulk and that addition of electron-withdrawing groups to the 3' or 4' positions of the phenyl ring leads to improved DAT binding affinity. In particular, the optimal substituents were found to be those whose bulk is mainly in the plane of the phenyl ring. Substituents with significant bulk above or below the plane of the ring led to decreased binding affinity. Suggested alterations to be explored in the design of new compounds are the placement at the 3' and 4' position of the phenyl ring of electron-withdrawing groups that lie chiefly in the plane of the ring, for example, halogen substituents on the 3',4'-benzo analog, 79. A complementary 2D-QSAR approach-partial least squares analysis using a reduced set of Molconn-Z descriptors-supports the CoMFA structure-activity interpretation that phenyl ring substitution is a major determinant of DAT binding affinity. The potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl)acetate, an analog not in the original data set, to be in good agreement with the experimental value. Copyright © 2010 Elsevier Ltd. All rights reserved.

First direct measurements of behavioural responses by Cuvier's beaked whales to mid-frequency active sonar.

PubMed

DeRuiter, Stacy L; Southall, Brandon L; Calambokidis, John; Zimmer, Walter M X; Sadykova, Dinara; Falcone, Erin A; Friedlaender, Ari S; Joseph, John E; Moretti, David; Schorr, Gregory S; Thomas, Len; Tyack, Peter L

2013-08-23

Most marine mammal- strandings coincident with naval sonar exercises have involved Cuvier's beaked whales (Ziphius cavirostris). We recorded animal movement and acoustic data on two tagged Ziphius and obtained the first direct measurements of behavioural responses of this species to mid-frequency active (MFA) sonar signals. Each recording included a 30-min playback (one 1.6-s simulated MFA sonar signal repeated every 25 s); one whale was also incidentally exposed to MFA sonar from distant naval exercises. Whales responded strongly to playbacks at low received levels (RLs; 89-127 dB re 1 µPa): after ceasing normal fluking and echolocation, they swam rapidly, silently away, extending both dive duration and subsequent non-foraging interval. Distant sonar exercises (78-106 dB re 1 µPa) did not elicit such responses, suggesting that context may moderate reactions. The observed responses to playback occurred at RLs well below current regulatory thresholds; equivalent responses to operational sonars could elevate stranding risk and reduce foraging efficiency.

Defining syndromes using cattle meat inspection data for syndromic surveillance purposes: a statistical approach with the 2005-2010 data from ten French slaughterhouses.

PubMed

Dupuy, Céline; Morignat, Eric; Maugey, Xavier; Vinard, Jean-Luc; Hendrikx, Pascal; Ducrot, Christian; Calavas, Didier; Gay, Emilie

2013-04-30

The slaughterhouse is a central processing point for food animals and thus a source of both demographic data (age, breed, sex) and health-related data (reason for condemnation and condemned portions) that are not available through other sources. Using these data for syndromic surveillance is therefore tempting. However many possible reasons for condemnation and condemned portions exist, making the definition of relevant syndromes challenging.The objective of this study was to determine a typology of cattle with at least one portion of the carcass condemned in order to define syndromes. Multiple factor analysis (MFA) in combination with clustering methods was performed using both health-related data and demographic data. Analyses were performed on 381,186 cattle with at least one portion of the carcass condemned among the 1,937,917 cattle slaughtered in ten French abattoirs. Results of the MFA and clustering methods led to 12 clusters considered as stable according to year of slaughter and slaughterhouse. One cluster was specific to a disease of public health importance (cysticercosis). Two clusters were linked to the slaughtering process (fecal contamination of heart or lungs and deterioration lesions). Two clusters respectively characterized by chronic liver lesions and chronic peritonitis could be linked to diseases of economic importance to farmers. Three clusters could be linked respectively to reticulo-pericarditis, fatty liver syndrome and farmer's lung syndrome, which are related to both diseases of economic importance to farmers and herd management issues. Three clusters respectively characterized by arthritis, myopathy and Dark Firm Dry (DFD) meat could notably be linked to animal welfare issues. Finally, one cluster, characterized by bronchopneumonia, could be linked to both animal health and herd management issues. The statistical approach of combining multiple factor analysis with cluster analysis showed its relevance for the detection of syndromes using available large and complex slaughterhouse data. The advantages of this statistical approach are to i) define groups of reasons for condemnation based on meat inspection data, ii) help grouping reasons for condemnation among a list of various possible reasons for condemnation for which a consensus among experts could be difficult to reach, iii) assign each animal to a single syndrome which allows the detection of changes in trends of syndromes to detect unusual patterns in known diseases and emergence of new diseases.

Effects of post-deposition magnetic field annealing on magnetic properties of NiO/Co90Fe10 bilayers

NASA Astrophysics Data System (ADS)

Zheng, Chao; Su, Shan; Chiu, Chun-Cheng; Skoropata, Elizabeth; Desautels, Ryan D.; van Lierop, Johan; Lin, Ko-Wei; Pong, Philip W. T.

2018-01-01

The ferromagnetic (FM)/antiferromagnetic (AF) bilayer structures have drawn intensive attention because of their wide applications in modern spintronic devices. While abundant published works have been reported on the interface effects of the FM/AF bilayers caused by the magnetic field annealing (MFA) process, the volume effects caused by the MFA treatment have been rarely considered. In this work, the microstructural and magnetic properties of the NiO/CoFe bilayers with various CoFe thicknesses were investigated under different annealing temperatures. At high annealing temperature, the interlayer mixing and exchange coupling between NiO and CoFe layers were promoted and consequently the interface effects were facilitated. The interfacial oxides acted as pinning centers and randomly pinned the FM domains, leading to an increase of coercivity and a considerable degradation of uniaxial anisotropy. The increase of coercivity was also contributed by the enhancement of the interfacial exchange coupling between the NiO and CoFe layers after MFA. As the CoFe thickness increased, the volume effects tended to dominate over the interface effects, resulting in the preservation the uniaxially anisotropic features of CoFe. These results indicate that both the coercivity and anisotropic features of the NiO/CoFe bilayers can be directly affected by the MFA process, opening up the possibility of modifying the magnetism in the NiO/CoFe bilayers and offering an effective way to improve the performance of modern spintronic devices.

Design new P-glycoprotein modulators based on molecular docking and CoMFA study of α, β-unsaturated carbonyl-based compounds and oxime analogs as anticancer agents

NASA Astrophysics Data System (ADS)

Sepehri, Bakhtyar; Ghavami, Raouf

2017-02-01

In this research, molecular docking and CoMFA were used to determine interactions of α, β-unsaturated carbonyl-based compounds and oxime analogs with P-glycoprotein and prediction of their activity. Molecular docking study shown these molecules establish strong Van der Waals interactions with side chain of PHE-332, PHE-728 and PHE-974. Based on the effect of component numbers on squared correlation coefficient for cross validation tests (including leave-one-out and leave-many-out), CoMFA models with five components were built to predict pIC50 of molecules in seven cancer cell lines (including Panc-1 (pancreas cancer cell line), PaCa-2 (pancreatic carcinoma cell line), MCF-7 (breast cancer cell line), A-549 (epithelial), HT-29 (colon cancer cell line), H-460 (lung cancer cell line), PC-3 (prostate cancer cell line)). R2 values for training and test sets were in the range of 0.94-0.97 and 0.84 to 0.92, respectively, and for LOO and LMO cross validation test, q2 values were in the range of 0.75-0.82 and 0.65 to 0.73, respectively. Based on molecular docking results and extracted steric and electrostatic contour maps for CoMFA models, four new molecules with higher activity with respect to the most active compound in data set were designed.

Assessing environmental risks for high intensity agriculture using the material flow analysis method--a case study of the Dongting Lake basin in South Central China.

PubMed

Yin, Guanyi; Liu, Liming; Yuan, Chengcheng

2015-07-01

This study primarily examined the assessment of environmental risk in high intensity agricultural areas. Dongting Lake basin was taken as a case study, which is one of the major grain producing areas in China. Using data obtained from 1989 to 2012, we applied Material Flow Analysis (MFA) to show the material consumption, pollutant output and production storage in the agricultural-environmental system and assessed the environmental risk index on the basis of the MFA results. The results predicted that the status of the environmental quality of the Dongting Lake area is unsatisfactory for the foreseeable future. The direct material input (DMI) declined by 13.9%, the domestic processed output (DPO) increased by 28.21%, the intensity of material consumption (IMC) decreased by 36.7%, the intensity of material discharge (IMD) increased by 10%, the material productivity (MP) increased by 27 times, the environmental efficiency (EE) increased by 15.31 times, and the material storage (PAS) increased by 0.23%. The DMI and DPO was higher at rural places on the edge of cities, whereas the risk of urban agriculture has arisen due to the higher increasing rate of DMI and DPO in cities compared with the counties. The composite environmental risk index increased from 0.33 to 0.96, indicating that the total environmental risk changed gradually but seriously during the 24 years assessed. The driving factors that affect environmental risk in high intensity agriculture can be divided into five classes: social, economic, human, natural and disruptive incidents. This study discussed a number of effective measures for protecting the environment while ensuring food production yields. Additional research in other areas and certain improvements of this method in future studies may be necessary to develop a more effective method of managing and controlling agricultural-environmental interactions.

Analogue based design of MMP-13 (Collagenase-3) inhibitors.

PubMed

Sarma, J A R P; Rambabu, G; Srikanth, K; Raveendra, D; Vithal, M

2002-10-07

3D-QSAR studies using MFA and RSA methods were performed on a series of 39MMP-13 inhibitors. Model developed by MFA method has a r(2)(cv) (cross-validated) of 0.616 while its r(2) (conventional) value is 0.822. For the RSA model r(2)(cv) and r(2) are 0.681 and 0.847, respectively. Both the models indicate good internal as well as external predictive abilities. These models provide crucial information about the field descriptors for the design of potential inhibitors of MMP-13.

An integrated molecular modeling approach for in silico design of new tetracyclic derivatives as ALK inhibitors.

PubMed

Peddi, Saikiran Reddy; Sivan, Sree Kanth; Manga, Vijjulatha

2016-10-01

Anaplastic lymphoma kinase (ALK), a promising therapeutic target for treatment of human cancers, is a receptor tyrosine kinase that instigates the activation of several signal transduction pathways. In the present study, in silico methods have been employed in order to explore the structural features and functionalities of a series of tetracyclic derivatives displaying potent inhibitory activity toward ALK. Initially docking was performed using GLIDE 5.6 to probe the bioactive conformation of all the compounds and to understand the binding modes of inhibitors. The docking results revealed that ligand interaction with Met 1199 plays a crucial role in binding of inhibitors to ALK. Further to establish a robust 3D-QSAR model using CoMFA and CoMSIA methods, the whole dataset was divided into three splits. Model obtained from Split 3 showed high accuracy ([Formula: see text] of 0.700 and 0.682, [Formula: see text] of 0.971 and 0.974, [Formula: see text] of 0.673 and 0.811, respectively for CoMFA and CoMSIA). The key structural requirements for enhancing the inhibitory activity were derived from CoMFA and CoMSIA contours in combination with site map analysis. Substituting small electronegative groups at Position 8 by replacing either morpholine or piperidine rings and maintaining hydrophobic character at Position 9 in tetracyclic derivatives can enhance the inhibitory potential. Finally, we performed molecular dynamics simulations in order to investigate the stability of protein ligand interactions and MM/GBSA calculations to compare binding free energies of co-crystal ligand and newly designed molecule N1. Based on the coherence of outcome of various molecular modeling studies, a set of 11 new molecules having potential predicted inhibitory activity were designed.

High-throughput sequencing reveals key genes and immune homeostatic pathways activated in myeloid dendritic cells by Porphyromonas gingivalis 381 and its fimbrial mutants.

PubMed

Arjunan, P; El-Awady, A; Dannebaum, R O; Kunde-Ramamoorthy, G; Cutler, C W

2016-02-01

The human microbiome consists of highly diverse microbial communities that colonize our skin and mucosal surfaces, aiding in maintenance of immune homeostasis. The keystone pathogen Porphyromonas gingivalis induces a dysbiosis and disrupts immune homeostasis through as yet unclear mechanisms. The fimbrial adhesins of P. gingivalis facilitate biofilm formation, invasion of and dissemination by blood dendritic cells; hence, fimbriae may be key factors in disruption of immune homeostasis. In this study we employed RNA-sequencing transcriptome profiling to identify differentially expressed genes (DEGs) in human monocyte-derived dendritic cells (MoDCs) in response to in vitro infection/exposure by Pg381 or its isogenic mutant strains that solely express minor-Mfa1 fimbriae (DPG3), major-FimA fimbriae (MFI) or are deficient in both fimbriae (MFB) relative to uninfected control. Our results yielded a total of 479 DEGs that were at least two-fold upregulated and downregulated in MoDCs significantly (P ≤ 0.05) by all four strains and certain DEGs that were strain-specific. Interestingly, the gene ontology biological and functional analysis shows that the upregulated genes in DPG3-induced MoDCs were more significant than other strains and associated with inflammation, immune response, anti-apoptosis, cell proliferation, and other homeostatic functions. Both transcriptome and quantitative polymerase chain reaction results show that DPG3, which solely expresses Mfa1, increased ZNF366, CD209, LOX1, IDO1, IL-10, CCL2, SOCS3, STAT3 and FOXO1 gene expression. In conclusion, we have identified key DC-mediated immune homeostatic pathways that could contribute to dysbiosis in periodontal infection with P. gingivalis. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A pharmacophore model specific to active site of CYP1A2 with a novel molecular modeling explorer and CoMFA.

PubMed

Zhang, Tao; Wei, Dong-Qing; Chou, Kuo-Chen

2012-03-01

Comparative molecular field analysis (CoMFA) is a widely used 3D-QSAR method by which we can investigate the potential relation between biological activity of compounds and their structural features. In this study, a new application of this approach is presented by combining the molecular modeling with a new developed pharmacophore model specific to CYP1A2 active site. During constructing the model, we used the molecular dynamics simulation and molecular docking method to select the sensible binding conformations for 17 CYP1A2 substrates based on the experimental data. Subsequently, the results obtained via the alignment of binding conformations of substrates were projected onto the active- site residues, upon which a simple blueprint of active site was produced. It was validated by the experimental and computational results that the model did exhibit the high degree of rationality and provide useful insights into the substrate binding. It is anticipated that our approach can be extended to investigate the protein-ligand interactions for many other enzyme-catalyzed systems as well.

Electronic waste management approaches: An overview

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

Kiddee, Peeranart; Cooperative Research Centre for Contamination Assessment and Remediation of the Environment, Mawson Lakes Campus, Adelaide, SA 5095; Naidu, Ravi, E-mail: ravi.naidu@crccare.com

2013-05-15

Highlights: ► Human toxicity of hazardous substances in e-waste. ► Environmental impacts of e-waste from disposal processes. ► Life Cycle Assessment (LCA), Material Flow Analysis (MFA), Multi Criteria Analysis (MCA) and Extended Producer Responsibility (EPR) to and solve e-waste problems. ► Key issues relating to tools managing e-waste for sustainable e-waste management. - Abstract: Electronic waste (e-waste) is one of the fastest-growing pollution problems worldwide given the presence if a variety of toxic substances which can contaminate the environment and threaten human health, if disposal protocols are not meticulously managed. This paper presents an overview of toxic substances present inmore » e-waste, their potential environmental and human health impacts together with management strategies currently being used in certain countries. Several tools including Life Cycle Assessment (LCA), Material Flow Analysis (MFA), Multi Criteria Analysis (MCA) and Extended Producer Responsibility (EPR) have been developed to manage e-wastes especially in developed countries. The key to success in terms of e-waste management is to develop eco-design devices, properly collect e-waste, recover and recycle material by safe methods, dispose of e-waste by suitable techniques, forbid the transfer of used electronic devices to developing countries, and raise awareness of the impact of e-waste. No single tool is adequate but together they can complement each other to solve this issue. A national scheme such as EPR is a good policy in solving the growing e-waste problems.« less

Prognostic value of computed tomography classification systems for intra-articular calcaneus fractures.

PubMed

Swords, Michael P; Alton, Timothy B; Holt, Sarah; Sangeorzan, Bruce J; Shank, John R; Benirschke, Stephen K

2014-10-01

There are several published computed tomography (CT) classification systems for calcaneus fractures, each validated by a different standard. The goal of this study was to measure which system would best predict clinical outcomes as measured by a widely used and validated musculoskeletal health status questionnaire. Forty-nine patients with isolated intra-articular joint depression calcaneus fractures more than 2 years after treatment were identified. All had preoperative CT studies and were treated with open reduction and plate fixation using a lateral extensile approach. Four different blinded reviewers classified injuries according to the CT classification systems of Crosby and Fitzgibbons, Eastwood, and Sanders. Functional outcomes evaluated with a Musculoskeletal Functional Assessment (MFA). The mean follow-up was 4.3 years. The mean MFA score was 15.7 (SD = 11.6), which is not significantly different from published values for midfoot injuries, hindfoot injuries, or both, 1 year after injury (mean = 22.1, SD = 18.4). The classification systems of Crosby and Fitzgibbons, Eastwood, and Sanders, the number of fragments of the posterior facet, and payer status were not significantly associated with outcome as determined by the MFA. The Sanders classification trended toward significance. Anterior process comminution and surgeon's overall impression of severity were significantly associated with functional outcome. The amount of anterior process comminution was an important determinant of functional outcome with increasing anterior process comminution significantly associated with worsened functional outcome (P = .04). In addition, the surgeon's overall impression of severity of injury was predictive of functional outcome (P = .02), as determined by MFA. Level III, comparative series. © The Author(s) 2014.

Computer-aided design of negative allosteric modulators of metabotropic glutamate receptor 5 (mGluR5): Comparative molecular field analysis of aryl ether derivatives.

PubMed

Selvam, Chelliah; Thilagavathi, Ramasamy; Narasimhan, Balasubramanian; Kumar, Pradeep; Jordan, Brian C; Ranganna, Kasturi

2016-02-15

The metabotropic glutamate receptors (mGlu receptors) have emerged as attractive targets for number of neurological and psychiatric disorders. Recently, mGluR5 negative allosteric modulators (NAMs) have gained considerable attention in pharmacological research. Comparative molecular field analysis (CoMFA) was performed on 73 analogs of aryl ether which were reported as mGluR5 NAMs. The study produced a statistically significant model with high correlation coefficient and good predictive abilities. Published by Elsevier Ltd.

3D-QSAR based on quantum-chemical molecular fields: toward an improved description of halogen interactions.

PubMed

Güssregen, Stefan; Matter, Hans; Hessler, Gerhard; Müller, Marco; Schmidt, Friedemann; Clark, Timothy

2012-09-24

Current 3D-QSAR methods such as CoMFA or CoMSIA make use of classical force-field approaches for calculating molecular fields. Thus, they can not adequately account for noncovalent interactions involving halogen atoms like halogen bonds or halogen-π interactions. These deficiencies in the underlying force fields result from the lack of treatment of the anisotropy of the electron density distribution of those atoms, known as the "σ-hole", although recent developments have begun to take specific interactions such as halogen bonding into account. We have now replaced classical force field derived molecular fields by local properties such as the local ionization energy, local electron affinity, or local polarizability, calculated using quantum-mechanical (QM) techniques that do not suffer from the above limitation for 3D-QSAR. We first investigate the characteristics of QM-based local property fields to show that they are suitable for statistical analyses after suitable pretreatment. We then analyze these property fields with partial least-squares (PLS) regression to predict biological affinities of two data sets comprising factor Xa and GABA-A/benzodiazepine receptor ligands. While the resulting models perform equally well or even slightly better in terms of consistency and predictivity than the classical CoMFA fields, the most important aspect of these augmented field-types is that the chemical interpretation of resulting QM-based property field models reveals unique SAR trends driven by electrostatic and polarizability effects, which cannot be extracted directly from CoMFA electrostatic maps. Within the factor Xa set, the interaction of chlorine and bromine atoms with a tyrosine side chain in the protease S1 pocket are correctly predicted. Within the GABA-A/benzodiazepine ligand data set, PLS models of high predictivity resulted for our QM-based property fields, providing novel insights into key features of the SAR for two receptor subtypes and cross-receptor selectivity of the ligands. The detailed interpretation of regression models derived using improved QM-derived property fields thus provides a significant advantage by revealing chemically meaningful correlations with biological activity and helps in understanding novel structure-activity relationship features. This will allow such knowledge to be used to design novel molecules on the basis of interactions additional to steric and hydrogen-bonding features.

The development of bactericidal yeast strains by expressing the Pediococcus acidilactici pediocin gene (pedA) in Saccharomyces cerevisiae.

PubMed

Schoeman, H; Vivier, M A; Du Toit, M; Dicks, L M; Pretorius, I S

1999-06-15

The excessive use of sulphur dioxide and other chemical preservatives in wine, beer and other fermented food and beverage products to prevent the growth of unwanted microbes holds various disadvantages for the quality of the end-products and is confronted by mounting consumer resistance. The objective of this study was to investigate the feasibility of controlling spoilage bacteria during yeast-based fermentations by engineering bactericidal strains of Saccharomyces cerevisiae. To test this novel concept, we have successfully expressed a bacteriocin gene in yeast. The pediocin operon of Pediococcus acidilactici PAC1.0 consists of four clustered genes, namely pedA (encoding a 62 amino acid precursor of the PA-1 pediocin), pedB (encoding an immunity factor), pedC (encoding a PA-1 transport protein) and pedD (encoding a protein involved in the transport and processing of PA-1). The pedA gene was inserted into a yeast expression/secretion cassette and introduced as a multicopy episomal plasmid into a laboratory strain (Y294) of S. cerevisiae. Northern blot analysis confirmed that the pedA structural gene in this construct (ADH1P-MFa1S-pedA-ADH1T, designated PED1), was efficiently expressed under the control of the yeast alcohol dehydrogenase I gene promoter (ADH1P) and terminator (ADH1T). Secretion of the PED1-encoded pediocin PA-1 was directed by the yeast mating pheromone alpha-factor's secretion signal (MFa1S). The presence of biologically active antimicrobial peptides produced by the yeast transformants was indicated by agar diffusion assays against sensitive indicator bacteria (e.g. Listeria monocytogenes B73). Protein analysis indicated the secreted heterologous peptide to be approximately 4.6 kDa, which conforms to the expected size. The heterologous peptide was present at relatively low levels in the yeast supernatant but pediocin activity was readily detected when intact yeast colonies were used in sensitive strain overlays. This study could lead to the development of bactericidal yeast strains where S. cerevisiae starter cultures not only conduct the fermentations in the wine, brewing and baking industries but also act as biological control agents to inhibit the growth of spoilage bacteria.

QSAR analyses on avian influenza virus neuraminidase inhibitors using CoMFA, CoMSIA, and HQSAR

NASA Astrophysics Data System (ADS)

Zheng, Mingyue; Yu, Kunqian; Liu, Hong; Luo, Xiaomin; Chen, Kaixian; Zhu, Weiliang; Jiang, Hualiang

2006-09-01

The recent wide spreading of the H5N1 avian influenza virus (AIV) in Asia, Europe and Africa and its ability to cause fatal infections in human has raised serious concerns about a pending global flu pandemic. Neuraminidase (NA) inhibitors are currently the only option for treatment or prophylaxis in humans infected with this strain. However, drugs currently on the market often meet with rapidly emerging resistant mutants and only have limited application as inadequate supply of synthetic material. To dig out helpful information for designing potent inhibitors with novel structures against the NA, we used automated docking, CoMFA, CoMSIA, and HQSAR methods to investigate the quantitative structure-activity relationship for 126 NA inhibitors (NIs) with great structural diversities and wide range of bioactivities against influenza A virus. Based on the binding conformations discovered via molecular docking into the crystal structure of NA, CoMFA and CoMSIA models were successfully built with the cross-validated q 2 of 0.813 and 0.771, respectively. HQSAR was also carried out as a complementary study in that HQSAR technique does not require 3D information of these compounds and could provide a detailed molecular fragment contribution to the inhibitory activity. These models also show clearly how steric, electrostatic, hydrophobicity, and individual fragments affect the potency of NA inhibitors. In addition, CoMFA and CoMSIA field distributions are found to be in well agreement with the structural characteristics of the corresponding binding sites. Therefore, the final 3D-QSAR models and the information of the inhibitor-enzyme interaction should be useful in developing novel potent NA inhibitors.

3D QSAR studies on protein tyrosine phosphatase 1B inhibitors: comparison of the quality and predictivity among 3D QSAR models obtained from different conformer-based alignments.

PubMed

Pandey, Gyanendra; Saxena, Anil K

2006-01-01

A set of 65 flexible peptidomimetic competitive inhibitors (52 in the training set and 13 in the test set) of protein tyrosine phosphatase 1B (PTP1B) has been used to compare the quality and predictive power of 3D quantitative structure-activity relationship (QSAR) comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models for the three most commonly used conformer-based alignments, namely, cocrystallized conformer-based alignment (CCBA), docked conformer-based alignment (DCBA), and global minima energy conformer-based alignment (GMCBA). These three conformers of 5-[(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)3-oxo-3-pentylamino)propyl]-2-(carboxymethoxy)benzoic acid (compound number 66) were obtained from the X-ray structure of its cocrystallized complex with PTP1B (PDB ID: 1JF7), its docking studies, and its global minima by simulated annealing. Among the 3D QSAR models developed using the above three alignments, the CCBA provided the optimal predictive CoMFA model for the training set with cross-validated r2 (q2)=0.708, non-cross-validated r2=0.902, standard error of estimate (s)=0.165, and F=202.553 and the optimal CoMSIA model with q2=0.440, r2=0.799, s=0.192, and F=117.782. These models also showed the best test set prediction for the 13 compounds with predictive r2 values of 0.706 and 0.683, respectively. Though the QSAR models derived using the other two alignments also produced statistically acceptable models in the order DCBA>GMCBA in terms of the values of q2, r2, and predictive r2, they were inferior to the corresponding models derived using CCBA. Thus, the order of preference for the alignment selection for 3D QSAR model development may be CCBA>DCBA>GMCBA, and the information obtained from the CoMFA and CoMSIA contour maps may be useful in designing specific PTP1B inhibitors.

Binding site exploration of CCR5 using in silico methodologies: a 3D-QSAR approach.

PubMed

Gadhe, Changdev G; Kothandan, Gugan; Cho, Seung Joo

2013-01-01

Chemokine receptor 5 (CCR5) is an important receptor used by human immunodeficiency virus type 1 (HIV-1) to gain viral entry into host cell. In this study, we used a combined approach of comparative modeling, molecular docking, and three dimensional quantitative structure activity relationship (3D-QSAR) analyses to elucidate detailed interaction of CCR5 with their inhibitors. Docking study of the most potent inhibitor from a series of compounds was done to derive the bioactive conformation. Parameters such as random selection, rational selection, different charges and grid spacing were utilized in the model development to check their performance on the model predictivity. Final comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were chosen based on the rational selection method, Gasteiger-Hückel charges and a grid spacing of 0.5 Å. Rational model for CoMFA (q(2) = 0.722, r(2) = 0.884, Q(2) = 0.669) and CoMSIA (q(2) = 0.712, r(2) = 0.825, Q(2) = 0.522) was obtained with good statistics. Mapping of contour maps onto CCR5 interface led us to better understand of the ligand-protein interaction. Docking analysis revealed that the Glu283 is crucial for interaction. Two new amino acid residues, Tyr89 and Thr167 were identified as important in ligand-protein interaction. No site directed mutagenesis studies on these residues have been reported.

Design of novel quinazolinone derivatives as inhibitors for 5HT7 receptor.

PubMed

Chitta, Aparna; Jatavath, Mohan Babu; Fatima, Sabiha; Manga, Vijjulatha

2012-02-01

To study the pharmacophore properties of quinazolinone derivatives as 5HT(7) inhibitors, 3D QSAR methodologies, namely Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were applied, partial least square (PLS) analysis was performed and QSAR models were generated. The derived model showed good statistical reliability in terms of predicting the 5HT(7) inhibitory activity of the quinazolione derivative, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like q(2) (cross validated correlation coefficient) of 0.642, 0.602 and r(2) (conventional correlation coefficient) of 0.937, 0.908 for CoMFA and CoMSIA respectively. The predictive ability of the models to determine 5HT(7) antagonistic activity is validated using a test set of 26 molecules that were not included in the training set and the predictive r(2) obtained for the test set was 0.512 & 0.541. Further, the results of the derived model are illustrated by means of contour maps, which give an insight into the interaction of the drug with the receptor. The molecular fields so obtained served as the basis for the design of twenty new ligands. In addition, ADME (Adsorption, Distribution, Metabolism and Elimination) have been calculated in order to predict the relevant pharmaceutical properties, and the results are in conformity with required drug like properties.

Molecular modeling-driven approach for identification of Janus kinase 1 inhibitors through 3D-QSAR, docking and molecular dynamics simulations.

PubMed

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

2017-10-01

Janus kinase 1 (JAK 1) belongs to the JAK family of intracellular nonreceptor tyrosine kinase. JAK-signal transducer and activator of transcription (JAK-STAT) pathway mediate signaling by cytokines, which control survival, proliferation and differentiation of a variety of cells. Three-dimensional quantitative structure activity relationship (3 D-QSAR), molecular docking and molecular dynamics (MD) methods was carried out on a dataset of Janus kinase 1(JAK 1) inhibitors. Ligands were constructed and docked into the active site of protein using GLIDE 5.6. Best docked poses were selected after analysis for further 3 D-QSAR analysis using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methodology. Employing 60 molecules in the training set, 3 D-QSAR models were generate that showed good statistical reliability, which is clearly observed in terms of r 2 ncv and q 2 loo values. The predictive ability of these models was determined using a test set of 25 molecules that gave acceptable predictive correlation (r 2 Pred ) values. The key amino acid residues were identified by means of molecular docking, and the stability and rationality of the derived molecular conformations were also validated by MD simulation. The good consonance between the docking results and CoMFA/CoMSIA contour maps provides helpful clues about the reasonable modification of molecules in order to design more efficient JAK 1 inhibitors. The developed models are expected to provide some directives for further synthesis of highly effective JAK 1 inhibitors.

Graph embedding and extensions: a general framework for dimensionality reduction.

PubMed

Yan, Shuicheng; Xu, Dong; Zhang, Benyu; Zhang, Hong-Jiang; Yang, Qiang; Lin, Stephen

2007-01-01

Over the past few decades, a large family of algorithms - supervised or unsupervised; stemming from statistics or geometry theory - has been designed to provide different solutions to the problem of dimensionality reduction. Despite the different motivations of these algorithms, we present in this paper a general formulation known as graph embedding to unify them within a common framework. In graph embedding, each algorithm can be considered as the direct graph embedding or its linear/kernel/tensor extension of a specific intrinsic graph that describes certain desired statistical or geometric properties of a data set, with constraints from scale normalization or a penalty graph that characterizes a statistical or geometric property that should be avoided. Furthermore, the graph embedding framework can be used as a general platform for developing new dimensionality reduction algorithms. By utilizing this framework as a tool, we propose a new supervised dimensionality reduction algorithm called Marginal Fisher Analysis in which the intrinsic graph characterizes the intraclass compactness and connects each data point with its neighboring points of the same class, while the penalty graph connects the marginal points and characterizes the interclass separability. We show that MFA effectively overcomes the limitations of the traditional Linear Discriminant Analysis algorithm due to data distribution assumptions and available projection directions. Real face recognition experiments show the superiority of our proposed MFA in comparison to LDA, also for corresponding kernel and tensor extensions.

Model-free adaptive control of supercritical circulating fluidized-bed boilers

DOEpatents

Cheng, George Shu-Xing; Mulkey, Steven L

2014-12-16

A novel 3-Input-3-Output (3.times.3) Fuel-Air Ratio Model-Free Adaptive (MFA) controller is introduced, which can effectively control key process variables including Bed Temperature, Excess O2, and Furnace Negative Pressure of combustion processes of advanced boilers. A novel 7-input-7-output (7.times.7) MFA control system is also described for controlling a combined 3-Input-3-Output (3.times.3) process of Boiler-Turbine-Generator (BTG) units and a 5.times.5 CFB combustion process of advanced boilers. Those boilers include Circulating Fluidized-Bed (CFB) Boilers and Once-Through Supercritical Circulating Fluidized-Bed (OTSC CFB) Boilers.

Chemical transformations of glucose to value added products using Cu-based catalytic systems.

PubMed

Yepez, Alfonso; Pineda, Antonio; Garcia, Angel; Romero, Antonio A; Luque, Rafael

2013-08-07

Cu nanoparticles have been supported by two types of aluminosilicate materials with and without Zn in their composition in view of their application in the microwave-assisted conversion of glucose to valuable products via tandem formic acid-promoted dehydration (to 5-hydroxymethylfurfural--HMF) and further selective hydrogenation to 5-methylfurfuryl alcohol (MFA). Results show that interesting selectivities (up to 60% to MFA or HMF) could be achieved after short times of reaction (typically 2-30 min) using Cu-containing nanomaterials. Zn was found to play an interesting role in the selectivity to reduced products, even if present in very small quantities (0.2 wt%).

Space Magnets Attracting Interest on Earth: Applications of Physical and Biological Techniques In the Study of Gravisensing and Response System of Plants

NASA Technical Reports Server (NTRS)

Hasenstein, Karl H.; Boody, April; Cox, David (Technical Monitor)

2002-01-01

The BioTube/Magnetic Field Apparatus (MFA) research is designed to provide insight into the organization and operation of the gravity sensing systems of plants and other small organisms. This experiment on STS-107 uses magnetic fields to manipulate sensory cells in plant roots, thus using magnetic fields as a tool to study gravity-related phenomena. The experiment will be located in the SPACEHAB module and is about the size of a household microwave oven. The goal of the experiment is to improve our understanding of the basic phenomenon of how plants respond to gravity. The BioTube/MFA experiment specifically examines how gravitational forces serve as a directional signal for growth in the low-gravity environment of space. As with all basic research, this study will contribute to an improved understanding of how plants grow and will have important implications for improving plant growth and productivity on Earth. In BioTube/MFA, magnetic fields will be used to determine whether the distribution of subcellular starch grains, called amyloplasts, within plant cells predicts the direction in which roots will grow and curve in microgravity.

Defining syndromes using cattle meat inspection data for syndromic surveillance purposes: a statistical approach with the 2005–2010 data from ten French slaughterhouses

PubMed Central

2013-01-01

Background The slaughterhouse is a central processing point for food animals and thus a source of both demographic data (age, breed, sex) and health-related data (reason for condemnation and condemned portions) that are not available through other sources. Using these data for syndromic surveillance is therefore tempting. However many possible reasons for condemnation and condemned portions exist, making the definition of relevant syndromes challenging. The objective of this study was to determine a typology of cattle with at least one portion of the carcass condemned in order to define syndromes. Multiple factor analysis (MFA) in combination with clustering methods was performed using both health-related data and demographic data. Results Analyses were performed on 381,186 cattle with at least one portion of the carcass condemned among the 1,937,917 cattle slaughtered in ten French abattoirs. Results of the MFA and clustering methods led to 12 clusters considered as stable according to year of slaughter and slaughterhouse. One cluster was specific to a disease of public health importance (cysticercosis). Two clusters were linked to the slaughtering process (fecal contamination of heart or lungs and deterioration lesions). Two clusters respectively characterized by chronic liver lesions and chronic peritonitis could be linked to diseases of economic importance to farmers. Three clusters could be linked respectively to reticulo-pericarditis, fatty liver syndrome and farmer’s lung syndrome, which are related to both diseases of economic importance to farmers and herd management issues. Three clusters respectively characterized by arthritis, myopathy and Dark Firm Dry (DFD) meat could notably be linked to animal welfare issues. Finally, one cluster, characterized by bronchopneumonia, could be linked to both animal health and herd management issues. Conclusion The statistical approach of combining multiple factor analysis with cluster analysis showed its relevance for the detection of syndromes using available large and complex slaughterhouse data. The advantages of this statistical approach are to i) define groups of reasons for condemnation based on meat inspection data, ii) help grouping reasons for condemnation among a list of various possible reasons for condemnation for which a consensus among experts could be difficult to reach, iii) assign each animal to a single syndrome which allows the detection of changes in trends of syndromes to detect unusual patterns in known diseases and emergence of new diseases. PMID:23628140

Metabolic flux profiling of MDCK cells during growth and canine adenovirus vector production.

PubMed

Carinhas, Nuno; Pais, Daniel A M; Koshkin, Alexey; Fernandes, Paulo; Coroadinha, Ana S; Carrondo, Manuel J T; Alves, Paula M; Teixeira, Ana P

2016-03-23

Canine adenovirus vector type 2 (CAV2) represents an alternative to human adenovirus vectors for certain gene therapy applications, particularly neurodegenerative diseases. However, more efficient production processes, assisted by a greater understanding of the effect of infection on producer cells, are required. Combining [1,2-(13)C]glucose and [U-(13)C]glutamine, we apply for the first time (13)C-Metabolic flux analysis ((13)C-MFA) to study E1-transformed Madin-Darby Canine Kidney (MDCK) cells metabolism during growth and CAV2 production. MDCK cells displayed a marked glycolytic and ammoniagenic metabolism, and (13)C data revealed a large fraction of glutamine-derived labelling in TCA cycle intermediates, emphasizing the role of glutamine anaplerosis. (13)C-MFA demonstrated the importance of pyruvate cycling in balancing glycolytic and TCA cycle activities, as well as occurrence of reductive alphaketoglutarate (AKG) carboxylation. By turn, CAV2 infection significantly upregulated fluxes through most central metabolism, including glycolysis, pentose-phosphate pathway, glutamine anaplerosis and, more prominently, reductive AKG carboxylation and cytosolic acetyl-coenzyme A formation, suggestive of increased lipogenesis. Based on these results, we suggest culture supplementation strategies to stimulate nucleic acid and lipid biosynthesis for improved canine adenoviral vector production.

Reutilisation-extended material flows and circular economy in China.

PubMed

Li, Nan; Zhang, Tianzhu; Liang, Sai

2013-06-01

Circular economy (CE), with its basic principle of Reduce, Reuse, and Recycle, has been determined as the key strategy for the national development plan by the Chinese government. Given the economy-wide material flow analysis (EW-MFA) that leaves the inner flow of resource reutilisation unidentified, the reutilisation-extended EW-MFA is first introduced to evaluate and analyse the material input, solid waste generation, and reutilisation simultaneously. The total amount of comprehensive reutilisation (CR) is divided into three sub-flows, namely, reutilisation, recycle, and reuse. Thus, this model is used to investigate the resource CR in China from 2000 to 2010. China's total amount of CR and its sub-flows, as well as the CR rate, remain to have a general upward trend. By the year 2010, about 60% of the overall solid waste generation had already been reutilised, and more than 20% of the total resource requirement was reutilised resource. Moreover, the growth patterns of the CR sub flows show different characteristics. Interpretations of resource reutilisation-related laws and regulations of CE and the corresponding policy suggestions are proposed based on the results. Copyright © 2013 Elsevier Ltd. All rights reserved.

Comprehensive and accurate tracking of carbon origin of LC-tandem mass spectrometry collisional fragments for 13C-MFA.

PubMed

Kappelmann, Jannick; Klein, Bianca; Geilenkirchen, Petra; Noack, Stephan

2017-03-01

In recent years the benefit of measuring positionally resolved 13 C-labeling enrichment from tandem mass spectrometry (MS/MS) collisional fragments for improved precision of 13 C-Metabolic Flux Analysis ( 13 C-MFA) has become evident. However, the usage of positional labeling information for 13 C-MFA faces two challenges: (1) The mass spectrometric acquisition of a large number of potentially interfering mass transitions may hamper accuracy and sensitivity. (2) The positional identity of carbon atoms of product ions needs to be known. The present contribution addresses the latter challenge by deducing the maximal positional labeling information contained in LC-ESI-MS/MS spectra of product anions of central metabolism as well as product cations of amino acids. For this purpose, we draw on accurate mass spectrometry, selectively labeled standards, and published fragmentation pathways to structurally annotate all dominant mass peaks of a large collection of metabolites, some of which with a complete fragmentation pathway. Compiling all available information, we arrive at the most detailed map of carbon atom fate of LC-ESI-MS/MS collisional fragments yet, comprising 170 intense and structurally annotated product ions with unique carbon origin from 76 precursor ions of 72 metabolites. Our 13 C-data proof that heuristic fragmentation rules often fail to yield correct fragment structures and we expose common pitfalls in the structural annotation of product ions. We show that the positionally resolved 13 C-label information contained in the product ions that we structurally annotated allows to infer the entire isotopomer distribution of several central metabolism intermediates, which is experimentally demonstrated for malate using quadrupole-time-of-flight MS technology. Finally, the inclusion of the label information from a subset of these fragments improves flux precision in a Corynebacterium glutamicum model of the central carbon metabolism.

Towards better monitoring of technology critical elements in Europe: Coupling of natural and anthropogenic cycles.

PubMed

Nuss, Philip; Blengini, Gian Andrea

2018-02-01

The characterization of elemental cycles has a rich history in biogeochemistry. Well known examples include the global carbon cycle, or the cycles of the 'grand nutrients' nitrogen, phosphorus, and sulfur. More recently, efforts have increased to better understand the natural cycling of technology critical elements (TCEs), i.e. elements with a high supply risk and economic importance in the EU. On the other hand, tools such as material-flow analysis (MFA) can help to understand how substances and goods are transported and accumulated in man-made technological systems ('anthroposphere'). However, to date both biogeochemical cycles and MFA studies suffer from narrow system boundaries, failing to fully illustrate relative anthropogenic and natural flow magnitude and the degree to which human activity has perturbed the natural cycling of elements. We discuss important interconnections between natural and anthropogenic cycles and relevant EU raw material dossiers. Increased integration of both cycles could help to better capture the transport and fate of elements in nature including their environmental/human health impacts, highlight potential future material stocks in the anthroposphere (in-use stocks) and in nature (e.g., in soils, tailings, or mining wastes), and estimate anticipated emissions of TCEs to nature in the future (based on dynamic stock modeling). A preliminary assessment of natural versus anthropogenic element fluxes indicates that anthropogenic fluxes induced by the EU-28 of palladium, platinum, and antimony (as a result of materials uses) might be greater than the respective global natural fluxes. Increased combination of MFA and natural cycle data at EU level could help to derive more complete material cycles and initiate a discussion between the research communities of biogeochemists and material flow analysts to more holistically address the issues of sustainable resource management. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

MaTrace: tracing the fate of materials over time and across products in open-loop recycling.

PubMed

Nakamura, Shinichiro; Kondo, Yasushi; Kagawa, Shigemi; Matsubae, Kazuyo; Nakajima, Kenichi; Nagasaka, Tetsuya

2014-07-01

Even for metals, open-loop recycling is more common than closed-loop recycling due, among other factors, to the degradation of quality in the end-of-life (EoL) phase. Open-loop recycling is subject to loss of functionality of original materials, dissipation in forms that are difficult to recover, and recovered metals might need dilution with primary metals to meet quality requirements. Sustainable management of metal resources calls for the minimization of these losses. Imperative to this is quantitative tracking of the fate of materials across different stages, products, and losses. A new input-output analysis (IO) based model of dynamic material flow analysis (MFA) is presented that can trace the fate of materials over time and across products in open-loop recycling taking explicit consideration of losses and the quality of scrap into account. Application to car steel recovered from EoL vehicles (ELV) showed that after 50 years around 80% of the steel is used in products, mostly buildings and civil engineering (infrastructure), with the rest mostly resided in unrecovered obsolete infrastructure and refinery losses. Sensitivity analysis was conducted to evaluate the effects of changes in product lifespan, and the quality of scrap.

Insight into the interaction mechanism of human SGLT2 with its inhibitors: 3D-QSAR studies, homology modeling, and molecular docking and molecular dynamics simulations.

PubMed

Dong, Lili; Feng, Ruirui; Bi, Jiawei; Shen, Shengqiang; Lu, Huizhe; Zhang, Jianjun

2018-03-06

Human sodium-dependent glucose co-transporter 2 (hSGLT2) is a crucial therapeutic target in the treatment of type 2 diabetes. In this study, both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to generate three-dimensional quantitative structure-activity relationship (3D-QSAR) models. In the most accurate CoMFA-based and CoMSIA-based QSAR models, the cross-validated coefficients (r 2 cv ) were 0.646 and 0.577, respectively, while the non-cross-validated coefficients (r 2 ) were 0.997 and 0.991, respectively, indicating that both models were reliable. In addition, we constructed a homology model of hSGLT2 in the absence of a crystal structure. Molecular docking was performed to explore the bonding mode of inhibitors to the active site of hSGLT2. Molecular dynamics (MD) simulations and binding free energy calculations using MM-PBSA and MM-GBSA were carried out to further elucidate the interaction mechanism. With regards to binding affinity, we found that hydrogen-bond interactions of Asn51 and Glu75, located in the active site of hSGLT2, with compound 40 were critical. Hydrophobic and electrostatic interactions were shown to enhance activity, in agreement with the results obtained from docking and 3D-QSAR analysis. Our study results shed light on the interaction mode between inhibitors and hSGLT2 and may aid in the development of C-aryl glucoside SGLT2 inhibitors.

Analysis of group-velocity dispersion of high-frequency Rayleigh waves for near-surface applications

USGS Publications Warehouse

Luo, Y.; Xia, J.; Xu, Y.; Zeng, C.

2011-01-01

The Multichannel Analysis of Surface Waves (MASW) method is an efficient tool to obtain the vertical shear (S)-wave velocity profile using the dispersive characteristic of Rayleigh waves. Most MASW researchers mainly apply Rayleigh-wave phase-velocity dispersion for S-wave velocity estimation with a few exceptions applying Rayleigh-wave group-velocity dispersion. Herein, we first compare sensitivities of fundamental surface-wave phase velocities with group velocities with three four-layer models including a low-velocity layer or a high-velocity layer. Then synthetic data are simulated by a finite difference method. Images of group-velocity dispersive energy of the synthetic data are generated using the Multiple Filter Analysis (MFA) method. Finally we invert a high-frequency surface-wave group-velocity dispersion curve of a real-world example. Results demonstrate that (1) the sensitivities of group velocities are higher than those of phase velocities and usable frequency ranges are wider than that of phase velocities, which is very helpful in improving inversion stability because for a stable inversion system, small changes in phase velocities do not result in a large fluctuation in inverted S-wave velocities; (2) group-velocity dispersive energy can be measured using single-trace data if Rayleigh-wave fundamental-mode energy is dominant, which suggests that the number of shots required in data acquisition can be dramatically reduced and the horizontal resolution can be greatly improved using analysis of group-velocity dispersion; and (3) the suspension logging results of the real-world example demonstrate that inversion of group velocities generated by the MFA method can successfully estimate near-surface S-wave velocities. ?? 2011 Elsevier B.V.

Electromyographic and cephalometric correlation with the predominant masticatory movement.

PubMed

Coelho-Ferraz, Maria Julia P; Berzin, Fausto; Amorim, Cesar Ferreira; Romano, Fabio Lourenco; de Paula Queluz, Dagmar

2010-01-01

This study aimed to evaluate the chewing muscular dynamics and correlate the side of the masticatory movement that is more vertical and/or more horizontal established by the photomeasurement Masticatory Functional Angle (MFA) to the muscular activity behavior, showed in the surface electromyography and in the radiographic images. Seventeen people were selected of both genders, with the average age of 25 years, without signs or apparent symptoms of masticatory muscular disorders. The teleradiographies were done in lateral norm and surface electromyography of the masseter muscles, anterior portion of temporal and supra-hyoids in rest position and maximal bite. The bite force measured with a metallic transducer that was connected to a force sensor (Strain Gauge) to measure the deformation of the material model SF4 (EMG SYSTEM DO BRASIL). A mandibular goniometer of the EMG System of Brazil was used to measure the opening size. The comparison and correlation were established between the groups with MFA>5 degrees and MFA<5 degrees by the test "t" of Student or test of Mann-Whitney conform the distribution was normal or not, respectively. The results showed significant differences between groups, although without sexual dimorphism, to masseter muscle in maximal bite. In conclusion, the anatomic-physiological aspects of temporomandibular disorders are related to the asymmetrical mandible function.

Hydration Characteristics of Low-Heat Cement Substituted by Fly Ash and Limestone Powder.

PubMed

Kim, Si-Jun; Yang, Keun-Hyeok; Moon, Gyu-Don

2015-09-01

This study proposed a new binder as an alternative to conventional cement to reduce the heat of hydration in mass concrete elements. As a main cementitious material, low-heat cement (LHC) was considered, and then fly ash (FA), modified FA (MFA) by vibrator mill, and limestone powder (LP) were used as a partial replacement of LHC. The addition of FA delayed the induction period at the hydration heat curve and the maximum heat flow value ( q max ) increased compared with the LHC based binder. As the proportion and fineness of the FA increased, the induction period of the hydration heat curve was extended, and the q max increased. The hydration production of Ca(OH)₂ was independent of the addition of FA or MFA up to an age of 7 days, beyond which the amount of Ca(OH)₂ gradually decreased owing to their pozzolanic reaction. In the case of LP being used as a supplementary cementitious material, the induction period of the hydration heat curve was reduced by comparison with the case of LHC based binder, and monocarboaluminate was observed as a hydration product. The average pore size measured at an age of 28 days was smaller for LHC with FA or MFA than for 100% LHC.

Bose-Einstein condensation of triplons with a weakly broken U(1) symmetry

NASA Astrophysics Data System (ADS)

Khudoyberdiev, Asliddin; Rakhimov, Abdulla; Schilling, Andreas

2017-11-01

The low-temperature properties of certain quantum magnets can be described in terms of a Bose-Einstein condensation (BEC) of magnetic quasiparticles (triplons). Some mean-field approaches (MFA) to describe these systems, based on the standard grand canonical ensemble, do not take the anomalous density into account and leads to an internal inconsistency, as it has been shown by Hohenberg and Martin, and may therefore produce unphysical results. Moreover, an explicit breaking of the U(1) symmetry as observed, for example, in TlCuCl3 makes the application of MFA more complicated. In the present work, we develop a self-consistent MFA approach, similar to the Hartree-Fock-Bogolyubov approximation in the notion of representative statistical ensembles, including the effect of a weakly broken U(1) symmetry. We apply our results on experimental data of the quantum magnet TlCuCl3 and show that magnetization curves and the energy dispersion can be well described within this approximation assuming that the BEC scenario is still valid. We predict that the shift of the critical temperature T c due to a finite exchange anisotropy is rather substantial even when the anisotropy parameter γ is small, e.g., {{Δ }}{T}{c}≈ 10 % of T c in H = 6 T and for γ ≈ 4 μ {eV}.

A force-based, parallel assay for the quantification of protein-DNA interactions.

PubMed

Limmer, Katja; Pippig, Diana A; Aschenbrenner, Daniela; Gaub, Hermann E

2014-01-01

Analysis of transcription factor binding to DNA sequences is of utmost importance to understand the intricate regulatory mechanisms that underlie gene expression. Several techniques exist that quantify DNA-protein affinity, but they are either very time-consuming or suffer from possible misinterpretation due to complicated algorithms or approximations like many high-throughput techniques. We present a more direct method to quantify DNA-protein interaction in a force-based assay. In contrast to single-molecule force spectroscopy, our technique, the Molecular Force Assay (MFA), parallelizes force measurements so that it can test one or multiple proteins against several DNA sequences in a single experiment. The interaction strength is quantified by comparison to the well-defined rupture stability of different DNA duplexes. As a proof-of-principle, we measured the interaction of the zinc finger construct Zif268/NRE against six different DNA constructs. We could show the specificity of our approach and quantify the strength of the protein-DNA interaction.

Framework for resilience in material supply chains, with a case study from the 2010 Rare Earth Crisis.

PubMed

Sprecher, Benjamin; Daigo, Ichiro; Murakami, Shinsuke; Kleijn, Rene; Vos, Matthijs; Kramer, Gert Jan

2015-06-02

In 2010, Chinese export restrictions caused the price of the rare earth element neodymium to increase by a factor of 10, only to return to almost normal levels in the following months. This despite the fact that the restrictions were not lifted. The significant price peak shows that this material supply chain was only weakly resistant to a major supply disruption. However, the fact that prices rapidly returned to lower levels implies a certain resilience. With the help of a novel approach, based on resilience theory combined with a material flow analysis (MFA) based representation of the neodymium magnet (NdFeB) supply chain, we show that supply chain resilience is composed of various mechanisms, including (a) resistance, (b) rapidity, and (c) flexibility, that originate from different parts of the supply chain. We make recommendations to improve the capacity of the NdFeB system to deal with future disruptions and discuss potential generalities for the resilience of other material supply chains.

Associations between food consumption patterns and saliva composition: Specificities of eating difficulties children.

PubMed

Morzel, Martine; Truntzer, Caroline; Neyraud, Eric; Brignot, Hélène; Ducoroy, Patrick; Lucchi, Géraldine; Canlet, Cécile; Gaillard, Ségolène; Nicod, Florian; Nicklaus, Sophie; Peretti, Noël; Feron, Gilles

2017-05-01

Identifying objective markers of diet would be beneficial to research fields such as nutritional epidemiology. As a preliminary study on the validity of using saliva for this purpose, and in order to explore the relationship between saliva and diet, we focused on clearly contrasted groups of children: children with eating difficulties (ED) receiving at least 50% of their energy intake through artificial nutrition vs healthy controls (C). Saliva of ED and C children was analyzed by various methods (targeted biochemical analyses, 2-D electrophoresis coupled to MS, 1 H NMR) and their diet was characterized using food frequency questionnaires, considering 148 food items grouped into 13 categories. Complete datasets were obtained for 16 ED and 16 C subjects (median age 4.7y and 5.0y, respectively) and the statistical link between salivary and dietary characteristics was studied by Multiple Factor Analysis (MFA). Overall, ED children showed as expected lower consumption frequency scores and higher food selectivity. The two groups of children differed in "diet/saliva" associations. Some distinctive salivary variables were common to both groups of children. For example, carbonic anhydrase 6 and the consumption frequency of biscuits & sweets and drinks were positively associated with the MFA axis 1 in C children, but oppositely associated in ED children. Specifically for ED children, abundant salivary proteins (cystatins, amylase, amylase fragments) and some metabolites (amino acids, galactose, lactate) correlated with axis 1, together with the consumption frequency of sauces & seasonings, bread & cereal products, ready-to-eat meals, fish, biscuits & sweets, drinks and potatoes. Specifically for C children, several proteins (serum albumin, haptoglobin, Igκ, apolipoprotein A-1, α-1 antitrypsin) correlated with axis 1, together with the consumption frequency of biscuits & sweets, milk & dairy products, drinks, fruit, meat and vegetables. This study demonstrates that the qualitative aspect of diet is linked to saliva composition, and that the associations between dietary consumption and salivary composition differ between groups of subjects with contrasted diets. Copyright © 2017 Elsevier Inc. All rights reserved.

Structure-activity relationships of seco-prezizaane terpenoids in gamma-aminobutyric acid receptors of houseflies and rats.

PubMed

Kuriyama, Tadahiko; Schmidt, Thomas J; Okuyama, Emi; Ozoe, Yoshihisa

2002-06-01

Thirteen seco-prezizaane terpenoids isolated from star anise species (Illcium floridanum, Illcium parviflorum, and Illcium verum) were investigated for their ability to inhibit the specific binding of [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist of gamma-aminobutyric acid (GABA) receptors, to housefly-head and rat-brain membranes. Veranisatin A was found to be the most potent inhibitor in both membranes, with an IC(50)(fly) of 78.5 nM and an IC(50)(rat) of 271 nM, followed by anisatin (IC(50)(fly)=123 nM; IC(50)(rat)=282 nM). Six of the other 11 tested compounds were effective only in housefly-head membranes. Pseudoanisatin proved to display a high (>26-fold) selectivity for housefly versus rat GABA receptors (IC(50)(fly)=376 nM; IC(50)(rat) >10,000 nM). Although pseudoanisatin does not structurally resemble EBOB, Scatchard plots indicated that the two compounds bind to the same site in housefly receptors. Anisatin and pseudoanisatin exhibited moderate insecticidal activity against German cockroaches. Comparative molecular field analysis (CoMFA), a method of three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis, demonstrated that seco-prezizaane terpenoids can bind to the same site as do picrotoxane terpenoids such as picrotoxinin and picrodendrins, and the CoMFA maps allowed us to identify the parts of the molecules essential to high activity in housefly GABA receptors.

Comparative molecular field analysis and molecular docking studies on novel aryl chalcone derivatives against an important drug target cysteine protease in Plasmodium falciparum.

PubMed

Thillainayagam, Mahalakshmi; Anbarasu, Anand; Ramaiah, Sudha

2016-08-21

The computational studies namely molecular docking simulations and Comparative Molecular Field Analysis (CoMFA) are executed on series of 52 novel aryl chalcones derivatives using Plasmodium falciparum cysteine proteases (falcipain - 2) as vital target. In the present study, the correlation between different molecular field effects namely steric and electrostatic interactions and chemical structures to the inhibitory activities of novel aryl chalcone derivatives is inferred to perceive the major structural prerequisites for the rational design and development of potent and novel lead anti-malarial compound. The apparent binding conformations of all the compounds at the active site of falcipain - 2 and the hydrogen-bond interactions which could be used to modify the inhibitory activities are identified by using Surflex-dock study. Statistically significant CoMFA model has been developed with the cross-validated correlation coefficient (q(2)) of 0.912 and the non-cross-validated correlation coefficient (r(2)) of 0.901. Standard error of estimation (SEE) of 0.210, with the optimum number of components is ten. The predictability of the derived model is examined with a test set consists of sixteen compounds and the predicted r(2) value is found to be 0.924. The docking and QSAR study results confer crucial suggestions for the optimization of novel 1,3-diphenyl-2-propen-1-one derivatives and synthesis of effective anti- malarial compounds. Copyright © 2016 Elsevier Ltd. All rights reserved.

Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations

PubMed Central

Wang, Yuan; Wu, Mingwei; Ai, Chunzhi; Wang, Yonghua

2015-01-01

Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q2 (cross-validated correlation coefficient) = 0.557, R2ncv (non-cross-validated correlation coefficient) = 0.740, R2pre (predicted correlation coefficient) = 0.749 and Q2 = 0.598, R2ncv = 0.767, R2pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors. PMID:26307982

Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations.

PubMed

Wang, Yuan; Wu, Mingwei; Ai, Chunzhi; Wang, Yonghua

2015-08-25

Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q(2) (cross-validated correlation coefficient) = 0.557, R(2)ncv (non-cross-validated correlation coefficient) = 0.740, R(2)pre (predicted correlation coefficient) = 0.749 and Q(2) = 0.598, R(2)ncv = 0.767, R(2)pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.

Flux-Enabled Exploration of the Role of Sip1 in Galactose Yeast Metabolism

DOE PAGES

Shymansky, Christopher M.; Wang, George; Baidoo, Edward E. K.; ...

2017-05-24

13C metabolic flux analysis ( 13C MFA) is an important systems biology technique that has been used to investigate microbial metabolism for decades. The heterotrimer Snf1 kinase complex plays a key role in the preference Saccharomyces cerevisiae exhibits for glucose over galactose, a phenomenon known as glucose repression or carbon catabolite repression. The SIP1 gene, encoding a part of this complex, has received little attention, presumably, because its knockout lacks a growth phenotype. We present a fluxomic investigation of the relative effects of the presence of galactose in classically glucose-repressing media and/or knockout of SIP1 using a multi-scale variant ofmore » 13C MFA known as 2-Scale 13C metabolic flux analysis (2S- 13C MFA). In this study, all strains have the galactose metabolism deactivated (gal1Δ background) so as to be able to separate the metabolic effects purely related to glucose repression from those arising from galactose metabolism. The resulting flux profiles reveal that the presence of galactose in classically glucose-repressing conditions, for a CEN.PK113-7D gal1Δ background, results in a substantial decrease in pentose phosphate pathway (PPP) flux and increased flow from cytosolic pyruvate and malate through the mitochondria toward cytosolic branched-chain amino acid biosynthesis. These fluxomic redistributions are accompanied by a higher maximum specific growth rate, both seemingly in violation of glucose repression. Deletion of SIP1 in the CEN.PK113-7D gal1Δ cells grown in mixed glucose/galactose medium results in a further increase. Knockout of this gene in cells grown in glucose-only medium results in no change in growth rate and a corresponding decrease in glucose and ethanol exchange fluxes and flux through pathways involved in aspartate/threonine biosynthesis. Glucose repression appears to be violated at a 1/10 ratio of galactose-to-glucose. Based on the scientific literature, we may have conducted our experiments near a critical sugar ratio that is known to allow galactose to enter the cell. Additionally, we report a number of fluxomic changes associated with these growth rate increases and unexpected flux profile redistributions resulting from deletion of SIP1 in glucose-only medium.« less

Flux-Enabled Exploration of the Role of Sip1 in Galactose Yeast Metabolism

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

Shymansky, Christopher M.; Wang, George; Baidoo, Edward E. K.

13C metabolic flux analysis ( 13C MFA) is an important systems biology technique that has been used to investigate microbial metabolism for decades. The heterotrimer Snf1 kinase complex plays a key role in the preference Saccharomyces cerevisiae exhibits for glucose over galactose, a phenomenon known as glucose repression or carbon catabolite repression. The SIP1 gene, encoding a part of this complex, has received little attention, presumably, because its knockout lacks a growth phenotype. We present a fluxomic investigation of the relative effects of the presence of galactose in classically glucose-repressing media and/or knockout of SIP1 using a multi-scale variant ofmore » 13C MFA known as 2-Scale 13C metabolic flux analysis (2S- 13C MFA). In this study, all strains have the galactose metabolism deactivated (gal1Δ background) so as to be able to separate the metabolic effects purely related to glucose repression from those arising from galactose metabolism. The resulting flux profiles reveal that the presence of galactose in classically glucose-repressing conditions, for a CEN.PK113-7D gal1Δ background, results in a substantial decrease in pentose phosphate pathway (PPP) flux and increased flow from cytosolic pyruvate and malate through the mitochondria toward cytosolic branched-chain amino acid biosynthesis. These fluxomic redistributions are accompanied by a higher maximum specific growth rate, both seemingly in violation of glucose repression. Deletion of SIP1 in the CEN.PK113-7D gal1Δ cells grown in mixed glucose/galactose medium results in a further increase. Knockout of this gene in cells grown in glucose-only medium results in no change in growth rate and a corresponding decrease in glucose and ethanol exchange fluxes and flux through pathways involved in aspartate/threonine biosynthesis. Glucose repression appears to be violated at a 1/10 ratio of galactose-to-glucose. Based on the scientific literature, we may have conducted our experiments near a critical sugar ratio that is known to allow galactose to enter the cell. Additionally, we report a number of fluxomic changes associated with these growth rate increases and unexpected flux profile redistributions resulting from deletion of SIP1 in glucose-only medium.« less

Flux-Enabled Exploration of the Role of Sip1 in Galactose Yeast Metabolism

PubMed Central

Shymansky, Christopher M.; Wang, George; Baidoo, Edward E. K.; Gin, Jennifer; Apel, Amanda Reider; Mukhopadhyay, Aindrila; García Martín, Héctor; Keasling, Jay D.

2017-01-01

13C metabolic flux analysis (13C MFA) is an important systems biology technique that has been used to investigate microbial metabolism for decades. The heterotrimer Snf1 kinase complex plays a key role in the preference Saccharomyces cerevisiae exhibits for glucose over galactose, a phenomenon known as glucose repression or carbon catabolite repression. The SIP1 gene, encoding a part of this complex, has received little attention, presumably, because its knockout lacks a growth phenotype. We present a fluxomic investigation of the relative effects of the presence of galactose in classically glucose-repressing media and/or knockout of SIP1 using a multi-scale variant of 13C MFA known as 2-Scale 13C metabolic flux analysis (2S-13C MFA). In this study, all strains have the galactose metabolism deactivated (gal1Δ background) so as to be able to separate the metabolic effects purely related to glucose repression from those arising from galactose metabolism. The resulting flux profiles reveal that the presence of galactose in classically glucose-repressing conditions, for a CEN.PK113-7D gal1Δ background, results in a substantial decrease in pentose phosphate pathway (PPP) flux and increased flow from cytosolic pyruvate and malate through the mitochondria toward cytosolic branched-chain amino acid biosynthesis. These fluxomic redistributions are accompanied by a higher maximum specific growth rate, both seemingly in violation of glucose repression. Deletion of SIP1 in the CEN.PK113-7D gal1Δ cells grown in mixed glucose/galactose medium results in a further increase. Knockout of this gene in cells grown in glucose-only medium results in no change in growth rate and a corresponding decrease in glucose and ethanol exchange fluxes and flux through pathways involved in aspartate/threonine biosynthesis. Glucose repression appears to be violated at a 1/10 ratio of galactose-to-glucose. Based on the scientific literature, we may have conducted our experiments near a critical sugar ratio that is known to allow galactose to enter the cell. Additionally, we report a number of fluxomic changes associated with these growth rate increases and unexpected flux profile redistributions resulting from deletion of SIP1 in glucose-only medium. PMID:28596955

3D-QSPR Method of Computational Technique Applied on Red Reactive Dyes by Using CoMFA Strategy

PubMed Central

Mahmood, Uzma; Rashid, Sitara; Ali, S. Ishrat; Parveen, Rasheeda; Zaheer-ul-Haq; Ambreen, Nida; Khan, Khalid Mohammed; Perveen, Shahnaz; Voelter, Wolfgang

2011-01-01

Cellulose fiber is a tremendous natural resource that has broad application in various productions including the textile industry. The dyes, which are commonly used for cellulose printing, are “reactive dyes” because of their high wet fastness and brilliant colors. The interaction of various dyes with the cellulose fiber depends upon the physiochemical properties that are governed by specific features of the dye molecule. The binding pattern of the reactive dye with cellulose fiber is called the ligand-receptor concept. In the current study, the three dimensional quantitative structure property relationship (3D-QSPR) technique was applied to understand the red reactive dyes interactions with the cellulose by the Comparative Molecular Field Analysis (CoMFA) method. This method was successfully utilized to predict a reliable model. The predicted model gives satisfactory statistical results and in the light of these, it was further analyzed. Additionally, the graphical outcomes (contour maps) help us to understand the modification pattern and to correlate the structural changes with respect to the absorptivity. Furthermore, the final selected model has potential to assist in understanding the charachteristics of the external test set. The study could be helpful to design new reactive dyes with better affinity and selectivity for the cellulose fiber. PMID:22272108

Fusion of spatial gray level dependency and fractal texture features for the characterization of thyroid lesions.

PubMed

Raghavendra, U; Rajendra Acharya, U; Gudigar, Anjan; Hong Tan, Jen; Fujita, Hamido; Hagiwara, Yuki; Molinari, Filippo; Kongmebhol, Pailin; Hoong Ng, Kwan

2017-05-01

Thyroid is a small gland situated at the anterior side of the neck and one of the largest glands of the endocrine system. The abrupt cell growth or malignancy in the thyroid gland may cause thyroid cancer. Ultrasound images distinctly represent benign and malignant lesions, but accuracy may be poor due to subjective interpretation. Computer Aided Diagnosis (CAD) can minimize the errors created due to subjective interpretation and assists to make fast accurate diagnosis. In this work, fusion of Spatial Gray Level Dependence Features (SGLDF) and fractal textures are used to decipher the intrinsic structure of benign and malignant thyroid lesions. These features are subjected to graph based Marginal Fisher Analysis (MFA) to reduce the number of features. The reduced features are subjected to various ranking methods and classifiers. We have achieved an average accuracy, sensitivity and specificity of 97.52%, 90.32% and 98.57% respectively using Support Vector Machine (SVM) classifier. The achieved maximum Area Under Curve (AUC) is 0.9445. Finally, Thyroid Clinical Risk Index (TCRI) a single number is developed using two MFA features to discriminate the two classes. This prototype system is ready to be tested with huge diverse database. Copyright © 2017 Elsevier B.V. All rights reserved.

3D-QSAR, homology modeling, and molecular docking studies on spiropiperidines analogues as agonists of nociceptin/orphanin FQ receptor.

PubMed

Liu, Ming; He, Lin; Hu, Xiaopeng; Liu, Peiqing; Luo, Hai-Bin

2010-12-01

The nociceptin/orphanin FQ receptor (NOP) has been implicated in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have a great potential to be developed into anxiolytics. However, the crystal structure of NOP is still not available. In the present work, both structure-based and ligand-based modeling methods have been used to achieve a comprehensive understanding on 67N-substituted spiropiperidine analogues as NOP agonists. The comparative molecular-field analysis method was performed to formulate a reasonable 3D-QSAR model (cross-validated coefficient q(2)=0.819 and conventional r(2)=0.950), whose robustness and predictability were further verified by leave-eight-out, Y-randomization, and external test-set validations. The excellent performance of CoMFA to the affinity differences among these compounds was attributed to the contributions of electrostatic/hydrogen-bonding and steric/hydrophobic interactions, which was supported by the Surflex-Dock and CDOCKER molecular-docking simulations based on the 3D model of NOP built by the homology modeling method. The CoMFA contour maps and the molecular docking simulations were integrated to propose a binding mode for the spiropiperidine analogues at the binding site of NOP. Copyright © 2010 Elsevier Ltd. All rights reserved.

Interactions between cycloguanil derivatives and wild type and resistance-associated mutant Plasmodium falciparum dihydrofolate reductases

NASA Astrophysics Data System (ADS)

Maitarad, Phornphimon; Kamchonwongpaisan, Sumalee; Vanichtanankul, Jarunee; Vilaivan, Tirayut; Yuthavong, Yongyuth; Hannongbua, Supa

2009-04-01

Comparative molecular field analysis (CoMFA) and quantum chemical calculations were performed on cycloguanil (Cyc) derivatives of the wild type and the quadruple mutant (Asn51Ile, Cys59Arg, Ser108Asn, Ile164Leu) of Plasmodium falciparum dihydrofolate reductase ( PfDHFR). The represented CoMFA models of wild type ( r_{{cv}}2 = 0.727 and r 2 = 0.985) and mutant type ( r_{{cv}}2 = 0.786 and r 2 = 0.979) can describe the differences of the Cyc structural requirements for the two types of PfDHFR enzymes and can be useful to guide the design of new inhibitors. Moreover, the obtained particular interaction energies between the Cyc and the surrounding residues in the binding pocket indicated that Asn108 of mutant enzyme was the cause of Cyc resistance by producing steric clash with p-Cl of Cyc. Consequently, comparing the energy contributions with the potent flexible WR99210 inhibitor, it was found that the key mutant residue, Asn108, demonstrates attractive interaction with this inhibitor and some residues, Leu46, Ile112, Pro113, Phe116, and Leu119, seem to perform as second binding site with WR99210. Therefore, quantum chemical calculations can be useful for investigating residue interactions to clarify the cause of drug resistance.

Isolation and survey of novel fluoroacetate-degrading bacteria belonging to the phylum Synergistetes.

PubMed

Davis, Carl K; Webb, Richard I; Sly, Lindsay I; Denman, Stuart E; McSweeney, Chris S

2012-06-01

Microbial dehalogenation of chlorinated compounds in anaerobic environments is well known, but the degradation of fluorinated compounds under similar conditions has rarely been described. Here, we report on the isolation of a bovine rumen bacterium that metabolizes fluoroacetate under anaerobic conditions, the mode of degradation and its presence in gut ecosystems. The bacterium was identified using 16S rRNA gene sequence analysis as belonging to the phylum Synergistetes and was designated strain MFA1. Growth was stimulated by amino acids with greater quantities of amino acids metabolized in the presence of fluoroacetate, but sugars were not fermented. Acetate, formate, propionate, isobutryate, isovalerate, ornithine and H(2) were end products of amino acid metabolism. Acetate was the primary end product of fluoroacetate dehalogenation, and the amount produced correlated with the stoichiometric release of fluoride which was confirmed using fluorine nuclear magnetic resonance ((19) F NMR) spectroscopy. Hydrogen and formate produced in situ were consumed during dehalogenation. The growth characteristics of strain MFA1 indicated that the bacterium may gain energy via reductive dehalogenation. This is the first study to identify a bacterium that can anaerobically dehalogenate fluoroacetate. Nested 16S rRNA gene-specific PCR assays detected the bacterium at low numbers in the gut of several herbivore species. © 2012 Commonwealth of Australia.

Tough Textiles Protect Payloads and Public Safety Officers

NASA Technical Reports Server (NTRS)

2009-01-01

In order to create the Mars Pathfinder s mission-critical airbags in the 1990s, NASA s Jet Propulsion Laboratory collaborated with New Ipswich, New Hampshire s Warwick Mills Inc. to weave multi-layer textiles for the airbags for both Pathfinder and the Mars Exploration Rovers. Warwick Mills applied techniques from the collaboration to its puncture- and impact-resistant TurtleSkin product line. The company's metal flex armor (MFA) vests offer stab protection comparable with rigid steel plates and over 50,000 of the vests have sold. The SoftPlate body armor offers protection from handgun bullets, and like the MFA, is designed to be more comfortable than rigid vests. International public safety and military customers are now benefiting from the TurtleSkin products.

Integration of a constraint-based metabolic model of Brassica napus developing seeds with 13C-metabolic flux analysis

PubMed Central

Hay, Jordan O.; Shi, Hai; Heinzel, Nicolas; Hebbelmann, Inga; Rolletschek, Hardy; Schwender, Jorg

2014-01-01

The use of large-scale or genome-scale metabolic reconstructions for modeling and simulation of plant metabolism and integration of those models with large-scale omics and experimental flux data is becoming increasingly important in plant metabolic research. Here we report an updated version of bna572, a bottom-up reconstruction of oilseed rape (Brassica napus L.; Brassicaceae) developing seeds with emphasis on representation of biomass-component biosynthesis. New features include additional seed-relevant pathways for isoprenoid, sterol, phenylpropanoid, flavonoid, and choline biosynthesis. Being now based on standardized data formats and procedures for model reconstruction, bna572+ is available as a COBRA-compliant Systems Biology Markup Language (SBML) model and conforms to the Minimum Information Requested in the Annotation of Biochemical Models (MIRIAM) standards for annotation of external data resources. Bna572+ contains 966 genes, 671 reactions, and 666 metabolites distributed among 11 subcellular compartments. It is referenced to the Arabidopsis thaliana genome, with gene-protein-reaction (GPR) associations resolving subcellular localization. Detailed mass and charge balancing and confidence scoring were applied to all reactions. Using B. napus seed specific transcriptome data, expression was verified for 78% of bna572+ genes and 97% of reactions. Alongside bna572+ we also present a revised carbon centric model for 13C-Metabolic Flux Analysis (13C-MFA) with all its reactions being referenced to bna572+ based on linear projections. By integration of flux ratio constraints obtained from 13C-MFA and by elimination of infinite flux bounds around thermodynamically infeasible loops based on COBRA loopless methods, we demonstrate improvements in predictive power of Flux Variability Analysis (FVA). Using this combined approach we characterize the difference in metabolic flux of developing seeds of two B. napus genotypes contrasting in starch and oil content. PMID:25566296

Assessment of energetic costs of AhR activation by β-naphthoflavone in rainbow trout (Oncorhynchus mykiss) hepatocytes using metabolic flux analysis

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

Nault, Rance, E-mail: naultran@msu.edu; Abdul-Fattah, Hiba; Mironov, Gleb G.

2013-08-15

Exposure to environmental contaminants such as activators of the aryl hydrocarbon receptor (AhR) leads to the induction of defense and detoxification mechanisms. While these mechanisms allow organisms to metabolize and excrete at least some of these environmental contaminants, it has been proposed that these mechanisms lead to significant energetic challenges. This study tests the hypothesis that activation of the AhR by the model agonist β-naphthoflavone (βNF) results in increased energetic costs in rainbow trout (Oncorhynchus mykiss) hepatocytes. To address this hypothesis, we employed traditional biochemical approaches to examine energy allocation and metabolism including the adenylate energy charge (AEC), protein synthesismore » rates, Na{sup +}/K{sup +}-ATPase activity, and enzyme activities. Moreover, we have used for the first time in a fish cell preparation, metabolic flux analysis (MFA) an in silico approach for the estimation of intracellular metabolic fluxes. Exposure of trout hepatocytes to 1 μM βNF for 48 h did not alter hepatocyte AEC, protein synthesis, or Na{sup +}/K{sup +}-ATPase activity but did lead to sparing of glycogen reserves and changes in activities of alanine aminotransferase and citrate synthase suggesting altered metabolism. Conversely, MFA did not identify altered metabolic fluxes, although we do show that the dynamic metabolism of isolated trout hepatocytes poses a significant challenge for this type of approach which should be considered in future studies. - Highlights: • Energetic costs of AhR activation by βNF was examined in rainbow trout hepatocytes. • Metabolic flux analysis was performed on a fish cell preparation for the first time. • Exposure to βNF led to sparing of glycogen reserves and altered enzyme activities. • Adenylate energy charge was maintained despite temporal changes in metabolism.« less

Step to improve neural cryptography against flipping attacks.

PubMed

Zhou, Jiantao; Xu, Qinzhen; Pei, Wenjiang; He, Zhenya; Szu, Harold

2004-12-01

Synchronization of neural networks by mutual learning has been demonstrated to be possible for constructing key exchange protocol over public channel. However, the neural cryptography schemes presented so far are not the securest under regular flipping attack (RFA) and are completely insecure under majority flipping attack (MFA). We propose a scheme by splitting the mutual information and the training process to improve the security of neural cryptosystem against flipping attacks. Both analytical and simulation results show that the success probability of RFA on the proposed scheme can be decreased to the level of brute force attack (BFA) and the success probability of MFA still decays exponentially with the weights' level L. The synchronization time of the parties also remains polynomial with L. Moreover, we analyze the security under an advanced flipping attack.

A 3D QSAR study of betulinic acid derivatives as anti-tumor agents using topomer CoMFA: model building studies and experimental verification.

PubMed

Ding, Weimin; Sun, Miao; Luo, Shaman; Xu, Tao; Cao, Yibo; Yan, Xiufeng; Wang, Yang

2013-08-22

Betulinic acid (BA) is a natural product that exerts its cytotoxicity against various malignant carcinomas without side effects by triggering the mitochondrial pathway to apoptosis. Betulin (BE), the 28-hydroxyl analog of BA, is present in large amounts (up to 30% dry weight) in the outer bark of birch trees, and shares the same pentacyclic triterpenoid core as BA, yet exhibits no significant cytotoxicity. Topomer CoMFA studies were performed on 37 BA and BE derivatives and their in vitro anti-cancer activity results (reported as IC₅₀ values) against HT29 human colon cancer cells in the present study. All derivatives share a common pentacyclic triterpenoid core and the molecules were split into three pieces by cutting at the C-3 and C-28 sites with a consideration toward structural diversity. The analysis gave a leave-one-out cross-validation q² value of 0.722 and a non-cross-validation r² value of 0.974, which suggested that the model has good predictive ability (q² > 0.2). The contour maps illustrated that bulky and electron-donating groups would be favorable for activity at the C-28 site, and a moderately bulky and electron-withdrawing group near the C-3 site would improve this activity. BE derivatives were designed and synthesized according to the modeling result, whereby bulky electronegative groups (maleyl, phthalyl, and hexahydrophthalyl groups) were directly introduced at the C-28 position of BE. The in vitro cytotoxicity values of the given analogs against HT29 cells were consistent with the predicted values, proving that the present topomer CoMFA model is successful and that it could potentially guide the synthesis of new betulinic acid derivatives with high anti-cancer activity. The IC₅₀ values of these three new compounds were also assayed in five other tumor cell lines. 28-O-hexahydrophthalyl BE exhibited the greatest anti-cancer activities and its IC₅₀ values were lower than those of BA in all cell lines, excluding DU145 cells.

Metabolic flux profiling of recombinant protein secreting Pichia pastoris growing on glucose:methanol mixtures

PubMed Central

2012-01-01

Background The methylotrophic yeast Pichia pastoris has emerged as one of the most promising yeast hosts for the production of heterologous proteins. Mixed feeds of methanol and a multicarbon source instead of methanol as sole carbon source have been shown to improve product productivities and alleviate metabolic burden derived from protein production. Nevertheless, systematic quantitative studies on the relationships between the central metabolism and recombinant protein production in P. pastoris are still rather limited, particularly when growing this yeast on mixed carbon sources, thus hampering future metabolic network engineering strategies for improved protein production. Results The metabolic flux distribution in the central metabolism of P. pastoris growing on a mixed feed of glucose and methanol was analyzed by Metabolic Flux Analysis (MFA) using 13C-NMR-derived constraints. For this purpose, we defined new flux ratios for methanol assimilation pathways in P. pastoris cells growing on glucose:methanol mixtures. By using this experimental approach, the metabolic burden caused by the overexpression and secretion of a Rhizopus oryzae lipase (Rol) in P. pastoris was further analyzed. This protein has been previously shown to trigger the unfolded protein response in P. pastoris. A series of 13C-tracer experiments were performed on aerobic chemostat cultivations with a control and two different Rol producing strains growing at a dilution rate of 0.09 h−1 using a glucose:methanol 80:20 (w/w) mix as carbon source. The MFA performed in this study reveals a significant redistristribution of carbon fluxes in the central carbon metabolism when comparing the two recombinant strains vs the control strain, reflected in increased glycolytic, TCA cycle and NADH regeneration fluxes, as well as higher methanol dissimilation rates. Conclusions Overall, a further 13C-based MFA development to characterise the central metabolism of methylotrophic yeasts when growing on mixed methanol:multicarbon sources has been implemented, thus providing a new tool for the investigation of the relationships between central metabolism and protein production. Specifically, the study points at a limited but significant impact of the conformational stress associated to secretion of recombinant proteins on the central metabolism, occurring even at modest production levels. PMID:22569166

QSAR, molecular docking studies of thiophene and imidazopyridine derivatives as polo-like kinase 1 inhibitors

NASA Astrophysics Data System (ADS)

Cao, Shandong

2012-08-01

The purpose of the present study was to develop in silico models allowing for a reliable prediction of polo-like kinase inhibitors based on a large diverse dataset of 136 compounds. As an effective method, quantitative structure activity relationship (QSAR) was applied using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The proposed QSAR models showed reasonable predictivity of thiophene analogs (Rcv2=0.533, Rpred2=0.845) and included four molecular descriptors, namely IC3, RDF075m, Mor02m and R4e+. The optimal model for imidazopyridine derivatives (Rcv2=0.776, Rpred2=0.876) was shown to perform good in prediction accuracy, using GATS2m and BEHe1 descriptors. Analysis of the contour maps helped to identify structural requirements for the inhibitors and served as a basis for the design of the next generation of the inhibitor analogues. Docking studies were also employed to position the inhibitors into the polo-like kinase active site to determine the most probable binding mode. These studies may help to understand the factors influencing the binding affinity of chemicals and to develop alternative methods for prescreening and designing of polo-like kinase inhibitors.

Naive, captive long-tailed macaques (Macaca fascicularis fascicularis) fail to individually and socially learn pound-hammering, a tool-use behaviour

PubMed Central

Tennie, Claudio

2018-01-01

A subspecies of long-tailed macaques (Macaca fascicularis aurea; Mfa) has been reported to use stone tools and a specific technique to process nuts in Southeast Asia, a behaviour known as ‘pound-hammering’. The aim of this study was to examine the development of pound-hammering in long-tailed macaques: whether this behavioural form can be individually learnt or whether it has to rely on some forms of social learning. Given the absence of Mfa from captivity, long-tailed macaques of a highly related subspecies (Macaca fascicularis fascicularis; Mff) were experimentally tested by providing them with the ecological materials necessary to show pound-hammering. A baseline was first carried out to observe whether pound-hammering would emerge spontaneously without social information. As this was not the case, different degrees of social information, culminating in a full demonstration of the behaviour, were provided. None of the subjects (n = 31) showed pound-hammering in any of the individual or social learning conditions. Although these data do not support the hypothesis that individual learning underlies this behaviour, no evidence was found that (at least) Mff learn pound-hammering socially either. We propose that other—potentially interacting—factors may determine whether this behaviour emerges in the various subspecies of long-tailed macaques, and provide a novel methodology to test the role of social and individual learning in the development of animal tool-use. PMID:29892375

Sequence-specific inhibition of Dicer measured with a force-based microarray for RNA ligands.

PubMed

Limmer, Katja; Aschenbrenner, Daniela; Gaub, Hermann E

2013-04-01

Malfunction of protein translation causes many severe diseases, and suitable correction strategies may become the basis of effective therapies. One major regulatory element of protein translation is the nuclease Dicer that cuts double-stranded RNA independently of the sequence into pieces of 19-22 base pairs starting the RNA interference pathway and activating miRNAs. Inhibiting Dicer is not desirable owing to its multifunctional influence on the cell's gene regulation. Blocking specific RNA sequences by small-molecule binding, however, is a promising approach to affect the cell's condition in a controlled manner. A label-free assay for the screening of site-specific interference of small molecules with Dicer activity is thus needed. We used the Molecular Force Assay (MFA), recently developed in our lab, to measure the activity of Dicer. As a model system, we used an RNA sequence that forms an aptamer-binding site for paromomycin, a 615-dalton aminoglycoside. We show that Dicer activity is modulated as a function of concentration and incubation time: the addition of paromomycin leads to a decrease of Dicer activity according to the amount of ligand. The measured dissociation constant of paromomycin to its aptamer was found to agree well with literature values. The parallel format of the MFA allows a large-scale search and analysis for ligands for any RNA sequence.

Configuration of Materially Retained Carbon in Our Society: A WIO-MFA-Based Approach for Japan.

PubMed

Ohno, Hajime; Sato, Hirokazu; Fukushima, Yasuhiro

2018-04-03

To achieve the goals of Paris Agreement, global society is directing much effort in substantially reducing greenhouse gas (GHG) emissions. In addition to energy-related efforts, prevention of carbon release into the atmosphere with carbon capture and storage (CCS) and/or utilization of biomass resources is considered indispensable to achieving the global objective. In this study, considering carbon-containing goods as carbon reservoirs in our society similar to forests and reservoirs enabling CCS, the flow of materially utilized carbon was quantified by input-output-based material flow analysis (IO-MFA). As a result, in 2011, 6.3 Mt-C of petroleum-derived carbon and 7.9 Mt-C of wood-derived carbon were introduced to the Japanese society as end-use products (e.g., automobiles and constructions) in various forms (e.g., plastics and synthetic rubbers). The total amount (14.2 Mt-C) corresponded to 4.1% (52.1 Mt-CO 2 ) of annual CO 2 emission in Japan in 2011. Subsequently, by referring to the technology that can treat carbon in the target forms in end-of-life products, the recoverability of carbon as a material has been discussed with respect to each form and end-use of carbon. By numerically showing the necessity and potential of implementing appropriate technologies, this study provides scientific direction for policymakers to establish a quality carbon cycle in our society.

General Purpose Electronegativity Relaxation Charge Models Applied to CoMFA and CoMSIA Study of GSK-3 Inhibitors.

PubMed

Tsareva, Daria A; Osolodkin, Dmitry I; Shulga, Dmitry A; Oliferenko, Alexander A; Pisarev, Sergey A; Palyulin, Vladimir A; Zefirov, Nikolay S

2011-03-14

Two fast empirical charge models, Kirchhoff Charge Model (KCM) and Dynamic Electronegativity Relaxation (DENR), had been developed in our laboratory previously for widespread use in drug design research. Both models are based on the electronegativity relaxation principle (Adv. Quantum Chem. 2006, 51, 139-156) and parameterized against ab initio dipole/quadrupole moments and molecular electrostatic potentials, respectively. As 3D QSAR studies comprise one of the most important fields of applied molecular modeling, they naturally have become the first topic to test our charges and thus, indirectly, the assumptions laid down to the charge model theories in a case study. Here these charge models are used in CoMFA and CoMSIA methods and tested on five glycogen synthase kinase 3 (GSK-3) inhibitor datasets, relevant to our current studies, and one steroid dataset. For comparison, eight other different charge models, ab initio through semiempirical and empirical, were tested on the same datasets. The complex analysis including correlation and cross-validation, charges robustness and predictability, as well as visual interpretability of 3D contour maps generated was carried out. As a result, our new electronegativity relaxation-based models both have shown stable results, which in conjunction with other benefits discussed render them suitable for building reliable 3D QSAR models. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DAT/SERT Selectivity of Flexible GBR 12909 Analogs Modeled Using 3D-QSAR Methods

PubMed Central

Gilbert, Kathleen M.; Boos, Terrence L.; Dersch, Christina M.; Greiner, Elisabeth; Jacobson, Arthur E.; Lewis, David; Matecka, Dorota; Prisinzano, Thomas E.; Zhang, Ying; Rothman, Richard B.; Rice, Kenner C.; Venanzi, Carol A.

2007-01-01

The dopamine reuptake inhibitor GBR 12909 (1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine, 1) and its analogs have been developed as tools to test the hypothesis that selective dopamine transporter (DAT) inhibitors will be useful therapeutics for cocaine addiction. This 3D-QSAR study focuses on the effect of substitutions in the phenylpropyl region of 1. CoMFA and CoMSIA techniques were used to determine a predictive and stable model for the DAT/serotonin transporter (SERT) selectivity (represented by pKi (DAT/SERT)) of a set of flexible analogs of 1, most of which have eight rotatable bonds. In the absence of a rigid analog to use as a 3D-QSAR template, six conformational families of analogs were constructed from six pairs of piperazine and piperidine template conformers identified by hierarchical clustering as representative molecular conformations. Three models stable to y-value scrambling were identified after a comprehensive CoMFA and CoMSIA survey with Region Focusing. Test set correlation validation led to an acceptable model, with q2 = 0.508, standard error of prediction = 0.601, two components, r2 = 0.685, standard error of estimate = 0.481, F value = 39, percent steric contribution = 65, and percent electrostatic contribution = 35. A CoMFA contour map identified areas of the molecule that affect pKi (DAT/SERT). This work outlines a protocol for deriving a stable and predictive model of the biological activity of a set of very flexible molecules. PMID:17127069

3D-QSAR studies on 1,2,4-triazolyl 5-azaspiro [2.4]-heptanes as D3R antagonists

NASA Astrophysics Data System (ADS)

Zhang, Xin; Zhang, Hui

2018-07-01

Dopamine D3 receptor has become an attractive target in the treatment of abused drugs. 3D-QSAR studies were performed on a novel series of D3 receptor antagonists, 1,2,4-triazolyl 5-azaspiro [2.4]-heptanes, using CoMFA and CoMSIA methods. Two predictive 3D-QSAR models have been generated for the modified design of D3R antagonists. Based on the steric, electrostatic, hydrophobic and hydrogen-bond acceptor information of contour maps, key structural factors affecting the bioactivity were explored. This work gives helpful suggestions on the design of novel D3R antagonists with increased activities.

Investigation on Quantitative Structure Activity Relationships and Pharmacophore Modeling of a Series of mGluR2 Antagonists

PubMed Central

Zhang, Meng-Qi; Zhang, Xiao-Le; Li, Yan; Fan, Wen-Jia; Wang, Yong-Hua; Hao, Ming; Zhang, Shu-Wei; Ai, Chun-Zhi

2011-01-01

MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson’s disease and schizophrenia. Herein, we report the three-dimensional quantitative structure–activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[ b][1,4]diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [3H]-LY354740; activity II: mGluR2 (1S,3R)-ACPD inhibition of forskolin stimulated cAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q2 of 0.513, R2 ncv of 0.868, R2 pred = 0.876, while the CoMSIA model yielded a Q2 of 0.450, R2 ncv = 0.899, R2 pred = 0.735. For activity II study, CoMFA model yielded statistics of Q2 = 0.5, R2 ncv = 0.715, R2 pred = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R7, R3 and position A benefit activity I of the antagonists, but decrease it when projected in R8 and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity. This work is the first report on 3D-QSAR modeling of these mGluR2 antagonists. All the conclusions may lead to a better understanding of the mechanism of antagonism and be helpful in the design of new potent mGluR2 antagonists. PMID:22016641

Investigation on quantitative structure activity relationships and pharmacophore modeling of a series of mGluR2 antagonists.

PubMed

Zhang, Meng-Qi; Zhang, Xiao-Le; Li, Yan; Fan, Wen-Jia; Wang, Yong-Hua; Hao, Ming; Zhang, Shu-Wei; Ai, Chun-Zhi

2011-01-01

MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson's disease and schizophrenia. Herein, we report the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[ b][1,4]diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [(3)H]-LY354740; activity II: mGluR2 (1S,3R)-ACPD inhibition of forskolin stimulated cAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q(2) of 0.513, R(2) (ncv) of 0.868, R(2) (pred) = 0.876, while the CoMSIA model yielded a Q(2) of 0.450, R(2) (ncv) = 0.899, R(2) (pred) = 0.735. For activity II study, CoMFA model yielded statistics of Q(2) = 0.5, R(2) (ncv) = 0.715, R(2) (pred) = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R(7), R(3) and position A benefit activity I of the antagonists, but decrease it when projected in R(8) and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity. This work is the first report on 3D-QSAR modeling of these mGluR2 antagonists. All the conclusions may lead to a better understanding of the mechanism of antagonism and be helpful in the design of new potent mGluR2 antagonists.

Material flows accounting for Scotland shows the merits of a circular economy and the folly of territorial carbon reporting.

PubMed

Pratt, Kimberley; Lenaghan, Michael; Mitchard, Edward T A

2016-12-01

It is essential that the human race limits the environmental damage created by our consumption. A realistic pathway to limiting consumption would be to transition to a system where materials are conserved and cycled through the economy as many times as possible and as slowly as possible, greatly reducing the greenhouse gas intensive processes of resource extraction, resource processing and waste management. Material flow analysis (MFA) is a method used to understand how materials are consumed within a nation. In this study, we attempt a MFA for Scotland which links carbon emissions to material consumption using data directly based on the mass of materials used in the Scottish economy. It is the first time such an analysis has been conducted for an economy in its entirety. This study aims to create a detailed material flow account (MFA) for Scotland, compare the environmental impacts and possible policy implications of different future material consumption scenarios and consider two materials, steel and neodymium, in detail. The model estimated that 11.4 Mg per capita of materials are consumed per year in Scotland, emitting 10.7 Mg CO 2 e per capita in the process, of which, 6.7 Mg CO 2 e per capita falls under territorial carbon accounting. Only the circular economy scenario for 2050 allowed for increases in living standards without increases in carbon emissions and material consumption. This result was mirrored in the steel and neodymium case studies-environmental impacts can be minimised by a national strategy that first reduces use, and then locally reuses materials. Material consumption accounts for a large proportion of the carbon emissions of Scotland. Strategic dematerialisation, particular of materials such as steel, could support future efforts to reduce environmental impact and meet climate change targets. However, policy makers should consider consumption carbon accounting boundaries, as well as territorial boundaries, if carbon savings are to be maximised. This is because imports and recyclate sent abroad can have significant effect on the carbon emissions from material consumption. We demonstrate that the more circular an economy is, the smaller the difference between global and territorial carbon emissions, and therefore that climate change targets based solely on territorial carbon emissions create perverse incentives. The study also found that there could be areas of economic development which are compatible with environmental aims, based around encouraging reprocessing activities in developed nations.

QSAR analyses of 3-(4-benzylpiperidin-1-yl)-N-phenylpropylamine derivatives as potent CCR5 antagonists.

PubMed

Roy, Kunal; Leonard, J Thomas

2005-01-01

CCR5 receptor binding affinity of a series of 3-(4-benzylpiperidin-1-yl)propylamine congeners was subjected to QSAR study using the linear free energy related (LFER) model of Hansch. Appropriate indicator variables encoding different group contributions and different physicochemical variables such as hydrophobicity (pi), electronic (Hammett sigma), and steric (molar refractivity, STERIMOL values) parameters of phenyl ring substituents of the compounds were used as predictor variables. The Hansch analysis explores the importance of the lipophilicity and electron-donating substituents for the binding affinity. However, this method could not give more insight into the structure-activity relationships because of the diverse molecular features in the data set. 3D-QSAR analyses of the same data set using Molecular Shape Analysis (MSA), Receptor Surface Analysis (RSA), and Molecular Field Analysis (MFA) techniques were also performed. The best model with acceptable statistical quality was derived from the MSA, which showed the importance of the relative negative charge (RNCG): substituents with a high RNCG value have more binding affinity than the unsubstituted piperidine and phenyl (R1 position) congeners. The relative negative charge surface area (RNCS) is detrimental (e.g. R2 = 3,4-Cl2) for the activity. An increase in the length of the molecule in the Z dimension (Lz) is conducive (e.g. R3 = sulfonylmorpholino), while an increase in the area of the molecular shadow in the XZ plane (Sxz) is detrimental (e.g. R1 = N-c-hexylmethyl-5-oxopyrrolidin-3-yl) for the binding affinity. The presence of a chiral center makes the molecule less active (e.g. R1 = N-methyl-5-oxopyrrolidin-3-yl). An increase in the van der Waals area, the molecular volume, and the difference between the volume of the individual molecule and the shape reference compound are conducive (e.g. R3 = (CH3)2NSO2-) for the binding affinity. Substituents with higher JursFPSA_2 values (fractional charged partial surface area) like the N-methylsulfonylpiperidin-4-yl (R1 position) group have better binding affinity than the substituents such as 4-chlorophenylamino (R1 position). Unsubstituted piperidines (R1 position) with less JursFNSA_1 values have lower binding affinity than the 4-chlorophenyl substituted compounds. The MFA derived equation shows interaction energies at different grid points, while the RSA model shows the importance of hydrophobicity and charge at different regions of the molecules. The models were validated through the leave-one-out, leave-15%-out, and leave-25%-out cross-validation techniques. The developed models were also subjected to a randomization test (99% confidence level). Although the MSA derived models had excellent statistical qualities both for the training as well as test sets, RSA and MFA results for the test sets are not comparable statistically with the MSA derived models.

Application of material flow analysis to municipal solid waste in Maputo City, Mozambique.

PubMed

Dos Muchangos, Leticia Sarmento; Tokai, Akihiro; Hanashima, Atsuko

2017-03-01

Understanding waste flows within an urban area is important for identifying the main problems and improvement opportunities for efficient waste management. Assessment tools such as material flow analysis (MFA), an extensively applied method in waste management studies, provide a structured and objective evaluating process to characterize the waste management system best, to identify its shortcomings and to propose suitable strategies. This paper presents the application of MFA to municipal solid waste management (MSWM) in Maputo City, the capital of Mozambique. The results included the identification and quantification of the main input and output flows of the MSWM system in 2007 and 2014, from the generation, material recovery and collection, to final disposal and the unaccounted flow of municipal solid waste (MSW). We estimated that the waste generation increased from 397×10 3  tonnes in 2007 to 437×10 3  tonnes in 2014, whereas the total material recovery was insignificant in both years - 3×10 3 and 7×10 3  tonnes, respectively. As for collection and final disposal, the official collection of waste to the local dumpsite in the inner city increased about threefold, from 76×10 3 to 253×10 6  tonnes. For waste unaccounted for, the estimates indicated a reduction during the study period from 300×10 3 to 158×10 3  tonnes, due to the increase of collection services. The emphasized aspects include the need for practical waste reduction strategies, the opportunity to explore the potential for material recovery, careful consideration regarding the growing trend of illegal dumping and the urgency in phasing-out from the harmful practice of open dumping.

Design, synthesis, antiviral activity and three-dimensional quantitative structure-activity relationship study of novel 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety.

PubMed

Gan, Xiuhai; Hu, Deyu; Li, Pei; Wu, Jian; Chen, Xuewen; Xue, Wei; Song, Baoan

2016-03-01

1,4-Pentadien-3-one and 1,3,4-oxadiazole derivatives possess good antiviral activities, and their substructure units are usually used in antiviral agent design. In order to discover novel molecules with high antiviral activities, a series of 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety were designed and synthesised. Bioassays showed that most of the title compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV) in vivo. The compound 8f possessing the best protective activity against TMV had an EC50 value of 135.56 mg L(-1) , which was superior to that of ribavirin (435.99 mg L(-1) ). Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were used in three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of protective activities, with values of q(2) and r(2) for the CoMFA and CoMSIA models of 0.751 and 0.775 and 0.936 and 0.925 respectively. Compound 8k with higher protective activity (EC50 = 123.53 mg L(-1) ) according to bioassay was designed and synthesised on the basis of the 3D-QSAR models. Some of the title compounds displayed good antiviral activities. 3D-QSAR models revealed that the appropriate compact electron-withdrawing and hydrophobic group at the benzene ring could enhance antiviral activity. These results could provide important structural insights for the design of highly active 1,4-pentadien-3-one derivatives. © 2015 Society of Chemical Industry.

Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β₂-adrenergic receptor.

PubMed

Plazinska, Anita; Pajak, Karolina; Rutkowska, Ewelina; Jimenez, Lucita; Kozocas, Joseph; Koolpe, Gary; Tanga, Mary; Toll, Lawrence; Wainer, Irving W; Jozwiak, Krzysztof

2014-01-01

The β₂-adrenergic receptor (β₂-AR) agonist [(3)H]-(R,R')-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4'-methoxyfenoterol analogs in which the length of the alkyl substituent at α' position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [(3)H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC₅₀ values, were determined in HEK293 cells expressing the β₂-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α' position. The results also indicate that the Ki values obtained using [(3)H]-(R,R')-methoxyfenoterol as the marker ligand modeled the EC₅₀ values obtained from cAMP stimulation better than the data obtained using [(3)H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β₂-AR conformation probed by [(3)H]-(R,R')-4'-methoxyfenoterol. The CoMFA model of the agonist-stabilized β₂-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β₂-AR is governed to a greater extend by steric effects than binding to the [(3)H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role. Copyright © 2013 Elsevier Ltd. All rights reserved.

Comparative Molecular Field Analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β2-adrenergic receptor

PubMed Central

Plazinska, Anita; Pajak, Karolina; Rutkowska, Ewelina; Jimenez, Lucita; Kozocas, Joseph; Koolpe, Gary; Tanga, Mary; Toll, Lawrence; Wainer, Irving W.; Jozwiak, Krzysztof

2014-01-01

The β2-adrenergic receptor (β2-AR) agonist [3H]-(R,R′)-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4′-methoxyfenoterol analogs in which the length of the alkyl substituent at α′ position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [3H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC50 values, were determined in HEK293 cells expressing the β2-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α′ position. The results also indicate that the Ki values obtained using [3H]-(R,R′)-methoxyfenoterol as the marker ligand modeled the EC50 values obtained from cAMP stimulation better than the data obtained using [3H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β2-AR conformation probed by [3H]-(R,R′)-4′-methoxyfenoterol. The CoMFA model of the agonist-stabilized β2-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β2-AR is governed to a greater extend by steric effects than binding to the [3H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role. PMID:24326276

Molecular Determinants of Juvenile Hormone Action as Revealed by 3D QSAR Analysis in Drosophila

PubMed Central

Beňo, Milan; Farkaš, Robert

2009-01-01

Background Postembryonic development, including metamorphosis, of many animals is under control of hormones. In Drosophila and other insects these developmental transitions are regulated by the coordinate action of two principal hormones, the steroid ecdysone and the sesquiterpenoid juvenile hormone (JH). While the mode of ecdysone action is relatively well understood, the molecular mode of JH action remains elusive. Methodology/Principal Findings To gain more insights into the molecular mechanism of JH action, we have tested the biological activity of 86 structurally diverse JH agonists in Drosophila melanogaster. The results were evaluated using 3D QSAR analyses involving CoMFA and CoMSIA procedures. Using this approach we have generated both computer-aided and species-specific pharmacophore fingerprints of JH and its agonists, which revealed that the most active compounds must possess an electronegative atom (oxygen or nitrogen) at both ends of the molecule. When either of these electronegative atoms are replaced by carbon or the distance between them is shorter than 11.5 Å or longer than 13.5 Å, their biological activity is dramatically decreased. The presence of an electron-deficient moiety in the middle of the JH agonist is also essential for high activity. Conclusions/Significance The information from 3D QSAR provides guidelines and mechanistic scope for identification of steric and electrostatic properties as well as donor and acceptor hydrogen-bonding that are important features of the ligand-binding cavity of a JH target protein. In order to refine the pharmacophore analysis and evaluate the outcomes of the CoMFA and CoMSIA study we used pseudoreceptor modeling software PrGen to generate a putative binding site surrogate that is composed of eight amino acid residues corresponding to the defined molecular interactions. PMID:19547707

Metabolic Flux Analysis of the Synechocystis sp. PCC 6803 ΔnrtABCD Mutant Reveals a Mechanism for Metabolic Adaptation to Nitrogen-Limited Conditions.

PubMed

Nakajima, Tsubasa; Yoshikawa, Katsunori; Toya, Yoshihiro; Matsuda, Fumio; Shimizu, Hiroshi

2017-03-01

Metabolic flux redirection during nitrogen-limited growth was investigated in the Synechocystis sp. PCC 6803 glucose-tolerant (GT) strain under photoautotrophic conditions by isotopically non-stationary metabolic flux analysis (INST-MFA). A ΔnrtABCD mutant of Synechocystis sp. PCC 6803 was constructed to reproduce phenotypes arising during nitrogen starvation. The ΔnrtABCD mutant and the wild-type GT strain were cultured under photoautotrophic conditions by a photobioreactor. Intracellular metabolites were labeled over a time course using NaH13CO3 as a carbon source. Based on these data, the metabolic flux distributions in the wild-type and ΔnrtABCD cells were estimated by INST-MFA. The wild-type GT and ΔnrtABCD strains displayed similar distribution patterns, although the absolute levels of metabolic flux were lower in ΔnrtABCD. Furthermore, the relative flux levels for glycogen metabolism, anaplerotic reactions and the oxidative pentose phosphate pathway were increased in ΔnrtABCD. This was probably due to the increased expression of enzyme genes that respond to nitrogen depletion. Additionally, we found that the ratio of ATP/NADPH demand increased slightly in the ΔnrtABCD mutant. These results indicated that futile ATP consumption increases under nitrogen-limited conditions because the Calvin-Benson cycle and the oxidative pentose phosphate pathway form a metabolic futile cycle that consumes ATP without CO2 fixation and NADPH regeneration. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Quasi-dynamic Material Flow Analysis applied to the Austrian Phosphorus cycle

NASA Astrophysics Data System (ADS)

Zoboli, Ottavia; Rechberger, Helmut

2013-04-01

Phosphorus (P) is one of the key elements that sustain life on earth and that allow achieving the current high levels of food production worldwide. It is a non-renewable resource, without any existing substitute. Because of its current dissipative use by mankind and to its very slow geochemical cycle, this resource is rapidly depleting and it is strongly connected to the problem of ensuring food security. Moreover P is also associated to important environmental problems. Its extraction often generates hazardous wastes, while its accumulation in water bodies can lead to eutrophication, with consequent severe ecological damages. It is therefore necessary to analyze and understand in detail the system of P, in regard to its use and management, to identify the processes that should be targeted in order to reduce the overall consumption of this resource. This work aims at establishing a generic quasi-dynamic model, which describes the Austrian P-budget and which allows investigating the trends of P use in the past, but also selected future scenarios. Given the importance of P throughout the whole anthropogenic metabolism, the model is based on a comprehensive system that encompasses several economic sectors, from agriculture and animal husbandry to industry, consumption and waste and wastewater treatment. Furthermore it includes the hydrosphere, to assess the losses of P into water bodies, due to the importance of eutrophication problems. The methodology applied is Material Flow Analysis (MFA), which is a systemic approach to assess and balance the stocks and flows of a material within a system defined in space and time. Moreover the model is integrated in the software STAN, a freeware tailor-made for MFA. Particular attention is paid to the characteristics and the quality of the data, in order to include data uncertainty and error propagation in the dynamic balance.

A Percutaneous Transtubular Middle Fossa Approach for Intracanalicular Tumors.

PubMed

Bernardo, Antonio; Evins, Alexander I; Tsiouris, Apostolos J; Stieg, Philip E

2015-07-01

In cases of small intracanalicular tumors (≤ 1.5 cm), the middle fossa approach (MFA) provides the ability for adequate tumor removal with preservation of existing auditory function. Application of a minimally invasive tubular retractor in this approach may help mitigate the risk of postoperative seizures, aphasia, and venous complications by minimizing intraoperative retraction of the temporal lobe. We propose a minimally invasive microscopic and/or endoscopic percutaneous transtubular MFA for the management of intracanalicular tumors. Subtemporal keyhole craniectomies were performed on 5 preserved cadaveric heads (10 sides), with 6 sides previously injected with a synthetic tumor model. A ViewSite Brain Access System tubular retractor (Vycor Medical, Inc., Boca Raton, Florida, USA) was used to provide minimal temporal retraction and protection of the surrounding anatomy. An extradural dissection of the internal auditory canal was performed under microscopic and endoscopic visualization with a minimally invasive surgical drill and tube shaft instruments, the intracanalicular tumors were removed, and degree of resection was assessed. All 10 approaches were completed successfully through the tubular retractor with minimal retraction of the temporal lobe. Excellent visualization of the structures within the internal auditory canal was achieved with both the microscope and 3-dimensional endoscope. On the 6 synthetic intracanalicular tumors resected, 5 gross total (Grade I) and 1 near total (Grade II) resections were achieved. A percutaneous transtubular MFA is a feasible minimally invasive option for resection of small intracanalicular tumors with potential preservation of auditory function, reduced temporal retraction, and enhanced protection of surrounding structures. Copyright © 2015 Elsevier Inc. All rights reserved.

A longitudinal study of maternal attachment and infant developmental outcomes.

PubMed

Alhusen, Jeanne L; Hayat, Matthew J; Gross, Deborah

2013-12-01

Extant research has demonstrated that compared to adults with insecure attachment styles, more securely attached parents tend to be more responsive, sensitive, and involved parents, resulting in improved outcomes for their children. Less studied is the influence of a mother's attachment style on her attachment to her unborn child during pregnancy and the consequent developmental outcomes of the child during early childhood. Thus, the aim of this prospective longitudinal study was to examine the relationship between maternal-fetal attachment (MFA) during pregnancy and infant and toddler outcomes and the role of mothers' attachment style on early childhood developmental outcomes in an economically disadvantaged sample of women and their children. Gamma regression modeling demonstrated that an avoidant maternal attachment style (b = .98, 95 % CI [.97, .98], p < 0.001) and post-partum depressive symptomatology (b = .97, 95 % CI [.96-.99], p = 0.03) were significant predictors of early childhood development. Women demonstrating higher avoidant attachment styles and greater depressive symptomatology were more likely to have children demonstrating early childhood developmental delays than those women with less avoidant attachment styles and less depressive symptomatology. Furthermore, women reporting higher MFA during pregnancy had more secure attachment styles, and their children had more optimal early childhood development than those women reporting lower MFA and less secure attachment styles. Findings have implications for enhancing early intervention programs aimed at improving maternal and childhood outcomes. An earlier identification of disruptions in attachment may be beneficial in tailoring interventions focused on the mother-child dyad.

Resource Use in Small Island States: Material Flows in Iceland and Trinidad and Tobago, 1961-2008.

PubMed

Krausmann, Fridolin; Richter, Regina; Eisenmenger, Nina

2014-04-01

Iceland and Trinidad and Tobago are small open, high-income island economies with very specific resource-use patterns. This article presents a material flow analysis (MFA) for the two countries covering a time period of nearly five decades. Both countries have a narrow domestic resource base, their economy being largely based on the exploitation of one or two key resources for export production. In the case of Trinidad and Tobago, the physical economy is dominated by oil and natural gas extraction and petrochemical industries, whereas Iceland's economy for centuries has been based on fisheries. More recently, abundant hydropower and geothermal heat were the basis for the establishment of large export-oriented metal processing industries, which fully depend on imported raw materials and make use of domestic renewable electricity. Both countries are highly dependent on these natural resources and vulnerable to overexploitation and price developments. We show how the export-oriented industries lead to high and growing levels of per capita material and energy use and carbon dioxide emissions resulting from large amounts of processing wastes and energy consumption in production processes. The example of small open economies with an industrial production system focused on few, but abundant, key resources and of comparatively low complexity provides interesting insights of how resource endowment paired with availability or absence of infrastructure and specific institutional arrangements drives domestic resource-use patterns. This also contributes to a better understanding and interpretation of MFA indicators, such as domestic material consumption.

Resource Use in Small Island States

PubMed Central

Krausmann, Fridolin; Richter, Regina; Eisenmenger, Nina

2014-01-01

Iceland and Trinidad and Tobago are small open, high-income island economies with very specific resource-use patterns. This article presents a material flow analysis (MFA) for the two countries covering a time period of nearly five decades. Both countries have a narrow domestic resource base, their economy being largely based on the exploitation of one or two key resources for export production. In the case of Trinidad and Tobago, the physical economy is dominated by oil and natural gas extraction and petrochemical industries, whereas Iceland's economy for centuries has been based on fisheries. More recently, abundant hydropower and geothermal heat were the basis for the establishment of large export-oriented metal processing industries, which fully depend on imported raw materials and make use of domestic renewable electricity. Both countries are highly dependent on these natural resources and vulnerable to overexploitation and price developments. We show how the export-oriented industries lead to high and growing levels of per capita material and energy use and carbon dioxide emissions resulting from large amounts of processing wastes and energy consumption in production processes. The example of small open economies with an industrial production system focused on few, but abundant, key resources and of comparatively low complexity provides interesting insights of how resource endowment paired with availability or absence of infrastructure and specific institutional arrangements drives domestic resource-use patterns. This also contributes to a better understanding and interpretation of MFA indicators, such as domestic material consumption. PMID:25505367

Integration of a constraint-based metabolic model of Brassica napus developing seeds with 13C-metabolic flux analysis

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

Hay, Jordan O.; Shi, Hai; Heinzel, Nicolas

The use of large-scale or genome-scale metabolic reconstructions for modeling and simulation of plant metabolism and integration of those models with large-scale omics and experimental flux data is becoming increasingly important in plant metabolic research. Here we report an updated version of bna572, a bottom-up reconstruction of oilseed rape (Brassica napus L.; Brassicaceae) developing seeds with emphasis on representation of biomass-component biosynthesis. New features include additional seed-relevant pathways for isoprenoid, sterol, phenylpropanoid, flavonoid, and choline biosynthesis. Being now based on standardized data formats and procedures for model reconstruction, bna572+ is available as a COBRA-compliant Systems Biology Markup Language (SBML) modelmore » and conforms to the Minimum Information Requested in the Annotation of Biochemical Models (MIRIAM) standards for annotation of external data resources. Bna572+ contains 966 genes, 671 reactions, and 666 metabolites distributed among 11 subcellular compartments. It is referenced to the Arabidopsis thaliana genome, with gene-protein-reaction (GPR) associations resolving subcellular localization. Detailed mass and charge balancing and confidence scoring were applied to all reactions. Using B. napus seed specific transcriptome data, expression was verified for 78% of bna572+ genes and 97% of reactions. Alongside bna572+ we also present a revised carbon centric model for 13C-Metabolic Flux Analysis ( 13C-MFA) with all its reactions being referenced to bna572+ based on linear projections. By integration of flux ratio constraints obtained from 13C-MFA and by elimination of infinite flux bounds around thermodynamically infeasible loops based on COBRA loopless methods, we demonstrate improvements in predictive power of Flux Variability Analysis (FVA). In conclusion, using this combined approach we characterize the difference in metabolic flux of developing seeds of two B. napus genotypes contrasting in starch and oil content.« less

Integration of a constraint-based metabolic model of Brassica napus developing seeds with 13C-metabolic flux analysis

DOE PAGES

Hay, Jordan O.; Shi, Hai; Heinzel, Nicolas; ...

2014-12-19

The use of large-scale or genome-scale metabolic reconstructions for modeling and simulation of plant metabolism and integration of those models with large-scale omics and experimental flux data is becoming increasingly important in plant metabolic research. Here we report an updated version of bna572, a bottom-up reconstruction of oilseed rape (Brassica napus L.; Brassicaceae) developing seeds with emphasis on representation of biomass-component biosynthesis. New features include additional seed-relevant pathways for isoprenoid, sterol, phenylpropanoid, flavonoid, and choline biosynthesis. Being now based on standardized data formats and procedures for model reconstruction, bna572+ is available as a COBRA-compliant Systems Biology Markup Language (SBML) modelmore » and conforms to the Minimum Information Requested in the Annotation of Biochemical Models (MIRIAM) standards for annotation of external data resources. Bna572+ contains 966 genes, 671 reactions, and 666 metabolites distributed among 11 subcellular compartments. It is referenced to the Arabidopsis thaliana genome, with gene-protein-reaction (GPR) associations resolving subcellular localization. Detailed mass and charge balancing and confidence scoring were applied to all reactions. Using B. napus seed specific transcriptome data, expression was verified for 78% of bna572+ genes and 97% of reactions. Alongside bna572+ we also present a revised carbon centric model for 13C-Metabolic Flux Analysis ( 13C-MFA) with all its reactions being referenced to bna572+ based on linear projections. By integration of flux ratio constraints obtained from 13C-MFA and by elimination of infinite flux bounds around thermodynamically infeasible loops based on COBRA loopless methods, we demonstrate improvements in predictive power of Flux Variability Analysis (FVA). In conclusion, using this combined approach we characterize the difference in metabolic flux of developing seeds of two B. napus genotypes contrasting in starch and oil content.« less

Studies of New Fused Benzazepine as Selective Dopamine D3 Receptor Antagonists Using 3D-QSAR, Molecular Docking and Molecular Dynamics

PubMed Central

Liu, Jing; Li, Yan; Zhang, Shuwei; Xiao, Zhengtao; Ai, Chunzhi

2011-01-01

In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q2 = 0.603, R2ncv = 0.829, R2pre = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q2 = 0.506, R2ncv =0.838, R2pre = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R3 substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R1 substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists. PMID:21541053

Studies of new fused benzazepine as selective dopamine D3 receptor antagonists using 3D-QSAR, molecular docking and molecular dynamics.

PubMed

Liu, Jing; Li, Yan; Zhang, Shuwei; Xiao, Zhengtao; Ai, Chunzhi

2011-02-18

In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q(2) = 0.603, R(2) (ncv) = 0.829, R(2) (pre) = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q(2) = 0.506, R(2) (ncv) =0.838, R(2) (pre) = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R(3) substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R(1) substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists.

ARC-2006-ACD06-0213-013

NASA Image and Video Library

2006-09-25

Ames and Moffett Field (MFA) historical sites and memorials Entry of building N-210 Ames Flight System Research Laboratory architectural detail. Eastside showing NACA brass inset wing over front doors, light fixtures flanking the doors and glass brick window wall above the doors

ARC-2006-ACD06-0213-014

NASA Image and Video Library

2006-09-25

Ames and Moffett Field (MFA) historical sites and memorials Entry of building N-210 Ames Flight System Research Laboratory architectural detail. Eastside showing NACA brass inset wing over front doors, light fixtures flanking the doors and glass brick window wall above the doors

Porphyromonas gingivalis Uses Specific Domain Rearrangements and Allelic Exchange to Generate Diversity in Surface Virulence Factors.

PubMed

Dashper, Stuart G; Mitchell, Helen L; Seers, Christine A; Gladman, Simon L; Seemann, Torsten; Bulach, Dieter M; Chandry, P Scott; Cross, Keith J; Cleal, Steven M; Reynolds, Eric C

2017-01-01

Porphyromonas gingivalis is a keystone pathogen of chronic periodontitis. The virulence of P. gingivalis is reported to be strain related and there are currently a number of strain typing schemes based on variation in capsular polysaccharide, the major and minor fimbriae and adhesin domains of Lys-gingipain (Kgp), amongst other surface proteins. P. gingivalis can exchange chromosomal DNA between strains by natural competence and conjugation. The aim of this study was to determine the genetic variability of P. gingivalis strains sourced from international locations over a 25-year period and to determine if variability in surface virulence factors has a phylogenetic basis. Whole genome sequencing was performed on 13 strains and comparison made to 10 previously sequenced strains. A single nucleotide polymorphism-based phylogenetic analysis demonstrated a shallow tri-lobed phylogeny. There was a high level of reticulation in the phylogenetic network, demonstrating extensive horizontal gene transfer between the strains. Two highly conserved variants of the catalytic domain of the major virulence factor the Kgp proteinase (Kgp cat I and Kgp cat II) were found. There were three variants of the fourth Kgp C-terminal cleaved adhesin domain. Specific variants of the cell surface proteins FimA, FimCDE, MfaI, RagAB, Tpr, and PrtT were also identified. The occurrence of all these variants in the P. gingivalis strains formed a mosaic that was not related to the SNP-based phylogeny. In conclusion P. gingivalis uses domain rearrangements and genetic exchange to generate diversity in specific surface virulence factors.

Studies in regard to the classification and putative toxicity of Fridericia japurensis (Arrabidaea japurensis) in Brazil

USDA-ARS?s Scientific Manuscript database

Numerous plant species worldwide including Palicourea marcgravii(Rubiaceae) and Tanaecium bilabiatum (Bignoniaceae) in Brazil cause acute cardiac failure (sudden death) and are known to contain monofluoroacetate (MFA). Other Bignoniaceae species including Fridericia japurensis (Arrabidaea japurensis...

Identification of bottlenecks in the accumulation of cyclic fatty acids in camelina seed oil

DOE PAGES

Yu, Xiao-Hong; Cahoon, Rebecca E.; Horn, Patrick J.; ...

2017-09-20

Modified fatty acids (mFA) have diverse uses, e.g., cyclopropane fatty acids (CPA) are feedstocks for producing coatings, lubricants, plastics, and cosmetics. The expression of mFA-producing enzymes in crop and model plants generally results in lower levels of mFA accumulation than in their natural-occurring source plants. In order to further our understanding of metabolic bottlenecks that limit mFA accumulation, we generated transgenic Camelina sativa lines co-expressing Escherichia coli cyclopropane synthase (EcCPS) and Sterculia foetida lysophosphatidic acid acyltransferase (SfLPAT). In contrast to transgenic CPA-accumulating Arabidopsis, CPA accumulation in camelina caused only minor changes in seed weight, germination rate, oil accumulation, and seedlingmore » development. CPA accumulated to much higher levels in membrane than storage lipids, comprising more than 60% of total fatty acid in both phosphatidylcholine (PC) and phosphatidylethanolamine (PE) versus 26% in diacylglycerol (DAG) and 12% in triacylglycerol (TAG) indicating bottlenecks in the transfer of CPA from PC to DAG and from DAG to TAG. Upon coexpression of SfLPAT with EcCPS, di-CPA-PC increased by ~50% relative to lines expressing EcCPS alone with the di-CPA-PC primarily observed in the embryonic axis and mono-CPA-PC primarily in cotyledon tissue. EcCPS-SfLPAT lines revealed a redistribution of CPA from the sn-1 to sn-2 positions within PC and PE that was associated with a doubling of CPA accumulation in both DAG and TAG. Finally, the identification of metabolic bottlenecks in acyl transfer between site of synthesis (phospholipids) and deposition in storage oils (TAGs) lays the foundation for the optimizing CPA accumulation through directed engineering of oil synthesis in target crops.« less

Identification of bottlenecks in the accumulation of cyclic fatty acids in camelina seed oil

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

Yu, Xiao-Hong; Cahoon, Rebecca E.; Horn, Patrick J.

Modified fatty acids (mFA) have diverse uses, e.g., cyclopropane fatty acids (CPA) are feedstocks for producing coatings, lubricants, plastics, and cosmetics. The expression of mFA-producing enzymes in crop and model plants generally results in lower levels of mFA accumulation than in their natural-occurring source plants. In order to further our understanding of metabolic bottlenecks that limit mFA accumulation, we generated transgenic Camelina sativa lines co-expressing Escherichia coli cyclopropane synthase (EcCPS) and Sterculia foetida lysophosphatidic acid acyltransferase (SfLPAT). In contrast to transgenic CPA-accumulating Arabidopsis, CPA accumulation in camelina caused only minor changes in seed weight, germination rate, oil accumulation, and seedlingmore » development. CPA accumulated to much higher levels in membrane than storage lipids, comprising more than 60% of total fatty acid in both phosphatidylcholine (PC) and phosphatidylethanolamine (PE) versus 26% in diacylglycerol (DAG) and 12% in triacylglycerol (TAG) indicating bottlenecks in the transfer of CPA from PC to DAG and from DAG to TAG. Upon coexpression of SfLPAT with EcCPS, di-CPA-PC increased by ~50% relative to lines expressing EcCPS alone with the di-CPA-PC primarily observed in the embryonic axis and mono-CPA-PC primarily in cotyledon tissue. EcCPS-SfLPAT lines revealed a redistribution of CPA from the sn-1 to sn-2 positions within PC and PE that was associated with a doubling of CPA accumulation in both DAG and TAG. Finally, the identification of metabolic bottlenecks in acyl transfer between site of synthesis (phospholipids) and deposition in storage oils (TAGs) lays the foundation for the optimizing CPA accumulation through directed engineering of oil synthesis in target crops.« less

Experimental poisoning by Niedenzuella stannea in cattle and corresponding detection of monofluoroacetate

USDA-ARS?s Scientific Manuscript database

In Brazil monofluoroacetate (MFA) containing plants are represented by 16 species that belong to three principle genera: Palicourea (Rubiaceae), Amorimia (Malpighiaceae), and Tanaecium (Bignoniaceae). These plants can cause acute cardiac failure often referred to as sudden death syndrome. The object...

A rapid HPLC-APCI-MS method to detect fluoroacetate in plants

USDA-ARS?s Scientific Manuscript database

Many plant species worldwide can cause sudden death of grazing livestock. One diagnostic differential is the presence of monofluoroacetate (MFA) that is metabolised to fluorocitrate that subsequently inhibits the Kreb’s Cycle (the tricarboxylic acid cycle) leading to cellular respiration dysfunction...

3D-QSAR and docking studies on 1-hydroxypyridin-2-one compounds as mutant isocitrate dehydrogenase 1 inhibitors

NASA Astrophysics Data System (ADS)

Wang, Zhenya; Chang, Yiqun; Han, Yushui; Liu, Kangjia; Hou, Jinsong; Dai, Chengli; Zhai, Yuanhao; Guo, Jialiang; Sun, Pinghua; Lin, Jing; Chen, Weimin

2016-11-01

Mutation of isocitrate dehydrogenase 1 (IDH1) which is frequently found in certain cancers such as glioma, sarcoma and acute myeloid leukemia, has been proven to be a potent drug target for cancer therapy. In silico methodologies such as 3D-QSAR and molecular docking were performed to explore compounds with better mutant isocitrate dehydrogenase 1 (MIDH1) inhibitory activity using a series of 40 newly reported 1-hydroxypyridin-2-one compounds as MIDH1 inhibitors. The satisfactory CoMFA and CoMSIA models obtained after internal and external cross-validation gave q2 values of 0.691 and 0.535, r2 values of 0.984 and 0.936, respectively. 3D contour maps generated from CoMFA and CoMSIA along with the docking results provided information about the structural requirements for better MIDH1 inhibitory activity. Based on the structure-activity relationship, 17 new potent molecules with better predicted activity than the most active compound in the literature have been designed.

Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure-activity relationships and molecular docking

NASA Astrophysics Data System (ADS)

Xie, Aihua; Odde, Srinivas; Prasanna, Sivaprakasam; Doerksen, Robert J.

2009-07-01

One of the most promising anticancer and recent antimalarial targets is the heterodimeric zinc-containing protein farnesyltransferase (FT). In this work, we studied a highly diverse series of 192 Abbott-initiated imidazole-containing compounds and their FT inhibitory activities using 3D-QSAR and docking, in order to gain understanding of the interaction of these inhibitors with FT to aid development of a rational strategy for further lead optimization. We report several highly significant and predictive CoMFA and CoMSIA models. The best model, composed of CoMFA steric and electrostatic fields combined with CoMSIA hydrophobic and H-bond acceptor fields, had r 2 = 0.878, q 2 = 0.630, and r pred 2 = 0.614. Docking studies on the statistical outliers revealed that some of them had a different binding mode in the FT active site based on steric bulk and available active site space, explaining why the predicted activities differed from the experimental activities.

Russia and Beyond -- A Case for European Missile Defense

DTIC Science & Technology

2009-04-01

capability will continue. Western observers must be careful not to mirror Western concepts of power structure and rationality onto the Iranian...loyalty. The MFA has had to overcome the reputation of several of its ministers to reach its current position of influence. Andrei Kozyrev , the first

A combined pharmacophore modeling, 3D-QSAR and molecular docking study of substituted bicyclo-[3.3.0]oct-2-enes as liver receptor homolog-1 (LRH-1) agonists

NASA Astrophysics Data System (ADS)

Lalit, Manisha; Gangwal, Rahul P.; Dhoke, Gaurao V.; Damre, Mangesh V.; Khandelwal, Kanchan; Sangamwar, Abhay T.

2013-10-01

A combined pharmacophore modelling, 3D-QSAR and molecular docking approach was employed to reveal structural and chemical features essential for the development of small molecules as LRH-1 agonists. The best HypoGen pharmacophore hypothesis (Hypo1) consists of one hydrogen-bond donor (HBD), two general hydrophobic (H), one hydrophobic aromatic (HYAr) and one hydrophobic aliphatic (HYA) feature. It has exhibited high correlation coefficient of 0.927, cost difference of 85.178 bit and low RMS value of 1.411. This pharmacophore hypothesis was cross-validated using test set, decoy set and Cat-Scramble methodology. Subsequently, validated pharmacophore hypothesis was used in the screening of small chemical databases. Further, 3D-QSAR models were developed based on the alignment obtained using substructure alignment. The best CoMFA and CoMSIA model has exhibited excellent rncv2 values of 0.991 and 0.987, and rcv2 values of 0.767 and 0.703, respectively. CoMFA predicted rpred2 of 0.87 and CoMSIA predicted rpred2 of 0.78 showed that the predicted values were in good agreement with the experimental values. Molecular docking analysis reveals that π-π interaction with His390 and hydrogen bond interaction with His390/Arg393 is essential for LRH-1 agonistic activity. The results from pharmacophore modelling, 3D-QSAR and molecular docking are complementary to each other and could serve as a powerful tool for the discovery of potent small molecules as LRH-1 agonists.

Co-production of hydrogen and ethanol from glucose by modification of glycolytic pathways in Escherichia coli - from Embden-Meyerhof-Parnas pathway to pentose phosphate pathway.

PubMed

Seol, Eunhee; Sekar, Balaji Sundara; Raj, Subramanian Mohan; Park, Sunghoon

2016-02-01

Hydrogen (H2) production from glucose by dark fermentation suffers from the low yield. As a solution to this problem, co-production of H2 and ethanol, both of which are good biofuels, has been suggested. To this end, using Escherichia coli, activation of pentose phosphate (PP) pathway, which can generate more NADPH than the Embden-Meyhof-Parnas (EMP) pathway, was attempted. Overexpression of two key enzymes in the branch nodes of the glycolytic pathway, Zwf and Gnd, significantly improved the co-production of H2 and ethanol with concomitant reduction of pyruvate secretion. Gene expression analysis and metabolic flux analysis (MFA) showed that, upon overexpression of Zwf and Gnd, glucose assimilation through the PP pathway, compared with that of the EMP or Entner-Doudoroff (ED) pathway, was greatly enhanced. The maximum co-production yields were 1.32 mol H2 mol(-1) glucose and 1.38 mol ethanol mol(-1) glucose, respectively. It is noteworthy that the glycolysis and the amount of NAD(P)H formed under anaerobic conditions could be altered by modifying (the activity of) several key enzymes. Our strategy could be applied for the development of industrial strains for biological production of reduced chemicals and biofuels which suffers from lack of reduced co-factors. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Induction and transfer of resistance to poisoning by Amorimia (Macagnia) septentrionalis in goats

USDA-ARS?s Scientific Manuscript database

Amorimia septentrionalis contains sodium monofluoroactetate (MFA) and can cause acute heart failure in ruminants when ingested in toxic doses. In this study, we demonstrate that resistance to poisoning by A. septentrionalis can be improved in goats by the repeated administration of non-toxic doses ...

A Drug Discovery Partnership for Personalized Breast Cancer Therapy

DTIC Science & Technology

2012-09-01

flexible searches of compound databases using detailed pharmacophore and CoMFA QSAR results. (Months 9-24). 1,3,8-trihydroxyanthraquinone was taken...Cytochrome P450 Inhibitors- A Study of Their Potency and Selectivity”, J. Sridhar, J. Liu, C.L.K. Stevens, and M. Foroozesh, Society of Toxicology

Induction and transfer of resistance to poisoning by Amorimia (Mascagnia) septentrionalis in goats

USDA-ARS?s Scientific Manuscript database

Amorimia septentrionalis contains sodium monofluoroactetate (MFA) and can cause acute heart failure in ruminants when ingested in toxic doses. In this study, we demonstrate that resistance to poisoning by A. septentrionalis can be improved in goats by the repeated administration of non-toxic doses o...

ARC-2006-ACD06-0213-011

NASA Image and Video Library

2006-10-03

Ames and Moffett Field (MFA) historical sites and memorials Unitary Plan Wind Tunned plaza; display and historical site plaques with the NASA logo on the Wind Tunnel valve as a backdrop. shown is the Unitary International Historic Mechanical Engineering Landmark Dedication plaque (American Society of Mechanical Engineers) May 5, 1995

Reliability Prediction Models for Discrete Semiconductor Devices

DTIC Science & Technology

1988-07-01

influence failure rate were device construction, semiconductor material, junction temperature, electrical stress, circuit application., a plication...found to influence failure rate were device construction, semiconductor material, junction temperature, electrical stress, circuit application...MFA Airbreathlng 14issile, Flight MFF Missile, Free Flight ML Missile, Launch MMIC Monolithic Microwave Integrated Circuits MOS Metal-Oxide

ARC-2006-ACD06-0213-058

NASA Image and Video Library

2006-11-29

Ames and Moffett Field (MFA) historical sites and memorials Site of the John W. Whisman Home. Headquarters and stopping place of the first stagecoach line between San Jose and San Francisco. Started in early autumn of 1849. Located at R.T.Jones Road and the Ames Child Care Center fence boundary.

Albania’s Road Toward Integrated and Accession into the European Union

DTIC Science & Technology

2014-06-13

50 vii Regional issues and international obligations ........................................................51...88 viii ACRONYMS AI Amnesty International APL Albanian Party of Labor CARDS Community Assistance for Reconstruction, Development...IMF International Monetary Fund IPA Instrument for Pre-accession assistance MEI Ministry of European Integration MFA Ministry of Foreign Affairs

Comparative Analysis of Pharmacophore Features and Quantitative Structure-Activity Relationships for CD38 Covalent and Non-covalent Inhibitors.

PubMed

Zhang, Shuang; Xue, Xiwen; Zhang, Liangren; Zhang, Lihe; Liu, Zhenming

2015-12-01

In the past decade, the discovery, synthesis, and evaluation for hundreds of CD38 covalent and non-covalent inhibitors has been reported sequentially by our group and partners; however, a systematic structure-based guidance is still lacking for rational design of CD38 inhibitor. Here, we carried out a comparative analysis of pharmacophore features and quantitative structure-activity relationships for CD38 inhibitors. The results uncover that the essential interactions between key residues and covalent/non-covalent CD38 inhibitors include (i) hydrogen bond and hydrophobic interactions with residues Glu226 and Trp125, (ii) electrostatic or hydrogen bond interaction with the positively charged residue Arg127 region, and (iii) the hydrophobic interaction with residue Trp189. For covalent inhibitors, besides the covalent effect with residue Glu226, the electrostatic interaction with residue Arg127 is also necessary, while another hydrogen/non-bonded interaction with residues Trp125 and Trp189 can also be detected. By means of the SYBYL multifit alignment function, the best CoMFA and CoMSIA with CD38 covalent inhibitors presented cross-validated correlation coefficient values (q(2)) of 0.564 and 0.571, and non-cross-validated values (r(2)) of 0.967 and 0.971, respectively. The CD38 non-covalent inhibitors can be classified into five groups according to their chemical scaffolds, and the residues Glu226, Trp189, and Trp125 are indispensable for those non-covalent inhibitors binding to CD38, while the residues Ser126, Arg127, Asp155, Thr221, and Phe222 are also important. The best CoMFA and CoMSIA with the F12 analogues presented cross-validated correlation coefficient values (q(2)) of 0.469 and 0.454, and non-cross-validated values (r(2)) of 0.814 and 0.819, respectively. © 2015 John Wiley & Sons A/S.

Dynamic probabilistic material flow analysis of nano-SiO2, nano iron oxides, nano-CeO2, nano-Al2O3, and quantum dots in seven European regions.

PubMed

Wang, Yan; Nowack, Bernd

2018-04-01

Static environmental exposure assessment models based on material flow analysis (MFA) have previously been used to estimate flows of engineered nanomaterials (ENMs) to the environment. However, such models do not account for changes in the system behavior over time. Dynamic MFA used in this study includes the time-dependent development of the modelling system by considering accumulation of ENMs in stocks and the environment, and the dynamic release of ENMs from nano-products. In addition, this study also included regional variations in population, waste management systems, and environmental compartments, which subsequently influence the environmental release and concentrations of ENMs. We have estimated the flows and release concentrations of nano-SiO 2 , nano-iron oxides, nano-CeO 2 , nano-Al 2 O 3 , and quantum dots in the EU and six geographical sub-regions in Europe (Central Europe, Northern Europe, Southern Europe, Eastern Europe, South-eastern Europe, and Switzerland). The model predicts that a large amount of ENMs are accumulated in stocks (not considering further transformation). For example, in the EU 2040 Mt of nano-SiO 2 are stored in the in-use stock, 80,400 tonnes have been accumulated in sediments and 65,600 tonnes in natural and urban soil from 1990 to 2014. The magnitude of flows in waste management processes in different regions varies because of differences in waste handling. For example, concentrations in landfilled waste are lowest in South-eastern Europe due to dilution by the high amount of landfilled waste in the region. The flows predicted in this work can serve as improved input data for mechanistic environmental fate models and risk assessment studies compared to previous estimates using static models. Copyright © 2018 Elsevier Ltd. All rights reserved.

First report on 3D-QSAR and molecular dynamics based docking studies of GCPII inhibitors for targeted drug delivery applications

NASA Astrophysics Data System (ADS)

Pandit, Amit; Sengupta, Sagnik; Krishnan, Mena Asha; Reddy, Ramesh B.; Sharma, Rajesh; Venkatesh, Chelvam

2018-05-01

Prostate Specific Membrane Antigen (PSMA) or Glutamate carboxypeptidase II (GCPII) has been identified as an important target in diagnosis and therapy of prostate cancer. Among several types of inhibitors, urea based inhibitors are the most common and widely employed in preclinical and clinical studies. Computational studies have been carried out to uncover active sites and interaction of PSMA inhibitors with the protein by modifying the core structure of the ligand. Analysis of the literature, however, show lack of 3-D quantitative structure activity relationship (QSAR) and molecular dynamics based molecular docking study to identify structural modifications responsible for better GCPII inhibitory activity. The present study aims to fulfil this gap by analysing well known PSMA inhibitors reported in the literature with known experimental PSMA inhibition constants. Also in order to validate the in silico study, a new GCPII inhibitor 7 was designed, synthesized and experimental PSMA enzyme inhibition was evaluated by using freshly isolated PSMA protein from human cancer cell line derived from lymph node, LNCaP. 3D-QSAR CoMFA models on 58 urea based GCPII inhibitors were generated, and the best correlation was obtained in Gast-Huck charge assigning method with q2, r2 and predictive r2 values as 0.592, 0.995 and 0.842 respectively. Moreover, steric, electrostatic, and hydrogen bond donor field contribution analysis provided best statistical values from CoMSIA model (q2, r2 and predictive r2 as 0.527, 0.981 and 0.713 respectively). Contour maps study revealed that electrostatic field contribution is the major factor for discovering better binding affinity ligands. Further molecular dynamic assisted molecular docking was also performed on GCPII receptor (PDB ID 4NGM) and most active GCPII inhibitor, DCIBzL. 4NGM co-crystallised ligand, JB7 was used to validate the docking procedure and the amino acid interactions present in JB7 are compared with DCIBzL. The results suggest that Arg210, Asn257, Gly518, Tyr552, Lys699, and Tyr700 amino acid residues may play a crucial role in GCPII inhibition. Molecular Dynamics Simulation provides information about docked pose stability of DCIBzL. By combination of CoMFA-CoMSIA field analysis and docking interaction analysis studies, conclusive SAR was generated for urea based derivatives based on which GCPII inhibitor 7 was designed and chemically synthesized in our laboratory. Evaluation of GCPII inhibitory activity of 7 by performing NAALADase assay provided IC50 value of 113 nM which is in close agreement with in silico predicted value (119 nM). Thus we have successfully validated our 3D-QSAR and molecular docking based designing of GCPII inhibitors methodology through biological experiments. This conclusive SAR would be helpful to generate novel and more potent GCPII inhibitors for drug delivery applications.

Quantitative structure-activity relationship of organosulphur compounds as soybean 15-lipoxygenase inhibitors using CoMFA and CoMSIA.

PubMed

Caballero, Julio; Fernández, Michael; Coll, Deysma

2010-12-01

Three-dimensional quantitative structure-activity relationship studies were carried out on a series of 28 organosulphur compounds as 15-lipoxygenase inhibitors using comparative molecular field analysis and comparative molecular similarity indices analysis. Quantitative information on structure-activity relationships is provided for further rational development and direction of selective synthesis. All models were carried out over a training set including 22 compounds. The best comparative molecular field analysis model only included steric field and had a good Q² = 0.789. Comparative molecular similarity indices analysis overcame the comparative molecular field analysis results: the best comparative molecular similarity indices analysis model also only included steric field and had a Q² = 0.894. In addition, this model predicted adequately the compounds contained in the test set. Furthermore, plots of steric comparative molecular similarity indices analysis field allowed conclusions to be drawn for the choice of suitable inhibitors. In this sense, our model should prove useful in future 15-lipoxygenase inhibitor design studies. © 2010 John Wiley & Sons A/S.

Thermodynamics-Based Metabolic Flux Analysis

PubMed Central

Henry, Christopher S.; Broadbelt, Linda J.; Hatzimanikatis, Vassily

2007-01-01

A new form of metabolic flux analysis (MFA) called thermodynamics-based metabolic flux analysis (TMFA) is introduced with the capability of generating thermodynamically feasible flux and metabolite activity profiles on a genome scale. TMFA involves the use of a set of linear thermodynamic constraints in addition to the mass balance constraints typically used in MFA. TMFA produces flux distributions that do not contain any thermodynamically infeasible reactions or pathways, and it provides information about the free energy change of reactions and the range of metabolite activities in addition to reaction fluxes. TMFA is applied to study the thermodynamically feasible ranges for the fluxes and the Gibbs free energy change, ΔrG′, of the reactions and the activities of the metabolites in the genome-scale metabolic model of Escherichia coli developed by Palsson and co-workers. In the TMFA of the genome scale model, the metabolite activities and reaction ΔrG′ are able to achieve a wide range of values at optimal growth. The reaction dihydroorotase is identified as a possible thermodynamic bottleneck in E. coli metabolism with a ΔrG′ constrained close to zero while numerous reactions are identified throughout metabolism for which ΔrG′ is always highly negative regardless of metabolite concentrations. As it has been proposed previously, these reactions with exclusively negative ΔrG′ might be candidates for cell regulation, and we find that a significant number of these reactions appear to be the first steps in the linear portion of numerous biosynthesis pathways. The thermodynamically feasible ranges for the concentration ratios ATP/ADP, NAD(P)/NAD(P)H, and \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}{\\mathrm{H}}_{{\\mathrm{extracellular}}}^{+}/{\\mathrm{H}}_{{\\mathrm{intracellular}}}^{+}\\end{equation*}\\end{document} are also determined and found to encompass the values observed experimentally in every case. Further, we find that the NAD/NADH and NADP/NADPH ratios maintained in the cell are close to the minimum feasible ratio and maximum feasible ratio, respectively. PMID:17172310

Three-dimensional structure-activity relationship modeling of cocaine binding to two monoclonal antibodies by comparative molecular field analysis.

PubMed

Paula, Stefan; Tabet, Michael R; Keenan, Susan M; Welsh, William J; Ball, W James

2003-01-17

Successful immunotherapy of cocaine addiction and overdoses requires cocaine-binding antibodies with specific properties, such as high affinity and selectivity for cocaine. We have determined the affinities of two cocaine-binding murine monoclonal antibodies (mAb: clones 3P1A6 and MM0240PA) for cocaine and its metabolites by [3H]-radioligand binding assays. mAb 3P1A6 (K(d) = 0.22 nM) displayed a 50-fold higher affinity for cocaine than mAb MM0240PA (K(d) = 11 nM) and also had a greater specificity for cocaine. For the systematic exploration of both antibodies' binding specificities, we used a set of approximately 35 cocaine analogues as structural probes by determining their relative binding affinities (RBAs) using an enzyme-linked immunosorbent competition assay. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models on the basis of comparative molecular field analysis (CoMFA) techniques correlated the binding data with structural features of the ligands. The analysis indicated that despite the mAbs' differing specificities for cocaine, the relative contributions of the steric (approximately 80%) and electrostatic (approximately 20%) field interactions to ligand-binding were similar. Generated three-dimensional CoMFA contour plots then located the specific regions about cocaine where the ligand/receptor interactions occurred. While the overall binding patterns of the two mAbs had many features in common, distinct differences were observed about the phenyl ring and the methylester group of cocaine. Furthermore, using previously published data, a 3D-QSAR model was developed for cocaine binding to the dopamine reuptake transporter (DAT) that was compared to the mAb models. Although the relative steric and electrostatic field contributions were similar to those of the mAbs, the DAT cocaine-binding site showed a preference for negatively charged ligands. Besides establishing molecular level insight into the interactions that govern cocaine binding specificity by biopolymers, the three-dimensional images obtained reflect the properties of the mAbs binding pockets and provide the initial information needed for the possible design of novel antibodies with properties optimized for immunotherapy. Copyright 2003 Elsevier Science Ltd.

Fatty Acid-Based Monomers as Styrene Replacements for Liquid Molding Resins

DTIC Science & Technology

2005-05-01

fatty acid length and unsaturation level on resin and polymer properties. Fig. 2. The addition of fatty acids ( oleic acid ) to glycidyl methacylate to...the synthetic route used to form the methacrylated fatty acids (MFA). The carboxylic acid of fatty acids undergoes a simple addition reaction with... form methacrylated fatty acid monomer

Determination of toxicity in rabbits and corresponding detection of monofluoroacetate in four Palicourea (Rubiaceae) species from the Amazonas state, Brazil

USDA-ARS?s Scientific Manuscript database

Numerous monofluoroacetate (MFA)-containing plants in Brazil cause sudden death syndrome precipitated by exercise in livestock, which is characterized by loss of balance, ataxia, labored breathing, muscle tremors, and recumbence leading to death. Four species of Palicourea collected at six farms wer...

Poets Teaching Poets: Self and the World.

ERIC Educational Resources Information Center

Orr, Gregory, Ed.; Voigt, Ellen Bryant, Ed.

This anthology collects essays by current and former lecturers at the Warren Wilson College (North Carolina) MFA Program for Writers. Some of the poets whose essays are included are: Joan Aleshire, Marianne Boruch, Carl Dennis, Stephen Dobyns, Reginald Gibbons, Louise Gluck, Allen Grossman, Robert Hass, Tony Hoagland, Heather McHugh, Gregory Orr,…

Thinking through Art at the Boston Museum of Fine Arts

ERIC Educational Resources Information Center

Longhenry, Susan

2005-01-01

Can going to an art museum make elementary school students better learners? It can if they are participating in Thinking Through Art, an innovative partnership uniting the Museum of Fine Arts, Boston (MFA), Boston Public Schools (BPS), and Visual Understanding in Education (VUE), a nonprofit educational research group committed to improving…

"Math for America" Isn't

ERIC Educational Resources Information Center

Wolfmeyer, Mark

2014-01-01

Aspects of the Math for America organization's actions, aims and affiliations are analyzed for their effects on urban schools and society at large. These aspects are argued as evidence to consider MfA as an agent working against democratic practice and in favor of furthering profit and its resultant inequitable resource distribution. The…

Pyridones as NNRTIs against HIV-1 mutants: 3D-QSAR and protein informatics

NASA Astrophysics Data System (ADS)

Debnath, Utsab; Verma, Saroj; Jain, Surabhi; Katti, Setu B.; Prabhakar, Yenamandra S.

2013-07-01

CoMFA and CoMSIA based 3D-QSAR of HIV-1 RT wild and mutant (K103, Y181C, and Y188L) inhibitory activities of 4-benzyl/benzoyl pyridin-2-ones followed by protein informatics of corresponding non-nucleoside inhibitors' binding pockets from pdbs 2BAN, 3MED, 1JKH, and 2YNF were analysed to discover consensus features of the compounds for broad-spectrum activity. The CoMFA/CoMSIA models indicated that compounds with groups which lend steric-cum-electropositive fields in the vicinity of C5, hydrophobic field in the vicinity of C3 of pyridone region and steric field in aryl region produce broad-spectrum anti-HIV-1 RT activity. Also, a linker rendering electronegative field between pyridone and aryl moieties is common requirement for the activities. The protein informatics showed considerable alteration in residues 181 and 188 characteristics on mutation. Also, mutants' isoelectric points shifted in acidic direction. The study offered fresh avenues for broad-spectrum anti-HIV-1 agents through designing new molecules seeded with groups satisfying common molecular fields and concerns of mutating residues.

Analyzing the substitution effect on the CoMFA results within the framework of density functional theory (DFT).

PubMed

Morales-Bayuelo, Alejandro

2016-07-01

Though QSAR was originally developed in the context of physical organic chemistry, it has been applied very extensively to chemicals (drugs) which act on biological systems, in this idea one of the most important QSAR methods is the 3D QSAR model. However, due to the complexity of understanding the results it is necessary to postulate new methodologies to highlight their physical-chemical meaning. In this sense, this work postulates new insights to understand the CoMFA results using molecular quantum similarity and chemical reactivity descriptors within the framework of density functional theory. To obtain these insights a simple theoretical scheme involving quantum similarity (overlap, coulomb operators, their euclidean distances) and chemical reactivity descriptors such as chemical potential (μ), hardness (ɳ), softness (S), electrophilicity (ω), and the Fukui functions, was used to understand the substitution effect. In this sense, this methodology can be applied to analyze the biological activity and the stabilization process in the non-covalent interactions on a particular molecular set taking a reference compound.

Competitive adsorption of Pb2+ and Zn2+ ions from aqueous solutions by modified coal fly ash

NASA Astrophysics Data System (ADS)

Astuti, Widi; Martiani, Wulan; Any Ismawati Khair, N.

2017-03-01

Coal fly ash (CFA), which is a solid waste generated in large amounts worldwide, is mainly composed of some oxides having high crystallinity, including quartz (SiO2) and mullite (3Al2O3 2SiO2), and unburned carbon as a mesopore material that enables it to act as a dual site adsorbent. To decrease the crystallinity, CFA was modified by sodium hydroxide treatment. The modified fly ash (MFA) contains lower amount of Si and Al and has a higher specific surface area than the untreated fly ash (CFA). The objective of this study is to investigate the competitive adsorption of Pb2+ and Zn2+ from aqueous solutions by CFA and MFA. The effect of pH, contact time and initial concentration was investigated. Effective pH for Pb2+ and Zn2+ removal was 4. A greater percentage of Pb2+ and Zn2+ was removed with a decrease in the initial concentration of Pb2+ and Zn2+. Quasi-equilibrium reached in 240 min.

3D-QSAR and docking studies on 4-anilinoquinazoline and 4-anilinoquinoline epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors

NASA Astrophysics Data System (ADS)

Assefa, Haregewein; Kamath, Shantaram; Buolamwini, John K.

2003-08-01

The overexpression and/or mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase has been observed in many human solid tumors, and is under intense investigation as a novel anticancer molecular target. Comparative 3D-QSAR analyses using different alignments were undertaken employing comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) for 122 anilinoquinazoline and 50 anilinoquinoline inhibitors of EGFR kinase. The SYBYL multifit alignment rule was applied to three different conformational templates, two obtained from a MacroModel Monte Carlo conformational search, and one from the bound conformation of erlotinib in complex with EGFR in the X-ray crystal structure. In addition, a flexible ligand docking alignment obtained with the GOLD docking program, and a novel flexible receptor-guided consensus dynamics alignment obtained with the DISCOVER program in the INSIGHTII modeling package were also investigated. 3D-QSAR models with q2 values up to 0.70 and r2 values up to 0.97 were obtained. Among the 4-anilinoquinazoline set, the q2 values were similar, but the ability of the different conformational models to predict the activities of an external test set varied considerably. In this regard, the model derived using the X-ray crystallographically determined bioactive conformation of erlotinib afforded the best predictive model. Electrostatic, hydrophobic and H-bond donor descriptors contributed the most to the QSAR models of the 4-anilinoquinazolines, whereas electrostatic, hydrophobic and H-bond acceptor descriptors contributed the most to the 4-anilinoquinoline QSAR, particularly the H-bond acceptor descriptor. A novel receptor-guided consensus dynamics alignment has also been introduced for 3D-QSAR studies. This new alignment method may incorporate to some extent ligand-receptor induced fit effects into 3D-QSAR models.

The mass flow and proposed management of bisphenol A in selected Norwegian waste streams.

PubMed

Arp, Hans Peter H; Morin, Nicolas A O; Hale, Sarah E; Okkenhaug, Gudny; Breivik, Knut; Sparrevik, Magnus

2017-02-01

Current initiatives for waste-handling in a circular economy favor prevention and recycling over incineration or landfilling. However, the impact of such a transition on environmental emissions of contaminants like bisphenol A (BPA) during waste-handling is not fully understood. To address this, a material flow analysis (MFA) was constructed for selected waste categories in Norway, for which the amount recycled is expected to increase in the future; glass, vehicle, electronic, plastic and combustible waste. Combined, 92tons/y of BPA are disposed of via these waste categories in Norway, with 98.5% associated with plastic and electronic waste. During the model year 2011, the MFA showed that BPA in these waste categories was destroyed through incineration (60%), exported for recycling into new products (35%), stored in landfills (4%) or released into the environment (1%). Landfilling led to the greatest environmental emissions (up to 13% of landfilled BPA), and incinerating the smallest (0.001% of incinerated BPA). From modelling different waste management scenarios, the most effective way to reduce BPA emissions are to incinerate BPA-containing waste and avoid landfilling it. A comparison of environmental and human BPA concentrations with CoZMoMAN exposure model estimations suggested that waste emissions are an insignificant regional source. Nevertheless, from monitoring studies, landfill emissions can be a substantial local source of BPA. Regarding the transition to a circular economy, it is clear that disposing of less BPA-containing waste and less landfilling would lead to lower environmental emissions, but several uncertainties remain regarding emissions of BPA during recycling, particularly for paper and plastics. Future research should focus on the fate of BPA, as well as BPA alternatives, in emerging reuse and recycling processes, as part of the transition to a circular economy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparison of production-phase environmental impact metrics derived at the farm- and national-scale for United States agricultural commodities

NASA Astrophysics Data System (ADS)

Costello, Christine; Xue, Xiaobo; Howarth, Robert W.

2015-11-01

Agricultural production is critical for human survival and simultaneously contributes to ecosystem degradation. There is a need for transparent, rapid methods for evaluating the environmental impacts of agricultural production at the system-level in order to develop sustainable food supplies. We have developed a method for estimating the greenhouse gas (GHG), land use and reactive nitrogen inputs associated with the agricultural production phase of major crop and livestock commodities produced in the United States (US). Materials flow analysis (MFA) and life cycle assessment (LCA) techniques were applied to national inventory datasets. The net anthropogenic nitrogen inputs (NANI) toolbox served as the primary accounting tool for LCA and MFA. NANI was updated to create links between nitrogen fertilizer and nitrogen fixation associated with feed crops and animal food commodities. Results for the functional units kilogram (kg) of product and kg of protein for 2002 data fall within ranges of published LCA results from farm-scale studies across most metrics. Exceptions include eutrophication potential for milk and GHGs for chicken and eggs, these exceptions arise due to differing methods and boundary assumptions; suggestions for increasing agreement are identified. Land use for livestock commodities are generally higher than reported by other LCA studies due to the inclusion of all land identified as pasture or grazing land in the US in this study and given that most of the estimates from other LCAs were completed in Europe where land is less abundant. The method provides a view of the entire US agricultural system and could be applied to any year using publically available data. Additionally, utilizing a top-down approach reduces data collection and processing time making it possible to develop environmental inventory metrics rapidly for system-level decision-making.

Synthesis, fungicidal evaluation and 3D-QSAR studies of novel 1,3,4-thiadiazole xylofuranose derivatives

PubMed Central

Zong, Guanghui; Yan, Xiaojing; Bi, Jiawei; Jiang, Rui; Qin, Yinan; Yuan, Huizhu; Lu, Huizhe; Dong, Yanhong; Jin, Shuhui; Zhang, Jianjun

2017-01-01

1,3,4-Thiadiazole and sugar-derived molecules have proven to be promising agrochemicals with growth promoting, insecticidal and fungicidal activities. In the research field of agricultural fungicide, applying union of active group we synthesized a new set of 1,3,4-thiadiazole xylofuranose derivatives and all of the compounds were characterized by 1H NMR and HRMS. In precise toxicity measurement, some of compounds exhibited more potent fungicidal activities than the most widely used commercial fungicide Chlorothalonil, promoting further research and development. Based on our experimental data, 3D-QSAR (three-dimensional quantitative structure-activity relationship) was established and investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques, helping to better understand the structural requirements of lead compounds with high fungicidal activity and environmental compatibility. PMID:28746366

Modelling the Solid Waste Flow into Sungai Ikan Landfill Sites by Material Flow Analysis Method

NASA Astrophysics Data System (ADS)

Ghani, Latifah A.; Ali, Nora'aini; Hassan, Nur Syafiqah A.

2017-12-01

The purpose of this paper is to model the material flow of solid waste flows at Kuala Terengganu by using Material Flow Analysis (MFA) method, generated by STAN Software Analysis. Sungai Ikan Landfill has been operated for about 10 years. Average, Sungai Ikan Landfill receive an amount around 260 tons per day of solid waste. As for the variety source of the solid waste coming from, leachates that accumulated has been tested and measured. Highest reading of pH of the leachate is 8.29 which is still in the standard level before discharging the leachate to open water which pH in between 8.0-9.0. The percentages of the solid waste has been calculated and seven different types of solid waste has been segregated. That is, plastics, organic waste, paper, polystyrene, wood, fabric and can. The estimation of the solid waste that will be end as a residue are around 244 tons per day.

Advantages and limitations of classic and 3D QSAR approaches in nano-QSAR studies based on biological activity of fullerene derivatives

DOE PAGES

Jagiello, Karolina; Grzonkowska, Monika; Swirog, Marta; ...

2016-08-29

In this contribution, the advantages and limitations of two computational techniques that can be used for the investigation of nanoparticles activity and toxicity: classic nano-QSAR (Quantitative Structure–Activity Relationships employed for nanomaterials) and 3D nano-QSAR (three-dimensional Quantitative Structure–Activity Relationships, such us Comparative Molecular Field Analysis, CoMFA/Comparative Molecular Similarity Indices Analysis, CoMSIA analysis employed for nanomaterials) have been briefly summarized. Both approaches were compared according to the selected criteria, including: efficiency, type of experimental data, class of nanomaterials, time required for calculations and computational cost, difficulties in the interpretation. Taking into account the advantages and limitations of each method, we provide themore » recommendations for nano-QSAR modellers and QSAR model users to be able to determine a proper and efficient methodology to investigate biological activity of nanoparticles in order to describe the underlying interactions in the most reliable and useful manner.« less

Advantages and limitations of classic and 3D QSAR approaches in nano-QSAR studies based on biological activity of fullerene derivatives

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

Jagiello, Karolina; Grzonkowska, Monika; Swirog, Marta

In this contribution, the advantages and limitations of two computational techniques that can be used for the investigation of nanoparticles activity and toxicity: classic nano-QSAR (Quantitative Structure–Activity Relationships employed for nanomaterials) and 3D nano-QSAR (three-dimensional Quantitative Structure–Activity Relationships, such us Comparative Molecular Field Analysis, CoMFA/Comparative Molecular Similarity Indices Analysis, CoMSIA analysis employed for nanomaterials) have been briefly summarized. Both approaches were compared according to the selected criteria, including: efficiency, type of experimental data, class of nanomaterials, time required for calculations and computational cost, difficulties in the interpretation. Taking into account the advantages and limitations of each method, we provide themore » recommendations for nano-QSAR modellers and QSAR model users to be able to determine a proper and efficient methodology to investigate biological activity of nanoparticles in order to describe the underlying interactions in the most reliable and useful manner.« less

Induction and transfer of resistance to poisoning by Amorimia pubiflora in sheep with non-toxic doses of the plant and ruminal content

USDA-ARS?s Scientific Manuscript database

Amorimia pubiflora (Malpighiaceae), which contains sodium monofluoroacetate (MFA) is the main cause of “sudden death” in cattle in the Brazilian state of Mato Grosso. This research investigated the induction of resistance to the poisoning in sheep by the continuous administration of non-toxic doses ...

Challenging How English Is Done: Engaging the Ethical and the Human in a Community Literacies Seminar

ERIC Educational Resources Information Center

Weinstein, Susan; Cornelius, Jeremy; Kenny, Shannon; Leung, Muriel; Liew, Grace Shuyi; Lyons, Kieran; Torres, Alejandra; Tougas, Matthew; Webb, Sarah

2016-01-01

Eight English graduate students and a professor reflect on their semester-long exploration of community literacy studies. The students, some in a MFA Creative Writing program and some doing doctoral work in literature, rhetoric, or English Education, discuss how the community literacies lens unsettled their relationship to English Studies.

Impact of the foliar pathogen Swiss needle cast on wood quality of Douglas-fir.

Treesearch

G.R. Johnson; Amy T. Grotta; Barbara L. Gartner; Geoff. Downes

2005-01-01

Many stands of Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) near coastal areas of Oregon and Washington are heavily infected with the foliar pathogen causing Swiss needle cast (SNC) disease, and yet there is very little research on the resulting wood quality. Modulus of elasticity(MOE), modulus of rupture (MOR), microfibril angle (MFA), wood...

77 FR 35677 - Regulation of Fuel and Fuel Additives; Modification to Octamix Waiver (TOLAD)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-14

... to the Texas Methanol Corporation (Texas Methanol) under the Clean Air Act on February 8, 1988. This... titled ``Fuel and Fuel Additives; Modification of a Fuel Waiver Granted to the Texas Methanol Corporation.'' Today's notice approves the use of an alternative corrosion inhibitor, TOLAD MFA-10A, in Texas Methanol...

Generation Y, wine and alcohol. A semantic differential approach to consumption analysis in Tuscany.

PubMed

Marinelli, Nicola; Fabbrizzi, Sara; Alampi Sottini, Veronica; Sacchelli, Sandro; Bernetti, Iacopo; Menghini, Silvio

2014-04-01

The aim of the study is the elicitation of the consumer's semantic perception of different alcoholic beverages in order to provide information for the definition of communication strategies for both the private sector (and specifically the wine industry) and the public decision maker. Such information can be seen as the basis of a wider social marketing construct aimed at the promotion of responsible drinking among young consumers. The semantic differential approach was used in this study. The data collection was based on a survey to 430 consumers between 18 and 35years old in Tuscany, Italy. The database was organized in a three-way structure, indexing the data in a multiway matrix. The data were processed using a Multiple Factor Analysis (MFA). Moreover, homogeneous clusters of consumers were identified using a Hierarchical Clustering on Principal Components (HCPC) approach. The results of the study highlight that beer and spirits are mainly perceived as "Young", "Social", "Euphoric", "Happy", "Appealing" and "Trendy" beverages, while wine is associated mostly with terms such as "Pleasure", "Quality" and "Comfortable". Furthermore, the cluster analysis allowed for the identification of three groups of individuals with different approaches to alcohol drinking. The results of the study supply a useful information framework for the elaboration of specific communication strategies that, based on the drinking habits of young consumers and their perception of different beverages, can use a language that is very close to the consumer typologies. Such information can be helpful for both private and public communication strategies. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Relationships of density, microfibril angle, and sound velocity with stiffness and strength in mature wood of Douglas-fir

Treesearch

B. Lachenbruch; G.R. Johnson; G.M. Downes; R. Evans

2010-01-01

The relative importance of density, acoustic velocity, and microfibril angle (MFA) for the prediction of stiffness (MOE) and strength (MOR) has not been well established for Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco). MOE and MOR of small clear specimens of mature wood were better predicted by density and velocity than by either variable...

Supporting Museums--Serving Communities: An Evaluation of the Museums for America Program. Full Report

ERIC Educational Resources Information Center

Apley, Alice; Frankel, Susan; Goldman, Elizabeth; Streitburger, Kim

2011-01-01

The Institute of Museum and Library Services is the primary source of federal support for the nation's museums. Museums for America (MFA) is the largest IMLS grant program for museums; it supports institutions by investing in high-priority, high-value activities that are clearly linked to the institution's strategic plan and enhance its value to…

Adding palm oil to the diet of sheep alters fatty acids profile on yogurt: Benefits to consumers.

PubMed

Bianchi, Anderson E; Silva, Aleksandro S DA; Biazus, Angelisa H; Richards, Neila S P S; Pellegrini, Luis G; Baldissera, Matheus D; Macedo, Vicente P; Silveira, André L F DA

2017-01-01

The aim of this study was to modify the fatty acid profile of yogurt from sheep milk by the inclusion of different concentrations of palm oil into their diet. Thus, thirty-six sheep during lactation were separated in four groups with nine animals each, as described below: the group T0 (0%); the group T2 (inclusion of 2% of palm oil); the group T4 (inclusion of 4% of palm oil) and the group T6 (inclusion of 6% of palm oil). After 60 days of the supplementation, milk samples were collected and yogurt was produced, which was evaluated regarding the concentration of saturated fatty acids (SFA), monounsaturated fatty acids (MFA), and polyunsaturated fatty acids (PFA). A significant reduction (p<0.05) in most SFA and a significant increase (p<0.05) on MFA and PFA was observed in the yogurt of sheep supplemented with 4 and 6% of palm oil. Consequently, it is possible to conclude that palm oil supplementation exerts positive effects on yogurt, since it led to the reduction of undesirable fatty acids and increased fatty acids beneficial to human health.

Structure-activity relationships of the antimalarial agent artemisinin. 8. design, synthesis, and CoMFA studies toward the development of artemisinin-based drugs against leishmaniasis and malaria.

PubMed

Avery, Mitchell A; Muraleedharan, Kannoth M; Desai, Prashant V; Bandyopadhyaya, Achintya K; Furtado, Marise M; Tekwani, Babu L

2003-09-25

Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.

Calculation of exchange integrals and Curie temperature for La-substituted barium hexaferrites.

PubMed

Wu, Chuanjian; Yu, Zhong; Sun, Ke; Nie, Jinlan; Guo, Rongdi; Liu, Hai; Jiang, Xiaona; Lan, Zhongwen

2016-10-31

As the macro behavior of the strength of exchange interaction, state of the art of Curie temperature T c , which is directly proportional to the exchange integrals, makes sense to the high-frequency and high-reliability microwave devices. Challenge remains as finding a quantitative way to reveal the relationship between the Curie temperature and the exchange integrals for doped barium hexaferrites. Here in this report, for La-substituted barium hexaferrites, the electronic structure has been determined by the density functional theory (DFT) and generalized gradient approximation (GGA). By means of the comparison between the ground and relative state, thirteen exchange integrals have been calculated as a function of the effective value U eff . Furthermore, based on the Heisenberg model, the molecular field approximation (MFA) and random phase approximation (RPA), which provide an upper and lower bound of the Curie temperature T c , have been adopted to deduce the Curie temperature T c . In addition, the Curie temperature T c derived from the MFA are coincided well with the experimental data. Finally, the strength of superexchange interaction mainly depends on 2b-4f 1 , 4f 2 -12k, 2a-4f 1 , and 4f 1 -12k interactions.

In silico prediction of inhibitory effects of pyrazol-5-one and indazole derivatives on GSK3β kinase enzyme

NASA Astrophysics Data System (ADS)

Wang, Fangfang; Liu, Mengmeng; Liu, Jianling

2012-09-01

Glycogen synthase kinase-3 beta (GSK3β) plays an important role in a diverse number of regulatory pathways by phosphorylation of several different cellular targets and its inhibitors have been evaluated as promising drug candidates. In this work, 192 3-aryl-4-(arylhydrazono)-1H-pyrazol-5-one analogs (AHP) and indazoles (ID) derivatives possessing selective binding affinity for GSK3β kinase were studied using the 3D-QSAR/CoMFA/CoMSIA methodologies. The obtained CoMFA/CoMSIA models exhibit both good internal and external predictive abilities, i.e., Rcv2=0.551,Rpred2=0.698 for AHP derivatives and Rcv2=0.511,Rpred2=0.791 for ID analogs. Of paramount interest is the observation derived from the combination of molecular dynamics and molecular docking studies that Val135 and Asp133 are responsible for the binding recognition for AHP molecules, while residues Val135 and Pro136 are mainly involved in the specific ligand-kinase interactions for ID analogs. The developed models are seeking to be helpful for the rational design of novel potent GSK3β inhibitors.

The Coming Right-Brain Economy: Daniel H. Pink Says the MFA Is the New MBA

ERIC Educational Resources Information Center

Connection: The Journal of the New England Board of Higher Education, 2005

2005-01-01

According to a recent "Harvard Business Review" piece by author Daniel H. Pink, MBA graduates are, in many ways, becoming this century's blue-collar workers--people who entered a workforce that was full of promise only to see their jobs move overseas. At the same time, businesses are realizing that the only way to differentiate their goods and…

JMFA2—a graphically interactive Java program that fits microfibril angle X-ray diffraction data

Treesearch

Steve P. Verrill; David E. Kretschmann; Victoria L. Herian

2006-01-01

X-ray diffraction techniques have the potential to decrease the time required to determine microfibril angles dramatically. In this paper, we discuss the latest version of a curve-fitting toll that permits us to reduce the time required to evaluate MFA X-ray diffraction patterns. Further, because this tool reflects the underlying physics more accurately than existing...

Multilevel nonlinear mixed-effects models for the modeling of earlywood and latewood microfibril angle

Treesearch

Lewis Jordon; Richard F. Daniels; Alexander Clark; Rechun He

2005-01-01

Earlywood and latewood microfibril angle (MFA) was determined at I-millimeter intervals from disks at 1.4 meters, then at 3-meter intervals to a height of 13.7 meters, from 18 loblolly pine (Pinus taeda L.) trees grown in southeastern Texas. A modified three-parameter logistic function with mixed effects is used for modeling earlywood and latewood...

What Happens When the Apprentice Is the Master in a Cognitive Apprenticeship? The Experiences of Graduate Students Participating in Coursework and Fieldwork

ERIC Educational Resources Information Center

Lee, Bridget Kiger; Dawson, Kathryn; Cawthon, Stephanie

2016-01-01

The University of Texas at Austin Master of Fine Arts (MFA) program offers a cognitive apprenticeship for graduate students in drama-based pedagogy (DBP) through Drama for Schools (DFS), a professional development program for K-12 educators. This article presents findings from an exploratory case study investigation of graduate students'…

Low HAP Materials

DTIC Science & Technology

2009-09-01

Use maleinized triglycerides to replace UPE • Use novel bio-based reactive diluent to replace styrene Bio-Based Carbon Fibers and Thermosetting Resins...SERDP proposed new start, FY10 • Microbially breakdown lignin into oligomers that can be melt spun and carbonized • Modify renewable...D5045-93 • Designed plant oil-based toughening agents • Uses phase separation to capture MFA reactive diluent • Increases toughness while decreasing

In silico studies and fluorescence binding assays of potential anti-prion compounds reveal an important binding site for prion inhibition from PrP(C) to PrP(Sc).

PubMed

Pagadala, Nataraj S; Perez-Pineiro, Rolando; Wishart, David S; Tuszynski, Jack A

2015-02-16

To understand the pharmacophore properties of 2-aminothiazoles and design novel inhibitors against the prion protein, a highly predictive 3D quantitative structure-activity relationship (QSAR) has been developed by performing comparative molecular field analysis (CoMFA) and comparative similarity analysis (CoMSIA). Both CoMFA and CoMSIA maps reveal the presence of the oxymethyl groups in meta and para positions on the phenyl ring of compound 17 (N-[4-(3,4-dimethoxyphenyl)-1,3-thiazol-2-yl]quinolin-2-amine), is necessary for activity while electro-negative nitrogen of quinoline is highly favorable to enhance activity. The blind docking results for these compounds show that the compound with quinoline binds with higher affinity than isoquinoline and naphthalene groups. Out of 150 novel compounds retrieved using finger print analysis by pharmacophoric model predicted based on five test sets of compounds, five compounds with diverse scaffolds were selected for biological evaluation as possible PrP inhibitors. Molecular docking combined with fluorescence quenching studies show that these compounds bind to pocket-D of SHaPrP near Trp145. The new antiprion compounds 3 and 6, which bind with the interaction energies of -12.1 and -13.2 kcal/mol, respectively, show fluorescence quenching with binding constant (Kd) values of 15.5 and 44.14 μM, respectively. Further fluorescence binding assays with compound 5, which is similar to 2-aminothiazole as a positive control, also show that the molecule binds to the pocket-D with the binding constant (Kd) value of 84.7 μM. Finally, both molecular docking and a fluorescence binding assay of noscapine as a negative control reveals the same binding site on the surface of pocket-A near a rigid loop between β2 and α2 interacting with Arg164. This high level of correlation between molecular docking and fluorescence quenching studies confirm that these five compounds are likely to act as inhibitors for prion propagation while noscapine might act as a prion accelerator from PrP(C) to PrP(Sc). Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Molecular design of new aggrecanases-2 inhibitors.

PubMed

Shan, Zhi Jie; Zhai, Hong Lin; Huang, Xiao Yan; Li, Li Na; Zhang, Xiao Yun

2013-10-01

Aggrecanases-2 is a very important potential drug target for the treatment of osteoarthritis. In this study, a series of known aggrecanases-2 inhibitors was analyzed by the technologies of three-dimensional quantitative structure-activity relationships (3D-QSAR) and molecular docking. Two 3D-QSAR models, which based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods, were established. Molecular docking was employed to explore the details of the interaction between inhibitors and aggrecanases-2 protein. According to the analyses for these models, several new potential inhibitors with higher activity predicted were designed, and were supported by the simulation of molecular docking. This work propose the fast and effective approach to design and prediction for new potential inhibitors, and the study of the interaction mechanism provide a better understanding for the inhibitors binding into the target protein, which will be useful for the structure-based drug design and modifications. Copyright © 2013 Elsevier Ltd. All rights reserved.

PRO_LIGAND: an approach to de novo molecular design. 2. Design of novel molecules from molecular field analysis (MFA) models and pharmacophores.

PubMed

Waszkowycz, B; Clark, D E; Frenkel, D; Li, J; Murray, C W; Robson, B; Westhead, D R

1994-11-11

A computational approach for molecular design, PRO_LIGAND, has been developed within the PROMETHEUS molecular design and simulation system in order to provide a unified framework for the de novo generation of diverse molecules which are either similar or complementary to a specified target. In this instance, the target is a pharmacophore derived from a series of active structures either by a novel interpretation of molecular field analysis data or by a pharmacophore-mapping procedure based on clique detection. After a brief introduction to PRO_LIGAND, a detailed description is given of the two pharmacophore generation procedures and their abilities are demonstrated by the elucidation of pharmacophores for steroid binding and ACE inhibition, respectively. As a further indication of its efficacy in aiding the rational drug design process, PRO_LIGAND is then employed to build novel organic molecules to satisfy the physicochemical constraints implied by the pharmacophores.

A 3D QSAR CoMFA study of non-peptide angiotensin II receptor antagonists

NASA Astrophysics Data System (ADS)

Belvisi, Laura; Bravi, Gianpaolo; Catalano, Giovanna; Mabilia, Massimo; Salimbeni, Aldo; Scolastico, Carlo

1996-12-01

A series of non-peptide angiotensin II receptor antagonists was investigated with the aim of developing a 3D QSAR model using comparative molecular field analysis descriptors and approaches. The main goals of the study were dictated by an interest in methodologies and an understanding of the binding requirements to the AT1 receptor. Consistency with the previously derived activity models was always checked to contemporarily test the validity of the various hypotheses. The specific conformations chosen for the study, the procedures invoked to superimpose all structures, the conditions employed to generate steric and electrostatic field values and the various PCA/PLS runs are discussed in detail. The effect of experimental design techniques to select objects (molecules) and variables (descriptors) with respect to the predictive power of the QSAR models derived was especially analysed.

[Spatial-temporal pattern of sustainable intensification of agricultural land-use in Shandong Province, China.

PubMed

Niu, Shan Dong; Lyu, Xiao; Shi, Yang Yang

2018-02-01

Under the theoretical framework of sustainable intensification of agricultural land-use (SIALU), We used material flow analysis (MFA) method to establish evaluation index system for SIALU by utilizing data in 2000, 2005, 2010 and 2015 to quantify the level of SIALU of 17 cities in Shandong Province, and analyzed the variation in input-output of resources factors of agricultural land, spatial distribution of resource productivity and environmental economic efficiency, in order to reveal spatial-temporal differentiation of SIALU. Results showed that the direct material input to agricultural lands decreased, whereas hidden flow, stock and pollutant emissions increased gradually from 2000 to 2015. The material productivity of all cities in the province showed that the coastal areas in the peninsula were relatively lower than the southern region, and the level of material productivity in the northwest region was relatively higher. Environmental economic efficiency was gradually enhanced, and the western region was relatively higher than coastal area of the peninsula. During the period examined here, the spatial pattern of SIALU of various cities showed clustered distribution change, with the western region tending to gradually increase and the eastern region tending to gradually reduce. The dynamics of SIALU among different regions were divided into six grades: Northwestern Shandong > Northern Shandong > Southwestern Shandong > Southern Shandong > Central Shandong > Coastal areas of Shandong Peninsula.

SEAS (Surveillance Environmental Acoustic Support Program) Support

DTIC Science & Technology

1984-02-29

ASEPS software - Provide support for AMES - Support for OUTPOST CREOLE, BIG DIPPER and MFA , First, a summary of the tasks as delineated in the contract...addition, the contractor will provide an engineer/scientist to support the BIG DIPPER data processing activities at NOSC. Task 3: SEAS Inventory - The...SI to provide support to SEAS for the OUTPOST -’ CREOLE III exercise which followed immediately after the BIG DIPPER .. exercise. OUTPOST CREOLE III

Behavioral Responses of Odontocetes to Playback of Anthropogenic and Natural Sounds

DTIC Science & Technology

2011-09-30

risk. Conservation Ecology 6(1):11 Ford JKB. 1989. Acoustic behavior of resident killer whales (Orcinus orca) off Vancouver Island, British...to natural sounds such as those from killer whales ; and to measure exposure parameters for sounds that evoke a behavioral response. APPROACH The...overall timing and bandwidth similar to the MFA stimulus, and recorded calls of killer whales (ORCA). The protocol put the highest priority on

Cellulose microfibril orientation of Picea abies and its variability at the micron-level determined by Raman imaging.

PubMed

Gierlinger, Notburga; Luss, Saskia; König, Christian; Konnerth, Johannes; Eder, Michaela; Fratzl, Peter

2010-01-01

The functional characteristics of plant cell walls depend on the composition of the cell wall polymers, as well as on their highly ordered architecture at scales from a few nanometres to several microns. Raman spectra of wood acquired with linear polarized laser light include information about polymer composition as well as the alignment of cellulose microfibrils with respect to the fibre axis (microfibril angle). By changing the laser polarization direction in 3 degrees steps, the dependency between cellulose and laser orientation direction was investigated. Orientation-dependent changes of band height ratios and spectra were described by quadratic linear regression and partial least square regressions, respectively. Using the models and regressions with high coefficients of determination (R(2) > 0.99) microfibril orientation was predicted in the S1 and S2 layers distinguished by the Raman imaging approach in cross-sections of spruce normal, opposite, and compression wood. The determined microfibril angle (MFA) in the different S2 layers ranged from 0 degrees to 49.9 degrees and was in coincidence with X-ray diffraction determination. With the prerequisite of geometric sample and laser alignment, exact MFA prediction can complete the picture of the chemical cell wall design gained by the Raman imaging approach at the micron level in all plant tissues.

3D-QSAR studies and molecular docking on [5-(4-amino-1 H-benzoimidazol-2-yl)-furan-2-yl]-phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors

NASA Astrophysics Data System (ADS)

Lan, Ping; Xie, Mei-Qi; Yao, Yue-Mei; Chen, Wan-Na; Chen, Wei-Min

2010-12-01

Fructose-1,6-biphophatase has been regarded as a novel therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). 3D-QSAR and docking studies were performed on a series of [5-(4-amino-1 H-benzoimidazol-2-yl)-furan-2-yl]-phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors. The CoMFA and CoMSIA models using thirty-seven molecules in the training set gave r cv 2 values of 0.614 and 0.598, r 2 values of 0.950 and 0.928, respectively. The external validation indicated that our CoMFA and CoMSIA models possessed high predictive powers with r 0 2 values of 0.994 and 0.994, r m 2 values of 0.751 and 0.690, respectively. Molecular docking studies revealed that a phosphonic group was essential for binding to the receptor, and some key features were also identified. A set of forty new analogues were designed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models. The findings can be quite useful to aid the designing of new fructose-1,6-biphophatase inhibitors with improved biological response.

Geographical Variations in the Interaction of Relative Age Effects in Youth and Adult Elite Soccer.

PubMed

Steingröver, Christina; Wattie, Nick; Baker, Joseph; Helsen, Werner F; Schorer, Jörg

2017-01-01

Selection biases based on the use of cut-off dates and the timing of athletes' birthdates have been termed relative age effects. These effects have been shown to differentially affect individuals involved in sport. For example, young male soccer players born early in their age group are overrepresented in elite teams while studies in adult soccer indicated potential carry-over effects from talent development systems. This two-study approach focuses on the processes within multi-year age groups in youth and adult elite soccer and on the role of players' age position within the age band with regard to players' birth year and birth month. Study 1 tests for an interaction of two different types of relative age effects among data from participants in the last five Under-17 FIFA World Cups (2007-2015). Analyses revealed a significant global within-year effect and varying birthdate distributions were found between confederations. Even stronger effects were found for constituent year effects. For the total sample, a multi-way frequency analysis (MFA) revealed an interaction with a pattern of a stronger within-year effect for the younger year group. This study highlights the need to consider interactions between different types of age effects. The main aim of Study 2 was to test for carry-over effects from previously found constituent year effects among players participating in the 2014 soccer World Cup and, therefore, to test for long-term effects of age grouping structures used during earlier stages of talent development. A secondary purpose of this study was to replicate findings on the existence of within-year effects and to test whether effects vary between continental confederations. No significant interaction between constituent year and within-year effects was shown by the MFA among the World Cup sample and previous findings on varying within-year effects were replicated. Results indicate that long-term effects of age grouping structures in earlier high-level talent development structures exist.

Microwave assisted synthesis for A2E and development of LC-ESI-MS method for quantification of ocular bisretinoids in human retina.

PubMed

Kotnala, A; Senthilkumari, S; Halder, N; Kumar, A; Velpandian, T

2018-01-15

To develop a microwave assisted method for the rapid synthesis of A2E and also to develop a method to quantify N-retinylidene-N-retinylethanolamine(A2E), all-trans retinal dimer (ATRD), A2-glycerophospho ethanolamine (A2GPE), dihydropyridine phosphatidyl ethanolamine (A2DHPE) and monofuran A2E (MFA2E) in age matched retina. The development of microwave assisted synthesis of A2E, its purification and characterization for its utility in quantification in human retina. The semi-quantitative method development using LC-ESI-MS, LC-ESI-MS/MS and LC-APCI-MS/MS from pooled macula and peripheral retina for the bisretinoid analysis has been done. Maximum A2E conversion using microwave assisted process took place at 80°C for 45min with a yield of 55.01%. Highly sensitive and specific mass spectrometric method was developed using reverse phase C-18 separation with positive electrospray ionization and positive atmospheric phase chemical ionization of tandom mass spectrometry. A gradient mobile phase separation was achieved using water and methanol with 0.1% TFA. Multiple reaction monitoring acquisition for ESI and APCI was performed at ATRD m/z 551.2/522.2, A2GPE m/z 746.4/729.5, A2DHPEm/z 594.4/576.5, MFA2E m/z 608.2/591.2, A2E m/z 592.4/418.2. Method was validated using LC-ESI-SIM mode to determine selectivity, linearity, sensitivity, precision and accuracy. An attempt towards optimization of the synthetic procedure of A2E was made so as to reduce the lengthy reaction time without compromising the yield. Developed method was capable enough for the detection of low level of bisretinids in retina. Copyright © 2017 Elsevier B.V. All rights reserved.

Geographical Variations in the Interaction of Relative Age Effects in Youth and Adult Elite Soccer

PubMed Central

Steingröver, Christina; Wattie, Nick; Baker, Joseph; Helsen, Werner F.; Schorer, Jörg

2017-01-01

Selection biases based on the use of cut-off dates and the timing of athletes’ birthdates have been termed relative age effects. These effects have been shown to differentially affect individuals involved in sport. For example, young male soccer players born early in their age group are overrepresented in elite teams while studies in adult soccer indicated potential carry-over effects from talent development systems. This two-study approach focuses on the processes within multi-year age groups in youth and adult elite soccer and on the role of players’ age position within the age band with regard to players’ birth year and birth month. Study 1 tests for an interaction of two different types of relative age effects among data from participants in the last five Under-17 FIFA World Cups (2007–2015). Analyses revealed a significant global within-year effect and varying birthdate distributions were found between confederations. Even stronger effects were found for constituent year effects. For the total sample, a multi-way frequency analysis (MFA) revealed an interaction with a pattern of a stronger within-year effect for the younger year group. This study highlights the need to consider interactions between different types of age effects. The main aim of Study 2 was to test for carry-over effects from previously found constituent year effects among players participating in the 2014 soccer World Cup and, therefore, to test for long-term effects of age grouping structures used during earlier stages of talent development. A secondary purpose of this study was to replicate findings on the existence of within-year effects and to test whether effects vary between continental confederations. No significant interaction between constituent year and within-year effects was shown by the MFA among the World Cup sample and previous findings on varying within-year effects were replicated. Results indicate that long-term effects of age grouping structures in earlier high-level talent development structures exist. PMID:28326044

Access to Network Login by Three-Factor Authentication for Effective Information Security.

PubMed

Vaithyasubramanian, S; Christy, A; Saravanan, D

2016-01-01

Today's technology development in the field of computer along with internet of things made huge difference in the transformation of our lives. Basic computer framework and web client need to make significant login signify getting to mail, long range interpersonal communication, internet keeping money, booking tickets, perusing online daily papers, and so forth. The login user name and secret key mapping validate if the logging user is the intended client. Secret key is assumed an indispensable part in security. The objective of MFA is to make a layered safeguard and make it more troublesome for an unauthenticated entity to get to an objective, for example, a physical area, processing gadget, system, or database. In the event that one element is bargained or broken, the assailant still has two more boundaries to rupture before effectively breaking into the objective. An endeavor has been made by utilizing three variable types of authentication. In this way managing additional secret key includes an additional layer of security.

Access to Network Login by Three-Factor Authentication for Effective Information Security

PubMed Central

Vaithyasubramanian, S.; Christy, A.; Saravanan, D.

2016-01-01

Today's technology development in the field of computer along with internet of things made huge difference in the transformation of our lives. Basic computer framework and web client need to make significant login signify getting to mail, long range interpersonal communication, internet keeping money, booking tickets, perusing online daily papers, and so forth. The login user name and secret key mapping validate if the logging user is the intended client. Secret key is assumed an indispensable part in security. The objective of MFA is to make a layered safeguard and make it more troublesome for an unauthenticated entity to get to an objective, for example, a physical area, processing gadget, system, or database. In the event that one element is bargained or broken, the assailant still has two more boundaries to rupture before effectively breaking into the objective. An endeavor has been made by utilizing three variable types of authentication. In this way managing additional secret key includes an additional layer of security. PMID:27006976

A critical review on sustainability assessment of recycled water schemes.

PubMed

Chen, Zhuo; Ngo, Huu Hao; Guo, Wenshan

2012-06-01

Recycled water provides a viable opportunity to supplement water supplies as well as alleviate environmental loads. To further expand current schemes and explore new recycled water end uses, this study reviews several environmental assessment tools, including Life Cycle Assessment (LCA), Material Flow Analysis (MFA) and Environmental Risk Assessment (ERA) in terms of their types, characteristics and weaknesses in evaluating the sustainability of recycled water schemes. Due to the limitations in individual models, the integrated approaches are recommended in most cases, of which the outputs could be further combined with additional economic and social assessments in multi-criteria decision making framework. The study also proposes several management strategies in improving the environmental scores. The discussion and suggestions could help decision makers in making a sound judgement as well as recognising the challenges and tasks in the future. Copyright © 2012 Elsevier B.V. All rights reserved.

The role of the mitochondrial pyruvate carrier in substrate regulation

PubMed Central

Vacanti, Nathaniel M.; Divakaruni, Ajit S.; Green, Courtney R.; Parker, Seth J.; Henry, Robert R.; Ciaraldi, Theodore P.; Murphy, Anne N.; Metallo, Christian M.

2014-01-01

SUMMARY Pyruvate lies at a central biochemical node connecting carbohydrate, amino acid, and fatty acid metabolism, and the regulation of pyruvate flux into mitochondria represents a critical step in intermediary metabolism impacting numerous diseases. To characterize changes in mitochondrial substrate utilization in the context of compromised mitochondrial pyruvate transport, we applied 13C metabolic flux analysis (MFA) to cells after transcriptional or pharmacological inhibition of the mitochondrial pyruvate carrier (MPC). Despite profound suppression of both glucose and pyruvate oxidation, cell growth, oxygen consumption, and tricarboxylic acid (TCA) metabolism were surprisingly maintained. Oxidative TCA flux was achieved through enhanced reliance on glutaminolysis through malic enzyme and pyruvate dehydrogenase (PDH) as well as fatty acid and branched chain amino acid oxidation. Thus, in contrast to inhibition of complex I or PDH, suppression of pyruvate transport induces a form of metabolic flexibility associated with use of lipids and amino acids as catabolic and anabolic fuels. PMID:25458843

Translations on Eastern Europe Political, Sociological, and Military Affairs No. 1390.

DTIC Science & Technology

1977-05-20

MFA into three groups: the left, rallied around Vasco Gonsalves, the "group of nine", rallied around Melo Antonis, and the extreme left, rallied...visit by Dr Manuel Pinto Da Costa, secretary general of the Liberation Movement of Sao Tome E Principe [MLSTP] and president of the Democratic...chairman of the GDR state council, Dr Manuel Pinto da Costa, secre- tary general of the MLSTP and president of the DRSTP, paid an official friend

Evolution of the structure and the phase composition of a bainitic structural steel during plastic deformation

NASA Astrophysics Data System (ADS)

Nikitina, E. N.; Glezer, A. M.; Ivanov, Yu. F.; Aksenova, K. V.; Gromov, V. E.; Kazimirov, S. A.

2017-10-01

The evolution of the phase composition and the imperfect substructure of the 30Kh2N2MFA bainitic structural steel subjected to compressive deformation by 36% is quantitatively analyzed. It is shown that deformation is accompanied by an increase in the scalar dislocation density, a decrease in the longitudinal fragment sizes, an increase in the number of stress concentrators, the dissolution of cementite particles, and the transformation of retained austenite.

Envisioning Nano Release Dynamics in a Changing World: Using Dynamic Probabilistic Modeling to Assess Future Environmental Emissions of Engineered Nanomaterials.

PubMed

Sun, Tian Yin; Mitrano, Denise M; Bornhöft, Nikolaus A; Scheringer, Martin; Hungerbühler, Konrad; Nowack, Bernd

2017-03-07

The need for an environmental risk assessment for engineered nanomaterials (ENM) necessitates the knowledge about their environmental emissions. Material flow models (MFA) have been used to provide predicted environmental emissions but most current nano-MFA models consider neither the rapid development of ENM production nor the fact that a large proportion of ENM are entering an in-use stock and are released from products over time (i.e., have a lag phase). Here we use dynamic probabilistic material flow modeling to predict scenarios of the future flows of four ENM (nano-TiO 2 , nano-ZnO, nano-Ag and CNT) to environmental compartments and to quantify their amounts in (temporary) sinks such as the in-use stock and ("final") environmental sinks such as soil and sediment. In these scenarios, we estimate likely future amounts if the use and distribution of ENM in products continues along current trends (i.e., a business-as-usual approach) and predict the effect of hypothetical trends in the market development of nanomaterials, such as the emergence of a new widely used product or the ban on certain substances, on the flows of nanomaterials to the environment in years to come. We show that depending on the scenario and the product type affected, significant changes of the flows occur over time, driven by the growth of stocks and delayed release dynamics.

Cellulose microfibril orientation of Picea abies and its variability at the micron-level determined by Raman imaging

PubMed Central

Gierlinger, Notburga; Luss, Saskia; König, Christian; Konnerth, Johannes; Eder, Michaela; Fratzl, Peter

2010-01-01

The functional characteristics of plant cell walls depend on the composition of the cell wall polymers, as well as on their highly ordered architecture at scales from a few nanometres to several microns. Raman spectra of wood acquired with linear polarized laser light include information about polymer composition as well as the alignment of cellulose microfibrils with respect to the fibre axis (microfibril angle). By changing the laser polarization direction in 3° steps, the dependency between cellulose and laser orientation direction was investigated. Orientation-dependent changes of band height ratios and spectra were described by quadratic linear regression and partial least square regressions, respectively. Using the models and regressions with high coefficients of determination (R2 > 0.99) microfibril orientation was predicted in the S1 and S2 layers distinguished by the Raman imaging approach in cross-sections of spruce normal, opposite, and compression wood. The determined microfibril angle (MFA) in the different S2 layers ranged from 0° to 49.9° and was in coincidence with X-ray diffraction determination. With the prerequisite of geometric sample and laser alignment, exact MFA prediction can complete the picture of the chemical cell wall design gained by the Raman imaging approach at the micron level in all plant tissues. PMID:20007198

13C-MFA delineates the photomixotrophic metabolism of Synechocystis sp. PCC 6803 under light- and carbon-sufficient conditions.

PubMed

You, Le; Berla, Bert; He, Lian; Pakrasi, Himadri B; Tang, Yinjie J

2014-05-01

The central carbon metabolism of cyanobacteria is under debate. For over 50 years, the lack of α-ketoglutarate dehydrogenase has led to the belief that cyanobacteria have an incomplete TCA cycle. Recent in vitro enzymatic experiments suggest that this cycle may in fact be closed. The current study employed (13) C isotopomers to delineate pathways in the cyanobacterium Synechocystis sp. PCC 6803. By tracing the incorporation of supplemented glutamate into the downstream metabolites in the TCA cycle, we observed a direct in vivo transformation of α-ketoglutarate to succinate. Additionally, isotopic tracing of glyoxylate did not show a functional glyoxylate shunt and glyoxylate was used for glycine synthesis. The photomixotrophic carbon metabolism was then profiled with (13) C-MFA under light and carbon-sufficient conditions. We observed that: (i) the in vivo flux through the TCA cycle reactions (α-ketoglutarate → succinate) was minimal (<2%); (ii) the flux ratio of CO2 fixation was six times higher than that of glucose utilization; (iii) the relative flux through the oxidative pentose phosphate pathway was low (<2%); (iv) high flux through malic enzyme served as a main route for pyruvate synthesis. Our results improve the understanding of the versatile metabolism in cyanobacteria and shed light on their application for photo-biorefineries. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Nonlinear Monte Carlo model of superdiffusive shock acceleration with magnetic field amplification

NASA Astrophysics Data System (ADS)

Bykov, Andrei M.; Ellison, Donald C.; Osipov, Sergei M.

2017-03-01

Fast collisionless shocks in cosmic plasmas convert their kinetic energy flow into the hot downstream thermal plasma with a substantial fraction of energy going into a broad spectrum of superthermal charged particles and magnetic fluctuations. The superthermal particles can penetrate into the shock upstream region producing an extended shock precursor. The cold upstream plasma flow is decelerated by the force provided by the superthermal particle pressure gradient. In high Mach number collisionless shocks, efficient particle acceleration is likely coupled with turbulent magnetic field amplification (MFA) generated by the anisotropic distribution of accelerated particles. This anisotropy is determined by fast particle transport, making the problem strongly nonlinear and multiscale. Here, we present a nonlinear Monte Carlo model of collisionless shock structure with superdiffusive propagation of high-energy Fermi accelerated particles coupled to particle acceleration and MFA, which affords a consistent description of strong shocks. A distinctive feature of the Monte Carlo technique is that it includes the full angular anisotropy of the particle distribution at all precursor positions. The model reveals that the superdiffusive transport of energetic particles (i.e., Lévy-walk propagation) generates a strong quadruple anisotropy in the precursor particle distribution. The resultant pressure anisotropy of the high-energy particles produces a nonresonant mirror-type instability that amplifies compressible wave modes with wavelengths longer than the gyroradii of the highest-energy protons produced by the shock.

Contractility in type III cochlear fibrocytes is dependent on non-muscle myosin II and intercellular gap junctional coupling.

PubMed

Kelly, John J; Forge, Andrew; Jagger, Daniel J

2012-08-01

The cochlear spiral ligament is a connective tissue that plays diverse roles in normal hearing. Spiral ligament fibrocytes are classified into functional sub-types that are proposed to carry out specialized roles in fluid homeostasis, the mediation of inflammatory responses to trauma, and the fine tuning of cochlear mechanics. We derived a secondary sub-culture from guinea pig spiral ligament, in which the cells expressed protein markers of type III or "tension" fibrocytes, including non-muscle myosin II (nmII), α-smooth muscle actin (αsma), vimentin, connexin43 (cx43), and aquaporin-1. The cells formed extensive stress fibers containing αsma, which were also associated intimately with nmII expression, and the cells displayed the mechanically contractile phenotype predicted by earlier modeling studies. cx43 immunofluorescence was evident within intercellular plaques, and the cells were coupled via dye-permeable gap junctions. Coupling was blocked by meclofenamic acid (MFA), an inhibitor of cx43-containing channels. The contraction of collagen lattice gels mediated by the cells could be prevented reversibly by blebbistatin, an inhibitor of nmII function. MFA also reduced the gel contraction, suggesting that intercellular coupling modulates contractility. The results demonstrate that these cells can impart nmII-dependent contractile force on a collagenous substrate, and support the hypothesis that type III fibrocytes regulate tension in the spiral ligament-basilar membrane complex, thereby determining auditory sensitivity.

New p-methylsulfonamido phenylethylamine analogues as class III antiarrhythmic agents: design, synthesis, biological assay, and 3D-QSAR analysis.

PubMed

Liu, Hong; Ji, Ming; Luo, Xiaomin; Shen, Jianhua; Huang, Xiaoqin; Hua, Weiyi; Jiang, Hualiang; Chen, Kaixian

2002-07-04

Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrane action potential duration (APD). Using dofetilide (2) as a template of class III antiarrhythmic agents, we designed and synthesized 16 methylsulfonamido phenylethylamine analogues (4a-d and 5a-l). Pharmacological assay indicated that all of these compounds showed activity for increasing the ERP in isolated animal atrium; among them, the effective concentration of compound 4a is 1.6 x 10(-8) mol/L in increasing ERP by 10 ms, slightly less potent than that of 2, 1.1 x 10(-8) mol/L. Compound 4a also produced a slightly lower change in ERP at 10(-5) M, DeltaERP% = 17.5% (DeltaERP% = 24.0% for dofetilide). On the basis of this bioassay result, these 16 compounds together with dofetilide were investigated by the three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques of comparative molecular field analysis (CoMFA), comparative molecular similarity index analysis (CoMSIA), and the hologram QSAR (HQSAR). The 3D-QSAR models were tested with another 11 compounds (4e-h and 5m-s) that we synthesized later. Results revealed that the CoMFA, CoMSIA, and HQSAR predicted activities for the 11 newly synthesized compounds that have a good correlation with their experimental value, r(2) = 0.943, 0.891, and 0.809 for the three QSAR models, respectively. This indicates that the 3D-QSAR models proved a good predictive ability and could describe the steric, electrostatic, and hydrophobic requirements for recognition forces of the receptor site. On the basis of these results, we designed and synthesized another eight new analogues of methanesulfonamido phenylethyamine (6a-h) according to the clues provided by the 3D-QSAR analyses. Pharmacological assay indicated that the effective concentrations of delaying the ERP by 10 ms of these newly designed compounds correlated well with the 3D-QSAR predicted values. It is remarkable that the percent change of delaying ERP at 10(-5) M compound 6c is much higher than that of dofetilide; the effective concentration of compound 6c is 5.0 x 10(-8)mol/L in increasing the ERP by 10 ms, which is slightly lower than that of 2. The results showed that the 3D-QSAR models are reliable and can be extended to design new antiarrhythmic agents.

Combined untargeted and targeted fingerprinting by comprehensive two-dimensional gas chromatography: revealing fructose-induced changes in mice urinary metabolic signatures.

PubMed

Bressanello, Davide; Liberto, Erica; Collino, Massimo; Chiazza, Fausto; Mastrocola, Raffaella; Reichenbach, Stephen E; Bicchi, Carlo; Cordero, Chiara

2018-04-01

This study exploits the information potential of comprehensive two-dimensional gas chromatography configured with a parallel dual secondary column-dual detection by mass spectrometry and flame ionization (GC×2GC-MS/FID) to study changes in urinary metabolic signatures of mice subjected to high-fructose diets. Samples are taken from mice fed with normal or fructose-enriched diets provided either in aqueous solution or in solid form and analyzed at three stages of the dietary intervention (1, 6, and 12 weeks). Automated Untargeted and Targeted fingerprinting for 2D data elaboration is adopted for the most inclusive data mining of GC×GC patterns. The UT fingerprinting strategy performs a fully automated peak-region features fingerprinting and combines results from pre-targeted compounds and unknowns across the sample-set. The most informative metabolites, with statistically relevant differences between sample groups, are obtained by unsupervised multivariate analysis (MVA) and cross-validated by multi-factor analysis (MFA) with external standard quantitation by GC-MS. Results indicate coherent clustering of mice urine signatures according to dietary manipulation. Notably, the metabolite fingerprints of mice fed with liquid fructose exhibited greater derangement in fructose, glucose, citric, pyruvic, malic, malonic, gluconic, cis-aconitic, succinic and 2-keto glutaric acids, glycine acyl derivatives (N-carboxy glycine, N-butyrylglycine, N-isovaleroylglycine, N-phenylacetylglycine), and hippuric acid. Untargeted fingerprinting indicates some analytes which were not a priori pre-targeted which provide additional insights: N-acetyl glucosamine, N-acetyl glutamine, malonyl glycine, methyl malonyl glycine, and glutaric acid. Visual features fingerprinting is used to track individual variations during experiments, thereby extending the panorama of possible data elaboration tools. Graphical abstract ᅟ.

Material flow analysis of scarce metals: sources, functions, end-uses and aspects for future supply.

PubMed

Peiró, Laura Talens; Méndez, Gara Villalba; Ayres, Robert U

2013-03-19

A number of metals that are now important to the electronic industry (and others) will become much more important in the future if current trends in technology continue. Most of these metals are byproducts (or hitch-hikers) of a small number of important industrial metals (attractors). By definition, the metals in the hitch-hiker group are not mined by themselves, and thus their production is limited by the demand for the major attractors. This article presents a material flow analysis (MFA) of the complex inter-relationships between these groups of metals. First, it surveys the main sources of geologically scarce (byproduct) metals currently considered critical by one or other of several recent studies. This is followed by a detailed survey of their major functions and the quantities contained in intermediate and end-products. The purpose is to identify the sectors and products where those metals are used and stocked and thus potentially available for future recycling. It concludes with a discussion of the limitations of possible substitution and barriers to recycling.

Coexistence of Cu, Fe, Pb, and Zn oxides and chlorides as a determinant of chlorinated aromatics generation in municipal solid waste incinerator fly ash.

PubMed

Fujimori, Takashi; Tanino, Yuta; Takaoka, Masaki

2014-01-01

We investigated chemical determinants of the generation of chlorinated aromatic compounds (aromatic-Cls), such as polychlorinated biphenyls (PCBs) and chlorobenzenes (CBzs), in fly ash from municipal solid waste incineration. The influences of the following on aromatic-Cls formation in model fly ash (MFA) were systematically examined quantitatively and statistically: (i) inorganic chlorides (KCl, NaCl, CaCl2), (ii) base materials (SiO2, Al2O3, CaCO3), (iii) metal oxides (CuO, Fe2O3, PbO, ZnO), (iv) metal chlorides (CuCl2, FeCl3, PbCl2, ZnCl2), and (v) "coexisting multi-models." On the basis of aromatic-Cls concentrations, the ∑CBzs/∑PCBs ratio, and the similarity between distribution patterns, MFAs were categorized into six groups. The results and analysis indicated that the formation of aromatic-Cls depended strongly on the "coexistence condition", namely multimodels composed of not only metal chlorides, but also of metal oxides. The precise replication of metal chloride to oxide ratios, such as the precise ratios of Cu-, Fe-, Pb-, and Zn-chlorides and oxides, may be an essential factor in changing the thermochemical formation patterns of aromatic-Cls. Although CuCl2 acted as a promoter of aromatic-Cls generation, statistical analyses implied that FeCl3 also largely influenced the generation of aromatic-Cls under mixture conditions. Various additional components of fly ash were also comprehensively analyzed.

Profiling the interaction mechanism of quinoline/quinazoline derivatives as MCHR1 antagonists: an in silico method.

PubMed

Wu, Mingwei; Li, Yan; Fu, Xinmei; Wang, Jinghui; Zhang, Shuwei; Yang, Ling

2014-09-01

Melanin concentrating hormone receptor 1 (MCHR1), a crucial regulator of energy homeostasis involved in the control of feeding and energy metabolism, is a promising target for treatment of obesity. In the present work, the up-to-date largest set of 181 quinoline/quinazoline derivatives as MCHR1 antagonists was subjected to both ligand- and receptor-based three-dimensional quantitative structure-activity (3D-QSAR) analysis applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The optimal predictable CoMSIA model exhibited significant validity with the cross-validated correlation coefficient (Q²) = 0.509, non-cross-validated correlation coefficient (R²(ncv)) = 0.841 and the predicted correlation coefficient (R²(pred)) = 0.745. In addition, docking studies and molecular dynamics (MD) simulations were carried out for further elucidation of the binding modes of MCHR1 antagonists. MD simulations in both water and lipid bilayer systems were performed. We hope that the obtained models and information may help to provide an insight into the interaction mechanism of MCHR1 antagonists and facilitate the design and optimization of novel antagonists as anti-obesity agents.

ARC-2006-ACD06-0213-010

NASA Image and Video Library

2006-10-03

Ames and Moffett Field (MFA) historical sites and memorials Unitary Plan Wind Tunned plaza; display and historical site plaques with the NASA logo on the Wind Tunnel valve as a backdrop. Plaque depicts that Ames Unitary Plan Wind Tunnel has been designated a National Historic Landmark by the National Park Service, United States Department of the Interior 1985 The plaque reads; This site possesses national significance in commemorating the history of the United States of America. That ceremony took place on September 12, 1990

Behavioral Responses of Naive Cuvier’s Beaked Whales in the Ligurian Sea to Playback of Anthropogenic and Natural Sounds

DTIC Science & Technology

2013-09-30

cavirostris) to MFA sonar signals. Secondary goals included conducting a killer whale playback that has not been preceded by a sonar playback (as in Tyack...et al. 2011) and collecting more baseline data on Ziphius. OBJECTIVES This investigation set out to safely test responses of Ziphius to sonar ...signals and to determine the exposure level required to elicit a response in a site where strandings have been associated with sonar exercises and

Behavioral Responses of Naive Cuvier’s Beaked Whales in the Ligurian Sea to Playback of Anthropogenic and Natural Sounds

DTIC Science & Technology

2012-09-30

cavirostris) to MFA sonar signals. A secondary goal of conducting a killer whale playback that has not been preceded by a sonar playback (as in Tyack et al...2011) was also planned. OBJECTIVES This investigation set out to safely test responses of Ziphius to sonar signals and to determine the...exposure level required to elicit a response in a site where strandings have been associated with sonar exercises and where the whales seldom hear sonar

U.S. Clothing and Textile Trade with China and the World: Trends Since the End of Quotas

DTIC Science & Technology

2007-07-10

the road to quota-free trade for clothing and textiles, the MFA expanded the scope of the LTA to include wool and man-made fibers. However, concerns...starting a 10-year process of eliminating quotas for international trade in clothing and textiles. The ATC’s quota phase-out contained two concurrent...goods. The ATC also required that products from different categories — textiles and clothing, wool , cotton or man-made fibres, etc. — be included in

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

Schwender, Jorg; Konig, Christina; Klapperstuck, Matthias

An attempt has been made to define the extent to which metabolic flux in central plant metabolism is reflected by changes in the transcriptome and metabolome, based on an analysis of in vitro cultured immature embryos of two oilseed rape (Brassica napus) accessions which contrast for seed lipid accumulation. Metabolic flux analysis (MFA) was used to constrain a flux balance metabolic model which included 671 biochemical and transport reactions within the central metabolism. This highly confident flux information was eventually used for comparative analysis of flux vs. transcript (metabolite). Metabolite profiling succeeded in identifying 79 intermediates within the central metabolism,more » some of which differed quantitatively between the two accessions and displayed a significant shift corresponding to flux. An RNA-Seq based transcriptome analysis revealed a large number of genes which were differentially transcribed in the two accessions, including some enzymes/proteins active in major metabolic pathways. With a few exceptions, differential activity in the major pathways (glycolysis, TCA cycle, amino acid, and fatty acid synthesis) was not reflected in contrasting abundances of the relevant transcripts. The conclusion was that transcript abundance on its own cannot be used to infer metabolic activity/fluxes in central plant metabolism. Lastly, this limitation needs to be borne in mind in evaluating transcriptome data and designing metabolic engineering experiments.« less

Modification of polychlorinated phenols and evaluation of their toxicity, biodegradation and bioconcentration using three-dimensional quantitative structure-activity relationship models.

PubMed

Tong, Lidan; Guo, Lixin; Lv, Xiaojun; Li, Yu

2017-01-01

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were established by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Experimental toxicity data in Poecilia reticulata (pLC 50 ) and physico-chemical properties for 12 polychlorinated phenols were used as dependent and as independent variables, respectively. Among the 12 polychlorinated phenols, nine were randomly selected and used as a training set to construct the 3D-QSAR models through the SYBYL-X software to predict the pLC 50 values of the remaining 8 polychlorinated phenols congeners, and the other three polychlorinated phenols were used as a test set to evaluate the 3D-QSAR models (the training set and test set were arranged randomly, shuffled 60 times). Pentachlorophenol (PCP), which is the most toxic among the 20 polychlorinated phenols used in this experiment, was selected as an example for modification using contour maps produced using the established 3D-QSAR models. The aim was to decrease its toxicity and bioconcentration, increase its biodegradation, and maintain or better its effectiveness as a pesticide. The 3D-QSAR models were robust and had good predictive abilities with cross-validation correlation coefficients (q 2 ) of 0.858-0.992 (>0.5), correlation coefficients (r 2 ) of 0.966-1.000 (>0.9), and standard errors of prediction (SEP) of 0.004-0.159. CoMFA showed that the toxicity of the polychlorinated phenols arose mainly from electrostatic (42.7-66.7%) and steric (33.3-7.3%) contributions. By comparison, CoMSIA showed that the toxicity of polychlorinated phenols was dominated by electrostatic (57.5-76.9%) and hydrophobic (19.8-25.7%) contributions, with lesser contributions from the steric (0.7-1.0%) hydrogen bond donor (0.1-20.3%), and hydrogen bond acceptor (0-0.9%). 3D-QSAR electrostatic contour maps were used to modify PCP and design 11 new compounds with lower toxicity. The effectiveness of each of these molecules as a pesticide was verified using a 3D-QSAR model for polychlorinated phenol toxicity against Tetrahymena pyriformis. Four of these compounds, with -Br, -I, -OH and -NH 2 groups in place of chlorine at the 3-position on PCP, were all at least as effective as PCP against T. Pyriformis. The first-order rate constants (K b ) of these four compounds were predicted using a 3D-QSAR model for polychlorinated phenol degradation, which showed they were more biodegradable than PCP. Furthermore, a 3D-QSAR model for polychlorinated phenols bioconcentration in fish (containing Poecilia reticulata, Oncorhynchus mykiss, Pimephales promelas and Oryzias latipes) showed that there was no significant difference between the bioconcentration factors of the four new compounds and that of PCP. The results obtained are hoped to provide a new route for lowering the POPs characteristics of those polychlorinated phenol homologues and derivatives in use. Copyright © 2016 Elsevier Inc. All rights reserved.

Radio Evolution of Supernova Remnants Including Nonlinear Particle Acceleration: Insights from Hydrodynamic Simulations

NASA Astrophysics Data System (ADS)

Pavlović, Marko Z.; Urošević, Dejan; Arbutina, Bojan; Orlando, Salvatore; Maxted, Nigel; Filipović, Miroslav D.

2018-01-01

We present a model for the radio evolution of supernova remnants (SNRs) obtained by using three-dimensional hydrodynamic simulations coupled with nonlinear kinetic theory of cosmic-ray (CR) acceleration in SNRs. We model the radio evolution of SNRs on a global level by performing simulations for a wide range of the relevant physical parameters, such as the ambient density, supernova (SN) explosion energy, acceleration efficiency, and magnetic field amplification (MFA) efficiency. We attribute the observed spread of radio surface brightnesses for corresponding SNR diameters to the spread of these parameters. In addition to our simulations of Type Ia SNRs, we also considered SNR radio evolution in denser, nonuniform circumstellar environments modified by the progenitor star wind. These simulations start with the mass of the ejecta substantially higher than in the case of a Type Ia SN and presumably lower shock speed. The magnetic field is understandably seen as very important for the radio evolution of SNRs. In terms of MFA, we include both resonant and nonresonant modes in our large-scale simulations by implementing models obtained from first-principles, particle-in-cell simulations and nonlinear magnetohydrodynamical simulations. We test the quality and reliability of our models on a sample consisting of Galactic and extragalactic SNRs. Our simulations give Σ ‑ D slopes between ‑4 and ‑6 for the full Sedov regime. Recent empirical slopes obtained for the Galactic samples are around ‑5, while those for the extragalactic samples are around ‑4.

Resistance of Select Winter Wheat (Triticum aestivum) Cultivars to Rhopalosiphum padi (Hemiptera: Aphididae).

PubMed

Girvin, John; Whitworth, R Jeff; Rojas, Lina Maria Aguirre; Smith, C Michael

2017-08-01

The bird cherry-oat aphid (Rhopalosiphum padi L.) is a global pest of wheat and vectors some of the most damaging strains of barley yellow dwarf virus (BYDV). In years of heavy R. padi infestation, R. padi and BYDV together reduce wheat yields by 30-40% in Kansas and other states of the U.S. Great Plains wheat production area. Cultivation of wheat cultivars resistant to R. padi can greatly reduce production costs and mitigate R. padi-BYDV yield losses, and increase producer profits. This study identified cultivars of hard red and soft white winter wheat with R. padi resistance that suppress R. padi populations or tolerate the effects of R. padi feeding damage. 'Pioneer (S) 25R40,' 'MFA (S) 2248,' 'Pioneer (S) 25R77,' and 'Limagrain LCS Mint' significantly reduced R. padi populations. MFA (S) 2248, Pioneer (S) 25R40, and 'Limagrain LS Wizard' exhibited tolerance expressed as significantly greater aboveground biomass. These findings are significant in that they have identified wheat cultivars currently available to producers, enabling the immediate improvement of tactics to manage R. padi and BYDV in heavily infested areas. Secondarily, these results identify cultivars that are good candidates for use in breeding and genetic analyses of arthropod resistance genes in wheat. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Characterization of a bacterial tyrosine kinase in Porphyromonas gingivalis involved in polymicrobial synergy.

PubMed

Wright, Christopher J; Xue, Peng; Hirano, Takanori; Liu, Chengcheng; Whitmore, Sarah E; Hackett, Murray; Lamont, Richard J

2014-06-01

Interspecies communication between Porphyromonas gingivalis and Streptococcus gordonii underlies the development of synergistic dual species communities. Contact with S. gordonii initiates signal transduction within P. gingivalis that is based on protein tyrosine (de)phosphorylation. In this study, we characterize a bacterial tyrosine (BY) kinase (designated Ptk1) of P. gingivalis and demonstrate its involvement in interspecies signaling. Ptk1 can utilize ATP for autophosphorylation and is dephosphorylated by the P. gingivalis tyrosine phosphatase, Ltp1. Community development with S. gordonii is severely abrogated in a ptk1 mutant of P. gingivalis, indicating that tyrosine kinase activity is required for maximal polymicrobial synergy. Ptk1 controls the levels of the transcriptional regulator CdhR and the fimbrial adhesin Mfa1 which mediates binding to S. gordonii. The ptk1 gene is in an operon with two genes involved in exopolysaccharide synthesis, and similar to other BY kinases, Ptk1 is necessary for exopolysaccharide production in P. gingivalis. Ptk1 can phosphorylate the capsule related proteins PGN_0224, a UDP-acetyl-mannosamine dehydrogenase, and PGN_0613, a UDP-glucose dehydrogenase, in P. gingivalis. Knockout of ptk1 in an encapsulated strain of P. gingivalis resulted in loss of capsule production. Collectively these results demonstrate that the P. gingivalis Ptk1 BY kinase regulates interspecies communication and controls heterotypic community development with S. gordonii through adjusting the levels of the Mfa1 adhesin and exopolysaccharide. © 2014 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

Spacelab system analysis: The modified free access protocol: An access protocol for communication systems with periodic and Poisson traffic

NASA Technical Reports Server (NTRS)

Ingels, Frank; Owens, John; Daniel, Steven

1989-01-01

The protocol definition and terminal hardware for the modified free access protocol, a communications protocol similar to Ethernet, are developed. A MFA protocol simulator and a CSMA/CD math model are also developed. The protocol is tailored to communication systems where the total traffic may be divided into scheduled traffic and Poisson traffic. The scheduled traffic should occur on a periodic basis but may occur after a given event such as a request for data from a large number of stations. The Poisson traffic will include alarms and other random traffic. The purpose of the protocol is to guarantee that scheduled packets will be delivered without collision. This is required in many control and data collection systems. The protocol uses standard Ethernet hardware and software requiring minimum modifications to an existing system. The modification to the protocol only affects the Ethernet transmission privileges and does not effect the Ethernet receiver.

Computer-aided design, synthesis and biological assay of p-methylsulfonamido phenylethylamine analogues.

PubMed

Liu, H; Ji, M; Jiang, H; Liu, L; Hua, W; Chen, K; Ji, R

2000-10-02

Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrance action potential duration (APD). Based on our previous studies, a set of 17 methylsulfonamido phenylethylamine analogues were investigated by 3D-QSAR techniques of CoMFA and CoMSIA. The 3D-QSAR models proved a good predictive ability, and could describe the steric, electrostatic and hydrophobic requirements for recognition forces of the receptor site. According to the clues provided by this 3D-QSAR analysis, we designed and synthesized a series of new analogues of methanesulfonamido phenylethylamine (VIa-i). Pharmacological assay indicated that the effective concentrations of delaying the functional refractory period (FRP) 10ms of these new compounds have a good correlation with the 3D-QSAR predicted values. It is remarkable that the maximal percent change of delaying FRP in microM of compound VIc is much higher than that of dofetilide. The results showed that the 3D-QSAR models are reliable.

Bidirectionality and compartmentation of metabolic fluxes are revealed in the dynamics of isotopomer networks.

PubMed

Schryer, David W; Peterson, Pearu; Paalme, Toomas; Vendelin, Marko

2009-04-17

Isotope labeling is one of the few methods of revealing the in vivo bidirectionality and compartmentalization of metabolic fluxes within metabolic networks. We argue that a shift from steady state to dynamic isotopomer analysis is required to deal with these cellular complexities and provide a review of dynamic studies of compartmentalized energy fluxes in eukaryotic cells including cardiac muscle, plants, and astrocytes. Knowledge of complex metabolic behaviour on a molecular level is prerequisite for the intelligent design of genetically modified organisms able to realize their potential of revolutionizing food, energy, and pharmaceutical production. We describe techniques to explore the bidirectionality and compartmentalization of metabolic fluxes using information contained in the isotopic transient, and discuss the integration of kinetic models with MFA. The flux parameters of an example metabolic network were optimized to examine the compartmentalization of metabolites and and the bidirectionality of fluxes in the TCA cycle of Saccharomyces uvarum for steady-state respiratory growth.

Metabolic engineering tools in model cyanobacteria.

PubMed

Carroll, Austin L; Case, Anna E; Zhang, Angela; Atsumi, Shota

2018-03-26

Developing sustainable routes for producing chemicals and fuels is one of the most important challenges in metabolic engineering. Photoautotrophic hosts are particularly attractive because of their potential to utilize light as an energy source and CO 2 as a carbon substrate through photosynthesis. Cyanobacteria are unicellular organisms capable of photosynthesis and CO 2 fixation. While engineering in heterotrophs, such as Escherichia coli, has result in a plethora of tools for strain development and hosts capable of producing valuable chemicals efficiently, these techniques are not always directly transferable to cyanobacteria. However, recent efforts have led to an increase in the scope and scale of chemicals that cyanobacteria can produce. Adaptations of important metabolic engineering tools have also been optimized to function in photoautotrophic hosts, which include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9, 13 C Metabolic Flux Analysis (MFA), and Genome-Scale Modeling (GSM). This review explores innovations in cyanobacterial metabolic engineering, and highlights how photoautotrophic metabolism has shaped their development. Copyright © 2018 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Isothermal and thermal-mechanical fatigue of VVER-440 reactor pressure vessel steels

NASA Astrophysics Data System (ADS)

Fekete, Balazs; Trampus, Peter

2015-09-01

The fatigue life of the structural materials 15Ch2MFA (CrMoV-alloyed ferritic steel) and 08Ch18N10T (CrNi-alloyed austenitic steel) of VVER-440 reactor pressure vessel under completely reserved total strain controlled low cycle fatigue tests were investigated. An advanced test facility was developed for GLEEBLE-3800 physical simulator which was able to perform thermomechanical fatigue experiments under in-service conditions of VVER nuclear reactors. The low cycle fatigue results were evaluated with the plastic strain based Coffin-Manson law, and plastic strain energy based model as well. It was shown that both methods are able to predict the fatigue life of reactor pressure vessel steels accurately. Interrupted fatigue tests were also carried out to investigate the kinetic of the fatigue evolution of the materials. On these samples microstructural evaluation by TEM was performed. The investigated low cycle fatigue behavior can provide reference for remaining life assessment and lifetime extension analysis.

Reliability Modeling of Critical Electronic Devices.

DTIC Science & Technology

1983-05-01

form are given below: 1) Xn = K 7E = AS + B 2) Xn = K TTE = A(S)B 3) Xn = K TE = A exp(BS) 24 A- where Xn = predicted normalized failure rate 0 0 K...naval, sheltered NS 5 7.3 a,. naval, unsheltered NU 10 16.8 naval, undersea , unsheltered NUU 14 20.6 naval, benign, submarine NSB 4 6.0 naval, hydrofoil... undersea , launch USL 18 37.1 3 S missile, free flight MFF 9 12.6 airbreathing missile, flight MFA 11 17.6 space, flight SF 2 2.1 Notes: (1) includes bomber

U.S.-China Strategic Dialogue, Phase IX Report

DTIC Science & Technology

2018-03-01

electron volt (eV) 1.602 177 × 10 –19 joule (J) erg 1 × 10 –7 joule (J) kiloton (kt) (TNT equivalent ) 4.184 × 10 12 joule (J) British...C kg –1 ) rad [absorbed dose] 1 × 10 –2 joule per kilogram (J kg –1 ) [gray (Gy)] rem [ equivalent and effective dose] 1 × 10–2 joule per kilogram...This “ non -governmental” association, with close ties to the Ministry of Foreign Affairs (MFA) and People’s Liberation Army (PLA), helped improve

A comparison of progestin and androgen receptor binding using the CoMFA technique

NASA Astrophysics Data System (ADS)

Loughney, Deborah A.; Schwender, Charles F.

1992-12-01

A series of 48 steroids has been studied with the SYBYL QSAR module using Relative Binding Affinities (RBAs) to progesterone and androgen receptors obtained from the literature. Models for the progesterone and androgen data were developed. Both models show regions where sterics and electrostatics correlate to binding affinity but are different for androgen and progesterone which suggests differences possibly important for receptor selectivity. The progesterone model is more predictive than the androgen (predictive r2 of 0.725 vs. 0.545 for progesterone and androgen, respectively).

Napping-Ultra Flash Profile as a Tool for Category Identification and Subsequent Model System Formulation of Caramel Corn Products.

PubMed

Mayhew, Emily; Schmidt, Shelly; Lee, Soo-Yeun

2016-07-01

In a novel approach to formulation, the flash descriptive profiling technique Napping-Ultra Flash Profile (Napping-UFP) was used to characterize a wide range of commercial caramel corn products. The objectives were to identify product categories, develop model systems based on product categories, and correlate analytical parameters with sensory terms generated through the Napping-UFP exercise. In one 2 h session, 12 panelists participated in 4 Napping-UFP exercises, describing and grouping, on a 43×56 cm paper sheet, 12 commercial caramel corn samples by degree of similarity, globally and in terms of aroma-by-mouth, texture, and taste. The coordinates of each sample's placement on the paper sheet and descriptive terms generated by the panelists were used to conduct Multiple Factor Analysis (MFA) and hierarchical clustering of the samples. Strong trends in the clustering of samples across the 4 Napping-UFP exercises resulted in the determination of 3 overarching types of commercial caramel corn: "small-scale dark" (typified by burnt, rich caramel corn), "large-scale light" (typified by light and buttery caramel corn), and "large-scale dark" (typified by sweet and molasses-like caramel corn). Representative samples that best exemplified the properties of each category were used as guides in the formulation of 3 model systems that represent the spread of commercial caramel corn products. Analytical testing of the commercial products, including aw measurement, moisture content determination, and thermal characterization via differential scanning calorimetry, were conducted and results related to sensory descriptors using Spearman's correlation. © 2016 Institute of Food Technologists®

Investigating Mixture Interactions of Astringent Stimuli Using the Isobole Approach

PubMed Central

Fleming, Erin E.; Ziegler, Gregory R.

2016-01-01

Abstract Astringents (alum, malic acid, tannic acid) representing 3 broad classes (multivalent salts, organic acids, and polyphenols) were characterized alone, and as 2- and 3-component mixtures using isoboles. In experiment 1, participants rated 7 attributes (“astringency,” the sub-qualities “drying,” “roughing,” and “puckering,” and the side tastes “bitterness,” “sourness,” and “sweetness”) using direct scaling. Quality specific power functions were calculated for each stimulus. In experiment 2, the same participants characterized 2- and 3-component mixtures. Multiple factor analysis (MFA) and hierarchical clustering on attribute ratings across stimuli indicate “astringency” is highly related to “bitterness” as well as “puckering,” and the subqualities “drying” and “roughing” are somewhat redundant. Moreover, power functions were used to calculate indices of interaction (I) for each attribute/mixture combination. For “astringency,” there was evidence of antagonism, regardless of the type of mixture. Conversely, for subqualities, the pattern of interaction depended on the mixture type. Alum/tannic acid and tannic acid/malic acid mixtures showed evidence of synergy for “drying” and “roughing”; alum/malic acid mixtures showed evidence of antagonism for “drying,” “roughing,” and “puckering.” Collectively, these data clarify some semantic ambiguity regarding astringency and its subqualities, as well as the nature of interactions of among different types of astringents. Present data are not inconsistent with the idea that astringency arises from multiple mechanisms, although it remains to be determined whether the synergy observed here might reflect simultaneous activation of these multiple mechanisms. PMID:27252355

¹³C-based metabolic flux analysis of Saccharomyces cerevisiae with a reduced Crabtree effect.

PubMed

Kajihata, Shuichi; Matsuda, Fumio; Yoshimi, Mika; Hayakawa, Kenshi; Furusawa, Chikara; Kanda, Akihisa; Shimizu, Hiroshi

2015-08-01

Saccharomyces cerevisiae shows a Crabtree effect that produces ethanol in a high glucose concentration even under fully aerobic condition. For efficient production of cake yeast or compressed yeast for baking, ethanol by-production is not desired since glucose limited chemostat or fed-batch cultivations are performed to suppress the Crabtree effect. In this study, the (13)C-based metabolic flux analysis ((13)C-MFA) was performed for the S288C derived S. cerevisiae strain to characterize a metabolic state under the reduced Crabtree effect. S. cerevisiae cells were cultured at a low dilution rate (0.1 h(-1)) under the glucose-limited chemostat condition. The estimated metabolic flux distribution showed that the acetyl-CoA in mitochondria was mainly produced from pyruvate by pyruvate dehydrogenase (PDH) reaction and that the level of the metabolic flux through the pentose phosphate pathway was much higher than that of the Embden-Meyerhof-Parnas pathway, which contributes to high biomass yield at low dilution rate by supplying NADPH required for cell growth. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the beta2 adrenergic receptor.

PubMed

Jozwiak, Krzysztof; Khalid, Chakir; Tanga, Mary J; Berzetei-Gurske, Ilona; Jimenez, Lucita; Kozocas, Joseph A; Woo, Anthony; Zhu, Weizhong; Xiao, Rui-Ping; Abernethy, Darrell R; Wainer, Irving W

2007-06-14

Stereoisomers of fenoterol and six fenoterol derivatives have been synthesized and their binding affinities for the beta2 adrenergic receptor (Kibeta2-AR), the subtype selectivity relative to the beta1-AR (Kibeta1-AR/Kibeta2-AR) and their functional activities were determined. Of the 26 compounds synthesized in the study, submicromolar binding affinities were observed for (R,R)-fenoterol, the (R,R)-isomer of the p-methoxy, and (R,R)- and (R,S)-isomers of 1-naphthyl derivatives and all of these compounds were active at submicromolar concentrations in cardiomyocyte contractility tests. The Kibeta1-AR/Kibeta2-AR ratios were >40 for (R,R)-fenoterol and the (R,R)-p-methoxy and (R,S)-1-naphthyl derivatives and 14 for the (R,R)-1-napthyl derivative. The binding data was analyzed using comparative molecular field analysis (CoMFA), and the resulting model indicated that the fenoterol derivatives interacted with two separate binding sites and one steric restricted site on the pseudo-receptor and that the chirality of the second stereogenic center affected Kibeta2 and subtype selectivity.

A Combined Pharmacophore Modeling, 3D QSAR and Virtual Screening Studies on Imidazopyridines as B-Raf Inhibitors

PubMed Central

Xie, Huiding; Chen, Lijun; Zhang, Jianqiang; Xie, Xiaoguang; Qiu, Kaixiong; Fu, Jijun

2015-01-01

B-Raf kinase is an important target in treatment of cancers. In order to design and find potent B-Raf inhibitors (BRIs), 3D pharmacophore models were created using the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). The best pharmacophore model obtained which was used in effective alignment of the data set contains two acceptor atoms, three donor atoms and three hydrophobes. In succession, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 39 imidazopyridine BRIs to build three dimensional quantitative structure-activity relationship (3D QSAR) models based on both pharmacophore and docking alignments. The CoMSIA model based on the pharmacophore alignment shows the best result (q2 = 0.621, r2pred = 0.885). This 3D QSAR approach provides significant insights that are useful for designing potent BRIs. In addition, the obtained best pharmacophore model was used for virtual screening against the NCI2000 database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMSIA model, and three potential BRIs with new skeletons were obtained. PMID:26035757

A Combined Pharmacophore Modeling, 3D QSAR and Virtual Screening Studies on Imidazopyridines as B-Raf Inhibitors.

PubMed

Xie, Huiding; Chen, Lijun; Zhang, Jianqiang; Xie, Xiaoguang; Qiu, Kaixiong; Fu, Jijun

2015-05-29

B-Raf kinase is an important target in treatment of cancers. In order to design and find potent B-Raf inhibitors (BRIs), 3D pharmacophore models were created using the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). The best pharmacophore model obtained which was used in effective alignment of the data set contains two acceptor atoms, three donor atoms and three hydrophobes. In succession, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 39 imidazopyridine BRIs to build three dimensional quantitative structure-activity relationship (3D QSAR) models based on both pharmacophore and docking alignments. The CoMSIA model based on the pharmacophore alignment shows the best result (q(2) = 0.621, r(2)(pred) = 0.885). This 3D QSAR approach provides significant insights that are useful for designing potent BRIs. In addition, the obtained best pharmacophore model was used for virtual screening against the NCI2000 database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMSIA model, and three potential BRIs with new skeletons were obtained.

Electronic waste management approaches: an overview.

PubMed

Kiddee, Peeranart; Naidu, Ravi; Wong, Ming H

2013-05-01

Electronic waste (e-waste) is one of the fastest-growing pollution problems worldwide given the presence if a variety of toxic substances which can contaminate the environment and threaten human health, if disposal protocols are not meticulously managed. This paper presents an overview of toxic substances present in e-waste, their potential environmental and human health impacts together with management strategies currently being used in certain countries. Several tools including life cycle assessment (LCA), material flow analysis (MFA), multi criteria analysis (MCA) and extended producer responsibility (EPR) have been developed to manage e-wastes especially in developed countries. The key to success in terms of e-waste management is to develop eco-design devices, properly collect e-waste, recover and recycle material by safe methods, dispose of e-waste by suitable techniques, forbid the transfer of used electronic devices to developing countries, and raise awareness of the impact of e-waste. No single tool is adequate but together they can complement each other to solve this issue. A national scheme such as EPR is a good policy in solving the growing e-waste problems. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Synthesis, fungicidal activity, structure-activity relationships (SARs) and density functional theory (DFT) studies of novel strobilurin analogues containing arylpyrazole rings.

PubMed

Liu, Yuanyuan; Lv, Kunzhi; Li, Yi; Nan, Qiuli; Xu, Jinyuan

2018-05-18

A series of novel strobilurin analogues (1a-1f, 2a-2e, 3a-3e) containing arylpyrazole rings were synthesized and characterized by NMR spectroscopy. The structures of 1f, 2b and 3b were also determined by single crystal X-ray diffraction analysis. These analogues were collected together with other twenty-eight similar compounds 4a-4f, 5a-5h, 6a-6h and 7a-7f from our previous studies, for in vitro bioassays and thorough structure-activity relationships (SARs) studies. Most compounds exhibited excellent-to-good fungicidal activity against Rhizoctonia solani, especially 5c, 7a, 6c, and 3b with 98.94%, 83.40%, 71.40% and 65.87% inhibition rates at 0.1 μg mL -1 , respectively, better than commercial pyraclostrobin. Comparative molecular field analysis (CoMFA) was employed to study three-dimensional quantitative structure-activity relationships (3D-QSARs). Density functional theory (DFT) calculation was also carried out to provide more information regarding SARs. The present work provided some hints for developing novel strobilurin fungicides.

Quantitative structure-property relationship modeling of Grätzel solar cell dyes.

PubMed

Venkatraman, Vishwesh; Åstrand, Per-Olof; Alsberg, Bjørn Kåre

2014-01-30

With fossil fuel reserves on the decline, there is increasing focus on the design and development of low-cost organic photovoltaic devices, in particular, dye-sensitized solar cells (DSSCs). The power conversion efficiency (PCE) of a DSSC is heavily influenced by the chemical structure of the dye. However, as far as we know, no predictive quantitative structure-property relationship models for DSSCs with PCE as one of the response variables have been reported. Thus, we report for the first time the successful application of comparative molecular field analysis (CoMFA) and vibrational frequency-based eigenvalue (EVA) descriptors to model molecular structure-photovoltaic performance relationships for a set of 40 coumarin derivatives. The results show that the models obtained provide statistically robust predictions of important photovoltaic parameters such as PCE, the open-circuit voltage (V(OC)), short-circuit current (J(SC)) and the peak absorption wavelength λ(max). Some of our findings based on the analysis of the models are in accordance with those reported in the literature. These structure-property relationships can be applied to the rational structural design and evaluation of new photovoltaic materials. Copyright © 2013 Wiley Periodicals, Inc.

Material Cycles and Chemicals: Dynamic Material Flow Analysis of Contaminants in Paper Recycling.

PubMed

Pivnenko, Kostyantyn; Laner, David; Astrup, Thomas F

2016-11-15

This study provides a systematic approach for assessment of contaminants in materials for recycling. Paper recycling is used as an illustrative example. Three selected chemicals, bisphenol A (BPA), diethylhexyl phthalate (DEHP) and mineral oil hydrocarbons (MOHs), are evaluated within the paper cycle. The approach combines static material flow analysis (MFA) with dynamic material and substance flow modeling. The results indicate that phasing out of chemicals is the most effective measure for reducing chemical contamination. However, this scenario was also associated with a considerable lag phase (between approximately one and three decades) before the presence of chemicals in paper products could be considered insignificant. While improved decontamination may appear to be an effective way of minimizing chemicals in products, this may also result in lower production yields. Optimized waste material source-segregation and collection was the least effective strategy for reducing chemical contamination, if the overall recycling rates should be maintained at the current level (approximately 70% for Europe). The study provides a consistent approach for evaluating contaminant levels in material cycles. The results clearly indicate that mass-based recycling targets are not sufficient to ensure high quality material recycling.

Isolation of Cryptococcus gattii molecular type VGIII, from Corymbia ficifolia detritus in Colombia.

PubMed

Escandón, P; Sánchez, A; Firacative, C; Castañeda, E

2010-06-01

An environmental sampling survey was carried out in different areas of Bogotá, Colombia, to obtain isolates of members of the Cryptococcus neoformans/C. gattii species complex from Corymbia ficifolia trees. During a 6-month period in 2007, 128 samples consisting of bark, soil around trunk bases, detritus, seeds and flowers were collected from 91 trees and processed according to standard procedures. The molecular type was determined using URA5 restriction fragment length polymorphism (RFLP) analysis and the mating type was established by PCR using specific primers for Mfalpha and Mfa C. gattii was isolated from 15 of the 128 (11.7%) samples, of which three (20%) were recovered from the red flower extract and the remaining 12 from C. ficifolia detritus. URA5 RFLP analysis revealed that all 15 isolates belonged to the molecular type VGIII and mating type specific PCR revealed that all were mating type a. The isolation of C. gattii from C. ficifolia represents an important finding since this is the first report revealing C. ficifolia as a habitat for C. gattii and adds additional information to the ever growing spectrum of tree species from which C. gattii can be recovered.

Comparison of benzil and trifluoromethyl ketone (TFK)-mediated carboxylesterase inhibition using classical and 3D-quantitative structure–activity relationship analysis

PubMed Central

Harada, Toshiyuki; Nakagawa, Yoshiaki; Wadkins, Randy M.; Potter, Philip M.; Wheelock, Craig E.

2009-01-01

Carboxylesterases are enzymes that hydrolyze a broad suite of endogenous and exogenous ester-containing compounds to the corresponding alcohol and carboxylic acid. These enzymes metabolize a number of therapeutics including the anti-tumor agent CPT-11, the anti-viral drug oseltamivir, and the anti-thrombogenic agent clopidogrel as well as many agrochemicals. In addition, carboxylesterases are involved in lipid homeostasis, including cholesterol metabolism and transport with a proposed role in the development of atherosclerosis. Several different scaffolds capable of inhibiting carboxylesterases have been reported, including organophosphates, carbamates, trifluoromethyl ketone-containing structures (TFKs), and aromatic ethane-1,2-diones. Of these varied groups, only the 1,2-diones evidence carboxylesterase isoform-selectivity, which is an important characteristic for therapeutic application and probing biological mechanisms. This study constructed a series of classical and 3D-QSAR models to examine the physiochemical parameters involved in the observed selectivity of three mammalian carboxylesterases: human intestinal carboxylesterase (hiCE), human carboxylesterase 1 (hCE1), and rabbit carboxylesterase (rCE). CoMFA-based models for the benzil-analogs described 88%, 95% and 76% of observed activity for hiCE, hCE1 and rCE, respectively. For TFK-containing compounds, two distinct models were constructed using either the ketone or gem-diol form of the inhibitor. For all three enzymes, the CoMFA ketone models comprised more biological activity than the corresponding gem-diol models; however the differences were small with described activity for all models ranging from 85–98%. A comprehensive model incorporating both benzil and TFK structures described 92%, 85% and 87% of observed activity for hiCE, hCE1 and rCE, respectively. Both classical and 3D-QSAR analysis showed that the observed isoform-selectivity with the benzil-analogs could be described by the volume parameter. This finding was successfully applied to examine substrate selectivity, demonstrating that the relative volumes of the alcohol and acid moieties of ester-containing substrates were predictive for whether hydrolysis was preferred by hiCE or hCE1. Based upon the integrated benzil and TFK model, the next generation inhibitors should combine the A-ring and the 1,2-dione of the benzil inhibitor with the long alkyl chain of the TFK-inhibitor in order to optimize selectivity and potency. These new inhibitors could be useful for elucidating the role of carboxylesterase activity in fatty acid homeostasis and the development of atherosclerosis as well as effecting the controlled activation of carboxylesterase-based prodrugs in situ. PMID:19062296

Comparison of benzil and trifluoromethyl ketone (TFK)-mediated carboxylesterase inhibition using classical and 3D-quantitative structure-activity relationship analysis.

PubMed

Harada, Toshiyuki; Nakagawa, Yoshiaki; Wadkins, Randy M; Potter, Philip M; Wheelock, Craig E

2009-01-01

Carboxylesterases are enzymes that hydrolyze a broad suite of endogenous and exogenous ester-containing compounds to the corresponding alcohol and carboxylic acid. These enzymes metabolize a number of therapeutics including the anti-tumor agent CPT-11, the anti-viral drug oseltamivir, and the anti-thrombogenic agent clopidogrel as well as many agrochemicals. In addition, carboxylesterases are involved in lipid homeostasis, including cholesterol metabolism and transport with a proposed role in the development of atherosclerosis. Several different scaffolds capable of inhibiting carboxylesterases have been reported, including organophosphates, carbamates, trifluoromethyl ketone-containing structures (TFKs), and aromatic ethane-1,2-diones. Of these varied groups, only the 1,2-diones evidence carboxylesterase isoform-selectivity, which is an important characteristic for therapeutic application and probing biological mechanisms. This study constructed a series of classical and 3D-QSAR models to examine the physiochemical parameters involved in the observed selectivity of three mammalian carboxylesterases: human intestinal carboxylesterase (hiCE), human carboxylesterase 1 (hCE1), and rabbit carboxylesterase (rCE). CoMFA-based models for the benzil-analogs described 88%, 95% and 76% of observed activity for hiCE, hCE1 and rCE, respectively. For TFK-containing compounds, two distinct models were constructed using either the ketone or gem-diol form of the inhibitor. For all three enzymes, the CoMFA ketone models comprised more biological activity than the corresponding gem-diol models; however the differences were small with described activity for all models ranging from 85-98%. A comprehensive model incorporating both benzil and TFK structures described 92%, 85% and 87% of observed activity for hiCE, hCE1 and rCE, respectively. Both classical and 3D-QSAR analysis showed that the observed isoform-selectivity with the benzil-analogs could be described by the volume parameter. This finding was successfully applied to examine substrate selectivity, demonstrating that the relative volumes of the alcohol and acid moieties of ester-containing substrates were predictive for whether hydrolysis was preferred by hiCE or hCE1. Based upon the integrated benzil and TFK model, the next generation inhibitors should combine the A-ring and the 1,2-dione of the benzil inhibitor with the long alkyl chain of the TFK-inhibitor in order to optimize selectivity and potency. These new inhibitors could be useful for elucidating the role of carboxylesterase activity in fatty acid homeostasis and the development of atherosclerosis as well as effecting the controlled activation of carboxylesterase-based prodrugs in situ.

Transcript abundance on its own cannot be used to infer fluxes in central metabolism

DOE PAGES

Schwender, Jorg; Konig, Christina; Klapperstuck, Matthias; ...

2014-11-28

An attempt has been made to define the extent to which metabolic flux in central plant metabolism is reflected by changes in the transcriptome and metabolome, based on an analysis of in vitro cultured immature embryos of two oilseed rape (Brassica napus) accessions which contrast for seed lipid accumulation. Metabolic flux analysis (MFA) was used to constrain a flux balance metabolic model which included 671 biochemical and transport reactions within the central metabolism. This highly confident flux information was eventually used for comparative analysis of flux vs. transcript (metabolite). Metabolite profiling succeeded in identifying 79 intermediates within the central metabolism,more » some of which differed quantitatively between the two accessions and displayed a significant shift corresponding to flux. An RNA-Seq based transcriptome analysis revealed a large number of genes which were differentially transcribed in the two accessions, including some enzymes/proteins active in major metabolic pathways. With a few exceptions, differential activity in the major pathways (glycolysis, TCA cycle, amino acid, and fatty acid synthesis) was not reflected in contrasting abundances of the relevant transcripts. The conclusion was that transcript abundance on its own cannot be used to infer metabolic activity/fluxes in central plant metabolism. Lastly, this limitation needs to be borne in mind in evaluating transcriptome data and designing metabolic engineering experiments.« less

Material flow analysis of NdFeB magnets for Denmark: a comprehensive waste flow sampling and analysis approach.

PubMed

Habib, Komal; Schibye, Peter Klausen; Vestbø, Andreas Peter; Dall, Ole; Wenzel, Henrik

2014-10-21

Neodymium-iron-boron (NdFeB) magnets have become highly desirable for modern hi-tech applications. These magnets, in general, contain two key rare earth elements (REEs), i.e., neodymium (Nd) and dysprosium (Dy), which are responsible for the very high strength of these magnets, allowing for considerable size and weight reduction in modern applications. This study aims to explore the current and future potential of a secondary supply of neodymium and dysprosium from recycling of NdFeB magnets. For this purpose, material flow analysis (MFA) has been carried out to perform the detailed mapping of stocks and flows of NdFeB magnets in Denmark. A novel element of this study is the value added to the traditionally practiced MFAs at national and/or global levels by complementing them with a comprehensive sampling and elemental analysis of NdFeB magnets, taken out from a sample of 157 different products representing 18 various product types. The results show that the current amount of neodymium and dysprosium in NdFeB magnets present in the Danish waste stream is only 3 and 0.2 Mg, respectively. However, this number is estimated to increase to 175 Mg of neodymium and 11.4 Mg of dysprosium by 2035. Nevertheless, efficient recovery of these elements from a very diverse electronic waste stream remains a logistic and economic challenge.

Towards discovering dual functional inhibitors against both wild type and K103N mutant HIV-1 reverse transcriptases: molecular docking and QSAR studies on 4,1-benzoxazepinone analogues

NASA Astrophysics Data System (ADS)

Zhang, Zhenshan; Zheng, Mingyue; Du, Li; Shen, Jianhua; Luo, Xiaomin; Zhu, Weiliang; Jiang, Hualiang

2006-05-01

To find useful information for discovering dual functional inhibitors against both wild type (WT) and K103N mutant reverse transcriptases (RTs) of HIV-1, molecular docking and 3D-QSAR approaches were applied to a set of twenty-five 4,1-benzoxazepinone analogues of efavirenz (SUSTIVA®), some of them are active against the two RTs. 3D-QSAR models were constructed, based on their binding conformations determined by molecular docking, with r 2 cv values ranging from 0.656 to 0.834 for CoMFA and CoMSIA, respectively. The models were then validated to be highly predictive and extrapolative by inhibitors in two test sets with different molecular skeletons. Furthermore, CoMFA models were found to be well matched with the binding sites of both WT and K103N RTs. Finally, a reasonable pharmacophore model of 4,1-benzoxazepinones were established. The application of the model not only successfully differentiated the experimentally determined inhibitors from non-inhibitors, but also discovered two potent inhibitors from the compound database SPECS. On the basis of both the 3D-QSAR and pharmacophore models, new clues for discovering and designing potent dual functional drug leads against HIV-1 were proposed: (i) adopting positively charged aliphatic group at the cis-substituent of C3; (ii) reducing the electronic density at the position of O4; (iii) positioning a small branched aliphatic group at position of C5; (iv) using the negatively charged bulky substituents at position of C7.

3D-QSAR pharmacophore-based virtual screening, molecular docking and molecular dynamics simulation toward identifying lead compounds for NS2B-NS3 protease inhibitors.

PubMed

Luo, Pei H; Zhang, Xuan R; Huang, Lan; Yuan, Lun; Zhou, Xang Z; Gao, X; Li, Ling S

2017-10-01

NS2B-NS3 protease has been identified to serve as lead drug design target due to its significant role in West Nile viral (WNV) and dengue virus (DENV) reproduction and replication. There are currently no approved chemotherapeutic drugs and effective vaccines to inhibit DENV and WNV infections. In this work, 3D-QSAR pharmacophore model has been developed to discover potential inhibitory candidates. Validation through Fischer's model and decoy test indicate that the developed 3D pharmacophore model is highly predictive for DENV inhibitors, which was then employed to screen ZINC chemical library to obtain reasonable hits. Following ADMET filtering, 15 hits were subjected to further filter through molecular docking and CoMFA modeling. Finally, top three hits were identified as lead compounds or potential inhibitory candidates with IC 50 values of ∼0.4637 µM and fitness of ∼57.73. It is implied from CoMFA modeling that substituents at the side site of benzotriazole such as a p-nitro group (e.g. biphenyl head) and a carbonyl (e.g. carboxylate function) at the side site of furan or amino group may improve bioactivity of ZINC85645245, respectively. Molecular dynamics simulations (MDS) were performed to discover new interactions and reinforce the binding modes from docking for the hits also. The QSAR and MDS results obtained from this work should be useful in determining structural requirements for inhibitor development as well as in designing more potential inhibitors for NS2B-NS3 protease.

Functional expression of KCNQ (Kv7) channels in guinea pig bladder smooth muscle and their contribution to spontaneous activity

PubMed Central

Anderson, U A; Carson, C; Johnston, L; Joshi, S; Gurney, A M; McCloskey, K D

2013-01-01

Background and Purpose The aim of the study was to determine whether KCNQ channels are functionally expressed in bladder smooth muscle cells (SMC) and to investigate their physiological significance in bladder contractility. Experimental Approach KCNQ channels were examined at the genetic, protein, cellular and tissue level in guinea pig bladder smooth muscle using RT-PCR, immunofluorescence, patch-clamp electrophysiology, calcium imaging, detrusor strip myography, and a panel of KCNQ activators and inhibitors. Key Results KCNQ subtypes 1–5 are expressed in bladder detrusor smooth muscle. Detrusor strips typically displayed TTX-insensitive myogenic spontaneous contractions that were increased in amplitude by the KCNQ channel inhibitors XE991, linopirdine or chromanol 293B. Contractility was inhibited by the KCNQ channel activators flupirtine or meclofenamic acid (MFA). The frequency of Ca2+-oscillations in SMC contained within bladder tissue sheets was increased by XE991. Outward currents in dispersed bladder SMC, recorded under conditions where BK and KATP currents were minimal, were significantly reduced by XE991, linopirdine, or chromanol, and enhanced by flupirtine or MFA. XE991 depolarized the cell membrane and could evoke transient depolarizations in quiescent cells. Flupirtine (20 μM) hyperpolarized the cell membrane with a simultaneous cessation of any spontaneous electrical activity. Conclusions and Implications These novel findings reveal the role of KCNQ currents in the regulation of the resting membrane potential of detrusor SMC and their important physiological function in the control of spontaneous contractility in the guinea pig bladder. PMID:23586426

Investigations of FAK inhibitors: a combination of 3D-QSAR, docking, and molecular dynamics simulations studies.

PubMed

Cheng, Peng; Li, Jiaojiao; Wang, Juan; Zhang, Xiaoyun; Zhai, Honglin

2018-05-01

Focal adhesion kinase (FAK) is one kind of tyrosine kinases that modulates integrin and growth factor signaling pathways, which is a promising therapeutic target because of involving in cancer cell migration, proliferation, and survival. To investigate the mechanism between FAK and triazinic inhibitors and design high activity inhibitors, a molecular modeling integrated with 3D-QSAR, molecular docking, molecular dynamics simulations, and binding free energy calculations was performed. The optimum CoMFA and CoMSIA models showed good reliability and satisfactory predictability (with Q 2  = 0.663, R 2  = 0.987, [Formula: see text] = 0.921 and Q 2  = 0.670, R 2  = 0.981, [Formula: see text] = 0.953). Its contour maps could provide structural features to improve inhibitory activity. Furthermore, a good consistency between contour maps, docking, and molecular dynamics simulations strongly demonstrates that the molecular modeling is reliable. Based on it, we designed several new compounds and their inhibitory activities were validated by the molecular models. We expect our studies could bring new ideas to promote the development of novel inhibitors with higher inhibitory activity for FAK.

Simultaneous material flow analysis of nickel, chromium, and molybdenum used in alloy steel by means of input-output analysis.

PubMed

Nakajima, Kenichi; Ohno, Hajime; Kondo, Yasushi; Matsubae, Kazuyo; Takeda, Osamu; Miki, Takahiro; Nakamura, Shinichiro; Nagasaka, Tetsuya

2013-05-07

Steel is not elemental iron but rather a group of iron-based alloys containing many elements, especially chromium, nickel, and molybdenum. Steel recycling is expected to promote efficient resource use. However, open-loop recycling of steel could result in quality loss of nickel and molybdenum and/or material loss of chromium. Knowledge about alloying element substance flow is needed to avoid such losses. Material flow analyses (MFAs) indicate the importance of steel recycling to recovery of alloying elements. Flows of nickel, chromium, and molybdenum are interconnected, but MFAs have paid little attention to the interconnected flow of materials/substances in supply chains. This study combined a waste input-output material flow model and physical unit input-output analysis to perform a simultaneous MFA for nickel, chromium, and molybdenum in the Japanese economy in 2000. Results indicated the importance of recovery of these elements in recycling policies for end-of-life (EoL) vehicles and constructions. Improvement in EoL sorting technologies and implementation of designs for recycling/disassembly at the manufacturing phase are needed. Possible solutions include development of sorting processes for steel scrap and introduction of easier methods for identifying the composition of secondary resources. Recovery of steel scrap with a high alloy content will reduce primary inputs of alloying elements and contribute to more efficient resource use.

Development of quantitative structure-activity relationships and its application in rational drug design.

PubMed

Yang, Guang-Fu; Huang, Xiaoqin

2006-01-01

Over forty years have elapsed since Hansch and Fujita published their pioneering work of quantitative structure-activity relationships (QSAR). Following the introduction of Comparative Molecular Field Analysis (CoMFA) by Cramer in 1998, other three-dimensional QSAR methods have been developed. Currently, combination of classical QSAR and other computational techniques at three-dimensional level is of greatest interest and generally used in the process of modern drug discovery and design. During the last several decades, a number of different mythologies incorporating a range of molecular descriptors and different statistical regression ways have been proposed and successfully applied in developing of new drugs, thus QSAR method has been proven to be indispensable in not only the reliable prediction of specific properties of new compounds, but also the help to elucidate the possible molecular mechanism of the receptor-ligand interactions. Here, we review the recent developments in QSAR and their applications in rational drug design, focusing on the reasonable selection of novel molecular descriptors and the construction of predictive QSAR models by the help of advanced computational techniques.

Structure-Activity Correlations for β-Phenethylamines at Human Trace Amine Receptor 1

PubMed Central

Lewin, Anita H.; Navarro, Hernán A.; Mascarella, S. Wayne

2008-01-01

A cell line in which RD-HGA16 cells were stably transfected with the hTAAR 1 receptor was created and utilized to carry out a systematic evaluation of a series of β-phenethylamines. Fair agreement was observed with data obtained for aryl and ethylene chain substituted analogs in an AV12-664 cell line in which hemagglutinin-tagged hTAAR 1 was stably co-expressed with rat Gαs. Analogs with multiple substituents as well as analogs with bulky groups were found to be partial agonists. Analogs in which the primary amino group was converted to a secondary or a tertiary amino group by N-methylation were also partial agonists. Comparative Molecular Field Analysis (CoMFA) using the potency data yielded a regression coefficient r2 of 0.824. The steric field contribution to the model was 61% with the balance (39%) contributed by the electrostatic field. The collective results suggest that increasing steric bulk at both the amino nitrogen, particularly by N-dimethylation, and at the 4-position of the aromatic ring, leads to low efficacy ligands. PMID:18602830

A machine learning approach using EEG data to predict response to SSRI treatment for major depressive disorder.

PubMed

Khodayari-Rostamabad, Ahmad; Reilly, James P; Hasey, Gary M; de Bruin, Hubert; Maccrimmon, Duncan J

2013-10-01

The problem of identifying, in advance, the most effective treatment agent for various psychiatric conditions remains an elusive goal. To address this challenge, we investigate the performance of the proposed machine learning (ML) methodology (based on the pre-treatment electroencephalogram (EEG)) for prediction of response to treatment with a selective serotonin reuptake inhibitor (SSRI) medication in subjects suffering from major depressive disorder (MDD). A relatively small number of most discriminating features are selected from a large group of candidate features extracted from the subject's pre-treatment EEG, using a machine learning procedure for feature selection. The selected features are fed into a classifier, which was realized as a mixture of factor analysis (MFA) model, whose output is the predicted response in the form of a likelihood value. This likelihood indicates the extent to which the subject belongs to the responder vs. non-responder classes. The overall method was evaluated using a "leave-n-out" randomized permutation cross-validation procedure. A list of discriminating EEG biomarkers (features) was found. The specificity of the proposed method is 80.9% while sensitivity is 94.9%, for an overall prediction accuracy of 87.9%. There is a 98.76% confidence that the estimated prediction rate is within the interval [75%, 100%]. These results indicate that the proposed ML method holds considerable promise in predicting the efficacy of SSRI antidepressant therapy for MDD, based on a simple and cost-effective pre-treatment EEG. The proposed approach offers the potential to improve the treatment of major depression and to reduce health care costs. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Investigating the binding mechanism of novel 6-aminonicotinate-based antagonists with P2Y12 by 3D-QSAR, docking and molecular dynamics simulations.

PubMed

Zhou, Shengfu; Fang, Danqing; Tan, Shepei; Lin, Weicong; Wu, Wenjuan; Zheng, Kangcheng

2017-10-01

P2Y 12 receptor is an attractive target for the anti-platelet therapies, treating various thrombotic diseases. In this work, a total of 107 6-aminonicotinate-based compounds as potent P2Y 12 antagonists were studies by a molecular modeling study combining three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations to explore the decisive binding conformations of these antagonists with P2Y 12 and the structural features for the activity. The optimum CoMFA and CoMSIA models identified satisfactory robustness and good predictive ability, with R 2  = .983, q 2  = .805, [Formula: see text] = .881 for CoMFA model, and R 2  = .935, q 2  = .762, [Formula: see text] = .690 for CoMSIA model, respectively. The probable binding modes of compounds and key amino acid residues were revealed by molecular docking. MD simulations and MM/GBSA free energy calculations were further performed to validate the rationality of docking results and to compare the binding modes of several compound pairs with different activities, and the key residues (Val102, Tyr105, Tyr109, His187, Val190, Asn191, Phe252, His253, Arg256, Tyr259, Thr260, Val279, and Lys280) for the higher activity were pointed out. The binding energy decomposition indicated that the hydrophobic and hydrogen bond interactions play important roles for the binding of compounds to P2Y 12 . We hope these results could be helpful in design of potent and selective P2Y 12 antagonists.

First long-term behavioral records from Cuvier's beaked whales (Ziphius cavirostris) reveal record-breaking dives.

PubMed

Schorr, Gregory S; Falcone, Erin A; Moretti, David J; Andrews, Russel D

2014-01-01

Cuvier's beaked whales (Ziphius cavirostris) are known as extreme divers, though behavioral data from this difficult-to-study species have been limited. They are also the species most often stranded in association with Mid-Frequency Active (MFA) sonar use, a relationship that remains poorly understood. We used satellite-linked tags to record the diving behavior and locations of eight Ziphius off the Southern California coast for periods up to three months. The effort resulted in 3732 hr of dive data with associated regional movements--the first dataset of its kind for any beaked whale--and included dives to 2992 m depth and lasting 137.5 min, both new mammalian dive records. Deep dives had a group mean depth of 1401 m (s.d. = 137.8, n = 1142) and duration of 67.4 min (s.d. = 6.9). The group mean time between deep dives was 102.3 min (s.d. = 30.8, n = 783). While the previously described stereotypic pattern of deep and shallow dives was apparent, there was considerable inter- and intra-individual variability in most parameters. There was significant diel behavioral variation, including increased time near the surface and decreased shallow diving at night. However, maximum depth and the proportion of time spent on deep dives (presumed foraging), varied little from day to night. Surprisingly, tagged whales were present within an MFA sonar training range for 38% of days locations were received, and though comprehensive records of sonar use during tag deployments were not available, we discuss the effects frequent acoustic disturbance may have had on the observed behaviors. These data better characterize the true behavioral range of this species, and suggest caution should be exercised when drawing conclusions about behavior using short-term datasets.

Multifunctional Agriculture: Conducting an Ecosystem Service Assessment for an Agricultural Watershed

NASA Astrophysics Data System (ADS)

Wacha, K.; Papanicolaou, T.; Wilson, C. G.

2012-12-01

To meet the food production demands on a finite area of land for an exponentially growing, global population, intensive agricultural management practices are being used. The implications of this these practices lead to soil degradation, loss of biodiversity, increased greenhouse gas emissions, and decreased water quality depending on the level of conservation practices implemented in a watershed. To offset these negative environmental effects, ecosystem services should be analyzed for possible economic valuation to provide incentives for good land stewardship. In this study a Multifunctional Agriculture (MFA) evaluation in a representative agricultural watershed in Iowa was performed by assessing the ecosystem services of water quality, crop/grain production, carbon sequestration, reduction in carbon dioxide emissions and biodiversity for representative land covers (e.g., corn-soybean rotation, alfalfa, oats, and Conservation Reserve Program, or CRP). The services were analyzed using a geo-spatial platform that simulated carbon dynamics with the biogeochemical model, CENTURY, as well as soil erosion/deposition and surface runoff with the Water Erosion Prediction Project (WEPP). Economic values given to the various services were based on current grain prices, water treatment costs, and hypothetical carbon storage credits. Results showed that crop/grain production for the corn-soybean rotations provided the largest service for the study site, followed by alfalfa. CRP provided the largest decrease in surface water runoff and CO2 emissions, while alfalfa provided the largest form of plant species diversity. The largest sequestration of carbon came from the corn-soybean rotation due to large amounts dead plant material being incorporated into the soil through tillage. Overall the MFA assessment can provide a framework for payment of ecosystem services supplied by agroecosystems which promote more sustainable land management practices.

Predictions of thermomagnetic properties of Laves phase compounds: TbAl2, GdAl2 and SmAl2 performed with ATOMIC MATTERS MFA computation system

NASA Astrophysics Data System (ADS)

Michalski, Rafał; Zygadło, Jakub

2018-04-01

Recent calculations of properties of TbAl2 GdAl2 and SmAl2 single crystals, performed with our new computation system called ATOMIC MATTERS MFA are presented. We applied localized electron approach to describe the thermal evolution of Fine Electronic Structure of Tb3+, Gd3+ and Sm3+ ions over a wide temperature range and estimate Magnetocaloric Effect (MCE). Thermomagnetic properties of TbAl2, GdAl2 and SmAl2 were calculated based on the fine electronic structure of the 4f8, 4f7 and 4f5 electronic configuration of the Tb3+ and Gd3+ and Sm3+ ions, respectively. Our calculations yielded: magnetic moment value and direction; single-crystalline magnetization curves in zero field and in external magnetic field applied in various directions m(T,Bext); the 4f-electronic components of specific heat c4f(T,Bext); and temperature dependence of the magnetic entropy and isothermal entropy change with external magnetic field - ΔS(T,Bext). The cubic universal CEF parameters values used for all CEF calculations was taken from literature and recalculated for universal cubic parameters set for the RAl2 series: A4 = +7.164 Ka04 and A6 = -1.038 Ka06. Magnetic properties were found to be anisotropic due to cubic Laves phase C15 crystal structure symmetry. These studies reveal the importance of multipolar charge interactions when describing thermomagnetic properties of real 4f electronic systems and the effectiveness of an applied self-consistent molecular field in calculations for magnetic phase transition simulation.

First environmental isolation of Cryptococcus gattii serotype B, from Cúcuta, Colombia.

PubMed

Firacative, Carolina; Torres, Germán; Rodríguez, María Claudia; Escandón, Patricia

2011-03-01

In Cúcuta, Cryptococcus gattii serotype B is commonly recovered from immunocompetent patients with cryptococcosis, but it has not been recovered from the environment in spite of its high incidence which is 77% out of reported cases. The aim of this work was to carry out an extensive environmental sampling in Cúcuta, in an attempt to isolate C. gattii serotype B and to expand our knowledge about the ecology and epidemiology of this important yeast. Samples associated with 3,634 trees from 40 zones of Cúcuta were collected and processed with 28 samples collected near the houses of four patients with cryptococcosis caused by C. gattii serotype B. The serotype of the recovered isolates was done using multiplex PCR, molecular patterns were determined by RFLP of the URA5 gene and mating type was determined using the primers MfαU, MfαL, MFa2U and MFa2L. In total, 4,389 samples were processed and one isolate of C. gattii serotype B (VGI/a), two isolates of C. gattii serotype C (VGIII/α) and three isolates of C. neoformans var. grubii, serotype A (VNI/α), were recovered. The density of the recovered isolates varied from 50 to 350 cfu/g of soil. This is the first report on the environmental isolation of C. gattii serotype B from Cúcuta. However, because of the low rate of recovery of isolates from soil only, the environmental niche of C. gattii has not been established and further environmental studies in Cúcuta are necessary, owing that this serotype is not only causing cryptococcosis but also has shown a higher virulence after the Vancouver outbreak.

Recognition of partially occluded threat objects using the annealed Hopefield network

NASA Technical Reports Server (NTRS)

Kim, Jung H.; Yoon, Sung H.; Park, Eui H.; Ntuen, Celestine A.

1992-01-01

Recognition of partially occluded objects has been an important issue to airport security because occlusion causes significant problems in identifying and locating objects during baggage inspection. The neural network approach is suitable for the problems in the sense that the inherent parallelism of neural networks pursues many hypotheses in parallel resulting in high computation rates. Moreover, they provide a greater degree of robustness or fault tolerance than conventional computers. The annealed Hopfield network which is derived from the mean field annealing (MFA) has been developed to find global solutions of a nonlinear system. In the study, it has been proven that the system temperature of MFA is equivalent to the gain of the sigmoid function of a Hopfield network. In our early work, we developed the hybrid Hopfield network (HHN) for fast and reliable matching. However, HHN doesn't guarantee global solutions and yields false matching under heavily occluded conditions because HHN is dependent on initial states by its nature. In this paper, we present the annealed Hopfield network (AHN) for occluded object matching problems. In AHN, the mean field theory is applied to the hybird Hopfield network in order to improve computational complexity of the annealed Hopfield network and provide reliable matching under heavily occluded conditions. AHN is slower than HHN. However, AHN provides near global solutions without initial restrictions and provides less false matching than HHN. In conclusion, a new algorithm based upon a neural network approach was developed to demonstrate the feasibility of the automated inspection of threat objects from x-ray images. The robustness of the algorithm is proved by identifying occluded target objects with large tolerance of their features.

Structural insights of Staphylococcus aureus FtsZ inhibitors through molecular docking, 3D-QSAR and molecular dynamics simulations.

PubMed

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

2018-02-01

Filamentous temperature-sensitive protein Z (FtsZ) is a protein encoded by the FtsZ gene that assembles into a Z-ring at the future site of the septum of bacterial cell division. Structurally, FtsZ is a homolog of eukaryotic tubulin but has low sequence similarity; this makes it possible to obtain FtsZ inhibitors without affecting the eukaryotic cell division. Computational studies were performed on a series of substituted 3-arylalkoxybenzamide derivatives reported as inhibitors of FtsZ activity in Staphylococcus aureus. Quantitative structure-activity relationship models (QSAR) models generated showed good statistical reliability, which is evident from r 2 ncv and r 2 loo values. The predictive ability of these models was determined and an acceptable predictive correlation (r 2 Pred ) values were obtained. Finally, we performed molecular dynamics simulations in order to examine the stability of protein-ligand interactions. This facilitated us to compare free binding energies of cocrystal ligand and newly designed molecule B1. The good concordance between the docking results and comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) contour maps afforded obliging clues for the rational modification of molecules to design more potent FtsZ inhibitors.

Studies of tricyclic piperazine/piperidine furnished molecules as novel integrin αvβ3/αIIbβ3 dual antagonists using 3D-QSAR and molecular docking.

PubMed

Yan, Yulian; Li, Yan; Zhang, Shuwei; Ai, Chunzhi

2011-02-01

The development of injectable integrin α(v)β(3)/α(IIb)β(3) dual antagonists attracts much attention of research for treating of acute ischemic diseases in recent years. In this work, based on a dataset composed of 102 tricyclic piperazine/piperidine furnished dual α(v)β(3) and α(IIb)β(3) antagonists, a variety of in silico modeling approaches including the comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), and molecular docking were applied to reveal the requisite 3D structural features impacting the biological activities. Our statistical results show that the ligand-based 3D-QSAR models for both the α(v)β(3) and α(IIb)β(3) studies exhibited satisfactory internal and external predictability, i.e., for the CoMFA models, results of Q(2)=0.48, R(ncv)(2)=0.87, R(pred)(2)=0.71 for α(v)β(3) and Q(2)=0.50, R(ncv)(2)=0.85, R(pred)(2)=0.72 for α(IIb)β(3) analysis were obtained, and for the CoMSIA ones, the outcomes of Q(2)=0.55, R(ncv)(2)=0.90, R(pred)(2)=0.72 for α(v)β(3) and Q(2)=0.52, R(ncv)(2)=0.88, R(pred)(2)=0.74 for α(IIb)β(3) were achieved respectively. In addition, through a comparison between 3D-QSAR contour maps and docking results, it is revealed that that the most crucial interactions occurring between the tricyclic piperazine/piperidine derivatives and α(v)β(3)/α(IIb)β(3) receptor ligand binding pocket are H-bonding, and the key amino acids impacting the interactions are Arg214, Asn215, Ser123, and Lys253 for α(v)β(3), but Arg214, Asn215, Ser123 and Tyr190 for α(IIb)β(3) receptors, respectively. Halogen-containing groups at position 15 and 16, benzene sulfonamide substituent at position 23, and the replacement of piperazine with 4-aminopiperidine of ring B may increase the α(v)β(3)/α(IIb)β(3) antagonistic activity. The potencies for antagonists to inhibit isolated α(v)β(3) and α(IIb)β(3) are linear correlated, indicating that similar interaction mechanisms may exist for the series of molecules. To our best knowledge this is the first report on 3D-QSAR modeling of these dual α(v)β(3)/α(IIb)β(3) antagonists. The results obtained should provide information for better understanding of the mechanism of antagonism and thus be helpful in design of novel potent dual α(v)β(3)/α(IIb)β(3) antagonists. Copyright © 2011 Elsevier Inc. All rights reserved.

The Physical Economy of the United States of America

PubMed Central

Gierlinger, Sylvia; Krausmann, Fridolin

2012-01-01

The United States is not only the world's largest economy, but it is also one of the world's largest consumers of natural resources. The country, which is inhabited by some 5% of the world's population, uses roughly one-fifth of the global primary energy supply and 15% of all extracted materials. This article explores long-term trends and patterns of material use in the United States. Based on a material flow account (MFA) that is fully consistent with current standards of economy-wide MFAs and covers domestic extraction, imports, and exports of materials for a 135-year period, we investigated the evolution of the U.S. industrial metabolism. This process was characterized by an 18-fold increase in material consumption, a multiplication of material use per capita, and a shift from renewable biomass toward mineral and fossil resources. In spite of considerable improvements in material intensity, no dematerialization has happened so far; in contrast to other high-income countries, material use has not stabilized since the 1970s, but has continued to grow. This article compares patterns and trends of material use in the United States with those in Japan and the United Kingdom and discusses the factors underlying the disproportionately high level of U.S. per capita resource consumption. PMID:24436632

A Method to Constrain Genome-Scale Models with 13C Labeling Data

PubMed Central

García Martín, Héctor; Kumar, Vinay Satish; Weaver, Daniel; Ghosh, Amit; Chubukov, Victor; Mukhopadhyay, Aindrila; Arkin, Adam; Keasling, Jay D.

2015-01-01

Current limitations in quantitatively predicting biological behavior hinder our efforts to engineer biological systems to produce biofuels and other desired chemicals. Here, we present a new method for calculating metabolic fluxes, key targets in metabolic engineering, that incorporates data from 13C labeling experiments and genome-scale models. The data from 13C labeling experiments provide strong flux constraints that eliminate the need to assume an evolutionary optimization principle such as the growth rate optimization assumption used in Flux Balance Analysis (FBA). This effective constraining is achieved by making the simple but biologically relevant assumption that flux flows from core to peripheral metabolism and does not flow back. The new method is significantly more robust than FBA with respect to errors in genome-scale model reconstruction. Furthermore, it can provide a comprehensive picture of metabolite balancing and predictions for unmeasured extracellular fluxes as constrained by 13C labeling data. A comparison shows that the results of this new method are similar to those found through 13C Metabolic Flux Analysis (13C MFA) for central carbon metabolism but, additionally, it provides flux estimates for peripheral metabolism. The extra validation gained by matching 48 relative labeling measurements is used to identify where and why several existing COnstraint Based Reconstruction and Analysis (COBRA) flux prediction algorithms fail. We demonstrate how to use this knowledge to refine these methods and improve their predictive capabilities. This method provides a reliable base upon which to improve the design of biological systems. PMID:26379153

Derivation of a 3D pharmacophore model for the angiotensin-II site one receptor

NASA Astrophysics Data System (ADS)

Prendergast, Kristine; Adams, Kym; Greenlee, William J.; Nachbar, Robert B.; Patchett, Arthur A.; Underwood, Dennis J.

1994-10-01

A systematic search has been used to derive a hypothesis for the receptor-bound conformation of A-II antagonists at the AT1 receptor. The validity of the pharmacophore hypothesis has been tested using CoMFA, which included 50 diverse A-II antagonists, spanning four orders of magnitude in activity. The resulting cross-validated R2 of 0.64 (conventional R2 of 0.76) is indicative of a good predictive model of activity, and has been used to estimate potency for a variety of non-peptidyl antagonists. The structural model for the non-peptide has been compared with respect to the natural substrate, A-II, by generating peptide to non-peptide overlays.

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.

A dynamic metabolic flux analysis of ABE (acetone-butanol-ethanol) fermentation by Clostridium acetobutylicum ATCC 824, with riboflavin as a by-product.

PubMed

Zhao, Xinhe; Kasbi, Mayssa; Chen, Jingkui; Peres, Sabine; Jolicoeur, Mario

2017-12-01

The present study reveals that supplementing sodium acetate (NaAc) strongly stimulates riboflavin production in acetone-butanol-ethanol (ABE) fermentation by Clostridium acetobutylicum ATCC 824 with xylose as carbon source. Riboflavin production increased from undetectable concentrations to ∼0.2 g L -1 (0.53 mM) when supplementing 60 mM NaAc. Of interest, solvents production and biomass yield were also promoted with fivefold acetone, 2.6-fold butanol, and 2.4-fold biomass adding NaAc. A kinetic metabolic model, developed to simulate ABE biosystem, with riboflavin production, revealed from a dynamic metabolic flux analysis (dMFA) simultaneous increase of riboflavin (ribA) and GTP (precursor of riboflavin) (PurM) synthesis flux rates under NaAc supplementation. The model includes 23 fluxes, 24 metabolites, and 72 kinetic parameters. It also suggested that NaAc condition has first stimulated the accumulation of intracellular metabolite intermediates during the acidogenic phase, which have then fed the solventogenic phase leading to increased ABE production. In addition, NaAc resulted in higher intracellular levels of NADH during the whole culture. Moreover, lower GTP-to-adenosine phosphates (ATP, ADP, AMP) ratio under NaAc supplemented condition suggests that GTP may have a minor role in the cell energetic metabolism compared to its contribution to riboflavin synthesis. © 2017 Wiley Periodicals, Inc.

Computational Study Exploring the Interaction Mechanism of Benzimidazole Derivatives as Potent Cattle Bovine Viral Diarrhea Virus Inhibitors.

PubMed

Wang, Jinghui; Yang, Yinfeng; Li, Yan; Wang, Yonghua

2016-07-27

Bovine viral diarrhea virus (BVDV) infections are prevailing in cattle populations on a worldwide scale. The BVDV RNA-dependent RNA polymerase (RdRp), as a promising target for new anti-BVDV drug development, has attracted increasing attention. To explore the interaction mechanism of 65 benzimidazole scaffold-based derivatives as BVDV inhibitors, presently, a computational study was performed based on a combination of 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations. The resultant optimum CoMFA and CoMSIA models present proper reliabilities and strong predictive abilities (with Q(2) = 0. 64, R(2)ncv = 0.93, R(2)pred = 0.80 and Q(2) = 0. 65, R(2)ncv = 0.98, R(2)pred = 0.86, respectively). In addition, there was good concordance between these models, molecular docking, and MD results. Moreover, the MM-PBSA energy analysis reveals that the major driving force for ligand binding is the polar solvation contribution term. Hopefully, these models and the obtained findings could offer better understanding of the interaction mechanism of BVDV inhibitors as well as benefit the new discovery of more potent BVDV inhibitors.

Chemical Structure-Biological Activity Models for Pharmacophores’ 3D-Interactions

PubMed Central

Putz, Mihai V.; Duda-Seiman, Corina; Duda-Seiman, Daniel; Putz, Ana-Maria; Alexandrescu, Iulia; Mernea, Maria; Avram, Speranta

2016-01-01

Within medicinal chemistry nowadays, the so-called pharmaco-dynamics seeks for qualitative (for understanding) and quantitative (for predicting) mechanisms/models by which given chemical structure or series of congeners actively act on biological sites either by focused interaction/therapy or by diffuse/hazardous influence. To this aim, the present review exposes three of the fertile directions in approaching the biological activity by chemical structural causes: the special computing trace of the algebraic structure-activity relationship (SPECTRAL-SAR) offering the full analytical counterpart for multi-variate computational regression, the minimal topological difference (MTD) as the revived precursor for comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analysis (CoMSIA); all of these methods and algorithms were presented, discussed and exemplified on relevant chemical medicinal systems as proton pump inhibitors belonging to the 4-indolyl,2-guanidinothiazole class of derivatives blocking the acid secretion from parietal cells in the stomach, the 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine congeners’ (HEPT ligands) antiviral activity against Human Immunodeficiency Virus of first type (HIV-1) and new pharmacophores in treating severe genetic disorders (like depression and psychosis), respectively, all involving 3D pharmacophore interactions. PMID:27399692

Discovery of unsymmetrical aromatic disulfides as novel inhibitors of SARS-CoV main protease: Chemical synthesis, biological evaluation, molecular docking and 3D-QSAR study.

PubMed

Wang, Li; Bao, Bo-Bo; Song, Guo-Qing; Chen, Cheng; Zhang, Xu-Meng; Lu, Wei; Wang, Zefang; Cai, Yan; Li, Shuang; Fu, Sheng; Song, Fu-Hang; Yang, Haitao; Wang, Jian-Guo

2017-09-08

The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (M pro ) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new anti-SARS agents, we have identified that a series of unsymmetrical aromatic disulfides inhibited SARS-CoV M pro significantly for the first time. Herein, 40 novel unsymmetrical aromatic disulfides were synthesized chemically and their biological activities were evaluated in vitro against SARS-CoV M pro . These novel compounds displayed excellent IC 50 data in the range of 0.516-5.954 μM. Preliminary studies indicated that these disulfides are reversible and mpetitive inhibitors. A possible binding mode was generated via molecular docking simulation and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationships. The present research therefore has provided some meaningful guidance to design and identify anti-SARS drugs with totally new chemical structures. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Contribution of plastic waste recovery to greenhouse gas (GHG) savings in Spain.

PubMed

Sevigné-Itoiz, Eva; Gasol, Carles M; Rieradevall, Joan; Gabarrell, Xavier

2015-12-01

This paper concentrates on the quantification of greenhouse gas (GHG) emissions of post-consumer plastic waste recovery (material or energy) by considering the influence of the plastic waste quality (high or low), the recycled plastic applications (virgin plastic substitution or non-plastic substitution) and the markets of recovered plastic (regional or global). The aim is to quantify the environmental consequences of different alternatives in order to evaluate opportunities and limitations to select the best and most feasible plastic waste recovery option to decrease the GHG emissions. The methodologies of material flow analysis (MFA) for a time period of thirteen years and consequential life cycle assessment (CLCA) have been integrated. The study focuses on Spain as a representative country for Europe. The results show that to improve resource efficiency and avoid more GHG emissions, the options for plastic waste management are dependent on the quality of the recovered plastic. The results also show that there is an increasing trend of exporting plastic waste for recycling, mainly to China, that reduces the GHG benefits from recycling, suggesting that a new focus should be introduced to take into account the split between local recycling and exporting. Copyright © 2015 Elsevier Ltd. All rights reserved.

Correlating the properties of different carioca bean cultivars (Phaseolus vulgaris) with their hydration kinetics.

PubMed

Miano, Alberto Claudio; Saldaña, Erick; Campestrini, Luciano Henrique; Chiorato, Alisson Fernando; Augusto, Pedro Esteves Duarte

2018-05-01

This work explained how the intrinsic properties of beans affects the hydration process. For that, different properties of six cultivars of carioca bean (a variety of common bean) were analyzed to verify the correlation with their hydration kinetics characteristics (hydration rate, lag phase time and equilibrium moisture content), using a Multiple Factorial Analysis (MFA): the chemical composition (starch, protein, lipids, minerals (Mg, P, S, K, Ca, Mn, Fe, Cu, Zn), functional groups from the seed coat analyzed by FT-IR), physical properties (size, 1000 grain weight, seed coat thickness, energy to penetrate the bean) and microstructure. Only few properties correlated with the hydration kinetics characteristics of the studied bean, comprising both composition and structure. The fat content, potassium content, specific surface, and the protein to lipids ratio correlated with the lag phase time, which is related with the seed coat impermeability to water. The necessary energy to perforate the seed coat correlated negatively with the hydration rate. It was concluded that the hydration of beans process is a complex phenomenon and that despite being from the same variety of legume, any change due to agronomic enhancement may affect their hydration process kinetics. Copyright © 2018 Elsevier Ltd. All rights reserved.

Toxicity of trifluoroacetate to aquatic organisms

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

Berends, A.G.; Rooij, C.G. de; Boutonnet, J.C.

1999-05-01

As a result of the atmospheric degradation of several hydrofluorocarbons and hydrochlorofluorocarbons, trifluoroacetate (TFA) will be formed. Through precipitation, TFA will enter aquatic ecosystems. To evaluate the impact on the aquatic environment, an aquatic toxicity testing program was carried out with sodium trifluoroacetate (NaTFA). During acute toxicity tests, no effects of NaTFA on water fleas (Daphnia magna) and zebra fish (Danio retrio) were found at a concentration of 1,200 mg/L. A 7-d study with duckweed (Lemna gibba Ge) revealed a NOEC of 300 mg/L. On the basis of the results of five toxicity tests with Selenastrum capricornutum, they determined amore » NOEC of 0.12 mg/L. However, algal toxicity tests with NaTFA and Chlorella vulgaris, Scenedesmus subspicatus, Chlamydomonas reinhardtii, Dunaliella tertiolecta, Eugelan gracilis, Phaeodactylum tricornutum, Navicula pelliculosa, Skeletonema costatum, Anabaena flos-aquae, and Microcystis aeruginosa resulted in EC50 values that were all higher than 100 mg/L. The toxicity of TFA to S. capricornutum could be due to metabolic defluorination to monofluoroacetate (MFA), which is known to inhibit the citric acid cycle. A toxicity test with MFA and S. capricornutum revealed it to be about three orders of magnitude more toxic than TFA. However, a bioactivation study revealed that defluorination of TFA was less than 4%. On the other hand, S. capricornutum exposed to a toxic concentration of NaTFA showed a recovery of growth when citric acid was added, suggesting that TFA (or a metabolite of TFA) interferes with the citric acid cycle. A recovery of the growth of S. capricornutum was also found when TFA was removed from the test solutions. Therefore, TFA should be considered algistatic and not algicidic for S. capricornutum. On the basis of the combined results of the laboratory tests and a previously reported semi-field study, they can consider a TFA concentration of 0.10 mg/L as safe for the aquatic ecosystem.« less

A virtual pebble game to ensemble average graph rigidity.

PubMed

González, Luis C; Wang, Hui; Livesay, Dennis R; Jacobs, Donald J

2015-01-01

The body-bar Pebble Game (PG) algorithm is commonly used to calculate network rigidity properties in proteins and polymeric materials. To account for fluctuating interactions such as hydrogen bonds, an ensemble of constraint topologies are sampled, and average network properties are obtained by averaging PG characterizations. At a simpler level of sophistication, Maxwell constraint counting (MCC) provides a rigorous lower bound for the number of internal degrees of freedom (DOF) within a body-bar network, and it is commonly employed to test if a molecular structure is globally under-constrained or over-constrained. MCC is a mean field approximation (MFA) that ignores spatial fluctuations of distance constraints by replacing the actual molecular structure by an effective medium that has distance constraints globally distributed with perfect uniform density. The Virtual Pebble Game (VPG) algorithm is a MFA that retains spatial inhomogeneity in the density of constraints on all length scales. Network fluctuations due to distance constraints that may be present or absent based on binary random dynamic variables are suppressed by replacing all possible constraint topology realizations with the probabilities that distance constraints are present. The VPG algorithm is isomorphic to the PG algorithm, where integers for counting "pebbles" placed on vertices or edges in the PG map to real numbers representing the probability to find a pebble. In the VPG, edges are assigned pebble capacities, and pebble movements become a continuous flow of probability within the network. Comparisons between the VPG and average PG results over a test set of proteins and disordered lattices demonstrate the VPG quantitatively estimates the ensemble average PG results well. The VPG performs about 20% faster than one PG, and it provides a pragmatic alternative to averaging PG rigidity characteristics over an ensemble of constraint topologies. The utility of the VPG falls in between the most accurate but slowest method of ensemble averaging over hundreds to thousands of independent PG runs, and the fastest but least accurate MCC.

Bioactivation of food genotoxicants 5-hydroxymethylfurfural and furfuryl alcohol by sulfotransferases from human, mouse and rat: a comparative study.

PubMed

Sachse, Benjamin; Meinl, Walter; Sommer, Yasmin; Glatt, Hansruedi; Seidel, Albrecht; Monien, Bernhard H

2016-01-01

5-Hydroxymethylfurfural (HMF) and furfuryl alcohol (FFA) are moderately potent rodent carcinogens that are present in thermally processed foodstuffs. The carcinogenic effects were hypothesized to originate from sulfotransferase (SULT)-mediated bioactivation yielding DNA-reactive and mutagenic sulfate esters, a confirmed metabolic pathway of HMF and FFA in mice. It is known that orthologous SULT forms substantially differ in substrate specificity and tissue distribution. This could influence HMF- and FFA-induced carcinogenic effects. Here, we studied HMF and FFA sulfoconjugation by 30 individual SULT forms of humans, mice and rats. The catalytic efficiencies (k cat/K M) of HMF sulfoconjugation of human SULT1A1 (13.7 s(-1) M(-1)), mouse Sult1a1 (15.8 s(-1) M(-1)) and 1d1 (4.8 s(-1) M(-1)) and rat Sult1a1 (5.3 s(-1) M(-1)) were considerably higher than those of all other SULT forms investigated (≤0.73 s(-1 )M(-1)). FFA sulfoconjugation was monitored using adenosine as a nucleophilic scavenger for the reactive 2-sulfoxymethylfuran (t 1/2 = 20 s at 37 °C). The resulting adduct N (6)-((furan-2-yl)methyl)-adenosine (N (6)-MF-A) was quantified by isotope-dilution UPLC-MS/MS. The rates of N (6)-MF-A formation showed that hSULT1A1 and its orthologues in mice and rats were also the most important contributors to FFA sulfoconjugation in each of the species. Taken together, the catalytic capacity of hSULT1A1 is comparable to that of mSult1a1 in mice, the species in which carcinogenic effects of HMF and FFA were detected. This is of primary concern due to the expression of hSULT1A1 in many different tissues.

Quantitative structure activity relationship studies of mushroom tyrosinase inhibitors

NASA Astrophysics Data System (ADS)

Xue, Chao-Bin; Luo, Wan-Chun; Ding, Qi; Liu, Shou-Zhu; Gao, Xing-Xiang

2008-05-01

Here, we report our results from quantitative structure-activity relationship studies on tyrosinase inhibitors. Interactions between benzoic acid derivatives and tyrosinase active sites were also studied using a molecular docking method. These studies indicated that one possible mechanism for the interaction between benzoic acid derivatives and the tyrosinase active site is the formation of a hydrogen-bond between the hydroxyl (aOH) and carbonyl oxygen atoms of Tyr98, which stabilized the position of Tyr98 and prevented Tyr98 from participating in the interaction between tyrosinase and ORF378. Tyrosinase, also known as phenoloxidase, is a key enzyme in animals, plants and insects that is responsible for catalyzing the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones. In the present study, the bioactivities of 48 derivatives of benzaldehyde, benzoic acid, and cinnamic acid compounds were used to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field (CoMFA) and comparative molecular similarity indices (CoMSIA) analyses. After superimposition using common substructure-based alignments, robust and predictive 3D-QSAR models were obtained from CoMFA ( q 2 = 0.855, r 2 = 0.978) and CoMSIA ( q 2 = 0.841, r 2 = 0.946), with 6 optimum components. Chemical descriptors, including electronic (Hammett σ), hydrophobic (π), and steric (MR) parameters, hydrogen bond acceptor (H-acc), and indicator variable ( I), were used to construct a 2D-QSAR model. The results of this QSAR indicated that π, MR, and H-acc account for 34.9, 31.6, and 26.7% of the calculated biological variance, respectively. The molecular interactions between ligand and target were studied using a flexible docking method (FlexX). The best scored candidates were docked flexibly, and the interaction between the benzoic acid derivatives and the tyrosinase active site was elucidated in detail. We believe that the QSAR models built here provide important information necessary for the design of novel tyrosinase inhibitors.

First Long-Term Behavioral Records from Cuvier’s Beaked Whales (Ziphius cavirostris) Reveal Record-Breaking Dives

PubMed Central

Schorr, Gregory S.; Falcone, Erin A.; Moretti, David J.; Andrews, Russel D.

2014-01-01

Cuvier’s beaked whales (Ziphius cavirostris) are known as extreme divers, though behavioral data from this difficult-to-study species have been limited. They are also the species most often stranded in association with Mid-Frequency Active (MFA) sonar use, a relationship that remains poorly understood. We used satellite-linked tags to record the diving behavior and locations of eight Ziphius off the Southern California coast for periods up to three months. The effort resulted in 3732 hr of dive data with associated regional movements – the first dataset of its kind for any beaked whale – and included dives to 2992 m depth and lasting 137.5 min, both new mammalian dive records. Deep dives had a group mean depth of 1401 m (s.d. = 137.8, n = 1142) and duration of 67.4 min (s.d. = 6.9). The group mean time between deep dives was 102.3 min (s.d. = 30.8, n = 783). While the previously described stereotypic pattern of deep and shallow dives was apparent, there was considerable inter- and intra-individual variability in most parameters. There was significant diel behavioral variation, including increased time near the surface and decreased shallow diving at night. However, maximum depth and the proportion of time spent on deep dives (presumed foraging), varied little from day to night. Surprisingly, tagged whales were present within an MFA sonar training range for 38% of days locations were received, and though comprehensive records of sonar use during tag deployments were not available, we discuss the effects frequent acoustic disturbance may have had on the observed behaviors. These data better characterize the true behavioral range of this species, and suggest caution should be exercised when drawing conclusions about behavior using short-term datasets. PMID:24670984

Discovery and quantitative structure-activity relationship study of lepidopteran HMG-CoA reductase inhibitors as selective insecticides.

PubMed

Zang, Yang-Yang; Li, Yuan-Mei; Yin, Yue; Chen, Shan-Shan; Kai, Zhen-Peng

2017-09-01

In a previous study we have demonstrated that insect 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) can be a potential selective insecticide target. Three series of inhibitors were designed on the basis of the difference in HMGR structures from Homo sapiens and Manduca sexta, with the aim of discovering potent selective insecticide candidates. An in vitro bioassay showed that gem-difluoromethylenated statin analogues have potent effects on JH biosynthesis of M. sexta and high selectivity between H. sapiens and M. sexta. All series II compounds {1,3,5-trisubstituted [4-tert-butyl 2-(5,5-difluoro-2,2-dimethyl-6-vinyl-4-yl) acetate] pyrazoles} have some effect on JH biosynthesis, whereas most of them are inactive on human HMGR. In particular, the IC 50 value of compound II-12 (37.8 nm) is lower than that of lovastatin (99.5 nm) and similar to that of rosuvastatin (24.2 nm). An in vivo bioassay showed that I-1, I-2, I-3 and II-12 are potential selective insecticides, especially for lepidopteran pest control. A predictable and statistically meaningful CoMFA model of 23 inhibitors (20 as training sets and three as test sets) was obtained with a value of q 2 and r 2 of 0.66 and 0.996 respectively. The final model suggested that a potent insect HMGR inhibitor should contain suitable small and non-electronegative groups in the ring part, and electronegative groups in the side chain. Four analogues were discovered as potent selective lepidopteran HMGR inhibitors, which can specifically be used for lepidopteran pest control. The CoMFA model will be useful for the design of new selective insect HMGR inhibitors that are structurally related to the training set compounds. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Rerouting of carbon flux in a glycogen mutant of cyanobacteria assessed via isotopically non-stationary 13 C metabolic flux analysis.

PubMed

Hendry, John I; Prasannan, Charulata; Ma, Fangfang; Möllers, K Benedikt; Jaiswal, Damini; Digmurti, Madhuri; Allen, Doug K; Frigaard, Niels-Ulrik; Dasgupta, Santanu; Wangikar, Pramod P

2017-10-01

Cyanobacteria, which constitute a quantitatively dominant phylum, have attracted attention in biofuel applications due to favorable physiological characteristics, high photosynthetic efficiency and amenability to genetic manipulations. However, quantitative aspects of cyanobacterial metabolism have received limited attention. In the present study, we have performed isotopically non-stationary 13 C metabolic flux analysis (INST- 13 C-MFA) to analyze rerouting of carbon in a glycogen synthase deficient mutant strain (glgA-I glgA-II) of the model cyanobacterium Synechococcus sp. PCC 7002. During balanced photoautotrophic growth, 10-20% of the fixed carbon is stored in the form of glycogen via a pathway that is conserved across the cyanobacterial phylum. Our results show that deletion of glycogen synthase gene orchestrates cascading effects on carbon distribution in various parts of the metabolic network. Carbon that was originally destined to be incorporated into glycogen gets partially diverted toward alternate storage molecules such as glucosylglycerol and sucrose. The rest is partitioned within the metabolic network, primarily via glycolysis and tricarboxylic acid cycle. A lowered flux toward carbohydrate synthesis and an altered distribution at the glucose-1-phosphate node indicate flexibility in the network. Further, reversibility of glycogen biosynthesis reactions points toward the presence of futile cycles. Similar redistribution of carbon was also predicted by Flux Balance Analysis. The results are significant to metabolic engineering efforts with cyanobacteria where fixed carbon needs to be re-routed to products of interest. Biotechnol. Bioeng. 2017;114: 2298-2308. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Structural Basis for Certain Naturally Occurring Bioflavonoids to Function as Reducing Co-Substrates of Cyclooxygenase I and II

PubMed Central

Zhu, Bao Ting

2010-01-01

Background Recent studies showed that some of the dietary bioflavonoids can strongly stimulate the catalytic activity of cyclooxygenase (COX) I and II in vitro and in vivo, presumably by facilitating enzyme re-activation. In this study, we sought to understand the structural basis of COX activation by these dietary compounds. Methodology/Principal Findings A combination of molecular modeling studies, biochemical analysis and site-directed mutagenesis assay was used as research tools. Three-dimensional quantitative structure-activity relationship analysis (QSAR/CoMFA) predicted that the ability of bioflavonoids to activate COX I and II depends heavily on their B-ring structure, a moiety known to be associated with strong antioxidant ability. Using the homology modeling and docking approaches, we identified the peroxidase active site of COX I and II as the binding site for bioflavonoids. Upon binding to this site, bioflavonoid can directly interact with hematin of the COX enzyme and facilitate the electron transfer from bioflavonoid to hematin. The docking results were verified by biochemical analysis, which reveals that when the cyclooxygenase activity of COXs is inhibited by covalent modification, myricetin can still stimulate the conversion of PGG2 to PGE2, a reaction selectively catalyzed by the peroxidase activity. Using the site-directed mutagenesis analysis, we confirmed that Q189 at the peroxidase site of COX II is essential for bioflavonoids to bind and re-activate its catalytic activity. Conclusions/Significance These findings provide the structural basis for bioflavonoids to function as high-affinity reducing co-substrates of COXs through binding to the peroxidase active site, facilitating electron transfer and enzyme re-activation. PMID:20808785

Nuclear energy in Europe: uranium flow modeling and fuel cycle scenario trade-offs from a sustainability perspective.

PubMed

Tendall, Danielle M; Binder, Claudia R

2011-03-15

The European nuclear fuel cycle (covering the EU-27, Switzerland and Ukraine) was modeled using material flow analysis (MFA).The analysis was based on publicly available data from nuclear energy agencies and industries, national trade offices, and nongovernmental organizations. Military uranium was not considered due to lack of accessible data. Nuclear fuel cycle scenarios varying spent fuel reprocessing, depleted uranium re-enrichment, enrichment assays, and use of fast neutron reactors, were established. They were then assessed according to environmental, economic and social criteria such as resource depletion, waste production, chemical and radiation emissions, costs, and proliferation risks. The most preferable scenario in the short term is a combination of reduced tails assay and enrichment grade, allowing a 17.9% reduction of uranium demand without significantly increasing environmental, economic, or social risks. In the long term, fast reactors could theoretically achieve a 99.4% decrease in uranium demand and nuclear waste production. However, this involves important costs and proliferation risks. Increasing material efficiency is not systematically correlated with the reduction of other risks. This suggests that an overall optimization of the nuclear fuel cycle is difficult to obtain. Therefore, criteria must be weighted according to stakeholder interests in order to determine the most sustainable solution. This paper models the flows of uranium and associated materials in Europe, and provides a decision support tool for identifying the trade-offs of the alternative nuclear fuel cycles considered.

Investigate the Metabolic Reprogramming of Saccharomyces cerevisiae for Enhanced Resistance to Mixed Fermentation Inhibitors via 13C Metabolic Flux Analysis

PubMed Central

Guo, Weihua; Chen, Yingying; Wei, Na; Feng, Xueyang

2016-01-01

The fermentation inhibitors from the pretreatment of lignocellulosic materials, e.g., acetic acid and furfural, are notorious due to their negative effects on the cell growth and chemical production. However, the metabolic reprogramming of the cells under these stress conditions, especially metabolic response for resistance to mixed inhibitors, has not been systematically investigated and remains mysterious. Therefore, in this study, 13C metabolic flux analysis (13C-MFA), a powerful tool to elucidate the intracellular carbon flux distributions, has been applied to two Saccharomyces cerevisiae strains with different tolerances to the inhibitors under acetic acid, furfural, and mixed (i.e., acetic acid and furfural) stress conditions to unravel the key metabolic responses. By analyzing the intracellular carbon fluxes as well as the energy and cofactor utilization under different conditions, we uncovered varied metabolic responses to different inhibitors. Under acetate stress, ATP and NADH production was slightly impaired, while NADPH tended towards overproduction. Under furfural stress, ATP and cofactors (including both NADH and NADPH) tended to be overproduced. However, under dual-stress condition, production of ATP and cofactors was severely impaired due to synergistic stress caused by the simultaneous addition of two fermentation inhibitors. Such phenomenon indicated the pivotal role of the energy and cofactor utilization in resisting the mixed inhibitors of acetic acid and furfural. Based on the discoveries, valuable insights are provided to improve the tolerance of S. cerevisiae strain and further enhance lignocellulosic fermentation. PMID:27532329

Xenopus Zic3 controls notochord and organizer development through suppression of the Wnt/β-catenin signaling pathway.

PubMed

Fujimi, Takahiko J; Hatayama, Minoru; Aruga, Jun

2012-01-15

Zic3 controls neuroectodermal differentiation and left-right patterning in Xenopus laevis embryos. Here we demonstrate that Zic3 can suppress Wnt/β-catenin signaling and control development of the notochord and Spemann's organizer. When we overexpressed Zic3 by injecting its RNA into the dorsal marginal zone of 2-cell-stage embryos, the embryos lost mesodermal dorsal midline structures and showed reduced expression of organizer markers (Siamois and Goosecoid) and a notochord marker (Xnot). Co-injection of Siamois RNA partially rescued the reduction of Xnot expression caused by Zic3 overexpression. Because the expression of Siamois in the organizer region is controlled by Wnt/β-catenin signaling, we subsequently examined the functional interaction between Zic3 and Wnt signaling. Co-injection of Xenopus Zic RNAs and β-catenin RNA with a reporter responsive to the Wnt/β-catenin cascade indicated that Zic1, Zic2, Zic3, Zic4, and Zic5 can all suppress β-catenin-mediated transcriptional activation. In addition, co-injection of Zic3 RNA inhibited the secondary axis formation caused by ventral-side injection of β-catenin RNA in Xenopus embryos. Zic3-mediated Wnt/β-catenin signal suppression required the nuclear localization of Zic3, and involved the reduction of β-catenin nuclear transport and enhancement of β-catenin degradation. Furthermore, Zic3 co-precipitated with Tcf1 (a β-catenin co-factor) and XIC (I-mfa domain containing factor required for dorsoanterior development). The findings in this report produce a novel system for fine-tuning of Wnt/β-catenin signaling. Copyright © 2011. Published by Elsevier Inc.

Influence of treatment conditions on the oxidation of micropollutants by Trametes versicolor laccase.

PubMed

Margot, Jonas; Maillard, Julien; Rossi, Luca; Barry, D A; Holliger, Christof

2013-09-25

Many organic compounds present at low concentrations in municipal wastewater, such as various pharmaceuticals and biocides, are recalcitrant in conventional wastewater treatment plants (WWTPs). To improve their biodegradation, oxidoreductase enzymes such as laccases were tested. The goal was to find optimal conditions for the transformation of two anti-inflammatory pharmaceuticals (diclofenac (DFC) and mefenamic acid (MFA)), one biocide (triclosan (TCN)) and one plastic additive (bisphenol A (BPA)) by Trametes versicolor laccase. Experiments were conducted in spiked solutions at different pH values (from 3 to 9), enzyme concentrations (70-1400 Ul(-1)), reaction times (0-26 hours) and temperatures (10, 25 and 40°C) following a Doehlert experimental design. A semi-empirical model was developed to understand better the combined effects of the four factors and to determine optimal values. This model was able to fit well the experimental data (R(2)>0.97) and showed good predictive ability. All four factors had a significant effect on the micropollutant oxidation with the greatest influence shown by pH. Results for single compounds were different from those obtained for mixtures of micropollutants. For instance, DFC transformation occurred at much higher rates in mixtures under alkaline conditions. Optimal conditions were compound-dependent, but were found to be between pH 4.5 to 6.5 and between 25°C to more than 40°C. A laccase concentration of 730 Ul(-1) was sufficient to obtain a high removal rate (>90%) of the four individual compounds (range of times: 40 min to 5 hours), showing the potential of laccases to improve biodegradation of environmentally persistent compounds. Copyright © 2013 Elsevier B.V. All rights reserved.

Quantitative insight into the design of compounds recognized by the L-type amino acid transporter 1 (LAT1).

PubMed

Ylikangas, Henna; Malmioja, Kalle; Peura, Lauri; Gynther, Mikko; Nwachukwu, Emmanuel O; Leppänen, Jukka; Laine, Krista; Rautio, Jarkko; Lahtela-Kakkonen, Maija; Huttunen, Kristiina M; Poso, Antti

2014-12-01

L-Type amino acid transporter 1 (LAT1) is a transmembrane protein expressed abundantly at the blood-brain barrier (BBB), where it ensures the transport of hydrophobic acids from the blood to the brain. Due to its unique substrate specificity and high expression at the BBB, LAT1 is an intriguing target for carrier-mediated transport of drugs into the brain. In this study, a comparative molecular field analysis (CoMFA) model with considerable statistical quality (Q(2) =0.53, R(2) =0.75, Q(2) SE=0.77, R(2) SE=0.57) and good external predictivity (CCC=0.91) was generated. The model was used to guide the synthesis of eight new prodrugs whose affinity for LAT1 was tested by using an in situ rat brain perfusion technique. This resulted in the creation of a novel LAT1 prodrug with L-tryptophan as the promoiety; it also provided a better understanding of the molecular features of LAT1-targeted high-affinity prodrugs, as well as their promoiety and parent drug. The results obtained will be beneficial in the rational design of novel LAT1-binding prodrugs and other compounds that bind to LAT1. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The discovery of novel histone lysine methyltransferase G9a inhibitors (part 1): molecular design based on a series of substituted 2,4-diamino-7- aminoalkoxyquinazoline by molecular-docking-guided 3D quantitative structure-activity relationship studies.

PubMed

Feng, Taotao; Wang, Hai; Zhang, Xiaojin; Sun, Haopeng; You, Qidong

2014-06-01

Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. This suggests that small molecular inhibitors of G9a might be attractive antitumor agents. Herein we report our efforts on the design of novel G9a inhibitor based on the 3D quantitative structure-activity relationship (3D-QSAR) analysis of a series of 2,4-diamino-7-aminoalkoxyquinazolineas G9a inhibitors. The 3D-QSAR model was generated from 47 compounds using docking based molecular alignment. The best predictions were obtained with CoMFA standard model (q2 =0.700, r2 = 0.952) and CoMSIA model combined with steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields (q2 = 0.724, r2 =0.960). The structural requirements for substituted 2,4-diamino-7-aminoalkoxyquinazoline for G9a inhibitory activity can be obtained by analysing the COMSIA plots. Based on the information, six novel follow-up analogs were designed.

Analysis of the holistic impact of the Hydrogen Economy on the coal industry

NASA Astrophysics Data System (ADS)

Lusk, Shannon Perry

As gas prices soar and energy demand continues to grow amidst increasingly stringent environmental regulations and an assortment of global pressures, implementing alternative energy sources while considering their linked economic, environmental and societal impacts becomes a more pressing matter. The Hydrogen Economy has been proposed as an answer to meeting the increasing energy demand for electric power generation and transportation in an environmentally benign way. Based on current hydrogen technology development, the most practical feedstock to fuel the Hydrogen Economy may prove to be coal via hydrogen production at FutureGen plants. The planned growth of the currently conceived Hydrogen Economy will cause dramatic impacts, some good and some bad, on the economy, the environment, and society, which are interlinked. The goal of this research is to provide tools to inform public policy makers in sorting out policy options related to coal and the Hydrogen Economy. This study examines the impact of a transition to a Hydrogen Economy on the coal industry by creating FutureGen penetration models, forecasting coal MFA's which clearly provide the impact on coal production and associated environmental impacts, and finally formulating a goal programming model that seeks the maximum benefit to society while analyzing the trade-offs between environmental, social, and economical concerns related to coal and the Hydrogen Economy.

An investigation on the potential of metal recovery from the municipal waste incinerator in Taiwan.

PubMed

Kuo, Nae-Wen; Ma, Hwong-Wen; Yang, Ya-Mei; Hsiao, Teng-Yuan; Huang, Chin-Ming

2007-01-01

This study aimed to identify distribution of metals and to estimate the amount of these metals that can be potentially recovered from incineration residues. First, the partitioning behavior of Cr, Cu, Fe, Cd, Al, Zn, and Pb in bottom ash and fly ash was investigated in one large municipal waste incinerator in Taiwan. In addition, the material flow analysis (MFA) method was used to estimate the material flux of metals within incinerator plant, and to calculate the amount of metal recovery. According to the findings of this study, six metals (Fe, Al, Cu, Zn, Cr, and Pb) concentrated in bottom ash mostly, while Cd existed primarily in fly ash. The weight percentages of Fe (4.49%), Al (5.24%), Cu (1.29%), Zn (2.21%), and Pb (0.58%) in incinerator ash are high, and even higher than the compositions of natural minerals. Finally, the amount of Cr, Cu, Fe, Cd, Al, Zn and Pb that can be potentially recovered from incineration residues will reach 2.69 x 10(2), 1.46 x 10(4), 4.91 x 10(4), 6.92 x 10(1), 5.10 x 10(4), 1.85 x 10(4) and 4.66 x 10(3) ton/yr, respectively.

Synthesis, Antifungal Activity and Structure-Activity Relationships of Novel 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic Acid Amides.

PubMed

Du, Shijie; Tian, Zaimin; Yang, Dongyan; Li, Xiuyun; Li, Hong; Jia, Changqing; Che, Chuanliang; Wang, Mian; Qin, Zhaohai

2015-05-08

A series of novel 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-yl)phenyl)-3-(difluoro-methyl)-1-methyl-1H-pyrazole-4-carboxamide (9m) exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.

3D-Quantitative structure-activity relationships of synthetic antileishmanial ring-substituted ether phospholipids.

PubMed

Kapou, Agnes; Benetis, Nikolas P; Avlonitis, Nikos; Calogeropoulou, Theodora; Koufaki, Maria; Scoulica, Efi; Nikolaropoulos, Sotiris S; Mavromoustakos, Thomas

2007-02-01

The application of 2D-NMR spectroscopy and Molecular Modeling in determining the active conformation of flexible molecules in 3D-QSAR was demonstrated in the present study. In particular, a series of 33 flexible synthetic phospholipids, either 2-(4-alkylidene-cyclohexyloxy)ethyl- or omega-cycloalkylidene-substituted ether phospholipids were systematically evaluated for their in vitro antileishmanial activity against the promastigote forms of Leishmania infantum and Leishmania donovani by CoMFA and CoMSIA 3D-QSAR studies. Steric and hydrophobic properties of the phospholipids under study appear to govern their antileishmanial activity against both strains, while the electrostatic properties have no significant contribution. The acknowledgment of these important properties of the pharmacophore will aid in the rational design of new analogues with higher activity.

3D-QSAR, molecular dynamics simulations and molecular docking studies of benzoxazepine moiety as mTOR inhibitor for the treatment of lung cancer.

PubMed

Chaube, Udit; Chhatbar, Dhara; Bhatt, Hardik

2016-02-01

According to WHO statistics, lung cancer is one of the leading causes of death among all other types of cancer. Many genes get mutated in lung cancer but involvement of EGFR and KRAS are more common. Unavailability of drugs or resistance to the available drugs is the major problem in the treatment of lung cancer. In the present research, mTOR was selected as an alternative target for the treatment of lung cancer which involves PI3K/AKT/mTOR pathway. 28 synthetic mTOR inhibitors were selected from the literature. Ligand based approach (CoMFA and CoMSIA) and structure based approach (molecular dynamics simulations assisted molecular docking study) were applied for the identification of important features of benzoxazepine moiety, responsible for mTOR inhibition. Three different alignments were tried to obtain best QSAR model, of which, distil was found to be the best method, as it gave good statistical results. In CoMFA, Leave One Out (LOO) cross validated coefficients (q(2)), conventional coefficient (r(2)) and predicted correlation coefficient (r(2)pred) values were found to be 0.615, 0.990 and 0.930, respectively. Similarly in CoMSIA, q(2), r(2)ncv and r(2)pred values were found to be 0.748, 0.986 and 0.933, respectively. Molecular dynamics and simulations study revealed that B-chain of mTOR protein was stable at and above 500 FS with respect to temperature (at and above 298 K), Potential energy (at and above 7669.72 kJ/mol) and kinetic energy (at and above 4009.77 kJ/mol). Molecular docking study was performed on simulated protein of mTOR which helped to correlate interactions of amino acids surrounded to the ligand with contour maps generated by QSAR method. Important features of benzoxazepine were identified by contour maps and molecular docking study which would be useful to design novel molecules as mTOR inhibitors for the treatment of lung cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

The JBEI quantitative metabolic modeling library (jQMM): a python library for modeling microbial metabolism.

PubMed

Birkel, Garrett W; Ghosh, Amit; Kumar, Vinay S; Weaver, Daniel; Ando, David; Backman, Tyler W H; Arkin, Adam P; Keasling, Jay D; Martín, Héctor García

2017-04-05

Modeling of microbial metabolism is a topic of growing importance in biotechnology. Mathematical modeling helps provide a mechanistic understanding for the studied process, separating the main drivers from the circumstantial ones, bounding the outcomes of experiments and guiding engineering approaches. Among different modeling schemes, the quantification of intracellular metabolic fluxes (i.e. the rate of each reaction in cellular metabolism) is of particular interest for metabolic engineering because it describes how carbon and energy flow throughout the cell. In addition to flux analysis, new methods for the effective use of the ever more readily available and abundant -omics data (i.e. transcriptomics, proteomics and metabolomics) are urgently needed. The jQMM library presented here provides an open-source, Python-based framework for modeling internal metabolic fluxes and leveraging other -omics data for the scientific study of cellular metabolism and bioengineering purposes. Firstly, it presents a complete toolbox for simultaneously performing two different types of flux analysis that are typically disjoint: Flux Balance Analysis and 13 C Metabolic Flux Analysis. Moreover, it introduces the capability to use 13 C labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale 13 C Metabolic Flux Analysis (2S- 13 C MFA). In addition, the library includes a demonstration of a method that uses proteomics data to produce actionable insights to increase biofuel production. Finally, the use of the jQMM library is illustrated through the addition of several Jupyter notebook demonstration files that enhance reproducibility and provide the capability to be adapted to the user's specific needs. jQMM will facilitate the design and metabolic engineering of organisms for biofuels and other chemicals, as well as investigations of cellular metabolism and leveraging -omics data. As an open source software project, we hope it will attract additions from the community and grow with the rapidly changing field of metabolic engineering.

The JBEI quantitative metabolic modeling library (jQMM): a python library for modeling microbial metabolism

DOE PAGES

Birkel, Garrett W.; Ghosh, Amit; Kumar, Vinay S.; ...

2017-04-05

Modeling of microbial metabolism is a topic of growing importance in biotechnology. Mathematical modeling helps provide a mechanistic understanding for the studied process, separating the main drivers from the circumstantial ones, bounding the outcomes of experiments and guiding engineering approaches. Among different modeling schemes, the quantification of intracellular metabolic fluxes (i.e. the rate of each reaction in cellular metabolism) is of particular interest for metabolic engineering because it describes how carbon and energy flow throughout the cell. In addition to flux analysis, new methods for the effective use of the ever more readily available and abundant -omics data (i.e. transcriptomics,more » proteomics and metabolomics) are urgently needed. The jQMM library presented here provides an open-source, Python-based framework for modeling internal metabolic fluxes and leveraging other -omics data for the scientific study of cellular metabolism and bioengineering purposes. Firstly, it presents a complete toolbox for simultaneously performing two different types of flux analysis that are typically disjoint: Flux Balance Analysis and 13C Metabolic Flux Analysis. Moreover, it introduces the capability to use 13C labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale 13C Metabolic Flux Analysis (2S- 13C MFA). In addition, the library includes a demonstration of a method that uses proteomics data to produce actionable insights to increase biofuel production. Finally, the use of the jQMM library is illustrated through the addition of several Jupyter notebook demonstration files that enhance reproducibility and provide the capability to be adapted to the user's specific needs. jQMM will facilitate the design and metabolic engineering of organisms for biofuels and other chemicals, as well as investigations of cellular metabolism and leveraging -omics data. As an open source software project, we hope it will attract additions from the community and grow with the rapidly changing field of metabolic engineering.« less

The JBEI quantitative metabolic modeling library (jQMM): a python library for modeling microbial metabolism

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

Birkel, Garrett W.; Ghosh, Amit; Kumar, Vinay S.

Modeling of microbial metabolism is a topic of growing importance in biotechnology. Mathematical modeling helps provide a mechanistic understanding for the studied process, separating the main drivers from the circumstantial ones, bounding the outcomes of experiments and guiding engineering approaches. Among different modeling schemes, the quantification of intracellular metabolic fluxes (i.e. the rate of each reaction in cellular metabolism) is of particular interest for metabolic engineering because it describes how carbon and energy flow throughout the cell. In addition to flux analysis, new methods for the effective use of the ever more readily available and abundant -omics data (i.e. transcriptomics,more » proteomics and metabolomics) are urgently needed. The jQMM library presented here provides an open-source, Python-based framework for modeling internal metabolic fluxes and leveraging other -omics data for the scientific study of cellular metabolism and bioengineering purposes. Firstly, it presents a complete toolbox for simultaneously performing two different types of flux analysis that are typically disjoint: Flux Balance Analysis and 13C Metabolic Flux Analysis. Moreover, it introduces the capability to use 13C labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale 13C Metabolic Flux Analysis (2S- 13C MFA). In addition, the library includes a demonstration of a method that uses proteomics data to produce actionable insights to increase biofuel production. Finally, the use of the jQMM library is illustrated through the addition of several Jupyter notebook demonstration files that enhance reproducibility and provide the capability to be adapted to the user's specific needs. jQMM will facilitate the design and metabolic engineering of organisms for biofuels and other chemicals, as well as investigations of cellular metabolism and leveraging -omics data. As an open source software project, we hope it will attract additions from the community and grow with the rapidly changing field of metabolic engineering.« less

An mRNA decapping mutant deficient in P body assembly limits mRNA stabilization in response to osmotic stress.

PubMed

Huch, Susanne; Nissan, Tracy

2017-03-14

Yeast is exposed to changing environmental conditions and must adapt its genetic program to provide a homeostatic intracellular environment. An important stress for yeast in the wild is high osmolarity. A key response to this stress is increased mRNA stability primarily by the inhibition of deadenylation. We previously demonstrated that mutations in decapping activators (edc3∆ lsm4∆C), which result in defects in P body assembly, can destabilize mRNA under unstressed conditions. We wished to examine whether mRNA would be destabilized in the edc3∆ lsm4∆C mutant as compared to the wild-type in response to osmotic stress, when P bodies are intense and numerous. Our results show that the edc3∆ lsm4∆C mutant limits the mRNA stability in response to osmotic stress, while the magnitude of stabilization was similar as compared to the wild-type. The reduced mRNA stability in the edc3∆ lsm4∆C mutant was correlated with a shorter PGK1 poly(A) tail. Similarly, the MFA2 mRNA was more rapidly deadenylated as well as significantly stabilized in the ccr4∆ deadenylation mutant in the edc3∆ lsm4∆C background. These results suggest a role for these decapping factors in stabilizing mRNA and may implicate P bodies as sites of reduced mRNA degradation.

Application of 3D-QSAR, Pharmacophore, and Molecular Docking in the Molecular Design of Diarylpyrimidine Derivatives as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors.

PubMed

Liu, Genyan; Wang, Wenjie; Wan, Youlan; Ju, Xiulian; Gu, Shuangxi

2018-05-11

Diarylpyrimidines (DAPYs), acting as HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs), have been considered to be one of the most potent drug families in the fight against acquired immunodeficiency syndrome (AIDS). To better understand the structural requirements of HIV-1 NNRTIs, three-dimensional quantitative structure⁻activity relationship (3D-QSAR), pharmacophore, and molecular docking studies were performed on 52 DAPY analogues that were synthesized in our previous studies. The internal and external validation parameters indicated that the generated 3D-QSAR models, including comparative molecular field analysis (CoMFA, q 2 = 0.679, R 2 = 0.983, and r pred 2 = 0.884) and comparative molecular similarity indices analysis (CoMSIA, q 2 = 0.734, R 2 = 0.985, and r pred 2 = 0.891), exhibited good predictive abilities and significant statistical reliability. The docking results demonstrated that the phenyl ring at the C₄-position of the pyrimidine ring was better than the cycloalkanes for the activity, as the phenyl group was able to participate in π⁻π stacking interactions with the aromatic residues of the binding site, whereas the cycloalkanes were not. The pharmacophore model and 3D-QSAR contour maps provided significant insights into the key structural features of DAPYs that were responsible for the activity. On the basis of the obtained information, a series of novel DAPY analogues of HIV-1 NNRTIs with potentially higher predicted activity was designed. This work might provide useful information for guiding the rational design of potential HIV-1 NNRTI DAPYs.

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARγ

PubMed Central

Zhang, Jun; Hao, Qing-Qing; Liu, Xin; Jing, Zhi; Jia, Wen-Qing; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling

2017-01-01

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\\pyridine derivatives with the IC50s of 0.49∼94.1 nM against AT1 and EC50s of 20∼3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q2=0.553, r2=0.954, SEE=0.127, r2pred=0.779 for AT1 and q2=0.503, r2=1.00, SEE=0.019, r2pred=0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists. PMID:28445965

An attributional life cycle assessment for an Italian residential multifamily building.

PubMed

Vitale, Pierluca; Arena, Umberto

2017-09-06

The study describes an attributional life cycle assessment carried out according to the ISO standards and focused on an Italian multifamily residential building. The aim was developing an exhaustive and reliable inventory of high-quality primary data, comparing the environmental impacts along the three stages of the building life cycle. The pre-use phase takes into account the production of all the construction materials, transportation, and on-site assembling. The use phase quantifies the resource consumptions for 50 years of the building utilization and ordinary maintenance. The end-of-life phase includes the building demolition and the management of generated wastes. The results quantify how the design criteria affect the environmental performances of the residential building along its life cycle. The role of the pre-use phase appears remarkable for global warming potential (GWP), due to the huge impacts of steel and concrete production processes. The use phase gives the largest contributions, which reach 77% and 84% of the total, for the categories of global warming and non-renewable energy. The end-of-life phase provides limited avoided impacts. A comparative analysis quantifies the improvements achievable with an alternative type of partitions and external walls. Acronyms: AC: air conditioning; C&DW: construction and demolition waste; CFL: compact fluorescent lamp; DHW: domestic hot water; EC: European Commission; EU: European Union; GDP: gross domestic product; GHG: greenhouse gases; GWP: global warming potential; LCA: life cycle assessment; LCI: life cycle inventory; LCIA: life cycle impact assessment; MFA: material flow analysis; NREP: non-renewable energy potential; RINP: respiratory inorganics potential; WFD: Waste Framework Directive.

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARg.

PubMed

Zhang, Jun; Hao, Qing-Qing; Liu, Xin; Jing, Zhi; Jia, Wen-Qing; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling

2017-04-11

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\\pyridine derivatives with the IC50s of 0.49~94.1 nM against AT1 and EC50s of 20~3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q2=0.553, r2=0.954, SEE=0.127, r2pred=0.779 for AT1 and q2=0.503, r2=1.00, SEE=0.019, r2pred=0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists.

A hybrid method for quantifying China's nitrogen footprint during urbanisation from 1990 to 2009.

PubMed

Cui, Shenghui; Shi, Yalan; Malik, Arunima; Lenzen, Manfred; Gao, Bing; Huang, Wei

2016-12-01

In this study, we devise a national nitrogen footprint method to evaluate the life cycle nitrogen flows through the national economy of China from 1990 to 2009. To this end, we build a hybrid method based on two well-established techniques, namely material flow analysis (MFA) and input-output analysis (IOA). This integration allows for the evaluation of the effects of international trade and interdependencies among economic sectors. Our results suggest that China's nitrogen footprint (NF) has increased from 30.3Teragrams (Tg) in 1990 to 54.0Tg in 2009, whereas the NF per capita has increased from 25.9 to 39.5kgN/yr. Relationship between the world NF per capita and human development index (HDI) appears to show an inverted U curve, whilst China shows an increase both in NF per capita and HDI. We find that an increase in China's NF is largely associated with high levels of urbanisation. Although the energy NF (E_NF) has increased more drastically than the food NF (F_NF), the latter still dominates China's total NNF, with proportions of 91% in 1990 and 82% in 2009. Taking international trade into account, our results demonstrate that China was a net exporter of F_NF, whilst a net importer of E_NF over this time period. There are many measures considered to reduce China's nitrogen footprint, including improvements in N use efficiency of food systems, transformation of meat-based diets and optimisation of China's economic structure. Copyright © 2016 Elsevier Ltd. All rights reserved.

The MFA ground states for the extended Bose-Hubbard model with a three-body constraint

NASA Astrophysics Data System (ADS)

Panov, Yu. D.; Moskvin, A. S.; Vasinovich, E. V.; Konev, V. V.

2018-05-01

We address the intensively studied extended bosonic Hubbard model (EBHM) with truncation of the on-site Hilbert space to the three lowest occupation states n = 0 , 1 , 2 in frames of the S = 1 pseudospin formalism. Similar model was recently proposed to describe the charge degree of freedom in a model high-T c cuprate with the on-site Hilbert space reduced to the three effective valence centers, nominally Cu1+;2+;3+. With small corrections the model becomes equivalent to a strongly anisotropic S = 1 quantum magnet in an external magnetic field. We have applied a generalized mean-field approach and quantum Monte-Carlo technique for the model 2D S = 1 system with a two-particle transport to find the ground state phase with its evolution under deviation from half-filling.

Elaborating the History of Our Cementing Societies: An in-Use Stock Perspective.

PubMed

Cao, Zhi; Shen, Lei; Løvik, Amund N; Müller, Daniel B; Liu, Gang

2017-10-03

Modern cities and societies are built fundamentally based on cement and concrete. The global cement production has risen sharply in the past decades due largely to urbanization and construction. Here we deployed a top-down dynamic material flow analysis (MFA) model to quantify the historical development of cement in-use stocks in residential, nonresidential, and civil engineering sectors of all world countries. We found that global cement production spreads unevenly among 184 countries, with China dominating the global production and consumption after the 1990s. Nearly all countries have shown an increasing trend of per capita cement in-use stock in the past century. The present per capita cement in-use stocks vary from 10 to 40 tonnes in major industrialized and transiting countries and are below 10 tonnes in developing countries. Evolutionary modes identified from historical patterns suggest that per capita in-use cement stock growth generally complies with an S-shape curve and relates closely to affluence and urbanization of a country, but more in-depth and bottom-up investigations are needed to better understand socioeconomic drivers behind stock growth. These identified in-use stock patterns can help us better estimate future demand of cement, explore strategies for emissions reduction in the cement industry, and inform CO 2 uptake potentials of cement based products and infrastructure in service.

LQTA-QSAR: a new 4D-QSAR methodology.

PubMed

Martins, João Paulo A; Barbosa, Euzébio G; Pasqualoto, Kerly F M; Ferreira, Márcia M C

2009-06-01

A novel 4D-QSAR approach which makes use of the molecular dynamics (MD) trajectories and topology information retrieved from the GROMACS package is presented in this study. This new methodology, named LQTA-QSAR (LQTA, Laboratório de Quimiometria Teórica e Aplicada), has a module (LQTAgrid) that calculates intermolecular interaction energies at each grid point considering probes and all aligned conformations resulting from MD simulations. These interaction energies are the independent variables or descriptors employed in a QSAR analysis. The comparison of the proposed methodology to other 4D-QSAR and CoMFA formalisms was performed using a set of forty-seven glycogen phosphorylase b inhibitors (data set 1) and a set of forty-four MAP p38 kinase inhibitors (data set 2). The QSAR models for both data sets were built using the ordered predictor selection (OPS) algorithm for variable selection. Model validation was carried out applying y-randomization and leave-N-out cross-validation in addition to the external validation. PLS models for data set 1 and 2 provided the following statistics: q(2) = 0.72, r(2) = 0.81 for 12 variables selected and 2 latent variables and q(2) = 0.82, r(2) = 0.90 for 10 variables selected and 5 latent variables, respectively. Visualization of the descriptors in 3D space was successfully interpreted from the chemical point of view, supporting the applicability of this new approach in rational drug design.

PCDD/F catalysis by metal chlorides and oxides.

PubMed

Zhang, Mengmei; Yang, Jie; Buekens, Alfons; Olie, Kees; Li, Xiaodong

2016-09-01

Model fly ash (MFA) samples were composed of silica, sodium chloride, and activated carbon, and doped with metal (0.1 wt% Cu, Cr, Ni, Zn and Cd) chloride or oxide. Each sample was de novo tested at 350 °C for 1 h, in a flow of gas (N2, N2 + 10% O2, +21% O2 or +10% H2) to investigate the effect of metal catalyst and gas composition on PCDD/F formation. Total PCDD/F yield rises rapidly with oxygen content, while the addition of hydrogen inhibits the formation and chlorination of PCDD/F. The amount of PCDD on average rises linearly with the oxygen concentration, while that of PCDF follows a reaction order of about 1/2; thus the PCDF to PCDD ratio drops when more oxygen becomes available. Some samples do not follow this trend. Chlorides are much more active than oxides, yet there are marked differences between individual metals. Principal component analysis (PCA) was applied to study the signatures from all samples, showing their unique specificity and diversity. Each catalyst shows a different signature within its individual homologue groups, demonstrating that these signatures are not thermodynamically controlled. Average congener patterns do not vary considerably with oxygen content changing from oxidising (air) to reducing (nitrogen, hydrogen). Copyright © 2016 Elsevier Ltd. All rights reserved.

First report on the structural exploration and prediction of new BPTES analogs as glutaminase inhibitors

NASA Astrophysics Data System (ADS)

Amin, Sk. Abdul; Adhikari, Nilanjan; Gayen, Shovanlal; Jha, Tarun

2017-09-01

Glutaminase is one of the important key enzymes regulating cellular metabolism, growth, and proliferation in cancer. Therefore, it is being explored as a crucial target regarding anticancer drug design and development. However, none of the potent and selective glutaminase inhibitors is available in the market though two prototype glutaminase inhibitors are reported namely DON as well as BPTES. Due to severe toxicity in clinical trials, the use of DON is restricted. However, BPTES is an allosteric glutaminase inhibitor with less toxic profile and, therefore, lead optimization of BPTES may be a good option to develop newer drug candidates. In this study, a multi-QSAR modeling is carried out on a series of BPTES analogs. A significant connection between different descriptors and the glutaminase inhibitory activities is noticed by employing multiple linear regression, artificial neural network and support vector machine techniques. The classification-based QSAR such as linear discriminant analysis and Bayesian classification modeling are also performed to search important molecular fingerprints or substructures that may help in classifying the probability of finding 'active' and 'inactive' BPTES analogs. Moreover, HQSAR and Topomer CoMFA analyses are also performed. In addition, the SAR observations are interpreted with all these validated computational models along with the structure-based contours. Finally, new twenty two compounds are designed and predicted for their probable glutaminase inhibitory activity.

Exploring the structure determinants of pyrazinone derivatives as PDE5 3HC8 inhibitors: an in silico analysis.

PubMed

Li, Yan; Wu, Wenzhao; Ren, Hong; Wang, Jinghui; Zhang, Shuwei; Li, Guohui; Yang, Ling

2012-09-01

Phosphodiesterase type 5 (PDE5) inhibitors are clinically indicated for the treatment of erectile dysfunction, pulmonary hypertension and various other diseases. In this work, both ligand- and receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 122 pyrazinone derivatives as PDE inhibitors. The resultant optimum 3D-QSAR model exhibits a proper predictive ability as indicated by the statistical results of Q² of 0.584, R(ncv)² of 0.884 and R(pre)² of 0.817, respectively. In addition, docking analysis and molecular dynamics (MD) simulation were also applied to elucidate the probable binding modes of these inhibitors. Our main findings are: (1) Introduction of bulky, electropositive and hydrophobic substituents at 12- and 19-positions can increase the biological activities. (2) N atom at 8-position is detrimental to the inhibitor activity, and the effect of N atoms at 5- and 6-positions on compound activity is co-determined by both the hydrophobic force and the π-π stacking interaction. (3) Bulky and hydrophilic substitutions are favored at the 27-position of ring D. (4) Electronegative and hydrophilic substitutions around 5- and 6-positions increase the inhibitory activity. (5) Hydrophobic forces and π-π stacking interaction with Phe786 and Phe820 are crucial in determining the binding of pyrazinone derivatives to PDE5. (6) Bulky substitutions around ring C favors selectivity against PDE11, while bulky groups near the 21-position disfavor the selectivity. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate future rational designs of novel PDE5 inhibitors with improved activity and selectivity. Copyright © 2012 Elsevier Inc. All rights reserved.

Metabolic flux analysis of recombinant Pichia pastoris growing on different glycerol/methanol mixtures by iterative fitting of NMR-derived (13)C-labelling data from proteinogenic amino acids.

PubMed

Jordà, Joel; de Jesus, Sérgio S; Peltier, Solenne; Ferrer, Pau; Albiol, Joan

2014-01-25

The yeast Pichia pastoris has emerged as one of the most promising yeast cell factories for the production of heterologous proteins. The readily available genetic tools and the ease of high-cell density cultivations using methanol or glycerol/methanol mixtures are among the key factors for this development. Previous studies have shown that the use of mixed feeds of glycerol and methanol seem to alleviate the metabolic burden derived from protein production, allowing for higher specific and volumetric process productivities. However, initial studies of glycerol/methanol co-metabolism in P. pastoris by classical metabolic flux analyses using (13)C-derived Metabolic Flux Ratio (METAFoR) constraints were hampered by the reduced labelling information obtained when using C3:C1 substrate mixtures in relation to the conventional C6 substrate, that is, glucose. In this study, carbon flux distributions through the central metabolic pathways in glycerol/methanol co-assimilation conditions have been further characterised using biosynthetically directed fractional (13)C labelling. In particular, metabolic flux distributions were obtained under 3 different glycerol/methanol ratios and growth rates by iterative fitting of NMR-derived (13)C-labelling data from proteinogenic amino acids using the software tool (13)CFlux2. Specifically, cells were grown aerobically in chemostat cultures fed with 80:20, 60:40 and 40:60 (w:w) glycerol/methanol mixtures at two dilutions rates (0.05 hour(-1) and 0.16 hour(-1)), allowing to obtain additional data (biomass composition and extracellular fluxes) to complement pre-existing datasets. The performed (13)C-MFA reveals a significant redistribution of carbon fluxes in the central carbon metabolism as a result of the shift in the dilution rate, while the ratio of carbon sources has a lower impact on carbon flux distribution in cells growing at the same dilution rate. At low growth rate, the percentage of methanol directly dissimilated to CO2 ranges between 50% and 70%. At high growth rate the methanol is completely dissimilated to CO2 by the direct pathway, in the two conditions of highest methanol content. Copyright © 2013 Elsevier B.V. All rights reserved.

KSC-08pd1902

NASA Image and Video Library

2008-07-02

CAPE CANAVERAL, Fla. – A United Space Alliance technician (right) hands off a component of the Orion Crew Module mockup to one of the other technicians inside the mockup. The technicians wear motion capture suits. The motion tracking aims to improve efficiency of assembly processes and identify potential ergonomic risks for technicians assembling the mockup, which was created and built at the New York Institute of Technology by a team led by Prof. Peter Voci, MFA Director at the College of Arts and Sciences. The motion tracking aims to improve efficiency of assembly processes and identify potential ergonomic risks for technicians assembling the mockup. The work is being performed in United Space Alliance's Human Engineering Modeling and Performance Lab in the RLV Hangar at NASA's Kennedy Space Center. Part of NASA's Constellation Program, the Orion spacecraft will return humans to the moon and prepare for future voyages to Mars and other destinations in our solar system.

TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma

PubMed Central

Hall, Daniel P.; Cost, Nicholas G.; Hegde, Shailaja; Kellner, Emily; Mikhaylova, Olga; Stratton, Yiwen; Ehmer, Birgit; Abplanalp, William A.; Pandey, Raghav; Biesiada, Jacek; Harteneck, Christian; Plas, David R.; Meller, Jarek; Czyzyk-Krzeska, Maria F.

2014-01-01

Summary Autophagy promotes tumor growth by generating nutrients from the degradation of intracellular structures. Here we establish, using shRNAs, a dominant negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A (LC3A) and MAP1LC3B (LC3B) autophagy. Increased expression of TRPM3 in RCC leads to Ca2+ influx, activation of CAMKK2, AMPK, and ULK1, and phagophore formation. In addition, TRPM3 Ca2+ and Zn2+ fluxes inhibit miR-214 which directly targets LC3A and LC3B. The von Hippel-Lindau tumor suppressor (VHL) represses TRPM3 through miR-204 directly and indirectly through another miR-204 target, Caveolin 1 (CAV1). PMID:25517751

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

He, Lian; Xiu, Yu; Jones, J. Andrew

Microbial fermentation conditions are dynamic, due to transcriptional induction, nutrient consumption, or changes to incubation conditions. In this paper, 13C-metabolic flux analysis was used to characterize two violacein-producing E. coli strains with vastly different productivities, and to profile their metabolic adjustments resulting from external perturbations during fermentation. The two strains were first grown at 37 °C in stage 1, and then the temperature was transitioned to 20 °C in stage 2 for the optimal expression of the violacein synthesis pathway. After induction, violacein production was minimal in stage 3, but accelerated in stage 4 (early production phase) and 5 (latemore » production phase) in the high producing strain, reaching a final concentration of 1.5 mmol/L. On the contrary, ~0.02 mmol/L of violacein was obtained from the low producing strain. To have a snapshot of the temporal metabolic changes in each stage, we performed 13C-MFA via isotopomer analysis of fast-turnover free metabolites. The results indicate strikingly stable flux ratios in the central metabolism throughout the early growth stages. In the late stages, however, the high producer rewired its flux distribution significantly, which featured an upregulated pentose phosphate pathway and TCA cycle, reflux from acetate utilization, negligible anabolic fluxes, and elevated maintenance loss, to compensate for nutrient depletion and drainage of some building blocks due to violacein overproduction. The low producer with stronger promoters shifted its relative fluxes in stage 5 by enhancing the flux through the TCA cycle and acetate overflow, while exhibiting a reduced biomass growth and a minimal flux towards violacein synthesis. Finally, interestingly, the addition of the violacein precursor (tryptophan) in the medium inhibited high producer but enhanced low producer's productivity, leading to hypotheses of unknown pathway regulations (such as metabolite channeling).« less

Assessing compartmentalized flux in lipid metabolism with isotopes

DOE PAGES

Allen, Doug K.

2016-03-18

Metabolism in plants takes place across multiple cell types and within distinct organelles. The distributions equate to spatial heterogeneity; though the limited means to experimentally assess metabolism frequently involve homogenizing tissues and mixing metabolites from different locations.Most current isotope investigations of metabolism therefore lack the ability to resolve spatially distinct events. Recognition of this limitation has resulted in inspired efforts to advance metabolic flux analysis and isotopic labeling techniques. Though a number of these efforts have been applied to studies in central metabolism; recent advances in instrumentation and techniques present an untapped opportunity to make similar progress in lipid metabolismmore » where the use of stable isotopes has been more limited. These efforts will benefit from sophisticated radiolabeling reports that continue to enrich our knowledge on lipid biosynthetic pathways and provide some direction for stable isotope experimental design and extension of MFA. Evidence for this assertion is presented through the review of several elegant stable isotope studies and by taking stock of what has been learned from radioisotope investigations when spatial aspects of metabolism were considered. The studies emphasize that glycerolipid production occurs across several locations with assembly of lipids in the ER or plastid, fatty acid biosynthesis occurring in the plastid, and the generation of acetyl-CoA and glycerol-3-phosphate taking place at multiple sites. Considering metabolism in this context underscores the cellular and subcellular organization that is important to enhanced production of glycerolipids in plants. An attempt is made to unify salient features from a number of reports into a diagrammatic model of lipid metabolism and propose where stable isotope labeling experiments and further flux analysis may help address questions in the field.« less

[Cointegration test and variance decomposition for the relationship between economy and environment based on material flow analysis in Tangshan City Hebei China].

PubMed

2015-12-01

The material flow account of Tangshan City was established by material flow analysis (MFA) method to analyze the periodical characteristics of material input and output in the operation of economy-environment system, and the impact of material input and output intensities on economic development. Using econometric model, the long-term interaction mechanism and relationship among the indexes of gross domestic product (GDP) , direct material input (DMI), domestic processed output (DPO) were investigated after unit root hypothesis test, Johansen cointegration test, vector error correction model, impulse response function and variance decomposition. The results showed that during 1992-2011, DMI and DPO both increased, and the growth rate of DMI was higher than that of DPO. The input intensity of DMI increased, while the intensity of DPO fell in volatility. Long-term stable cointegration relationship existed between GDP, DMI and DPO. Their interaction relationship showed a trend from fluctuation to gradual ste adiness. DMI and DPO had strong, positive impacts on economic development in short-term, but the economy-environment system gradually weakened these effects by short-term dynamically adjusting indicators inside and outside of the system. Ultimately, the system showed a long-term equilibrium relationship. The effect of economic scale on economy was gradually increasing. After decomposing the contribution of each index to GDP, it was found that DMI's contribution grew, GDP's contribution declined, DPO's contribution changed little. On the whole, the economic development of Tangshan City has followed the traditional production path of resource-based city, mostly depending on the material input which caused high energy consumption and serous environmental pollution.

Receptor-based 3D QSAR analysis of estrogen receptor ligands - merging the accuracy of receptor-based alignments with the computational efficiency of ligand-based methods

NASA Astrophysics Data System (ADS)

Sippl, Wolfgang

2000-08-01

One of the major challenges in computational approaches to drug design is the accurate prediction of binding affinity of biomolecules. In the present study several prediction methods for a published set of estrogen receptor ligands are investigated and compared. The binding modes of 30 ligands were determined using the docking program AutoDock and were compared with available X-ray structures of estrogen receptor-ligand complexes. On the basis of the docking results an interaction energy-based model, which uses the information of the whole ligand-receptor complex, was generated. Several parameters were modified in order to analyze their influence onto the correlation between binding affinities and calculated ligand-receptor interaction energies. The highest correlation coefficient ( r 2 = 0.617, q 2 LOO = 0.570) was obtained considering protein flexibility during the interaction energy evaluation. The second prediction method uses a combination of receptor-based and 3D quantitative structure-activity relationships (3D QSAR) methods. The ligand alignment obtained from the docking simulations was taken as basis for a comparative field analysis applying the GRID/GOLPE program. Using the interaction field derived with a water probe and applying the smart region definition (SRD) variable selection, a significant and robust model was obtained ( r 2 = 0.991, q 2 LOO = 0.921). The predictive ability of the established model was further evaluated by using a test set of six additional compounds. The comparison with the generated interaction energy-based model and with a traditional CoMFA model obtained using a ligand-based alignment ( r 2 = 0.951, q 2 LOO = 0.796) indicates that the combination of receptor-based and 3D QSAR methods is able to improve the quality of the underlying model.

Assessing compartmentalized flux in lipid metabolism with isotopes

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

Allen, Doug K.

Metabolism in plants takes place across multiple cell types and within distinct organelles. The distributions equate to spatial heterogeneity; though the limited means to experimentally assess metabolism frequently involve homogenizing tissues and mixing metabolites from different locations.Most current isotope investigations of metabolism therefore lack the ability to resolve spatially distinct events. Recognition of this limitation has resulted in inspired efforts to advance metabolic flux analysis and isotopic labeling techniques. Though a number of these efforts have been applied to studies in central metabolism; recent advances in instrumentation and techniques present an untapped opportunity to make similar progress in lipid metabolismmore » where the use of stable isotopes has been more limited. These efforts will benefit from sophisticated radiolabeling reports that continue to enrich our knowledge on lipid biosynthetic pathways and provide some direction for stable isotope experimental design and extension of MFA. Evidence for this assertion is presented through the review of several elegant stable isotope studies and by taking stock of what has been learned from radioisotope investigations when spatial aspects of metabolism were considered. The studies emphasize that glycerolipid production occurs across several locations with assembly of lipids in the ER or plastid, fatty acid biosynthesis occurring in the plastid, and the generation of acetyl-CoA and glycerol-3-phosphate taking place at multiple sites. Considering metabolism in this context underscores the cellular and subcellular organization that is important to enhanced production of glycerolipids in plants. An attempt is made to unify salient features from a number of reports into a diagrammatic model of lipid metabolism and propose where stable isotope labeling experiments and further flux analysis may help address questions in the field.« less

3D-QSAR and Molecular Docking Studies on Derivatives of MK-0457, GSK1070916 and SNS-314 as Inhibitors against Aurora B Kinase

PubMed Central

Zhang, Baidong; Li, Yan; Zhang, Huixiao; Ai, Chunzhi

2010-01-01

Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of Aurora B inhibitors based on three different series of derivatives of 108 molecules. The resultant optimum 3D-QSAR models exhibited (q2 = 0.605, r2pred = 0.826), (q2 = 0.52, r2pred = 0.798) and (q2 = 0.582, r2pred = 0.971) for MK-0457, GSK1070916 and SNS-314 classes, respectively, and the 3D contour maps generated from these models were analyzed individually. The contour map analysis for the MK-0457 model revealed the relative importance of steric and electrostatic effects for Aurora B inhibition, whereas, the electronegative groups with hydrogen bond donating capacity showed a great impact on the inhibitory activity for the derivatives of GSK1070916. Additionally, the predictive model of the SNS-314 class revealed the great importance of hydrophobic favorable contour, since hydrophobic favorable substituents added to this region bind to a deep and narrow hydrophobic pocket composed of residues that are hydrophobic in nature and thus enhanced the inhibitory activity. Moreover, based on the docking study, a further comparison of the binding modes was accomplished to identify a set of critical residues that play a key role in stabilizing the drug-target interactions. Overall, the high level of consistency between the 3D contour maps and the topographical features of binding sites led to our identification of several key structural requirements for more potency inhibitors. Taken together, the results will serve as a basis for future drug development of inhibitors against Aurora B kinase for various tumors. PMID:21151441

3D-QSAR and molecular docking studies on derivatives of MK-0457, GSK1070916 and SNS-314 as inhibitors against Aurora B kinase.

PubMed

Zhang, Baidong; Li, Yan; Zhang, Huixiao; Ai, Chunzhi

2010-11-02

Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of Aurora B inhibitors based on three different series of derivatives of 108 molecules. The resultant optimum 3D-QSAR models exhibited (q(2) = 0.605, r(2) (pred) = 0.826), (q(2) = 0.52, r(2) (pred) = 0.798) and (q(2) = 0.582, r(2) (pred) = 0.971) for MK-0457, GSK1070916 and SNS-314 classes, respectively, and the 3D contour maps generated from these models were analyzed individually. The contour map analysis for the MK-0457 model revealed the relative importance of steric and electrostatic effects for Aurora B inhibition, whereas, the electronegative groups with hydrogen bond donating capacity showed a great impact on the inhibitory activity for the derivatives of GSK1070916. Additionally, the predictive model of the SNS-314 class revealed the great importance of hydrophobic favorable contour, since hydrophobic favorable substituents added to this region bind to a deep and narrow hydrophobic pocket composed of residues that are hydrophobic in nature and thus enhanced the inhibitory activity. Moreover, based on the docking study, a further comparison of the binding modes was accomplished to identify a set of critical residues that play a key role in stabilizing the drug-target interactions. Overall, the high level of consistency between the 3D contour maps and the topographical features of binding sites led to our identification of several key structural requirements for more potency inhibitors. Taken together, the results will serve as a basis for future drug development of inhibitors against Aurora B kinase for various tumors.

Global flows of critical metals necessary for low-carbon technologies: the case of neodymium, cobalt, and platinum.

PubMed

Nansai, Keisuke; Nakajima, Kenichi; Kagawa, Shigemi; Kondo, Yasushi; Suh, Sangwon; Shigetomi, Yosuke; Oshita, Yuko

2014-01-01

This study, encompassing 231 countries and regions, quantifies the global transfer of three critical metals (neodymium, cobalt, and platinum) considered vital for low-carbon technologies by means of material flow analysis (MFA), using trade data (BACI) and the metal contents of trade commodities, resolving the optimization problem to ensure the material balance of the metals within each country and region. The study shows that in 2005 international trade led to global flows of 18.6 kt of neodymium, 154 kt of cobalt, and 402 t of platinum and identifies the main commodities and top 50 bilateral trade links embodying these metals. To explore the issue of consumption efficiency, the flows were characterized according to the technological level of each country or region and divided into three types: green ("efficient use"), yellow ("moderately efficient use"), and red ("inefficient use"). On this basis, the shares of green, yellow, and red flows in the aggregate global flow of Nd were found to be 1.2%, 98%, and 1.2%, respectively. For Co, the respective figures are 53%, 28%, and 19%, and for Pt 15%, 84%, and 0.87%. Furthermore, a simple indicator focusing on the composition of the three colored flows for each commodity was developed to identify trade commodities that should be prioritized for urgent technical improvement to reduce wasteful use of the metals. Based on the indicator, we discuss logical, strategic identification of the responsibilities and roles of the countries involved in the global flows.

Sulfur flows and biosolids processing: Using Material Flux Analysis (MFA) principles at wastewater treatment plants.

PubMed

Fisher, R M; Alvarez-Gaitan, J P; Stuetz, R M; Moore, S J

2017-08-01

High flows of sulfur through wastewater treatment plants (WWTPs) may cause noxious gaseous emissions, corrosion of infrastructure, inhibit wastewater microbial communities, or contribute to acid rain if the biosolids or biogas is combusted. Yet, sulfur is an important agricultural nutrient and the direct application of biosolids to soils enables its beneficial re-use. Flows of sulfur throughout the biosolids processing of six WWTPs were investigated to identify how they were affected by biosolids processing configurations. The process of tracking sulfur flows through the sites also identified limitations in data availability and quality, highlighting future requirements for tracking substance flows. One site was investigated in more detail showing sulfur speciation throughout the plant and tracking sulfur flows in odour control systems in order to quantify outflows to air, land and ocean sinks. While the majority of sulfur from WWTPs is removed as sulfate in the secondary effluent, the sulfur content of biosolids is valuable as it can be directly returned to soils to combat the potential sulfur deficiencies. Biosolids processing configurations, which focus on maximising solids recovery, through high efficiency separation techniques in primary sedimentation tanks, thickeners and dewatering centrifuges retain more sulfur in the biosolids. However, variations in sulfur loads and concentrations entering the WWTPs affect sulfur recovery in the biosolids, suggesting industrial emitters, and chemical dosing of iron salts are responsible for differences in recovery between sites. Copyright © 2017 Elsevier Ltd. All rights reserved.

Designing the molecular future.

PubMed

Schneider, Gisbert

2012-01-01

Approximately 25 years ago the first computer applications were conceived for the purpose of automated 'de novo' drug design, prominent pioneering tools being ALADDIN, CAVEAT, GENOA, and DYLOMMS. Many of these early concepts were enabled by innovative techniques for ligand-receptor interaction modeling like GRID, MCSS, DOCK, and CoMFA, which still provide the theoretical framework for several more recently developed molecular design algorithms. After a first wave of software tools and groundbreaking applications in the 1990s--expressly GROW, GrowMol, LEGEND, and LUDI representing some of the key players--we are currently witnessing a renewed strong interest in this field. Innovative ideas for both receptor and ligand-based drug design have recently been published. We here provide a personal perspective on the evolution of de novo design, highlighting some of the historic achievements as well as possible future developments of this exciting field of research, which combines multiple scientific disciplines and is, like few other areas in chemistry, subject to continuous enthusiastic discussion and compassionate dispute.

Apheresis in food allergies.

PubMed

Dahdah, Lamia; Leone, Giovanna; Artesani, Mariacristina; Riccardi, Carla; Mazzina, Oscar

2017-06-01

The prevalence of IgE-mediated food allergy and anaphylaxis has risen rapidly in developed countries, and countries with rapid industrialization may follow. Therapies include elimination diets, Oral ImmunoTherapy, and the administration of biologics, but high serum IgE levels may preclude their use. Consequently, decreasing IgE becomes a rational approach and could be obtained by immunoapheresis. The aim of this review is to evaluate the rationale and advantages of immunoapheresis. The majority of the available adsorbers remove aspecifically all classes of immunoglobulins. Recently, IgE-specific adsorbers have been approved. Data on immunoapheresis for the treatment of allergic diseases with pathologically elevated IgE levels are emerging. In atopic dermatitis, this therapy alone seems to be beneficial. IgE-selective apheresis appears to be sufficient to reduce the risk of anaphylaxis in multiple food allergy (MFA) and, when IgE titers are high, to open the way to treatment with Omalizumab. Prospective studies, with well designed protocols, are needed to assess the efficacy, tolerability, and cost-effectiveness of immunoapheresis in the field of food allergy.

Designing the molecular future

NASA Astrophysics Data System (ADS)

Schneider, Gisbert

2012-01-01

Approximately 25 years ago the first computer applications were conceived for the purpose of automated `de novo' drug design, prominent pioneering tools being ALADDIN, CAVEAT, GENOA, and DYLOMMS. Many of these early concepts were enabled by innovative techniques for ligand-receptor interaction modeling like GRID, MCSS, DOCK, and CoMFA, which still provide the theoretical framework for several more recently developed molecular design algorithms. After a first wave of software tools and groundbreaking applications in the 1990s—expressly GROW, GrowMol, LEGEND, and LUDI representing some of the key players—we are currently witnessing a renewed strong interest in this field. Innovative ideas for both receptor and ligand-based drug design have recently been published. We here provide a personal perspective on the evolution of de novo design, highlighting some of the historic achievements as well as possible future developments of this exciting field of research, which combines multiple scientific disciplines and is, like few other areas in chemistry, subject to continuous enthusiastic discussion and compassionate dispute.

Two-Scale 13C Metabolic Flux Analysis for Metabolic Engineering.

PubMed

Ando, David; Garcia Martin, Hector

2018-01-01

Accelerating the Design-Build-Test-Learn (DBTL) cycle in synthetic biology is critical to achieving rapid and facile bioengineering of organisms for the production of, e.g., biofuels and other chemicals. The Learn phase involves using data obtained from the Test phase to inform the next Design phase. As part of the Learn phase, mathematical models of metabolic fluxes give a mechanistic level of comprehension to cellular metabolism, isolating the principle drivers of metabolic behavior from the peripheral ones, and directing future experimental designs and engineering methodologies. Furthermore, the measurement of intracellular metabolic fluxes is specifically noteworthy as providing a rapid and easy-to-understand picture of how carbon and energy flow throughout the cell. Here, we present a detailed guide to performing metabolic flux analysis in the Learn phase of the DBTL cycle, where we show how one can take the isotope labeling data from a 13 C labeling experiment and immediately turn it into a determination of cellular fluxes that points in the direction of genetic engineering strategies that will advance the metabolic engineering process.For our modeling purposes we use the Joint BioEnergy Institute (JBEI) Quantitative Metabolic Modeling (jQMM) library, which provides an open-source, python-based framework for modeling internal metabolic fluxes and making actionable predictions on how to modify cellular metabolism for specific bioengineering goals. It presents a complete toolbox for performing different types of flux analysis such as Flux Balance Analysis, 13 C Metabolic Flux Analysis, and it introduces the capability to use 13 C labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale 13 C Metabolic Flux Analysis (2S- 13 C MFA) [1]. In addition to several other capabilities, the jQMM is also able to predict the effects of knockouts using the MoMA and ROOM methodologies. The use of the jQMM library is illustrated through a step-by-step demonstration, which is also contained in a digital Jupyter Notebook format that enhances reproducibility and provides the capability to be adopted to the user's specific needs. As an open-source software project, users can modify and extend the code base and make improvements at will, providing a base for future modeling efforts.

Transcriptome profiling of radiata pine branches reveals new insights into reaction wood formation with implications in plant gravitropism.

PubMed

Li, Xinguo; Yang, Xiaohui; Wu, Harry X

2013-11-08

Formation of compression (CW) and opposite wood (OW) in branches and bent trunks is an adaptive feature of conifer trees in response to various displacement forces, such as gravity, wind, snow and artificial bending. Several previous studies have characterized tracheids, wood and gene transcription in artificially or naturally bent conifer trunks. These studies have provided molecular basis of reaction wood formation in response to bending forces and gravity stimulus. However, little is known about reaction wood formation and gene transcription in conifer branches under gravity stress. In this study SilviScan® technology was used to characterize tracheid and wood traits in radiate pine (Pinus radiata D. Don) branches and genes differentially transcribed in CW and OW were investigated using cDNA microarrays. CW drastically differed from OW in tracheids and wood traits with increased growth, thicker tracheid walls, larger microfibril angle (MFA), higher density and lower stiffness. However, CW and OW tracheids had similar diameters in either radial or tangential direction. Thus, gravity stress largely influenced wood growth, secondary wall deposition, cellulose microfibril orientation and wood properties, but had little impact on primary wall expansion. Microarray gene transcription revealed about 29% of the xylem transcriptomes were significantly altered in CW and OW sampled in both spring and autumn, providing molecular evidence for the drastic variation in tracheid and wood traits. Genes involved in cell division, cellulose biosynthesis, lignin deposition, and microtubules were mostly up-regulated in CW, conferring its greater growth, thicker tracheid walls, higher density, larger MFA and lower stiffness. However, genes with roles in cell expansion and primary wall formation were differentially transcribed in CW and OW, respectively, implicating their similar diameters of tracheid walls and different tracheid lengths. Interestingly, many genes related to hormone and calcium signalling as well as various environmental stresses were exclusively up-regulated in CW, providing important clues for earlier molecular signatures of reaction wood formation under gravity stimulus. The first comprehensive investigation of tracheid characteristics, wood properties and gene transcription in branches of a conifer species revealed more accurate and new insights into reaction wood formation in response to gravity stress. The identified differentially transcribed genes with diverse functions conferred or implicated drastic CW and OW variation observed in radiata pine branches. These genes are excellent candidates for further researches on the molecular mechanisms of reaction wood formation with a view to plant gravitropism.

Predicting Monoamine Oxidase Inhibitory Activity through Ligand-Based Models

PubMed Central

Vilar, Santiago; Ferino, Giulio; Quezada, Elias; Santana, Lourdes; Friedman, Carol

2013-01-01

The evolution of bio- and cheminformatics associated with the development of specialized software and increasing computer power has produced a great interest in theoretical in silico methods applied in drug rational design. These techniques apply the concept that “similar molecules have similar biological properties” that has been exploited in Medicinal Chemistry for years to design new molecules with desirable pharmacological profiles. Ligand-based methods are not dependent on receptor structural data and take into account two and three-dimensional molecular properties to assess similarity of new compounds in regards to the set of molecules with the biological property under study. Depending on the complexity of the calculation, there are different types of ligand-based methods, such as QSAR (Quantitative Structure-Activity Relationship) with 2D and 3D descriptors, CoMFA (Comparative Molecular Field Analysis) or pharmacophoric approaches. This work provides a description of a series of ligand-based models applied in the prediction of the inhibitory activity of monoamine oxidase (MAO) enzymes. The controlled regulation of the enzymes’ function through the use of MAO inhibitors is used as a treatment in many psychiatric and neurological disorders, such as depression, anxiety, Alzheimer’s and Parkinson’s disease. For this reason, multiple scaffolds, such as substituted coumarins, indolylmethylamine or pyridazine derivatives were synthesized and assayed toward MAO-A and MAO-B inhibition. Our intention is to focus on the description of ligand-based models to provide new insights in the relationship between the MAO inhibitory activity and the molecular structure of the different inhibitors, and further study enzyme selectivity and possible mechanisms of action. PMID:23231398