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Sample records for dna model compounds

  1. Experimental and computer graphics simulation analyses of the DNA interaction of 1,8-bis-(2-diethylaminoethylamino)-anthracene-9,10-dione, a compound modelled on doxorubicin.

    PubMed

    Islam, S A; Neidle, S; Gandecha, B M; Brown, J R

    1983-09-15

    The crystal structure of the anthraquinone derivative 1,8-bis-(2-diethylaminoethylamino)-anthracene-9,10-dione has been established. This compound was prepared as a potential DNA-intercalating agent based on the proven intercalators doxorubicin and mitoxantrone. Its DNA-binding properties have been examined experimentally by spectroscopic, thermal denaturation and ccc-DNA unwinding techniques: the results are consistent with an intercalative mode of binding to DNA. Computer graphics stimulation of the intercalative docking of this compound into the self-complementary dimer of d(CpG) has provided a minimum energy geometrical arrangement for the bound drug in the intercalation site comparable to that for proflavine when intercalated into the same d(CpG) model system. Entry of the compound into the site can only occur via the major groove.

  2. XAFS Model Compound Library

    DOE Data Explorer

    Newville, Matthew

    The XAFS Model Compound Library contains XAFS data on model compounds. The term "model" compounds refers to compounds of homogeneous and well-known crystallographic or molecular structure. Each data file in this library has an associated atoms.inp file that can be converted to a feff.inp file using the program ATOMS. (See the related Searchable Atoms.inp Archive at http://cars9.uchicago.edu/~newville/adb/) This Library exists because XAFS data on model compounds is useful for several reasons, including comparing to unknown data for "fingerprinting" and testing calculations and analysis methods. The collection here is currently limited, but is growing. The focus to date has been on inorganic compounds and minerals of interest to the geochemical community. [Copied, with editing, from http://cars9.uchicago.edu/~newville/ModelLib/

  3. Modeling DNA Replication.

    ERIC Educational Resources Information Center

    Bennett, Joan

    1998-01-01

    Recommends the use of a model of DNA made out of Velcro to help students visualize the steps of DNA replication. Includes a materials list, construction directions, and details of the demonstration using the model parts. (DDR)

  4. Modeling DNA Replication Intermediates

    SciTech Connect

    Broyde, S.; Roy, D.; Shapiro, R.

    1997-06-01

    While there is now available a great deal of information on double stranded DNA from X-ray crystallography, high resolution NMR and computer modeling, very little is known about structures that are representative of the DNA core of replication intermediates. DNA replication occurs at a single strand/double strand junction and bulged out intermediates near the junction can lead to frameshift mutations. The single stranded domains are particularly challenging. Our interest is focused on strategies for modeling the DNA of these types of replication intermediates. Modeling such structures presents special problems in addressing the multiple minimum problem and in treating the electrostatic component of the force field. We are testing a number of search strategies for locating low energy structures of these types and we are also investigating two different distance dependent dielectric functions in the coulombic term of the force field. We are studying both unmodified DNA and DNA damaged by aromatic amines, carcinogens present in the environment in tobacco smoke, barbecued meats and automobile exhaust. The nature of the structure adopted by the carcinogen modified DNA at the replication fork plays a key role in determining whether the carcinogen will cause a mutation during replication that can initiate the carcinogenic process. In the present work results are presented for unmodified DNA.

  5. Preventing metal-mediated oxidative DNA damage with selenium compounds.

    PubMed

    Battin, Erin E; Zimmerman, Matthew T; Ramoutar, Ria R; Quarles, Carolyn E; Brumaghim, Julia L

    2011-05-01

    Copper and iron are two widely studied transition metals associated with hydroxyl radical (˙OH) generation, oxidative damage, and disease development. Because antioxidants ameliorate metal-mediated DNA damage, DNA gel electrophoresis assays were used to quantify the ability of ten selenium-containing compounds to inhibit metal-mediated DNA damage by hydroxyl radical. In the Cu(I)/H(2)O(2) system, selenocystine, selenomethionine, and methyl-selenocysteine inhibit DNA damage with IC(50) values ranging from 3.34 to 25.1 μM. Four selenium compounds also prevent DNA damage from Fe(II) and H(2)O(2). Additional gel electrophoresis experiments indicate that Cu(I) or Fe(II) coordination is responsible for the selenium antioxidant activity. Mass spectrometry studies show that a 1 : 1 stoichiometry is the most common for iron and copper complexes of the tested compounds, even if no antioxidant activity is observed, suggesting that metal coordination is necessary but not sufficient for selenium antioxidant activity. A majority of the selenium compounds are electroactive, regardless of antioxidant activity, and the glutathione peroxidase activities of the selenium compounds show no correlation to DNA damage inhibition. Thus, metal binding is a primary mechanism of selenium antioxidant activity, and both the chemical functionality of the selenium compound and the metal ion generating damaging hydroxyl radical significantly affect selenium antioxidant behavior. PMID:21286651

  6. DNA nanostructures based biosensor for the determination of aromatic compounds.

    PubMed

    Gayathri, S Baby; Kamaraj, P; Arthanareeswari, M; Devikala, S

    2015-10-15

    Graphite electrode was modified using multi-walled carbon nanotubes (MWCNT), chitosan (CS), glutaraldehyde (GTA) and DNA nanostructures (nsDNA). DNA nanostructures of 50 nm in size were produced from single DNA template sequence using a simple two step procedure and were confirmed using TEM and AFM analysis. The modified electrode was applied to the electrochemical detection of aromatic compounds using EIS. The modified electrode was characterized using differential pulse voltammetry (DPV), electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). For comparison, electrochemical results derived from single stranded (50 bp length) and double stranded (50 bp length) DNA based biosensors were used. The results indicate that the modified electrode prior to nsDNA immobilization provides a viable platform that effectively promotes electron transfer between nsDNA and the electrode. The mode of binding between the nsDNA and aromatic compounds was investigated using EIS, indicating that the dominant interaction is non-covalent. nsDNA based biosensor was observed to act as an efficient biosensor in selective and sensitive identification of aromatic compounds.

  7. Polyimidazopyrrolone model compounds.

    NASA Technical Reports Server (NTRS)

    Young, P. R.

    1972-01-01

    The model reactions between phthalic anhydride and o-phenylenediamine were studied under conditions analogous to the polymerization and post-cyclization of dianhydrides with bis(o-diamines) to form polyimidazopyrrolones (Pyrrones). The route from the initial amide-acid-amine to the tetracyclic Pyrrone model when the reactions are conducted in aprotic solvents is highly competitive between isolatable benzimidazole-acid and imide-amine intermediates. Solid-state thermal conversion of the amide-acid-amine affords a unique dimeric species containing amide, imide, and benzimidazole functions. It was confirmed that melt techniques lead to disproportionation products. The application of these findings to related polymer synthesis is discussed.

  8. Polyimidazopyrrolone model compounds.

    NASA Technical Reports Server (NTRS)

    Young, P. R.

    1972-01-01

    Study of model reactions between phthalic anhydride and o-phenylenediamine under conditions analogous to the polymerization and post cyclization of dianhydrides with bis(o-diamines) to form polyimidazopyrrolones (Pyrrones). Solid-state thermal conversion of the amide-acid-amine affords a unique dimeric species containing amide, imide, and benzimidazole functions. It was confirmed that melt techniques lead to disproportionation products. The application of these findings to related polymer syntheses is discussed.

  9. DNA Biosensor for Rapid Detection of Genotoxic Compounds in Soil Samples

    PubMed Central

    Bagni, Graziana; Hernandez, Silvia; Mascini, Marco; Sturchio, Elena; Boccia, Priscilla; Marconi, Simona

    2005-01-01

    An electrochemical DNA-based biosensor is proposed as a fast and easy screening method for the detection of genotoxic compounds in soil samples. The biosensor was assembled by immobilising double stranded Calf thymus DNA on screen-printed electrodes. The interactions between DNA and environmental pollutants can cause variations of the electrochemical proprieties of DNA when they cause a DNA damage. Preliminary studies were performed using benzene, naphthalene and anthracene derivatives as model compounds. The effect of these compounds on the surface-confined DNA was found to be linearly related to their concentration in solution. On the other hand, the objective was to optimise the ultrasonic extraction conditions of these compounds from artificially spiked soil samples. Then, the applicability of such a biosensor was evaluated by analysing soil samples from an Italian region with ecological risk (ACNA of Cengio, SV). DNA biosensor for qualitative analysis of soil presented a good correlation with a semi-quantitative method for aromatic ring systems determination as fixed wavelength fluorescence and interestingly, according results were found also with other bioassays. This kind of biosensors represent a new, easy and fast way of analysis of polluted sites, therefore they can be used as early warnings devices in areas with ecological risk as in situ measurement.

  10. Statistical Modelling of Compound Floods

    NASA Astrophysics Data System (ADS)

    Bevacqua, Emanuele; Maraun, Douglas; Vrac, Mathieu; Widmann, Martin; Manning, Colin

    2016-04-01

    In the recent special report of the Intergovernmental Panel on Climate Change (IPCC) on extreme events it has been highlighted that an important class of extreme events has received little attention so far: so-called compound events (CEs) (Seneviratne et al., 2012). Compound events (CEs) are multivariate extreme events in which the individual contributing events might not be extreme themselves, but their joint occurrence causes an extreme impact. Following Leonard et al., 2013, we define events as CEs only when the contributing events are statistically dependent. For many events analysed so far, the contributing events have not been statistically dependent (e.g. the floods in Rotterdam, Van den Brink et al., 2005). Two typical examples of CEs are severe drought in conjunction with a heatwave, and storm surges coinciding with heavy rain that cause the so-called Compound Floods in the lower section of a river. We develop a multivariate statistical model to represent and analyse the physical mechanisms driving CEs, and to quantify the risk associated with these events. The model is based on pair-copula construction theory, which has the advantage of building joint probability distributions modeling the marginal distributions separately from the dependence structure among variables. This allows to analyse the individual contributing variables underlying the CE separately to their dependence structure. Here is presented an application of the statistical model for Compound Floods, based on a conceptual case study. For these particular events it is not trivial to find satisfying data. Usually, water level stations are not present in the area of the river where both the influence of the sea and river are seen. The main reason being that this critical area is small and stakeholders have little interest in measuring both effect from the sea and from the river. For these reasons we have developed a conceptual case study which allows us to vary the system's physical parameters

  11. Multiscale modelling of DNA mechanics

    NASA Astrophysics Data System (ADS)

    Dršata, Tomáš; Lankaš, Filip

    2015-08-01

    Mechanical properties of DNA are important not only in a wide range of biological processes but also in the emerging field of DNA nanotechnology. We review some of the recent developments in modeling these properties, emphasizing the multiscale nature of the problem. Modern atomic resolution, explicit solvent molecular dynamics simulations have contributed to our understanding of DNA fine structure and conformational polymorphism. These simulations may serve as data sources to parameterize rigid base models which themselves have undergone major development. A consistent buildup of larger entities involving multiple rigid bases enables us to describe DNA at more global scales. Free energy methods to impose large strains on DNA, as well as bead models and other approaches, are also briefly discussed.

  12. Compound Poisson Processes and Clustered Damage of Radiation Induced DNA Double Strand Breaks

    NASA Astrophysics Data System (ADS)

    Gudowska-Nowak, E.; Ritter, S.; Taucher-Scholz, G.; Kraft, G.

    2000-05-01

    Recent experimental data have demonstrated that DNA damage induced by densely ionizing radiation in mammalian cells is distributed along the DNA molecule in the form of clusters. The principal constituent of DNA damage are double-strand breaks (DSB) which are formed when the breaks occur in both DNA strands and are directly opposite or separated by only a few base pairs. DSBs are believed to be most important lesions produced in chromosomes by radiation; interaction between DSBs can lead to cell killing, mutation or carcinogenesis. The paper discusses a model of clustered DSB formation viewed in terms of compound Poisson process along with the predictive essay of the formalism in application to experimental data.

  13. Highly cytotoxic DNA-interacting copper(II) coordination compounds.

    PubMed

    Brissos, Rosa F; Torrents, Ester; dos Santos Mello, Francyelli Mariana; Carvalho Pires, Wanessa; Silveira-Lacerda, Elisângela de Paula; Caballero, Ana B; Caubet, Amparo; Massera, Chiara; Roubeau, Olivier; Teat, Simon J; Gamez, Patrick

    2014-10-01

    Four new Schiff-base ligands have been designed and prepared by condensation reaction between hydrazine derivatives (i.e. 2-hydrazinopyridine or 2-hydrazinoquinoline) and mono- or dialdehyde (3-tert-butyl-2-hydroxybenzaldehyde and 5-tert-butyl-2-hydroxyisophthalaldehyde, respectively). Six copper(II) coordination compounds of various nuclearities have been obtained from these ligands, which are formulated as [Cu(L1)Cl](CH3OH) (1), [Cu(L2)NO3] (2), [Cu2(L3)(ClO4)2(CH3O)(CH3OH)](CH3OH) (3), [Cu2(L4)(ClO4)(OH)(CH3OH)](ClO4) (4), [Cu8(L3)4(NO3)4(OH)5](NO3)3(CH3OH)5(H2O)8 (5) and [Cu3(HL2')4Cl6](CH3OH)6 (6), as revealed by single-crystal X-ray studies. Their DNA-interacting abilities have been investigated using different characterization techniques, which suggest that the metal complexes act as efficient DNA binders. Moreover, cytotoxicity assays with several cancer cell lines show that some of them are very active, as evidenced by the sub-micromolar IC50 values achieved in some cases. PMID:25096758

  14. Highly cytotoxic DNA-interacting copper(II) coordination compounds.

    PubMed

    Brissos, Rosa F; Torrents, Ester; dos Santos Mello, Francyelli Mariana; Carvalho Pires, Wanessa; Silveira-Lacerda, Elisângela de Paula; Caballero, Ana B; Caubet, Amparo; Massera, Chiara; Roubeau, Olivier; Teat, Simon J; Gamez, Patrick

    2014-10-01

    Four new Schiff-base ligands have been designed and prepared by condensation reaction between hydrazine derivatives (i.e. 2-hydrazinopyridine or 2-hydrazinoquinoline) and mono- or dialdehyde (3-tert-butyl-2-hydroxybenzaldehyde and 5-tert-butyl-2-hydroxyisophthalaldehyde, respectively). Six copper(II) coordination compounds of various nuclearities have been obtained from these ligands, which are formulated as [Cu(L1)Cl](CH3OH) (1), [Cu(L2)NO3] (2), [Cu2(L3)(ClO4)2(CH3O)(CH3OH)](CH3OH) (3), [Cu2(L4)(ClO4)(OH)(CH3OH)](ClO4) (4), [Cu8(L3)4(NO3)4(OH)5](NO3)3(CH3OH)5(H2O)8 (5) and [Cu3(HL2')4Cl6](CH3OH)6 (6), as revealed by single-crystal X-ray studies. Their DNA-interacting abilities have been investigated using different characterization techniques, which suggest that the metal complexes act as efficient DNA binders. Moreover, cytotoxicity assays with several cancer cell lines show that some of them are very active, as evidenced by the sub-micromolar IC50 values achieved in some cases.

  15. Use of model compounds in coal chemistry

    SciTech Connect

    Collins, C J

    1980-01-01

    The use of model compounds in coal chemistry has been summarized. Several examples from the literature, and also from work at Oak Ridge National Laboratory have been used to illustrate the main principles involved. The current controversy on the subject of model compounds is believed to stem from a semantic misunderstanding owing to different definitions of what a model compound is. The definition of a model compound from the organic chemist's point of view is that it is a substance which may possess at least one property or structural feature suspected of being present in the sample investigated. The sample may be coal itself, a maceral, a coal-derived material or a hydrogen-donor solvent. It is stressed that a recognition of the structure-reactivity relationship in organic compounds is necessary to avoid false conclusions.

  16. Computed structures of polyimides model compounds

    NASA Technical Reports Server (NTRS)

    Tai, H.; Phillips, D. H.

    1990-01-01

    Using a semi-empirical approach, a computer study was made of 8 model compounds of polyimides. The compounds represent subunits from which NASA Langley Research Center has successfully synthesized polymers for aerospace high performance material application, including one of the most promising, LARC-TPI polymer. Three-dimensional graphic display as well as important molecular structure data pertaining to these 8 compounds are obtained.

  17. [Effect of biologically active compounds of divalent platinum on the properties of the liquid crystal "microphase" of DNA].

    PubMed

    Akimenko, N M; Kleinwächter, V; Evdokimov, Iu M

    1983-07-01

    The optical properties of the "microphases" modeling the state of the DNA molecule in the cell and formed of both the low molecular DNA and the DNA complexes with cis- and trans-isomers of dichlorodiamine platininum (II) were studied. It was shown that the intensive band characteristic of the circular dichroism spectrum of the initial DNA "microphase" was decreasing with binding of DNA to cis-Pt (II) or trans-Pt (II). The effect of cis-Pt (II) on the "microphase" optical properties was more significant than that of trans-Pt (II). The effect correlated with the biological activity of the cis- and trans-compounds of platinum. Possible causes of the decrease in the optical activity of the DNA "microphase" are discussed.

  18. BINDING OF CARCINOGENS TO DNA AND COVALENT ADDUCTS DNA DAMAGE - PAH, AROMATIC AMINES, NITRO-AROMATIC COMPOUNDS, AND HALOGENATED COMPOUNDS

    EPA Science Inventory

    DNA adducts are the covalent addition products resulting from binding of reactive chemical species to DNA bases. The cancer initiating role of DNA adducts is well-established, and is clearly reflected in the high cancer incidence observed in individuals with deficiencies in any o...

  19. Compound leaf development in model plant species.

    PubMed

    Bar, Maya; Ori, Naomi

    2015-02-01

    Plant leaves develop in accordance with a common basic program, which is flexibly adjusted to the species, developmental stage and environment. Two key stages of leaf development are morphogenesis and differentiation. In the case of compound leaves, the morphogenesis stage is prolonged as compared to simple leaves, allowing for the initiation of leaflets. Here, we review recent advances in the understanding of how plant hormones and transcriptional regulators modulate compound leaf development, yielding a substantial diversity of leaf forms, focusing on four model compound leaf organisms: cardamine (Cardamine hirsuta), tomato (Solanum lycopersicum), medicago (Medicago truncatula) and pea (Pisum sativum).

  20. Towards modeling DNA sequences as automata

    NASA Astrophysics Data System (ADS)

    Burks, Christian; Farmer, Doyne

    1984-01-01

    We seek to describe a starting point for modeling the evolution and role of DNA sequences within the framework of cellular automata by discussing the current understanding of genetic information storage in DNA sequences. This includes alternately viewing the role of DNA in living organisms as a simple scheme and as a complex scheme; a brief review of strategies for identifying and classifying patterns in DNA sequences; and finally, notes towards establishing DNA-like automata models, including a discussion of the extent of experimentally determined DNA sequence data present in the database at Los Alamos.

  1. A novel carbohydrate derived compound FCP5 causes DNA strand breaks and oxidative modifications of DNA bases in cancer cells.

    PubMed

    Czubatka, Anna; Sarnik, Joanna; Lucent, Del; Blasiak, Janusz; Witczak, Zbigniew J; Poplawski, Tomasz

    2015-02-01

    1,5-Anhydro-6-deoxy-methane-sulfamido-D-glucitol (FCP5) is a functionalized carbohydrate containing functional groups that render it potentially therapeutically useful. According to our concept of 'functional carb-pharmacophores' (FCPs) incorporation of the methanesulfonamido pharmacophore to 1,5 glucitol could create a therapeutically useful compound. Our previous studies revealed that FCP5 was cytotoxic to cancer cells. Therefore, in this work we assessed the cytotoxic mechanisms of FCP5 in four cancer cell lines - HeLa, LoVo, A549 and MCF-7, with particular focus on DNA damage and repair. A broad spectrum of methods, including comet assay with modifications, DNA repair enzyme assay, plasmid relaxation assay, and DNA fragmentation assay, were used. We also checked the potential for FCP5 to induce apoptosis. The results show that FCP5 can induce DNA strand breaks as well as oxidative modifications of DNA bases. DNA lesions induced by FCP5 were not entirely repaired in HeLa cells and DNA repair kinetics differs from other cell lines. Results from molecular docking and plasmid relaxation assay suggest that FCP5 binds to the major groove of DNA with a preference for adenosine-thymine base pair sequences and directly induces DNA strand breaks. Thus, FCP5 may represent a novel lead for the design of new major groove-binding compounds. The results also confirmed the validity of functional carb-pharmacophores as a new source of innovative drugs. PMID:25557509

  2. Structural Studies of the HIV-1 Integrase Protein: Compound Screening and Characterization of a DNA-Binding Inhibitor

    PubMed Central

    Hassounah, Said; Mesplède, Thibault; Wainberg, Mark A.

    2015-01-01

    Understanding the HIV integrase protein and mechanisms of resistance to HIV integrase inhibitors is complicated by the lack of a full length HIV integrase crystal structure. Moreover, a lentiviral integrase structure with co-crystallised DNA has not been described. For these reasons, we have developed a structural method that utilizes free software to create quaternary HIV integrase homology models, based partially on available full-length prototype foamy virus integrase structures as well as several structures of truncated HIV integrase. We have tested the utility of these models in screening of small anti-integrase compounds using randomly selected molecules from the ZINC database as well as a well characterized IN:DNA binding inhibitor, FZ41, and a putative IN:DNA binding inhibitor, HDS1. Docking studies showed that the ZINC compounds that had the best binding energies bound at the IN:IN dimer interface and that the FZ41 and HDS1 compounds docked at approximately the same location in integrase, i.e. behind the DNA binding domain, although there is some overlap with the IN:IN dimer interface to which the ZINC compounds bind. Thus, we have revealed two possible locations in integrase that could potentially be targeted by allosteric integrase inhibitors, that are distinct from the binding sites of other allosteric molecules such as LEDGF inhibitors. Virological and biochemical studies confirmed that HDS1 and FZ41 share a similar activity profile and that both can inhibit each of integrase and reverse transcriptase activities. The inhibitory mechanism of HDS1 for HIV integrase seems to be at the DNA binding step and not at either of the strand transfer or 3' processing steps of the integrase reaction. Furthermore, HDS1 does not directly interact with DNA. The modeling and docking methodology described here will be useful for future screening of integrase inhibitors as well as for the generation of models for the study of integrase drug resistance. PMID:26046987

  3. Natural Compounds: DNA Methyltransferase Inhibitors in Oral Squamous Cell Carcinoma.

    PubMed

    Jha, Meenakshi; Aggarwal, Ruchi; Jha, Abhimanyu Kumar; Shrivastava, Anju

    2015-10-01

    Oral squamous cell carcinoma (OSCC) is a multistep process which is modulated by several endogenous and environmental factors. Epigenetic changes have been found to be equally responsible for OSCC as genetic changes. A plethora of genes showing hypermethylation have been discovered in OSCC. Since these changes are reversible, a lot of emphasis is on using the natural compounds for their ability to cause demethylation which could lead to reactivation of the inactivated tumor suppressor genes. This review encompasses the promoter hypermethylation of tumor suppressor genes in OSCC and its possible reversal using natural compounds. In addition, new compounds which could be screened for their demethylating ability have also been proposed. PMID:26210787

  4. Model compound vulcanization studied by XANES

    NASA Astrophysics Data System (ADS)

    Taweepreda, W.; Nu-Mard, R.; Pattanasiriwisawa, W.; Songsiriritthigul, P.

    2009-11-01

    Squalene has been used as a model compound for the investigation of sulphur crosslink in the vulcanization process. The effects of the accelerator on the crosslink were deduced from the sulfur K-edge absorption spectra. The majority of the crosslinks for the squalene vulcanized with ZDEC or TMTD is likely disulfidic, while that vulcanized with CBS or MBTS is monosulfidic.

  5. Structure elucidation and DNA binding specificity of natural compounds from Cassia siamea leaves: A biophysical approach.

    PubMed

    Parveen, Mehtab; Ahmad, Faheem; Malla, Ali Mohammed; Khan, Mohd Sohrab; Rehman, Sayeed Ur; Tabish, Mohammad; Silva, Manuela Ramos; Silva, P S Pereira

    2016-06-01

    A novel isoflavone, 5,6,7-trimethoxy-3-(3',4',5'-trimethoxyphenyl)-4H-chromen-4-one (1) along with a known pyranocoumarin, Seselin (2) have been isolated from the ethanolic extract of the leaves of Cassia siamea (Family: Fabaceae). Compound 1 has been reported for the first time from any natural source and has not been synthesized so far. Their structures were elucidated on the basis of chemical and physical evidences viz. elemental analysis, UV, FT-IR, (1)H-NMR, (13)C-NMR and mass spectral analysis. Structure of compound (1) was further authenticated by single-crystal X-ray analysis and density functional theory (DFT) calculations. A multi-technique approach employing UV-Visible spectroscopy, fluorescence, KI quenching studies, competitive displacement assay, circular dichroism and viscosity studies have been utilized to probe the extent of interaction and possible binding modes of isolated compounds (1-2) with calf thymus DNA (CT-DNA). Both the compounds were found to interact with DNA via non-intercalative binding mode with moderate proficiencies. Groove binding was the major interaction mode in the case of compound 2 while compound 1 probably interacts with DNA through electrostatic interactions. These studies provide deeper insight in understanding of DNA-drug (natural products) interaction which could be helpful to improve their bioavailability for therapeutic purposes. PMID:27085054

  6. Quantitative risk modelling for new pharmaceutical compounds.

    PubMed

    Tang, Zhengru; Taylor, Mark J; Lisboa, Paulo; Dyas, Mark

    2005-11-15

    The process of discovering and developing new drugs is long, costly and risk-laden. Faced with a wealth of newly discovered compounds, industrial scientists need to target resources carefully to discern the key attributes of a drug candidate and to make informed decisions. Here, we describe a quantitative approach to modelling the risk associated with drug development as a tool for scenario analysis concerning the probability of success of a compound as a potential pharmaceutical agent. We bring together the three strands of manufacture, clinical effectiveness and financial returns. This approach involves the application of a Bayesian Network. A simulation model is demonstrated with an implementation in MS Excel using the modelling engine Crystal Ball. PMID:16257374

  7. DNA denaturation in the rodlike polyelectrolyte model

    NASA Astrophysics Data System (ADS)

    Passos, C. B.; Kuhn, P. S.; Barbosa, M. C.

    2014-11-01

    The denaturation of the DNA is analyzed using an analytic model. The DNA molecules are described in the Primitive Model of Polyelectrolytes (PMP), where the polyelectrolyte molecules are cylinders with charged sites. We show that the DNA stabilization arises as the result of the competition between the electrostatic repulsion of the phosphate groups and the attractive forces of the H-bonds. We also show that the addition of salt in the system screens the electrostatic interactions and favors the double strand configuration.

  8. An Organometallic Compound which Exhibits a DNA Topology-Dependent One-Stranded Intercalation Mode.

    PubMed

    Ma, Zhujun; Palermo, Giulia; Adhireksan, Zenita; Murray, Benjamin S; von Erlach, Thibaud; Dyson, Paul J; Rothlisberger, Ursula; Davey, Curt A

    2016-06-20

    Understanding how small molecules interact with DNA is essential since it underlies a multitude of pathological conditions and therapeutic interventions. Many different intercalator compounds have been studied because of their activity as mutagens or drugs, but little is known regarding their interaction with nucleosomes, the protein-packaged form of DNA in cells. Here, using crystallographic methods and molecular dynamics simulations, we discovered that adducts formed by [(η(6) -THA)Ru(ethylenediamine)Cl][PF6 ] (THA=5,8,9,10-tetrahydroanthracene; RAED-THA-Cl[PF6 ]) in the nucleosome comprise a novel one-stranded intercalation and DNA distortion mode. Conversely, the THA group in fact remains solvent exposed and does not disrupt base stacking in RAED-THA adducts on B-form DNA. This newly observed DNA binding mode and topology dependence may actually be prevalent and should be considered when studying covalently binding intercalating compounds. PMID:27184539

  9. First paraben substituted cyclotetraphosphazene compounds and DNA interaction analysis with a new automated biosensor.

    PubMed

    Çiftçi, Gönül Yenilmez; Şenkuytu, Elif; İncir, Saadet Elif; Yuksel, Fatma; Ölçer, Zehra; Yıldırım, Tuba; Kılıç, Adem; Uludağ, Yıldız

    2016-06-15

    Cancer, as one of the leading causes of death in the world, is caused by malignant cell division and growth that depends on rapid DNA replication. To develop anti-cancer drugs this feature of cancer could be exploited by utilizing DNA-damaging molecules. To achieve this, the paraben substituted cyclotetraphosphazene compounds have been synthesized for the first time and their effect on DNA (genotoxicity) has been investigated. The conventional genotoxicity testing methods are laborious, take time and are expensive. Biosensor based assays provide an alternative to investigate this drug/compound DNA interactions. Here for the first time, a new, easy and rapid screening method has been used to investigate the DNA damage, which is based on an automated biosensor device that relies on the real-time electrochemical profiling (REP™) technology. Using both the biosensor based screening method and the in vitro biological assay, the compounds 9 and 11 (propyl and benzyl substituted cyclotetraphosphazene compounds, respectively), have resulted in higher DNA damage than the others with 65% and 80% activity reduction, respectively. PMID:26852202

  10. Polyphenolic compounds from Salvia species protect cellular DNA from oxidation and stimulate DNA repair in cultured human cells.

    PubMed

    Ramos, Alice A; Azqueta, Amaya; Pereira-Wilson, Cristina; Collins, Andrew R

    2010-06-23

    DNA damage can lead to carcinogenesis if replication proceeds without proper repair. This study evaluated the effects of the water extracts of three Salvia sp., Salvia officinalis (SO), Salvia fruticosa (SF), and Salvia lavandulifolia (SL), and of the major phenolic constituents, rosmarinic acid (RA) and luteolin-7-glucoside (L-7-G), on DNA protection in Caco-2 and HeLa cells exposed to oxidative agents and on DNA repair in Caco-2 cells. The comet assay was used to measure DNA damage and repair capacity. The final concentration of each sage extract was 50 microg/mL, and concentrations of RA and L-7-G were 50 and 20 microM, respectively. After a short incubation (2 h), L-7-G protected DNA in Caco-2 cells from damage induced by H(2)O(2) (75 microM); also, after a long incubation (24 h), SF, RA, and L-7-G had protective effects in Caco-2 cells. In HeLa cells, SO, SF, and RA protected against damage induced by H(2)O(2) after 24 h of incubation. Assays of DNA repair show that SO, SF, and L-7-G increased the rate of DNA repair (rejoining of strand breaks) in Caco-2 cells treated with H(2)O(2). The incision activity of a Caco-2 cell extract on a DNA substrate containing specific damage (8-oxoGua) was also measured to evaluate effects on base excision repair (BER) activity. Preincubation for 24 h with SO and L-7-G had a BER inductive effect, increasing incision activity in Caco-2 cells. In conclusion, SO, SF, and the isolated compounds (RA and L-7-G) demonstrated chemopreventive activity by protecting cells against oxidative DNA damage and stimulating DNA repair (SO, SF, and L-7-G).

  11. Polyphenolic compounds from Salvia species protect cellular DNA from oxidation and stimulate DNA repair in cultured human cells.

    PubMed

    Ramos, Alice A; Azqueta, Amaya; Pereira-Wilson, Cristina; Collins, Andrew R

    2010-06-23

    DNA damage can lead to carcinogenesis if replication proceeds without proper repair. This study evaluated the effects of the water extracts of three Salvia sp., Salvia officinalis (SO), Salvia fruticosa (SF), and Salvia lavandulifolia (SL), and of the major phenolic constituents, rosmarinic acid (RA) and luteolin-7-glucoside (L-7-G), on DNA protection in Caco-2 and HeLa cells exposed to oxidative agents and on DNA repair in Caco-2 cells. The comet assay was used to measure DNA damage and repair capacity. The final concentration of each sage extract was 50 microg/mL, and concentrations of RA and L-7-G were 50 and 20 microM, respectively. After a short incubation (2 h), L-7-G protected DNA in Caco-2 cells from damage induced by H(2)O(2) (75 microM); also, after a long incubation (24 h), SF, RA, and L-7-G had protective effects in Caco-2 cells. In HeLa cells, SO, SF, and RA protected against damage induced by H(2)O(2) after 24 h of incubation. Assays of DNA repair show that SO, SF, and L-7-G increased the rate of DNA repair (rejoining of strand breaks) in Caco-2 cells treated with H(2)O(2). The incision activity of a Caco-2 cell extract on a DNA substrate containing specific damage (8-oxoGua) was also measured to evaluate effects on base excision repair (BER) activity. Preincubation for 24 h with SO and L-7-G had a BER inductive effect, increasing incision activity in Caco-2 cells. In conclusion, SO, SF, and the isolated compounds (RA and L-7-G) demonstrated chemopreventive activity by protecting cells against oxidative DNA damage and stimulating DNA repair (SO, SF, and L-7-G). PMID:20486687

  12. Mitochondrial DNA-deficient models and aging.

    PubMed

    Olgun, Abdullah; Akman, Serif

    2007-04-01

    Human mitochondrial DNA (mtDNA) encodes 13 subunits of oxidative phosphorylation (OXPHOS) enzyme complexes I, III, IV, and V except complex II. MtDNA is more sensitive to oxidative damage than nuclear DNA. MtDNA defects are involved in many pathologies including aging. Several mtDNA-deficient cell culture, yeast, and animal models were generated to study the role of mtDNA in many physiological processes. Ethidium bromide (EB), an agent that is known to inhibit mtDNA replication with a negligible effect on nuclear DNA, is generally used to generate mtDNA-deficient models. The antibiotics chloramphenicol and doxycycline, which were known to inhibit mitochondrial translation, were also used to generate the same phenotype. Cultured mtDNA-deficient cells need uridine and pyruvate to survive. At the organismal level, uridine can be supplemented, but pyruvate supplementation can cause a worser phenotype because of lactic acidosis. In C. elegans, EB, when used during larval development, increases life span, but decreases, when used after the beginning of adult stage. This should be kept in mind since mitochondria-related genes are generally detected in genome-wide screening studies for longevity. We believe that conditional knockout studies need to be carried out for these genes after reaching adulthood. MtDNA mutator mouse did not show an increase of free radical production. Therefore, the downstream phenomena to mtDNA defects are likely ineffective pyrimidine synthesis (dihydroorotate dehydrogenase, DHODH, needs a functional respiratory chain) and excess NADH (decreased NAD pool) in addition to free radicals. PMID:17460185

  13. Addressable microfluidic polymer chip for DNA-directed immobilization of oligonucleotide-tagged compounds.

    PubMed

    Schröder, Hendrik; Hoffmann, Linda; Müller, Joachim; Alhorn, Petra; Fleger, Markus; Neyer, Andreas; Niemeyer, Christof M

    2009-07-01

    A microfluidic polymer chip for the self-assembly of DNA conjugates through DNA-directed immobilization is developed. The chip is fabricated from two parts, one of which contains a microfluidic channel produced from poly(dimethylsiloxane) (PDMS) by replica-casting technique using a mold prepared by photolithographic techniques. The microfluidic part is sealed by covalent bonding with a chemically activated glass slide containing a DNA oligonucleotide microarray. The dimension of the PDMS-glass microfluidic chip is equivalent to standard microscope slides (76 x 26 mm(2)). The DNA microarray surface inside the microfluidic channels is configured through conventional spotting, and the resulting DNA patches can be conveniently addressed with compounds containing complementary DNA tags. To demonstrate the utility of the addressable surface within the microfluidic channel, DNA-directed immobilization (DDI) of DNA-modified gold nanoparticles (AuNPs) and DNA-conjugates of the enzymes glucose oxidase (GOx) and horseradish peroxidase (HRP) are carried out. DDI of AuNPs is used to demonstrate site selectivity and reversibility of the surface-modification process. In the case of the DNA-enzyme conjugates, the patterned assembly of the two enzymes allows the establishment and investigation of the coupled reaction of GOx and HRP, with particular emphasis on surface coverage and lateral flow rates. The results demonstrate that this addressable chip is well suited for the generation of fluidically coupled multi-enzyme microreactors.

  14. Coarse-grained modeling of DNA curvature

    NASA Astrophysics Data System (ADS)

    Freeman, Gordon S.; Hinckley, Daniel M.; Lequieu, Joshua P.; Whitmer, Jonathan K.; de Pablo, Juan J.

    2014-10-01

    The interaction of DNA with proteins occurs over a wide range of length scales, and depends critically on its local structure. In particular, recent experimental work suggests that the intrinsic curvature of DNA plays a significant role on its protein-binding properties. In this work, we present a coarse grained model of DNA that is capable of describing base-pairing, hybridization, major and minor groove widths, and local curvature. The model represents an extension of the recently proposed 3SPN.2 description of DNA [D. M. Hinckley, G. S. Freeman, J. K. Whitmer, and J. J. de Pablo, J. Chem. Phys. 139, 144903 (2013)], into which sequence-dependent shape and mechanical properties are incorporated. The proposed model is validated against experimental data including melting temperatures, local flexibilities, dsDNA persistence lengths, and minor groove width profiles.

  15. G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV

    PubMed Central

    Madireddy, Advaitha; Purushothaman, Pravinkumar; Loosbroock, Christopher P.; Robertson, Erle S.; Schildkraut, Carl L.; Verma, Subhash C.

    2016-01-01

    Kaposi's sarcoma associated herpesvirus (KSHV) establishes life-long latent infection by persisting as an extra-chromosomal episome in the infected cells and by maintaining its genome in dividing cells. KSHV achieves this by tethering its epigenome to the host chromosome by latency associated nuclear antigen (LANA), which binds in the terminal repeat (TR) region of the viral genome. Sequence analysis of the TR, a GC-rich DNA element, identified several potential Quadruplex G-Rich Sequences (QGRS). Since quadruplexes have the tendency to obstruct DNA replication, we used G-quadruplex stabilizing compounds to examine their effect on latent DNA replication and the persistence of viral episomes. Our results showed that these G-quadruplex stabilizing compounds led to the activation of dormant origins of DNA replication, with preferential bi-directional pausing of replications forks moving out of the TR region, implicating the role of the G-rich TR in the perturbation of episomal DNA replication. Over time, treatment with PhenDC3 showed a loss of viral episomes in the infected cells. Overall, these data show that G-quadruplex stabilizing compounds retard the progression of replication forks leading to a reduction in DNA replication and episomal maintenance. These results suggest a potential role for G-quadruplex stabilizers in the treatment of KSHV-associated diseases. PMID:26837574

  16. Zebrafish embryos as a screen for DNA methylation modifications after compound exposure.

    PubMed

    Bouwmeester, Manon C; Ruiter, Sander; Lommelaars, Tobias; Sippel, Josefine; Hodemaekers, Hennie M; van den Brandhof, Evert-Jan; Pennings, Jeroen L A; Kamstra, Jorke H; Jelinek, Jaroslav; Issa, Jean-Pierre J; Legler, Juliette; van der Ven, Leo T M

    2016-01-15

    Modified epigenetic programming early in life is proposed to underlie the development of an adverse adult phenotype, known as the Developmental Origins of Health and Disease (DOHaD) concept. Several environmental contaminants have been implicated as modifying factors of the developing epigenome. This underlines the need to investigate this newly recognized toxicological risk and systematically screen for the epigenome modifying potential of compounds. In this study, we examined the applicability of the zebrafish embryo as a screening model for DNA methylation modifications. Embryos were exposed from 0 to 72 h post fertilization (hpf) to bisphenol-A (BPA), diethylstilbestrol, 17α-ethynylestradiol, nickel, cadmium, tributyltin, arsenite, perfluoroctanoic acid, valproic acid, flusilazole, 5-azacytidine (5AC) in subtoxic concentrations. Both global and site-specific methylation was examined. Global methylation was only affected by 5AC. Genome wide locus-specific analysis was performed for BPA exposed embryos using Digital Restriction Enzyme Analysis of Methylation (DREAM), which showed minimal wide scale effects on the genome, whereas potential informative markers were not confirmed by pyrosequencing. Site-specific methylation was examined in the promoter regions of three selected genes vasa, vtg1 and cyp19a2, of which vasa (ddx4) was the most responsive. This analysis distinguished estrogenic compounds from metals by direction and sensitivity of the effect compared to embryotoxicity. In conclusion, the zebrafish embryo is a potential screening tool to examine DNA methylation modifications after xenobiotic exposure. The next step is to examine the adult phenotype of exposed embryos and to analyze molecular mechanisms that potentially link epigenetic effects and altered phenotypes, to support the DOHaD hypothesis.

  17. Zebrafish embryos as a screen for DNA methylation modifications after compound exposure.

    PubMed

    Bouwmeester, Manon C; Ruiter, Sander; Lommelaars, Tobias; Sippel, Josefine; Hodemaekers, Hennie M; van den Brandhof, Evert-Jan; Pennings, Jeroen L A; Kamstra, Jorke H; Jelinek, Jaroslav; Issa, Jean-Pierre J; Legler, Juliette; van der Ven, Leo T M

    2016-01-15

    Modified epigenetic programming early in life is proposed to underlie the development of an adverse adult phenotype, known as the Developmental Origins of Health and Disease (DOHaD) concept. Several environmental contaminants have been implicated as modifying factors of the developing epigenome. This underlines the need to investigate this newly recognized toxicological risk and systematically screen for the epigenome modifying potential of compounds. In this study, we examined the applicability of the zebrafish embryo as a screening model for DNA methylation modifications. Embryos were exposed from 0 to 72 h post fertilization (hpf) to bisphenol-A (BPA), diethylstilbestrol, 17α-ethynylestradiol, nickel, cadmium, tributyltin, arsenite, perfluoroctanoic acid, valproic acid, flusilazole, 5-azacytidine (5AC) in subtoxic concentrations. Both global and site-specific methylation was examined. Global methylation was only affected by 5AC. Genome wide locus-specific analysis was performed for BPA exposed embryos using Digital Restriction Enzyme Analysis of Methylation (DREAM), which showed minimal wide scale effects on the genome, whereas potential informative markers were not confirmed by pyrosequencing. Site-specific methylation was examined in the promoter regions of three selected genes vasa, vtg1 and cyp19a2, of which vasa (ddx4) was the most responsive. This analysis distinguished estrogenic compounds from metals by direction and sensitivity of the effect compared to embryotoxicity. In conclusion, the zebrafish embryo is a potential screening tool to examine DNA methylation modifications after xenobiotic exposure. The next step is to examine the adult phenotype of exposed embryos and to analyze molecular mechanisms that potentially link epigenetic effects and altered phenotypes, to support the DOHaD hypothesis. PMID:26712470

  18. Compound hierarchical correlated beta mixture with an application to cluster mouse transcription factor DNA binding data.

    PubMed

    Dai, Hongying; Charnigo, Richard

    2015-10-01

    Modeling correlation structures is a challenge in bioinformatics, especially when dealing with high throughput genomic data. A compound hierarchical correlated beta mixture (CBM) with an exchangeable correlation structure is proposed to cluster genetic vectors into mixture components. The correlation coefficient, [Formula: see text], is homogenous within a mixture component and heterogeneous between mixture components. A random CBM with [Formula: see text] brings more flexibility in explaining correlation variations among genetic variables. Expectation-Maximization (EM) algorithm and Stochastic Expectation-Maximization (SEM) algorithm are used to estimate parameters of CBM. The number of mixture components can be determined using model selection criteria such as AIC, BIC and ICL-BIC. Extensive simulation studies were conducted to compare EM, SEM and model selection criteria. Simulation results suggest that CBM outperforms the traditional beta mixture model with lower estimation bias and higher classification accuracy. The proposed method is applied to cluster transcription factor-DNA binding probability in mouse genome data generated by Lahdesmaki and others (2008, Probabilistic inference of transcription factor binding from multiple data sources. PLoS One, 3: , e1820). The results reveal distinct clusters of transcription factors when binding to promoter regions of genes in JAK-STAT, MAPK and other two pathways.

  19. Modelling of DNA-protein recognition

    NASA Technical Reports Server (NTRS)

    Rein, R.; Garduno, R.; Colombano, S.; Nir, S.; Haydock, K.; Macelroy, R. D.

    1980-01-01

    Computer model-building procedures using stereochemical principles together with theoretical energy calculations appear to be, at this stage, the most promising route toward the elucidation of DNA-protein binding schemes and recognition principles. A review of models and bonding principles is conducted and approaches to modeling are considered, taking into account possible di-hydrogen-bonding schemes between a peptide and a base (or a base pair) of a double-stranded nucleic acid in the major groove, aspects of computer graphic modeling, and a search for isogeometric helices. The energetics of recognition complexes is discussed and several models for peptide DNA recognition are presented.

  20. Radio- and photosensitization of DNA with compounds containing platinum and bromine atoms

    NASA Astrophysics Data System (ADS)

    Śmiałek, Małgorzata A.; Ptasińska, Sylwia; Gow, Jason; Vrønning Hoffmann, Søren; Mason, Nigel J.

    2015-05-01

    Irradiations of plasmid DNA by both X-rays and UV light in the presence and absence of compounds containing platinum and bromine atoms were performed in order to asses the sensitization potential of these compounds. Plasmid DNA pBR322 was incubated with platinum (II) bromide, hydrogen hexabromoplatinate (IV), hydrogen hexahydroxyplatinate (IV) and sodium hexahydroxyplatinate (IV). Incubation was followed by X-ray or UV irradiations. It was found that amongst the sensitizers tested, during irradiations carried out in the presence of platinum (II) bromide, the highest levels of double strand breaks formation upon X-ray treatment were recorded. In contrast much less damage was induced by UV light. Data presented here suggests that this compound may be a promising radiosensitizer for cancer treatment. Contribution to the Topical Issue "COST Action Nano-IBCT: Nano-scale Processes Behind Ion-Beam Cancer Therapy", edited by Andrey Solov'yov, Nigel Mason, Gustavo García, Eugene Surdutovich.

  1. Inhibition of human DNA topoisomerase IB by nonmutagenic ruthenium(II)-based compounds with antitumoral activity.

    PubMed

    de Camargo, Mariana S; da Silva, Monize M; Correa, Rodrigo S; Vieira, Sara D; Castelli, Silvia; D'Anessa, Ilda; De Grandis, Rone; Varanda, Eliana; Deflon, Victor M; Desideri, Alessandro; Batista, Alzir A

    2016-02-01

    Herein we synthesized two new ruthenium(II) compounds [Ru(pySH)(bipy)(dppb)]PF6 (1) and [Ru(HSpym)(bipy)(dppb)]PF6 (2) that are analogs to an antitumor agent recently described, [Ru(SpymMe2)(bipy)(dppb)]PF6 (3), where [(Spy) = 2-mercaptopyridine anion; (Spym) = 2-mercaptopyrimidine anion and (SpymMe2) = 4,6-dimethyl-2-mercaptopyrimidine anion]. In vitro cell culture experiments revealed significant anti-proliferative activity for 1-3 against HepG2 and MDA-MB-231 tumor cells, higher than the standard anti-cancer drugs doxorubicin and cisplatin. No mutagenicity is detected when compounds are evaluated by cytokinesis-blocked micronucleus cytome and Ames test in the presence and absence of S9 metabolic activation from rat liver. Interaction studies show that compounds 1-3 can bind to DNA through electrostatic interactions and to albumin through hydrophobic interactions. The three compounds are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (Top1). Compound 3 is the most efficient Top1 inhibitor and the inhibitory effect is enhanced upon pre-incubation with the enzyme. Analysis of different steps of Top1 catalytic cycle indicates that 3 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and slows down the religation reaction. Molecular docking shows that 3 preferentially binds closer to the residues of the active site when Top1 is free and lies on the DNA groove downstream of the cleavage site in the Top1-DNA complex. Thus, 3 can be considered in further studies for a possible use as an anticancer agent. PMID:26758075

  2. Synthesis of a naphthalene-hydroxynaphthalene polymer model compound

    SciTech Connect

    Not Available

    1991-10-02

    The objective of this project was the synthesis of one pound of a new naphthalene-hydroxynaphthalene polymer model compound for use in coal combustion studies. Since this compound was an unreported compound, this effort also required the development of a synthetic route to this compound (including routes to the unique and unreported intermediates leading to its synthesis).

  3. New compound with DNA Topo I inhibitory activity purified from Penicillium oxalicum HSY05.

    PubMed

    Liu, Bing; Wang, Hai-Feng; Zhang, Li-Hua; Liu, Fang; He, Feng-Jun; Bai, Jiao; Hua, Hui-Ming; Chen, Gang; Pei, Yue-Hu

    2015-01-01

    Strain HSY05 was isolated from sea sediment collected from the South China Sea and was later identified as Penicillium oxalicum by 16S rDNA sequence analysis. Various chromatographic processes led to the isolation and purification of two metabolites from the fermentation culture of HSY05, including one new compound, 2,2',4,4'-tetrahyoxy-8'-methyl-6-methoxy-acyl-ethyl-diphenylmethanone (1), and a known compound secalonic acid D (SAD, 2), as characterised by UV, IR, 1D, 2D-NMR and MS data. The inhibitory activities against topoisomerase I of these two compounds were evaluated. The result showed that in addition to the known topo I inhibitor SAD (2), compound 1 also exhibited a moderate inhibitory effect.

  4. Chromosomal aneuploidies and DNA fragmentation of human spermatozoa from patients exposed to perfluorinated compounds.

    PubMed

    Governini, L; Guerranti, C; De Leo, V; Boschi, L; Luddi, A; Gori, M; Orvieto, R; Piomboni, P

    2015-11-01

    This study investigated chromosomal aneuploidies and DNA damage in spermatozoa from male patients contaminated by perfluorinated compounds (PFCs) in whole blood and seminal plasma. Sperm aneuploidy and diploidy rate for chromosomes 18, X and Y were evaluated by FISH; sperm DNA fragmentation was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling technique coupled to flow cytometry. Our results indicated that PFC contamination was present in 58% of subjects included in the study. A significant increase in alterations of sperm parameters was observed in PFC-positive subjects compared to PFC-negative subjects. As regards the sperm aneuploidy, both disomy and diploidy rates resulted significantly increased in subjects positive for PFC contamination compared to PFC-negative samples. In addition, sperm DNA fragmentation index resulted significantly increased in PFC-contaminated subjects compared to PFC-non-contaminated subjects, with a significant increased level of dimmer DNA fragmentation index. Our results clearly indicate that PFC contamination may detrimentally affect spermatogenesis, disturbing both meiotic segregation and DNA integrity. We could therefore suggest cautions to reduce or eliminate any contact with these compounds because the long-term effects of PFC accumulation in the body are not predictable.

  5. Replication fork-stimulated eIF-4A from Plasmodium cynomolgi unwinds DNA in the 3' to 5' direction and is inhibited by DNA-interacting compounds.

    PubMed

    Tuteja, Renu; Tuteja, Narendra; Malhotra, Pawan; Singh Chauhan, Virander

    2003-06-01

    Plasmodium cynomolgi DEAD-box DNA helicase 45 (PcDDH45) is an ATP-dependent DNA-unwinding enzyme with intrinsic DNA-dependent ATPase activity and is highly homologous to eIF-4A. In this study, we have further characterized and tested the effect of various DNA-interacting compounds on the DNA-unwinding activity of PcDDH45. The results show that PcDDH45 translocates in the 3' to 5' direction along the bound strand, a replication fork-like structure of the substrate stimulates its DNA-unwinding activity, and it failed to unwind blunt-ended duplex DNA. Of various compounds tested, only cisplatin, 4',6'-diamidino-2-phenylindole, daunorubicin, and nogalamycin were inhibitory to the unwinding activity of PcDDH45 with apparent IC(50) values of 1.0, 4.0, 7.5, and 1.7 microM, respectively. These results suggest that the interaction of these compounds with duplex DNA generate a complex that probably impedes the translocation of PcDDH45, resulting in inhibition of unwinding activity. This study is one of the first to demonstrate the effect of various DNA-binding compounds on a malaria parasite DNA helicase and should make an important contribution to our better understanding of the nucleic acid transactions in the parasite.

  6. Mathematical modelling of eukaryotic DNA replication.

    PubMed

    Hyrien, Olivier; Goldar, Arach

    2010-01-01

    Eukaryotic DNA replication is a complex process. Replication starts at thousand origins that are activated at different times in S phase and terminates when converging replication forks meet. Potential origins are much more abundant than actually fire within a given S phase. The choice of replication origins and their time of activation is never exactly the same in any two cells. Individual origins show different efficiencies and different firing time probability distributions, conferring stochasticity to the DNA replication process. High-throughput microarray and sequencing techniques are providing increasingly huge datasets on the population-averaged spatiotemporal patterns of DNA replication in several organisms. On the other hand, single-molecule replication mapping techniques such as DNA combing provide unique information about cell-to-cell variability in DNA replication patterns. Mathematical modelling is required to fully comprehend the complexity of the chromosome replication process and to correctly interpret these data. Mathematical analysis and computer simulations have been recently used to model and interpret genome-wide replication data in the yeast Saccharomyces cerevisiae and Schizosaccharomyces pombe, in Xenopus egg extracts and in mammalian cells. These works reveal how stochasticity in origin usage confers robustness and reliability to the DNA replication process. PMID:20205354

  7. Global DNA hypomethylation is associated with in utero exposure to cotinine and perfluorinated alkyl compounds

    PubMed Central

    Goldman, Lynn R; Brebi-Mieville, Priscilla; Ili-Gangas, Carmen; LeBron, Cynthia; Hernandez-Arroyo, Mireya; Witter, Frank R; Apelberg, Ben J; Roystacher, Marina; Jaffe, Andrew; Halden, Rolf U; Sidransky, David

    2010-01-01

    Environmental exposures in utero may alter the epigenome, thus impacting chromosomal stability and gene expression. We hypothesized that in utero exposures to maternal smoking and perfluoroalkyl compounds (PFCs) are associated with global DNA hypomethylation in umbilical cord serum. Our objective was to determine if global DNA methylation could be used as a biomarker of in utero exposures to maternal smoking and PFCs. Using an ELISA-based method, global DNA methylation was quantified in umbilical cord serum from 30 newborns with high (>10 ng/ml, mean 123.8 ng/ml), low (range 1–10 ng/ml, mean 1.6 ng/ml) and very low (<1 ng/ml, mean 0.06 ng/ml) cord serum cotinine levels. Y chromosome analysis was performed to rule out maternal DNA cross-contamination. Cord serum global DNA methylation showed an inverse dose response to serum cotinine levels (p < 0.001). Global DNA methylation levels in cord blood were the lowest among newborns with smoking mothers (mean = 15.04%; 95% CI, 8.4, 21.7) when compared to babies of mothers who were second-hand smokers (21.1%; 95% CI, 16.6, 25.5) and non-smokers (mean = 29.2%; 95% CI, 20.1, 38.1). Global DNA methylation was inversely correlated with serum PFOA (r = -0.35, p = 0.06) but not PFOS levels. Serum Y chromosome analyses did not detect maternal DNA cross-contamination. This study supports the use of global DNA methylation status as a biomarker of in utero exposure to cigarette smoke and PFCs. PMID:20523118

  8. Scaling Theory and Modeling of DNA Evolution

    NASA Astrophysics Data System (ADS)

    Buldyrev, Sergey V.

    1998-03-01

    We present evidence supporting the possibility that the nucleotide sequence in noncoding DNA is power-law correlated. We do not find such long-range correlation in the coding regions of the gene, so we build a ``coding sequence finder'' to locate the coding regions of an unknown DNA sequence. We also propose a different coding sequence finding algorithm, based on the concept of mutual information(I. Große, S. V. Buldyrev, H. Herzel, H. E. Stanley, (preprint).). We describe our recent work on quantification of DNA patchiness, using long-range correlation measures (G. M. Viswanathan, S. V. Buldyrev, S. Havlin, and H. E. Stanley, Biophysical Journal 72), 866-875 (1997).. We also present our recent study of the simple repeat length distributions. We find that the distributions of some simple repeats in noncoding DNA have long power-law tails, while in coding DNA all simple repeat distributions decay exponentially. (N. V. Dokholyan, S. V. Buldyrev, S. Havlin, and H. E. Stanley, Phys. Rev. Lett (in press).) We discuss several models based on insertion-deletion and mutation-duplication mechanisms that relate long-range correlations in non-coding DNA to DNA evolution. Specifically, we relate long-range correlations in non-coding DNA to simple repeat expansion, and propose an evolutionary model that reproduces the power law distribution of simple repeat lengths. We argue that the absence of long-range correlations in protein coding sequences is related to their highly conserved primary structure which is necessary to insure protein folding.

  9. Ligand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity

    PubMed Central

    Adhireksan, Zenita; Davey, Gabriela E.; Campomanes, Pablo; Groessl, Michael; Clavel, Catherine M.; Yu, Haojie; Nazarov, Alexey A.; Yeo, Charmian Hui Fang; Ang, Wee Han; Dröge, Peter; Rothlisberger, Ursula; Dyson, Paul J.; Davey, Curt A.

    2014-01-01

    Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents—the cytotoxic antiprimary tumour compound [(η6-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η6-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]—and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel ‘atom-to-cell’ approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells. PMID:24637564

  10. Flash vacuum pyrolysis of lignin model compounds

    SciTech Connect

    Cooney, M.J.; Britt, P.F.; Buchanan, A.C. III

    1997-03-01

    Despite the extensive research into the pyrolysis of lignin, the underlying chemical reactions that lead to product formation are poorly understood. Detailed mechanistic studies on the pyrolysis of biomass and lignin under conditions relevant to current process conditions could provide insight into utilizing this renewable resource for the production of chemicals and fuel. Currently, flash or fast pyrolysis is the most promising process to maximize the yields of liquid products (up to 80 wt %) from biomass by rapidly heating the substrate to moderate temperatures, typically 500{degrees}C, for short residence times, typically less than two seconds. To provide mechanistic insight into the primary reaction pathways under process relevant conditions, we are investigating the flash vacuum pyrolysis (FVP) of lignin model compounds that contain a {beta}-ether. linkage and {alpha}- or {gamma}-alcohol, which are key structural elements in lignin. The dominant products from the FVP of PhCH{sub 2}CH{sub 2}OPh (PPE), PhC(OH)HCH{sub 2}OPh, and PhCH{sub 2}CH(CH{sub 2}OH)OPh at 500{degrees}C can be attributed to homolysis of the weakest bond in the molecule (C-O bond) or 1,2-elimination. Surprisingly, the hydroxy-substituent dramatically increases the decomposition of PPE. It is proposed that internal hydrogen bonding is accelerating the reaction.

  11. All-atom polarizable force field for DNA based on the classical Drude oscillator model.

    PubMed

    Savelyev, Alexey; MacKerell, Alexander D

    2014-06-15

    Presented is a first generation atomistic force field (FF) for DNA in which electronic polarization is modeled based on the classical Drude oscillator formalism. The DNA model is based on parameters for small molecules representative of nucleic acids, including alkanes, ethers, dimethylphosphate, and the nucleic acid bases and empirical adjustment of key dihedral parameters associated with the phosphodiester backbone, glycosidic linkages, and sugar moiety of DNA. Our optimization strategy is based on achieving a compromise between satisfying the properties of the underlying model compounds in the gas phase targeting quantum mechanical (QM) data and reproducing a number of experimental properties of DNA duplexes in the condensed phase. The resulting Drude FF yields stable DNA duplexes on the 100-ns time scale and satisfactorily reproduce (1) the equilibrium between A and B forms of DNA and (2) transitions between the BI and BII substates of B form DNA. Consistency with the gas phase QM data for the model compounds is significantly better for the Drude model as compared to the CHARMM36 additive FF, which is suggested to be due to the improved response of the model to changes in the environment associated with the explicit inclusion of polarizability. Analysis of dipole moments associated with the nucleic acid bases shows the Drude model to have significantly larger values than those present in CHARMM36, with the dipoles of individual bases undergoing significant variations during the MD simulations. Additionally, the dipole moment of water was observed to be perturbed in the grooves of DNA. PMID:24752978

  12. Braiding DNA: Experiments, Simulations, and Models

    PubMed Central

    Charvin, G.; Vologodskii, A.; Bensimon, D.; Croquette, V.

    2005-01-01

    DNA encounters topological problems in vivo because of its extended double-helical structure. As a consequence, the semiconservative mechanism of DNA replication leads to the formation of DNA braids or catenanes, which have to be removed for the completion of cell division. To get a better understanding of these structures, we have studied the elastic behavior of two braided nicked DNA molecules using a magnetic trap apparatus. The experimental data let us identify and characterize three regimes of braiding: a slightly twisted regime before the formation of the first crossing, followed by genuine braids which, at large braiding number, buckle to form plectonemes. Two different approaches support and quantify this characterization of the data. First, Monte Carlo (MC) simulations of braided DNAs yield a full description of the molecules' behavior and their buckling transition. Second, modeling the braids as a twisted swing provides a good approximation of the elastic response of the molecules as they are intertwined. Comparisons of the experiments and the MC simulations with this analytical model allow for a measurement of the diameter of the braids and its dependence upon entropic and electrostatic repulsive interactions. The MC simulations allow for an estimate of the effective torsional constant of the braids (at a stretching force F = 2 pN): Cb ∼ 48 nm (as compared with C ∼100 nm for a single unnicked DNA). Finally, at low salt concentrations and for sufficiently large number of braids, the diameter of the braided molecules is observed to collapse to that of double-stranded DNA. We suggest that this collapse is due to the partial melting and fraying of the two nicked molecules and the subsequent right- or left-handed intertwining of the stretched single strands. PMID:15778439

  13. Mitochondrial DNA damage and efficiency of ATP biosynthesis: mathematical model.

    PubMed

    Beregovskaya, N; Maiboroda, R

    1995-01-21

    The role of mitochondrial DNA (mtDNA) damage in ageing processes and in malignant transformation of a cell is discussed. A mathematical model of the mtDNA population in a cell and in tissue is constructed. The model describes the effects of mtDNA damages accumulated during ageing and some features of malignant transformation and regeneration.

  14. Assessing Uncertainty of Interspecies Correlation Estimation Models for Aromatic Compounds

    EPA Science Inventory

    We developed Interspecies Correlation Estimation (ICE) models for aromatic compounds containing 1 to 4 benzene rings to assess uncertainty in toxicity extrapolation in two data compilation approaches. ICE models are mathematical relationships between surrogate and predicted test ...

  15. Computational studies on DNA recognition of novel organic and copper anti-tumor compounds

    NASA Astrophysics Data System (ADS)

    Nascimento, Rafael R.; Gonçalves, Marcos B.; Petrilli, Helena M.; Ferreira, Ana M. D. C.; Ippoliti, Emiliano; Dreyer, Jens; Carloni, Paolo

    2013-03-01

    The ability of many organic and coordination compounds to bind to DNA and/or damage cellular structures has been largely exploited in anticancer research. Identifying DNA recognition mechanisms have thus important impact on the chemical biology of gene expression and the development of new drugs and therapies. Previous studies on copper(II) complexes with oxindole-Schiff base ligands have shown their potential anti-tumor activity towards different cells, inducing apoptosis through a preferential attack to DNA and/or mitochondria [SIL11]. The binding mechanism of the organic and copper(II) complexes [Cu(isaepy)2]2 + (1) and [Cu(isaenim)]2 + (2) and their modulation at DNA is investigated through theoretical studies. Here we adopted a multi-scale procedure to simulate this large system using molecular docking and classical molecular dynamics. Hybrid Car-Parrinello/Molecular Mechanics calculations were applied to parameterize the copper(II) complexes by using the force matching approach. Free energies of binding are investigated by metadynamics enhanced sampling methods[VAR08]. [SIL11] V. C. da Silveira et. al. JIB 105 (2011) 1692.[VAR08] A. V. Vargiu et. al. Nucl. Acids Res. 36 (2008) 5910.

  16. Biomimetic polyorganosiloxanes: model compounds for new materials.

    PubMed

    Kociok-Köhn, Gabriele; Mahon, Mary F; Molloy, Kieran C; Price, Gareth J; Prior, Timothy J; Smith, Douglas R G

    2014-06-01

    The chemistry of N-organosilylalkyl-substituted heterocyclic bases (thymine, adenine and cytosine) is described, covering the structures of model compounds, the synthesis of substituted oligo-siloxanes and a preliminary report of the synthesis of a poly(organosiloxane) with pendant N-alkyl(heterocycle) functionalities. N-Alkenylthymines CH2=CH(CH2)(n)T (T = thymine, n = 1 (1), 2 (2), 3 (3)) have been prepared and 2 hydrosilylated to form PhMe2Si(CH2)4T (5). Alternatively, 5 was prepared by reaction of PhMe2Si(CH2)4Br (6) with (O,O-SiMe3)2T, a method which has also been used to prepare PhMe2Si(CH2)4A (7) and PhMe2Si(CH2)4C (8) (A = adenine, C = cytosine). Model di- and tri-siloxanes [Br(CH2)4(Me)2Si]2O (10), Me3SiOSi(Me)2(CH2)4Br (11), PhMe2SiOSi(Me)2(CH2)4Br (12) and (Me3SiO)2(Me)Si(CH2)4Br (13) have been prepared by hydrosilylation of H2C[double bond, length as m-dash]C(H)(CH2)4Br with an appropriate hydrosiloxane and used to prepare Me3SiO(Me)2Si(CH2)4T (14), Me3SiO(Me)2Si(CH2)4A (15) (both from 11), and (Me3SiO)2(Me)Si(CH2)4T (16), (Me3SiO)2(Me)Si(CH2)4A (17) (both from 13). 10 reacts with thymine to give a mixture of the pyrimidocyclophane cyclo-T-N,N-[(CH2)4(Me)2Si]2O (19) and [T(CH2)4Si(Me)2]2O (20), while cytosine reacts similarly to form cyclo-C-N,N-[(CH2)4(Me)2Si]2O (21; as an imine) and [C(CH2)4Si(Me)2]2O (22); adenine only generates [A(CH2)4Si(Me)2]2O (18) in an analogous synthesis. Using a related protocol, polymeric {[MeSi(O)(CH2)4Br]2[Me2SiO]98}n (23) has been converted to {[MeSi(O)(CH2)4T]2[Me2SiO]98}n (24) and {[MeSi(O)(CH2)4A]2[Me2SiO]98}n (25). The structures of 4, 5, 8, 19 and 21, along with a 2 : 1 adduct of 5 with Ni(dithiobiuret)2 (9) are reported.

  17. Designing Multi-target Compound Libraries with Gaussian Process Models.

    PubMed

    Bieler, Michael; Reutlinger, Michael; Rodrigues, Tiago; Schneider, Petra; Kriegl, Jan M; Schneider, Gisbert

    2016-05-01

    We present the application of machine learning models to selecting G protein-coupled receptor (GPCR)-focused compound libraries. The library design process was realized by ant colony optimization. A proprietary Boehringer-Ingelheim reference set consisting of 3519 compounds tested in dose-response assays at 11 GPCR targets served as training data for machine learning and activity prediction. We compared the usability of the proprietary data with a public data set from ChEMBL. Gaussian process models were trained to prioritize compounds from a virtual combinatorial library. We obtained meaningful models for three of the targets (5-HT2c , MCH, A1), which were experimentally confirmed for 12 of 15 selected and synthesized or purchased compounds. Overall, the models trained on the public data predicted the observed assay results more accurately. The results of this study motivate the use of Gaussian process regression on public data for virtual screening and target-focused compound library design.

  18. Designing Multi-target Compound Libraries with Gaussian Process Models.

    PubMed

    Bieler, Michael; Reutlinger, Michael; Rodrigues, Tiago; Schneider, Petra; Kriegl, Jan M; Schneider, Gisbert

    2016-05-01

    We present the application of machine learning models to selecting G protein-coupled receptor (GPCR)-focused compound libraries. The library design process was realized by ant colony optimization. A proprietary Boehringer-Ingelheim reference set consisting of 3519 compounds tested in dose-response assays at 11 GPCR targets served as training data for machine learning and activity prediction. We compared the usability of the proprietary data with a public data set from ChEMBL. Gaussian process models were trained to prioritize compounds from a virtual combinatorial library. We obtained meaningful models for three of the targets (5-HT2c , MCH, A1), which were experimentally confirmed for 12 of 15 selected and synthesized or purchased compounds. Overall, the models trained on the public data predicted the observed assay results more accurately. The results of this study motivate the use of Gaussian process regression on public data for virtual screening and target-focused compound library design. PMID:27492085

  19. How Aromatic Compounds Block DNA Binding of HcaR Catabolite Regulator.

    PubMed

    Kim, Youngchang; Joachimiak, Grazyna; Bigelow, Lance; Babnigg, Gyorgy; Joachimiak, Andrzej

    2016-06-17

    Bacterial catabolism of aromatic compounds from various sources including phenylpropanoids and flavonoids that are abundant in soil plays an important role in the recycling of carbon in the ecosystem. We have determined the crystal structures of apo-HcaR from Acinetobacter sp. ADP1, a MarR/SlyA transcription factor, in complexes with hydroxycinnamates and a specific DNA operator. The protein regulates the expression of the hca catabolic operon in Acinetobacter and related bacterial strains, allowing utilization of hydroxycinnamates as sole sources of carbon. HcaR binds multiple ligands, and as a result the transcription of genes encoding several catabolic enzymes is increased. The 1.9-2.4 Å resolution structures presented here explain how HcaR recognizes four ligands (ferulate, 3,4-dihydroxybenzoate, p-coumarate, and vanillin) using the same binding site. The ligand promiscuity appears to be an adaptation to match a broad specificity of hydroxycinnamate catabolic enzymes while responding to toxic thioester intermediates. Structures of apo-HcaR and in complex with a specific DNA hca operator when combined with binding studies of hydroxycinnamates show how aromatic ligands render HcaR unproductive in recognizing a specific DNA target. The current study contributes to a better understanding of the hca catabolic operon regulation mechanism by the transcription factor HcaR. PMID:27129205

  20. Polymers modified with double-tailed fluorous compounds for efficient DNA and siRNA delivery.

    PubMed

    He, Bingwei; Wang, Yitong; Shao, Naimin; Chang, Hong; Cheng, Yiyun

    2015-08-01

    Cationic polymers are widely used as gene carriers, however, these polymers are usually associated with low transfection efficacy and non-negligible toxicity. Fluorination on polymers significantly improves their performances in gene delivery, but a high density of fluorous chains must be conjugated on a single polymer. Here we present a new strategy to construct fluorinated polymers with minimal fluorous chains for efficient DNA and siRNA delivery. A double-tailed fluorous compound 2-chloro-4,6-bis[(perfluorohexyl)propyloxy]-1,3,5-triazine (CBT) was conjugated on dendrimers of different generations and low molecular weight polyethylenimine via a facile synthesis. The yielding products with average numbers of 1-2 conjugated CBT moieties showed much improved EGFP and luciferase transfection efficacy compared to unmodified polymers. In addition, these polymers show high siRNA delivery efficacy on different cell lines. Among the synthesized polymers, generation 1 (G1) dendrimer modified with an average number of 1.9 CBT moieties (G1-CBT1.9) shows the highest efficacy when delivering both DNA and siRNA and its efficacy approaches that of Lipofectamine 2000. G1-CBT1.9 also shows efficient gene silencing in vivo. All of the CBT-modified polymers exhibit minimal toxicity on the cells at their optimal transfection conditions. This study provides a new strategy to design efficient fluorous polymers for DNA and siRNA delivery.

  1. Methods for modeling cytoskeletal and DNA filaments

    NASA Astrophysics Data System (ADS)

    Andrews, Steven S.

    2014-02-01

    This review summarizes the models that researchers use to represent the conformations and dynamics of cytoskeletal and DNA filaments. It focuses on models that address individual filaments in continuous space. Conformation models include the freely jointed, Gaussian, angle-biased chain (ABC), and wormlike chain (WLC) models, of which the first three bend at discrete joints and the last bends continuously. Predictions from the WLC model generally agree well with experiment. Dynamics models include the Rouse, Zimm, stiff rod, dynamic WLC, and reptation models, of which the first four apply to isolated filaments and the last to entangled filaments. Experiments show that the dynamic WLC and reptation models are most accurate. They also show that biological filaments typically experience strong hydrodynamic coupling and/or constrained motion. Computer simulation methods that address filament dynamics typically compute filament segment velocities from local forces using the Langevin equation and then integrate these velocities with explicit or implicit methods; the former are more versatile and the latter are more efficient. Much remains to be discovered in biological filament modeling. In particular, filament dynamics in living cells are not well understood, and current computational methods are too slow and not sufficiently versatile. Although primarily a review, this paper also presents new statistical calculations for the ABC and WLC models. Additionally, it corrects several discrepancies in the literature about bending and torsional persistence length definitions, and their relations to flexural and torsional rigidities.

  2. Exploring the DNA binding mode of transition metal based biologically active compounds

    NASA Astrophysics Data System (ADS)

    Raman, N.; Sobha, S.

    2012-01-01

    Few novel 4-aminoantipyrine derived Schiff bases and their metal complexes were synthesized and characterized. Their structural features and other properties were deduced from the elemental analysis, magnetic susceptibility and molar conductivity as well as from mass, IR, UV-vis, 1H NMR and EPR spectral studies. The binding of the complexes with CT-DNA was analyzed by electronic absorption spectroscopy, viscosity measurement, and cyclic voltammetry. The interaction of the metal complexes with DNA was also studied by molecular modeling with special reference to docking. The experimental and docking results revealed that the complexes have the ability of interaction with DNA of minor groove binding mode. The intrinsic binding constants ( Kb) of the complexes with CT-DNA were found out which show that they are minor groove binders. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the pUC19 DNA in the presence of AH 2 (ascorbic acid). Moreover, the oxidative cleavage studies using distamycin revealed the minor groove binding for the newly synthesized 4-aminoantipyrine derived Schiff bases and their metal complexes. Evaluation of antibacterial activity of the complexes against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus epidermidis, and Klebsiella pneumoniae exhibited that the complexes have potent biocidal activity than the free ligands.

  3. Potential bioactive Schiff base compounds: Synthesis, characterization, X-ray structures, biological screenings and interaction with Salmon sperm DNA

    NASA Astrophysics Data System (ADS)

    Sirajuddin, Muhammad; Uddin, Noor; Ali, Saqib; Tahir, Muhammad Nawaz

    2013-12-01

    Three Schiff base compounds ofN‧-substituted benzohydrazide and sulfonohydrazide derivatives: N‧-(2-hydroxy-3-methoxybenzylidene)-4-tert-butyl- benzohydrazide (1), N‧-(5-bromo-2-hydroxybenzylidene)-4-tert-butylbenzohydrazide (2) and N‧-(2-hydroxy-3-methoxybenzylidene)-4-methylbenzenesulfonohydrazide (3) were synthesized and characterized by elemental analysis, FT-IR, 1H, 13C NMR spectroscopy and single crystal analysis. The title compounds have been screened for their biological activities including, antibacterial, antifungal, antioxidant, cytotoxic, enzymatic activities as well as interaction with SS-DNA which showed remarkable activities in each area of research. The DNA binding of the compounds 1-3 with SS-DNA has been carried out with absorption spectroscopy, which reveals the binding propensity towards SS-DNA via intercalation mode of interaction. The intercalative mode of interaction is also supported by viscometric results. The synthesized compounds were also found to be effective against alkaline phosphatase enzyme. They also show significant to good antimicrobial activity against six bacterial and five fungal strains. The MIC (minimum inhibitory concentration) for antibacterial activity ranges from 1.95-500 μg/mL. Compounds 1-3 show cytotoxic activity comparable to the control. At higher conc. (100 μg/L) compound 3 shows 100% activity means that it has killed all brine shrimps. They were also found to be effective antioxidant of 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and show almost comparable antioxidant activity to that of the standard and known antioxidant, ascorbic acid.

  4. Quinoxaline-2-carboxamide as a carrier ligand in two new platinum(II) compounds: Synthesis, crystal structure, cytotoxic activity and DNA interaction.

    PubMed

    Marqués-Gallego, Patricia; Gamiz-Gonzalez, M Amparo; Fortea-Pérez, Francisco R; Lutz, Martin; Spek, Anthony L; Pevec, Andrej; Kozlevčar, Bojan; Reedijk, Jan

    2010-06-01

    The search for platinum compounds structurally different from cisplatin has led to two new platinum(II) compounds containing quinoxaline-2-carboxamide as a carrier ligand, i.e. cis-[Pt(qnxca)(MeCN)Cl2] (1) and the [Pt(qnxca-H)(dmso)Cl] (2). Both compounds have been synthesized and characterized using different spectroscopic methods. In addition, single-crystal structures have been determined by X-Ray diffraction for both compounds. In each case a square planar Pt(II) is present; in (1) the qnxca is monodentate and neutral, whereas in (2) the ligand has lost a hydrogen, to form the anionic chelating ligand abbreviated as qnxca-H. The biological activity of both compounds has been investigated in a panel of seven human tumour cells, displaying poor cytotoxic activity, compared to cisplatin. The interaction of the new compounds with 1 or 2 equiv. of 9-ethylguanine has been studied using (1)H NMR, (195)Pt NMR and ESI-MS spectroscopy, finding poor reactivity of 1 towards the model base, forming only the monosubstituted adduct. Surprisingly, compound 2, which is more sterically crowded, interacts more efficiently with the 9-EtG, forming a bifunctional adduct with two 9-EtG with substitution of the dmso and the chloride ligand. Unwinding studies of pUC19 plasmid DNA by compound 1 show similar unwinding properties to cisplatin.

  5. An electrochemical DNA-sensor developed with the use of methylene blue as a redox indicator for the detection of DNA damage induced by endocrine-disrupting compounds.

    PubMed

    Lin, Xiaoyun; Ni, Yongnian; Kokot, Serge

    2015-03-31

    An electrochemical biosensor capable of indirect detection of DNA damage induced by any one of the three endocrine-disrupting compounds (EDCs) - bisphenol A (BPA), 4-nonylphenol (NP) and 4-t-octylphenol (OP), has been researched and developed. The methylene blue (MB) dye was used as the redox indicator. The glassy carbon electrode (GCE) was modified by the assembled dsDNA/graphene oxide-chitosan/gold nano-particles to produce a dsDNA/GO-CS/AuNPs/GCE sensor. It was characterized with the use of electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV) and scanning electron microscopy (SEM) techniques. The loading/release of the MB dye by the dsDNA/GO-CS/AuNPs film was investigated, and the results showed that the process was reversible. Based on this, the sensor was used to measure the difference between the loading capabilities of intact and damaged dsDNA in the films. The sensor was then successfully applied to detect DNA damage electrochemically. The differential pulse voltammetry (DPV) peak current ratio for MB, observed before and after DNA damage, increased linearly in the presence the BPA, NP or OP compounds; the treatment range was 10-60 min, and the respective damage rates were 0.0069, 0.0044 and 0.0031 min(-1), respectively. These results were confirmed by the binding constants: 2.09×10(6) M(-1) (BPA-DNA), 1.28×10(6) M(-1) (NP-DNA) and 9.33×10(5) M(-1) (OP-DNA), all of which were obtained with the use of differential pulse stripping voltammetry (DPSV).

  6. Chemotherapeutic Compounds Targeting the DNA Double-Strand Break Repair Pathways: The Good, the Bad, and the Promising

    PubMed Central

    Jekimovs, Christian; Bolderson, Emma; Suraweera, Amila; Adams, Mark; O’Byrne, Kenneth J.; Richard, Derek J.

    2014-01-01

    The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell’s genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers. The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining. Identifying chemotherapeutic compounds targeting proteins involved in these DNA repair pathways has shown promise as a cancer therapy for patients, either as a monotherapy or in combination with genotoxic drugs. From the beginning, there have been a number of chemotherapeutic compounds that have yielded successful responses in the clinic, a number that have failed (CGK-733 and iniparib), and a number of promising targets for future studies identified. This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process. PMID:24795863

  7. Synthesis of a naphthalene-hydroxynaphthalene polymer model compound

    SciTech Connect

    Kwong, C.D.

    1991-07-22

    The objective of this project is the synthesis of a new naphthalene-hydroxynaphthalene polymer model compound for use in coal combustion studies. Since this compound is an unreported compound, this effort also requires the development of a synthetic route to this compound, including the synthesis of unreported intermediates leading to its synthesis. Complex product mixtures have been consistently obtained with all of our approaches. As a result, we have been constantly making small modifications to our technical approach. These changes are discussed in this report. Our synthesis efforts resulted in a number of potential precursors and intermediates. When appropriate, these compounds were submitted to the Organic Chemistry Research Area's Analytical Section for characterization and identification.

  8. Synthesis of a naphthalene-hydroxynaphthalene polymer model compound

    SciTech Connect

    Kwong, C.D.

    1991-04-15

    The objective of this contract is the synthesis of a new naphthalene-hydroxynaphthalene polymer model compound for coal combustion studies. This effort also requires the development of a synthetic procedure for this compound since it has not been reported before. We can only report that we are still unable to provide the target polymer or even any of the key intermediates leading to this target Dr. Rao has been informed of our progress (or lack of progress), and he has suggested that we begin to design other alternative compounds which contain the functionalities required by the target compound. In response to this suggestion, we have quickly designed the potential targets shown in Scheme VIL We are currently evaluating the schemes further and we will continue designing routes to the other analogous compounds.

  9. Reactions of Lignin Model Compounds in Ionic Liquids

    SciTech Connect

    Holladay, John E.; Binder, Joseph B.; Gray, Michel J.; White, James F.; Zhang, Z. Conrad

    2009-09-15

    Lignin, a readily available form of biomass, awaits novel chemistry for converting it to valuable aromatic chemicals. Recent work has demonstrated that ionic liquids are excellent solvents for processing woody biomass and lignin. Seeking to exploit ionic liquids as media for depolymerization of lignin, we investigated reactions of lignin model compounds in these solvents. Using Brønsted acid catalysts in 1-ethyl-3-methylimidazolium triflate at moderate temperatures, we obtained up to 11.6% yield of the dealkylation product guaiacol from the model compound eugenol and cleaved phenethyl phenyl ether, a model for lignin ethers. Despite these successes, acid catalysis failed in dealkylation of the unsaturated model compound 4-ethylguaiacol and did not produce monomeric products from organosolv lignin, demonstrating that further work is required to understand the complex chemistry of lignin depolymerization.

  10. Irradiation effects on polymer-model compounds

    NASA Astrophysics Data System (ADS)

    Seguchi, Tadao; Katsumura, Yosuke; Hayashi, Nariyuki; Hayakawa, Naohiro; Tamura, Naoyuki; Tabata, Yoneho

    Irradiation effects on n-paraffins and squalane, used as models of polymers, were investigated by product analysis. Four n-paraffins, C 20H 42, C 21H 44, C 23H 48 and C 24H 50, and squalane (C 30H 62) were γ-irradiated under vacuum in liquid, crystalline and glassy states. The evolved gases were analyzed by gas chromatography and changes in molecular weight were analyzed by liquid chromatography and mass spectroscopy. G-values for crosslinking of n-paraffins were 1.2 for crystalline states (at 25°C) and 1.7 for liquid states (at 55°C), and showed no difference between odd and even carbon numbers. The G-value of liquid squalane was 1.7; it was 1.3 for the glassy state at low temperature (-77°C). Double bonds were common in the crosslinked products, especially after liquid-phase irradiation. The probability of chain scission was estimated as being negligible, though a small number of chain-scission products (which were products of scission at chain-ends or side chains) were observed by gas analysis.

  11. DNA Vaccines: Experiences in the Swine Model.

    PubMed

    Accensi, Francesc; Rodríguez, Fernando; Monteagudo, Paula L

    2016-01-01

    DNA vaccination is one of the most fascinating vaccine-strategies currently in development. Two of the main advantages of DNA immunization rely on its simplicity and flexibility, being ideal to dissect both the immune mechanisms and the antigens involved in protection against a given pathogen. Here, we describe several strategies used to enhance the immune responses induced and the protection afforded by experimental DNA vaccines tested in swine and provide with very basic protocol describing the generation and in vivo application of a prototypic DNA vaccine. Only time will tell the last word regarding the definitive implementation of DNA vaccination in the field.

  12. A model capturing novel strand symmetries in bacterial DNA

    SciTech Connect

    Sobottka, Marcelo; Hart, Andrew G.

    2011-07-15

    Highlights: {yields} We propose a simple stochastic model to construct primitive DNA sequences. {yields} The model provide an explanation for Chargaff's second parity rule in primitive DNA sequences. {yields} The model is also used to predict a novel type of strand symmetry in primitive DNA sequences. {yields} We extend the results for bacterial DNA sequences and compare distributional properties intrinsic to the model to statistical estimates from 1049 bacterial genomes. {yields} We find out statistical evidences that the novel type of strand symmetry holds for bacterial DNA sequences. -- Abstract: Chargaff's second parity rule for short oligonucleotides states that the frequency of any short nucleotide sequence on a strand is approximately equal to the frequency of its reverse complement on the same strand. Recent studies have shown that, with the exception of organellar DNA, this parity rule generally holds for double-stranded DNA genomes and fails to hold for single-stranded genomes. While Chargaff's first parity rule is fully explained by the Watson-Crick pairing in the DNA double helix, a definitive explanation for the second parity rule has not yet been determined. In this work, we propose a model based on a hidden Markov process for approximating the distributional structure of primitive DNA sequences. Then, we use the model to provide another possible theoretical explanation for Chargaff's second parity rule, and to predict novel distributional aspects of bacterial DNA sequences.

  13. Synthesis of a naphthalene-hydroxynaphthalene polymer model compound

    SciTech Connect

    Kwong, C.D.

    1990-10-09

    This goal is to synthesize a new naphthalene hydroxynaphthalene polymer model compound for use in coal combustion studies. na effort will also require the development of a synthetic procedure to synthesize this compound since it is unreported. As a result of our synthesis efforts, a number of potential precursors and Area's Analytical Section for characterization and identification. The synthesis of the pre-Bakefite intermediate has been identified as being key to the evaluation of our synthetic approach to the target compound. During this quarter, we have been reevaluating our synthetic approach while we have begun trying to synthesize this compound. As a result of our reevaluation, we also have been considering slightly modified target compounds which might be obtained by more direct routes or from commercially available materials. We also targeted simplified intermediates which would expedite our evaluation of the feasibility of the Bakelite process for the final polymerization, the key step of our suggested scheme. The results of our simplified model compound will also provide data to help us determine any modifications that will be required.

  14. Synthesis of a naphthalene-hydroxynaphthalene polymer model compound

    SciTech Connect

    Kwong, C.D.

    1991-01-15

    The goal is to synthesize a new naphthalene-hydroxynaphthalene polymer model compound for use in coal combustion studies. This effort will also require the development of a synthetic procedure to synthesize this compound since it is unreported. Our synthesis efforts have resulted in the preparation of a number of potential precursors and intermediates. These compounds were submitted to the Organic Chemistry Research Area's Analytical Section for characterization and identification. The synthesis of the pre-Bakelite intermediate has continued to be the focus of our efforts. We first modified the target intermediate slightly to allow this compound to be obtained by a more direct route, using commercially available materials. Since then, we have further simplified intermediate to expedite our evaluation of the feasibility of the Bakelite process for the final polymerization, the key step of our suggested scheme.

  15. Understanding DNA Under Oxidative Stress and Sensitization: The Role of Molecular Modeling

    NASA Astrophysics Data System (ADS)

    Monari, Antonio; Dumont, Elise

    2015-07-01

    DNA is constantly exposed to damaging threats coming from oxidative stress, i.e. from the presence of free radicals and reactive oxygen species. Sensitization from exogenous and endogenous compounds that strongly enhance the frequency of light-induced lesions also plays an important role. The experimental determination of DNA lesions, though a difficult subject, is somehow well established and allows to elucidate even extremely rare DNA lesions. In parallel, molecular modeling has become fundamental to clearly understand the fine mechanisms related to DNA defects induction. Indeed, it offers an unprecedented possibility to get access to an atomistic or even electronic resolution. Ab initio molecular dynamics may also describe the time-evolution of the molecular system and its reactivity. Yet the modeling of DNA (photo-)reactions does necessitate elaborate multi-scale methodologies to tackle a damage induction reactivity that takes place in a complex environment. The double-stranded DNA environment is first characterized by a very high flexibility, that dynamical effects are to be taken into account, but also a strongly inhomogeneous electrostatic embedding. Additionally, one aims at capturing more subtle effects, such as the sequence selectivity which is of critical important for DNA damage. The structure and dynamics of the DNA/sensitizers complexes, as well as the photo-induced electron- and energy-transfer phenomena taking place upon sensitization, should be carefully modeled. Finally the factors inducing different repair ratios for different lesions should also be rationalized. In this review we will critically analyze the different computational strategies used to model DNA lesions. A clear picture of the complex interplay between reactivity and structural factors will be sketched. The use of proper multi-scale modeling leads to the in-depth comprehension of DNA lesions mechanism and also to the rational design of new chemo-therapeutic agents.

  16. Understanding DNA under oxidative stress and sensitization: the role of molecular modeling

    PubMed Central

    Dumont, Elise; Monari, Antonio

    2015-01-01

    DNA is constantly exposed to damaging threats coming from oxidative stress, i.e., from the presence of free radicals and reactive oxygen species. Sensitization from exogenous and endogenous compounds that strongly enhance the frequency of light-induced lesions also plays an important role. The experimental determination of DNA lesions, though a difficult subject, is somehow well established and allows to elucidate even extremely rare DNA lesions. In parallel, molecular modeling has become fundamental to clearly understand the fine mechanisms related to DNA defects induction. Indeed, it offers an unprecedented possibility to get access to an atomistic or even electronic resolution. Ab initio molecular dynamics may also describe the time-evolution of the molecular system and its reactivity. Yet the modeling of DNA (photo-)reactions does necessitate elaborate multi-scale methodologies to tackle a damage induction reactivity that takes place in a complex environment. The double-stranded DNA environment is first characterized by a very high flexibility, but also a strongly inhomogeneous electrostatic embedding. Additionally, one aims at capturing more subtle effects, such as the sequence selectivity which is of critical important for DNA damage. The structure and dynamics of the DNA/sensitizers complexes, as well as the photo-induced electron- and energy-transfer phenomena taking place upon sensitization, should be carefully modeled. Finally the factors inducing different repair ratios for different lesions should also be rationalized. In this review we will critically analyze the different computational strategies used to model DNA lesions. A clear picture of the complex interplay between reactivity and structural factors will be sketched. The use of proper multi-scale modeling leads to the in-depth comprehension of DNA lesions mechanisms and also to the rational design of new chemo-therapeutic agents. PMID:26236706

  17. Synthesis of model compounds for coal liquification research

    SciTech Connect

    Sen, P.K.

    1990-10-08

    Research continued on the synthesis of model compounds for coal liquefaction research. This report covers the actual laboratory investigation performed during the reporting period in order to attain the stated objective of the project, viz, the synthesis of a model compound containing tetrahydronaphthalene, naphthalene and phenyl moieties linked by methylene, ethylene and ether bonds. The overall synthetic approach aimed at obtaining the end product has been broken down into three major steps that involve the synthesis of three key reactive intermediates. These are: (1) 3,5-dimethyl-5-bromobenzyl chloride, (2) 1-chloromethylene-2-hydroxytetralin and (3) 2-chloromethylene-1-hydroxynaphthalene.

  18. Triazene compounds induce apoptosis in O6-alkylguanine-DNA alkyltransferase deficient leukemia cell lines.

    PubMed

    Tentori, L; Graziani, G; Gilberti, S; Lacal, P M; Bonmassar, E; D'Atri, S

    1995-11-01

    Previous studies demonstrated that triazene compounds (TZC) possess antitumor, antimetastatic and immunosuppressive activity, and induce novel antigenic properties in neoplastic cells. Moreover, TZC showed marked antitumor activity in patients with acute myelogenous leukemias (AML). In most cases leukemic blasts with low levels of the repair enzyme O6-alkyl-guanine-DNA alkyltransferase (OGAT) were highly susceptible to TZC. Therefore the cytotoxic effects of TZC against human leukemic cells and the influence of OGAT modulation were investigated. Five leukemia cell lines were treated with the in vitro active derivative of dacarbazine: 5-(3-methyl-1-triazeno) imidazole-4-carboxamide (MTIC), or with temozolomide (TZM), which is readily cleaved to form the linear triazene MTIC in aqueous solution. The results showed that treatment with TZC at concentrations ranging between 62.5 and 250 microM significantly inhibited cell growth of U-937 and K-562 leukemia cell lines, both with undetectable OGAT activity. Growth inhibition was accompanied by DNA fragmentation and reduction of cell volume characteristic of cell undergoing apoptosis. In contrast, Daudi, HL-60 and Jurkat leukemia cell lines, characterized by high levels of the repair enzyme, were resistant to concentrations of TZC up to 500 microM. Treatment of resistant lines with O6-benzylguanine (BG, a specific inhibitor of OGAT) rendered HL-60 and Daudi but not Jurkat cells sensitive to cytotoxic effects and apoptosis mediated by MTIC. The results presented suggest that: (1) apoptosis is involved in cytotoxic activity of TZC; (2) OGAT could have a role in preventing programmed cell death induced by TZC; and (3) treatment with BG could potentiate cytotoxic and apoptotic effects of TZC on leukemic cell lines when high level of OGAT activity is the main factor involved in resistance to TZC.

  19. Modeling Natural Anti-Inflammatory Compounds by Molecular Topology

    PubMed Central

    Galvez-Llompart, María; Zanni, Riccardo; García-Domenech, Ramón

    2011-01-01

    One of the main pharmacological problems today in the treatment of chronic inflammation diseases consists of the fact that anti-inflammatory drugs usually exhibit side effects. The natural products offer a great hope in the identification of bioactive lead compounds and their development into drugs for treating inflammatory diseases. Computer-aided drug design has proved to be a very useful tool for discovering new drugs and, specifically, Molecular Topology has become a good technique for such a goal. A topological-mathematical model, obtained by linear discriminant analysis, has been developed for the search of new anti-inflammatory natural compounds. An external validation obtained with the remaining compounds (those not used in building up the model), has been carried out. Finally, a virtual screening on natural products was performed and 74 compounds showed actual anti-inflammatory activity. From them, 54 had been previously described as anti-inflammatory in the literature. This can be seen as a plus in the model validation and as a reinforcement of the role of Molecular Topology as an efficient tool for the discovery of new anti-inflammatory natural compounds. PMID:22272145

  20. A stochastic model for DNA electrotransfer with finite pulses

    NASA Astrophysics Data System (ADS)

    Yu, Miao; Lin, Hao

    2011-11-01

    Gene electrotransfer is a non-viral method to introduce foreign DNA into cells using electric fields. The fundamental mechanism for DNA transfer is unknown and under debate. While previous research investigated the role of DNA-membrane interaction and endocytosis, we here explore electrophoresis as a possible mechanism to assist translocation. In this model, DNA strands are treated as long-chain polymers driven through pores on the cell membrane by applied electric fields. A stochastic model is constructed, and solved numerically to parametrically study the time process of DNA translocation. Numerical results indicate that there exists an optimal pulse length beyond which DNA delivery probability no longer increases. The optimal length correlates inversely with applied field strength, and increases nonlinearly with DNA length. The results show good agreement with data from both solid-state nano-pore and electroporation experiments, and suggest that electrophoresis may play a key role in electroporation-mediated gene delivery.

  1. Rapid Diminution in the Level and Activity of DNA-Dependent Protein Kinase in Cancer Cells by a Reactive Nitro-Benzoxadiazole Compound

    PubMed Central

    Silva, Viviane A. O.; Lafont, Florian; Benhelli-Mokrani, Houda; Breton, Magali Le; Hulin, Philippe; Chabot, Thomas; Paris, François; Sakanyan, Vehary; Fleury, Fabrice

    2016-01-01

    The expression and activity of DNA-dependent protein kinase (DNA-PK) is related to DNA repair status in the response of cells to exogenous and endogenous factors. Recent studies indicate that Epidermal Growth Factor Receptor (EGFR) is involved in modulating DNA-PK. It has been shown that a compound 4-nitro-7-[(1-oxidopyridin-2-yl)sulfanyl]-2,1,3-benzoxadiazole (NSC), bearing a nitro-benzoxadiazole (NBD) scaffold, enhances tyrosine phosphorylation of EGFR and triggers downstream signaling pathways. Here, we studied the behavior of DNA-PK and other DNA repair proteins in prostate cancer cells exposed to compound NSC. We showed that both the expression and activity of DNA-PKcs (catalytic subunit of DNA-PK) rapidly decreased upon exposure of cells to the compound. The decline in DNA-PKcs was associated with enhanced protein ubiquitination, indicating the activation of cellular proteasome. However, pretreatment of cells with thioglycerol abolished the action of compound NSC and restored the level of DNA-PKcs. Moreover, the decreased level of DNA-PKcs was associated with the production of intracellular hydrogen peroxide by stable dimeric forms of Cu/Zn SOD1 induced by NSC. Our findings indicate that reactive oxygen species and electrophilic intermediates, generated and accumulated during the redox transformation of NBD compounds, are primarily responsible for the rapid modulation of DNA-PKcs functions in cancer cells. PMID:27187356

  2. Synthesis, spectroscopic characterization and structural investigations of new adduct compound of carbazole with picric acid: DNA binding and antimicrobial studies

    NASA Astrophysics Data System (ADS)

    Saravanabhavan, Munusamy; Sathya, Krishnan; Puranik, Vedavati G.; Sekar, Marimuthu

    2014-01-01

    Carbazole picrate (CP), a new organic compound has been synthesized, characterized by various analytical and spectroscopic technique such as FT-IR, UV-Vis, 1H and 13C NMR spectroscopy. An orthorhombic geometry was proposed based on single crystal XRD study. The thermal stability of the crystal was studied by using thermo-gravimetric and differential thermal analyses and found that it was stable up to 170 °C. Further, the newly synthesized title compound was tested for its in vitro antibacterial and antifungal activity against various bacterial and fungal species. Also, the compound was tested for its binding activity with Calf thymus (CT) DNA and the results show a considerable interaction between CP and CT-DNA.

  3. Modeling emissions of volatile organic compounds from silage

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Volatile organic compounds (VOCs), necessary reactants for photochemical smog formation, are emitted from numerous sources. Limited available data suggest that dairy farms emit VOCs with cattle feed, primarily silage, being the primary source. Process-based models of VOC transfer within and from si...

  4. Laccase-mediator catalyzed conversion of model lignin compounds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Laccases play an important role in the biological breakdown of lignin and have great potential in the deconstruction of lignocellulosic feedstocks. We examined a variety of laccases, both commercially prepared and crude extracts, for their ability to oxidize three model lignol compounds (p-coumaryl...

  5. Coarse-grained DNA modeling: Hybridization and ionic effects

    NASA Astrophysics Data System (ADS)

    Hinckley, Daniel M.

    Deoxyribonucleic acid (DNA) is a biopolymer of enormous significance in living systems. The utility of DNA in such systems is derived from the programmable nature of DNA and its unique mechanical properties. Recently, material scientists have harnessed these properties in order to create systems that spontaneous self-assemble on the nanoscale. Both biologists and material scientists are hindered by an incomplete understanding of the physical interactions that together govern DNA's behavior. Computer simulations, especially those at the coarse-grained (CG) level, can potentially complete this understanding by resolving details indiscernible with current experimental techniques. In this thesis, we advance the state-of-the-art of DNA CG simulations by first reviewing the relevant theory and the evolution of CG DNA models since their inception. Then we present 3SPN.2, an improved CG model for DNA that should provide new insights into biological and nanotechnological systems which incorporate DNA. We perform forward flux sampling simulations in order to examine the effect of sequence, oligomer length, and ionic strength on DNA oligomer hybridization. Due to the limitations inherent in continuum treatments of electrostatic interactions in biological systems, we generate a CG model of biological ions for use with 3SPN.2 and other CG models. Lastly, we illustrate the potential of 3SPN.2 and CG ions by using the models in simulations of viral capsid packaging experiments. The models and results described in this thesis will be useful in future modeling efforts that seek to identify the fundamental physics that govern behavior such as nucleosome positioning, DNA hybridization, and DNA nanoassembly.

  6. Mycofumigation by the Volatile Organic Compound-Producing Fungus Muscodor albus Induces Bacterial Cell Death through DNA Damage

    PubMed Central

    Alpha, Cambria J.; Campos, Manuel; Jacobs-Wagner, Christine

    2014-01-01

    Muscodor albus belongs to a genus of endophytic fungi that inhibit and kill other fungi, bacteria, and insects through production of a complex mixture of volatile organic compounds (VOCs). This process of mycofumigation has found commercial application for control of human and plant pathogens, but the mechanism of the VOC toxicity is unknown. Here, the mode of action of these volatiles was investigated through a series of genetic screens and biochemical assays. A single-gene knockout screen revealed high sensitivity for Escherichia coli lacking enzymes in the pathways of DNA repair, DNA metabolic process, and response to stress when exposed to the VOCs of M. albus. Furthermore, the sensitivity of knockouts involved in the repair of specific DNA alkyl adducts suggests that the VOCs may induce alkylation. Evidence of DNA damage suggests that these adducts lead to breaks during DNA replication or transcription if not properly repaired. Additional cytotoxicity profiling indicated that during VOC exposure, E. coli became filamentous and demonstrated an increase in cellular membrane fluidity. The volatile nature of the toxic compounds produced by M. albus and their broad range of inhibition make this fungus an attractive biological agent. Understanding the antimicrobial effects and the VOC mode of action will inform the utility and safety of potential mycofumigation applications for M. albus. PMID:25452287

  7. Mycofumigation by the volatile organic compound-producing Fungus Muscodor albus induces bacterial cell death through DNA damage.

    PubMed

    Alpha, Cambria J; Campos, Manuel; Jacobs-Wagner, Christine; Strobel, Scott A

    2015-02-01

    Muscodor albus belongs to a genus of endophytic fungi that inhibit and kill other fungi, bacteria, and insects through production of a complex mixture of volatile organic compounds (VOCs). This process of mycofumigation has found commercial application for control of human and plant pathogens, but the mechanism of the VOC toxicity is unknown. Here, the mode of action of these volatiles was investigated through a series of genetic screens and biochemical assays. A single-gene knockout screen revealed high sensitivity for Escherichia coli lacking enzymes in the pathways of DNA repair, DNA metabolic process, and response to stress when exposed to the VOCs of M. albus. Furthermore, the sensitivity of knockouts involved in the repair of specific DNA alkyl adducts suggests that the VOCs may induce alkylation. Evidence of DNA damage suggests that these adducts lead to breaks during DNA replication or transcription if not properly repaired. Additional cytotoxicity profiling indicated that during VOC exposure, E. coli became filamentous and demonstrated an increase in cellular membrane fluidity. The volatile nature of the toxic compounds produced by M. albus and their broad range of inhibition make this fungus an attractive biological agent. Understanding the antimicrobial effects and the VOC mode of action will inform the utility and safety of potential mycofumigation applications for M. albus.

  8. Composite material of DNA and cyclodextrin-immobilized poly(ethyleneimine): Accumulation of harmful compounds from multi-component solution.

    PubMed

    Yamada, Masanori; Hori, Minako; Tabuchi, Shinya

    2010-08-01

    Water-soluble beta-cyclodextrin-immobilized poly(ethyleneimine) (PEICD) was synthesized by the grafting of beta-cyclodextrin to the branched poly(ethyleneimine). In an aqueous solution, this PEICD polymer could encapsulate bisphenol A, known to be a harmful compound. Additionally, the stability constant of bisphenol A to the PEICD polymer was 1.1 x 10(4)M(-1). However, the water-solubility of PEICD has been making it difficult to utilize it as an environmental material. Therefore, we prepared the DNA-PEICD composite material by mixing the double-stranded DNA and PEICD. This DNA-PEICD composite material was extremely stable in water and possessed both properties of the intercalation into the double-stranded DNA and the encapsulation into the CD cavity. As a result, this material can accumulate various harmful compounds, such as dioxin- and polychlorobiphenyl (PCB)-derivatives and bisphenol A, from a multi-component solution. Therefore, the DNA-PEICD composite material may have the potential to be used as an environmental material.

  9. Modeling toxic compounds from nitric oxide emission measurements

    NASA Astrophysics Data System (ADS)

    Vallero, Daniel A.; Peirce, Jeffrey; Cho, Ki Don

    Determining the amount and rate of degradation of toxic pollutants in soil and groundwater is difficult and often requires invasive techniques, such as deploying extensive monitoring well networks. Even with these networks, degradation rates across entire systems cannot readily be extrapolated from the samples. When organic compounds are degraded by microbes, especially nitrifying bacteria, oxides or nitrogen (NO x) are released to the atmosphere. Thus, the flux of nitric oxide (NO) from the soil to the lower troposphere can be used to predict the rate at which organic compounds are degraded. By characterizing and applying biogenic and anthropogenic processes in soils the rates of degradation of organic compounds. Toluene was selected as a representative of toxic aromatic compounds, since it is inherently toxic, it is a substituted benzene compound and is listed as a hazardous air pollutant under Section 12 of the Clean Air Act Amendments of 1990. Measured toluene concentrations in soil, microbial population growth and NO fluxes in chamber studies were used to develop and parameterize a numerical model based on carbon and nitrogen cycling. These measurements, in turn, were used as indicators of bioremediation of air toxic (i.e. toluene) concentrations. The model found that chemical concentration, soil microbial abundance, and NO production can be directly related to the experimental results (significant at P < 0.01) for all toluene concentrations tested. This indicates that the model may prove useful in monitoring and predicting the fate of toxic aromatic contaminants in a complex soil system. It may also be useful in predicting the release of ozone precursors, such as changes in reservoirs of hydrocarbons and oxides of nitrogen. As such, the model may be a tool for decision makers in ozone non-attainment areas.

  10. A mathematical model and numerical method for thermoelectric DNA sequencing

    NASA Astrophysics Data System (ADS)

    Shi, Liwei; Guilbeau, Eric J.; Nestorova, Gergana; Dai, Weizhong

    2014-05-01

    Single nucleotide polymorphisms (SNPs) are single base pair variations within the genome that are important indicators of genetic predisposition towards specific diseases. This study explores the feasibility of SNP detection using a thermoelectric sequencing method that measures the heat released when DNA polymerase inserts a deoxyribonucleoside triphosphate into a DNA strand. We propose a three-dimensional mathematical model that governs the DNA sequencing device with a reaction zone that contains DNA template/primer complex immobilized to the surface of the lower channel wall. The model is then solved numerically. Concentrations of reactants and the temperature distribution are obtained. Results indicate that when the nucleoside is complementary to the next base in the DNA template, polymerization occurs lengthening the complementary polymer and releasing thermal energy with a measurable temperature change, implying that the thermoelectric conceptual device for sequencing DNA may be feasible for identifying specific genes in individuals.

  11. PiDNA: Predicting protein-DNA interactions with structural models.

    PubMed

    Lin, Chih-Kang; Chen, Chien-Yu

    2013-07-01

    Predicting binding sites of a transcription factor in the genome is an important, but challenging, issue in studying gene regulation. In the past decade, a large number of protein-DNA co-crystallized structures available in the Protein Data Bank have facilitated the understanding of interacting mechanisms between transcription factors and their binding sites. Recent studies have shown that both physics-based and knowledge-based potential functions can be applied to protein-DNA complex structures to deliver position weight matrices (PWMs) that are consistent with the experimental data. To further use the available structural models, the proposed Web server, PiDNA, aims at first constructing reliable PWMs by applying an atomic-level knowledge-based scoring function on numerous in silico mutated complex structures, and then using the PWM constructed by the structure models with small energy changes to predict the interaction between proteins and DNA sequences. With PiDNA, the users can easily predict the relative preference of all the DNA sequences with limited mutations from the native sequence co-crystallized in the model in a single run. More predictions on sequences with unlimited mutations can be realized by additional requests or file uploading. Three types of information can be downloaded after prediction: (i) the ranked list of mutated sequences, (ii) the PWM constructed by the favourable mutated structures, and (iii) any mutated protein-DNA complex structure models specified by the user. This study first shows that the constructed PWMs are similar to the annotated PWMs collected from databases or literature. Second, the prediction accuracy of PiDNA in detecting relatively high-specificity sites is evaluated by comparing the ranked lists against in vitro experiments from protein-binding microarrays. Finally, PiDNA is shown to be able to select the experimentally validated binding sites from 10,000 random sites with high accuracy. With PiDNA, the users can

  12. iDNA-Prot: identification of DNA binding proteins using random forest with grey model.

    PubMed

    Lin, Wei-Zhong; Fang, Jian-An; Xiao, Xuan; Chou, Kuo-Chen

    2011-01-01

    DNA-binding proteins play crucial roles in various cellular processes. Developing high throughput tools for rapidly and effectively identifying DNA-binding proteins is one of the major challenges in the field of genome annotation. Although many efforts have been made in this regard, further effort is needed to enhance the prediction power. By incorporating the features into the general form of pseudo amino acid composition that were extracted from protein sequences via the "grey model" and by adopting the random forest operation engine, we proposed a new predictor, called iDNA-Prot, for identifying uncharacterized proteins as DNA-binding proteins or non-DNA binding proteins based on their amino acid sequences information alone. The overall success rate by iDNA-Prot was 83.96% that was obtained via jackknife tests on a newly constructed stringent benchmark dataset in which none of the proteins included has ≥25% pairwise sequence identity to any other in a same subset. In addition to achieving high success rate, the computational time for iDNA-Prot is remarkably shorter in comparison with the relevant existing predictors. Hence it is anticipated that iDNA-Prot may become a useful high throughput tool for large-scale analysis of DNA-binding proteins. As a user-friendly web-server, iDNA-Prot is freely accessible to the public at the web-site on http://icpr.jci.edu.cn/bioinfo/iDNA-Prot or http://www.jci-bioinfo.cn/iDNA-Prot. Moreover, for the convenience of the vast majority of experimental scientists, a step-by-step guide is provided on how to use the web-server to get the desired results. PMID:21935457

  13. Modeling Emissions of Volatile Organic Compounds from New Carpets

    SciTech Connect

    Little, J.C.; Hodgson, A.T.; Gadgil, A.J.

    1993-02-01

    A simple model is proposed to account for observed emissions of volatile organic compounds (VOCs) from new carpets. The model assumes that the VOCs originate predominantly in a uniform slab of polymer backing material. Parameters for the model (the initial concentration of a VOC in the polymer, a diffusion coefficient and an equilibrium polymer/air partition coefficient) are obtained from experimental data produced by a previous chamber study. The diffusion coefficients generally decrease as the molecular weight of the VOCs increase, while the polymer/air partition coefficients generally increase as the vapor pressure of the compounds decrease. In addition, for two of the study carpets that have a styrene-butadiene rubber (SBR) backing, the diffusion and partition coefficients are similar to independently reported values for SBR. The results suggest that predictions of VOCs emissions from new carpets may be possible based solely on a knowledge of the physical properties of the relevant compounds and the carpet backing material. However, a more rigorous validation of the model is desirable.

  14. Capstan Friction Model for DNA Ejection from Bacteriophages

    NASA Astrophysics Data System (ADS)

    Ghosal, Sandip

    2012-12-01

    Bacteriophages infect cells by attaching to the outer membrane and injecting their DNA into the cell. The phage DNA is then transcribed by the cell’s transcription machinery. A number of physical mechanisms by which DNA can be translocated from the phage capsid into the cell have been identified. A fast ejection driven by the elastic and electrostatic potential energy of the compacted DNA within the viral capsid appears to be used by most phages, at least to initiate infection. In recent in vitro experiments, the speed of DNA translocation from a λ phage capsid has been measured as a function of ejected length over the entire duration of the event. Here, a mechanical model is proposed that is able to explain the observed dependence of exit velocity on ejected length, and that is also consistent with the accepted picture of the geometric arrangement of DNA within the viral capsid.

  15. Genotoxicity of tri- and hexavalent chromium compounds in vivo and their modes of action on DNA damage in vitro.

    PubMed

    Fang, Zhijia; Zhao, Min; Zhen, Hong; Chen, Lifeng; Shi, Ping; Huang, Zhiwei

    2014-01-01

    Chromium occurs mostly in tri- and hexavalent states in the environment. Hexavalent chromium [Cr(VI)] compounds are extensively used in diverse industries, and trivalent chromium [Cr(III)] salts are used as micronutrients and dietary supplements. In the present work, we report that they both induce genetic mutations in yeast cells. They both also cause DNA damage in both yeast and Jurkat cells and the effect of Cr(III) is greater than that of Cr(VI). We further show that Cr(III) and Cr(VI) cause DNA damage through different mechanisms. Cr(VI) intercalates DNA and Cr(III) interferes base pair stacking. Based on our results, we conclude that Cr(III) can directly cause genotoxicity in vivo. PMID:25111056

  16. Genotoxicity of Tri- and Hexavalent Chromium Compounds In Vivo and Their Modes of Action on DNA Damage In Vitro

    PubMed Central

    Fang, Zhijia; Zhao, Min; Zhen, Hong; Chen, Lifeng; Shi, Ping; Huang, Zhiwei

    2014-01-01

    Chromium occurs mostly in tri- and hexavalent states in the environment. Hexavalent chromium [Cr(VI)] compounds are extensively used in diverse industries, and trivalent chromium [Cr(III)] salts are used as micronutrients and dietary supplements. In the present work, we report that they both induce genetic mutations in yeast cells. They both also cause DNA damage in both yeast and Jurkat cells and the effect of Cr(III) is greater than that of Cr(VI). We further show that Cr(III) and Cr(VI) cause DNA damage through different mechanisms. Cr(VI) intercalates DNA and Cr(III) interferes base pair stacking. Based on our results, we conclude that Cr(III) can directly cause genotoxicity in vivo. PMID:25111056

  17. DNA Targeting Sequence Improves Magnetic Nanoparticle-Based Plasmid DNA Transfection Efficiency in Model Neurons

    PubMed Central

    Vernon, Matthew M.; Dean, David A.; Dobson, Jon

    2015-01-01

    Efficient non-viral plasmid DNA transfection of most stem cells, progenitor cells and primary cell lines currently presents an obstacle for many applications within gene therapy research. From a standpoint of efficiency and cell viability, magnetic nanoparticle-based DNA transfection is a promising gene vectoring technique because it has demonstrated rapid and improved transfection outcomes when compared to alternative non-viral methods. Recently, our research group introduced oscillating magnet arrays that resulted in further improvements to this novel plasmid DNA (pDNA) vectoring technology. Continued improvements to nanomagnetic transfection techniques have focused primarily on magnetic nanoparticle (MNP) functionalization and transfection parameter optimization: cell confluence, growth media, serum starvation, magnet oscillation parameters, etc. Noting that none of these parameters can assist in the nuclear translocation of delivered pDNA following MNP-pDNA complex dissociation in the cell’s cytoplasm, inclusion of a cassette feature for pDNA nuclear translocation is theoretically justified. In this study incorporation of a DNA targeting sequence (DTS) feature in the transfecting plasmid improved transfection efficiency in model neurons, presumably from increased nuclear translocation. This observation became most apparent when comparing the response of the dividing SH-SY5Y precursor cell to the non-dividing and differentiated SH-SY5Y neuroblastoma cells. PMID:26287182

  18. DNA Targeting Sequence Improves Magnetic Nanoparticle-Based Plasmid DNA Transfection Efficiency in Model Neurons.

    PubMed

    Vernon, Matthew M; Dean, David A; Dobson, Jon

    2015-01-01

    Efficient non-viral plasmid DNA transfection of most stem cells, progenitor cells and primary cell lines currently presents an obstacle for many applications within gene therapy research. From a standpoint of efficiency and cell viability, magnetic nanoparticle-based DNA transfection is a promising gene vectoring technique because it has demonstrated rapid and improved transfection outcomes when compared to alternative non-viral methods. Recently, our research group introduced oscillating magnet arrays that resulted in further improvements to this novel plasmid DNA (pDNA) vectoring technology. Continued improvements to nanomagnetic transfection techniques have focused primarily on magnetic nanoparticle (MNP) functionalization and transfection parameter optimization: cell confluence, growth media, serum starvation, magnet oscillation parameters, etc. Noting that none of these parameters can assist in the nuclear translocation of delivered pDNA following MNP-pDNA complex dissociation in the cell's cytoplasm, inclusion of a cassette feature for pDNA nuclear translocation is theoretically justified. In this study incorporation of a DNA targeting sequence (DTS) feature in the transfecting plasmid improved transfection efficiency in model neurons, presumably from increased nuclear translocation. This observation became most apparent when comparing the response of the dividing SH-SY5Y precursor cell to the non-dividing and differentiated SH-SY5Y neuroblastoma cells. PMID:26287182

  19. Structure-based modeling of protein: DNA specificity

    PubMed Central

    Joyce, Adam P.; Zhang, Chi; Bradley, Philip

    2015-01-01

    Protein:DNA interactions are essential to a range of processes that maintain and express the information encoded in the genome. Structural modeling is an approach that aims to understand these interactions at the physicochemical level. It has been proposed that structural modeling can lead to deeper understanding of the mechanisms of protein:DNA interactions, and that progress in this field can not only help to rationalize the observed specificities of DNA-binding proteins but also to allow researchers to engineer novel DNA site specificities. In this review we discuss recent developments in the structural description of protein:DNA interactions and specificity, as well as the challenges facing the field in the future. PMID:25414269

  20. Mutations induced by 1-nitrosopyrene and related compounds during DNA replication in human cells and induction of homologous recombination by these compounds.

    PubMed

    Maher, V M; Bhattacharyya, N P; Mah, M C; Boldt, J; Yang, J L; McCormick, J J

    1993-03-01

    The transformation of normal human cells into cancer cells is a multistep process. Evidence suggests that a minimum of five independent steps (changes) are required for the development of certain kinds of human cancer, as well as for malignant transformation of human cells in culture. Mutations are one of the mechanisms involved in bringing about such changes. A single DNA base substitution mutation can activate an oncogene or inactivate a tumor suppressor gene. Because the action of tumor suppressor genes is to prevent cells from becoming malignant, the activity of both copies of such genes must be eliminated before suppression is lifted. Homologous mitotic recombination between a mutant tumor suppressor gene allele and its non-mutant allele is one mechanism for accomplishing this. The present study was designed to investigate the mechanisms by which certain carcinogenic compounds found in diesel exhaust particles and structurally-related N-substituted aryl carcinogens induce such base substitution mutations and homologous recombination events in mammalian cells in culture, including human cells. The system we employed to determine rapidly the kinds of mutations induced by these compounds, as well as the location of the point mutations in the target gene, involved a circular DNA molecule (plasmid) carrying a small target gene, supF. The target gene was exposed in vitro to radiolabeled compounds and then was allowed to replicate in human cells where the mutations were formed. The sites of mutation induction were compared with the sites of stable binding of the carcinogens to the DNA (adducts). The system used to determine whether these agents could induce homologous recombination consisted of a thymidine kinase-deficient mouse L cell line with a recombination substrate stably integrated into the genome. To determine whether or not excision repair was involved in the mechanism by which carcinogens induced recombination, the recombination substrate was introduced

  1. Theory and modeling of particles with DNA-mediated interactions

    NASA Astrophysics Data System (ADS)

    Licata, Nicholas A.

    2008-05-01

    In recent years significant attention has been attracted to proposals which utilize DNA for nanotechnological applications. Potential applications of these ideas range from the programmable self-assembly of colloidal crystals, to biosensors and nanoparticle based drug delivery platforms. In Chapter I we introduce the system, which generically consists of colloidal particles functionalized with specially designed DNA markers. The sequence of bases on the DNA markers determines the particle type. Due to the hybridization between complementary single-stranded DNA, specific, type-dependent interactions can be introduced between particles by choosing the appropriate DNA marker sequences. In Chapter II we develop a statistical mechanical description of the aggregation and melting behavior of particles with DNA-mediated interactions. In Chapter III a model is proposed to describe the dynamical departure and diffusion of particles which form reversible key-lock connections. In Chapter IV we propose a method to self-assemble nanoparticle clusters using DNA scaffolds. A natural extension is discussed in Chapter V, the programmable self-assembly of nanoparticle clusters where the desired cluster geometry is encoded using DNA-mediated interactions. In Chapter VI we consider a nanoparticle based drug delivery platform for targeted, cell specific chemotherapy. In Chapter VII we present prospects for future research: the connection between DNA-mediated colloidal crystallization and jamming, and the inverse problem in self-assembly.

  2. A compound compensation method for car-following model

    NASA Astrophysics Data System (ADS)

    Zhu, Wen-Xing; Jun, Du; Zhang, Li-Dong

    2016-10-01

    A compound compensation mechanism was introduced into the car-following system. Two basic compensation methods were combined to generate a compound control strategy to improve the performance of the traffic flow system. The compensation effect was analyzed with unit step response in time domain and bode diagram in frequency domain, respectively. Two lemmas and one theorem were proved with the use of Routh criteria and small gain theorem. Numerical simulations were conducted in two situations under three types of condition. The simulation results verify the truth that with the increasing compensation parameters the stability of the car-following system is strengthened. It is shown that numerical results are in accordance with analytical results. In general, the performance of car-following model can be improved with an exterior control method.

  3. Lindley frailty model for a class of compound Poisson processes

    NASA Astrophysics Data System (ADS)

    Kadilar, Gamze Özel; Ata, Nihal

    2013-10-01

    The Lindley distribution gain importance in survival analysis for the similarity of exponential distribution and allowance for the different shapes of hazard function. Frailty models provide an alternative to proportional hazards model where misspecified or omitted covariates are described by an unobservable random variable. Despite of the distribution of the frailty is generally assumed to be continuous, it is appropriate to consider discrete frailty distributions In some circumstances. In this paper, frailty models with discrete compound Poisson process for the Lindley distributed failure time are introduced. Survival functions are derived and maximum likelihood estimation procedures for the parameters are studied. Then, the fit of the models to the earthquake data set of Turkey are examined.

  4. QSPR Modeling of Bioconcentration Factors of Nonionic Organic Compounds

    PubMed Central

    Deeb, Omar; Khadikar, Padmakar V.; Goodarzi, Mohammad

    2010-01-01

    The terms bioaccumulation and bioconcentration refer to the uptake and build-up of chemicals that can occur in living organisms. Experimental measurement of bioconcentration is time-consuming and expensive, and is not feasible for a large number of chemicals of potential regulatory concern. A highly effective tool depending on a quantitative structure-property relationship (QSPR) can be utilized to describe the tendency of chemical concentration organisms represented by, the important ecotoxicological parameter, the logarithm of Bio Concentration Factor (log BCF) with molecular descriptors for a large set of non-ionic organic compounds. QSPR models were developed using multiple linear regression, partial least squares and neural networks analyses. Linear and non-linear QSPR models to predict log BCF of the compounds developed for the relevant descriptors. The results obtained offer good regression models having good prediction ability. The descriptors used in these models depend on the volume, connectivity, molar refractivity, surface tension and the presence of atoms accepting H-bonds. PMID:20706622

  5. Kinetic model of DNA replication in eukaryotic organisms

    NASA Astrophysics Data System (ADS)

    Bechhoefer, John; Herrick, John; Bensimon, Aaron

    2001-03-01

    We introduce an analogy between DNA replication in eukaryotic organisms and crystal growth in one dimension. Drawing on models of crystallization kinetics developed in the 1930s to describe the freezing of metals, we formulate a kinetic model of DNA replication that quantitatively describes recent results on DNA replication in the in vitro system of Xenopus laevis prior to the mid-blastula transition. It allows one, for the first time, to determine the parameters governing the DNA replication program in a eukaryote on a genome-wide basis. In particular, we have determined the frequency of origin activation in time and space during the cell cycle. Although we focus on a specific stage of development, this model can easily be adapted to describe replication in many other organisms, including budding yeast.

  6. ATOMIC AND MOLECULAR PHYSICS: Modelling of a DNA packaging motor

    NASA Astrophysics Data System (ADS)

    Qian, Jun; Xie, Ping; Xue, Xiao-Guang; Wang, Peng-Ye

    2009-11-01

    During the assembly of many viruses, a powerful molecular motor packages the genome into a preassembled capsid. The Bacillus subtilis phage phi29 is an excellent model system to investigate the DNA packaging mechanism because of its highly efficient in vitro DNA packaging activity and the development of a single-molecule packaging assay. Here we make use of structural and biochemical experimental data to build a physical model of DNA packaging by the phi29 DNA packaging motor. Based on the model, various dynamic behaviours such as the packaging rate, pause frequency and slip frequency under different ATP concentrations, ADP concentrations, external loads as well as capsid fillings are studied by using Monte Carlo simulation. Good agreement is obtained between the simulated and available experimental results. Moreover, we make testable predictions that should guide future experiments related to motor function.

  7. A bivariate survival model with compound Poisson frailty.

    PubMed

    Wienke, A; Ripatti, S; Palmgren, J; Yashin, A

    2010-01-30

    A correlated frailty model is suggested for analysis of bivariate time-to-event data. The model is an extension of the correlated power variance function (PVF) frailty model (correlated three-parameter frailty model) (J. Epidemiol. Biostat. 1999; 4:53-60). It is based on a bivariate extension of the compound Poisson frailty model in univariate survival analysis (Ann. Appl. Probab. 1992; 4:951-972). It allows for a non-susceptible fraction (of zero frailty) in the population, overcoming the common assumption in survival analysis that all individuals are susceptible to the event under study. The model contains the correlated gamma frailty model and the correlated inverse Gaussian frailty model as special cases. A maximum likelihood estimation procedure for the parameters is presented and its properties are studied in a small simulation study. This model is applied to breast cancer incidence data of Swedish twins. The proportion of women susceptible to breast cancer is estimated to be 15 per cent.

  8. Modeling the Sensitivity of Field Surveys for Detection of Environmental DNA (eDNA).

    PubMed

    Schultz, Martin T; Lance, Richard F

    2015-01-01

    The environmental DNA (eDNA) method is the practice of collecting environmental samples and analyzing them for the presence of a genetic marker specific to a target species. Little is known about the sensitivity of the eDNA method. Sensitivity is the probability that the target marker will be detected if it is present in the water body. Methods and tools are needed to assess the sensitivity of sampling protocols, design eDNA surveys, and interpret survey results. In this study, the sensitivity of the eDNA method is modeled as a function of ambient target marker concentration. The model accounts for five steps of sample collection and analysis, including: 1) collection of a filtered water sample from the source; 2) extraction of DNA from the filter and isolation in a purified elution; 3) removal of aliquots from the elution for use in the polymerase chain reaction (PCR) assay; 4) PCR; and 5) genetic sequencing. The model is applicable to any target species. For demonstration purposes, the model is parameterized for bighead carp (Hypophthalmichthys nobilis) and silver carp (H. molitrix) assuming sampling protocols used in the Chicago Area Waterway System (CAWS). Simulation results show that eDNA surveys have a high false negative rate at low concentrations of the genetic marker. This is attributed to processing of water samples and division of the extraction elution in preparation for the PCR assay. Increases in field survey sensitivity can be achieved by increasing sample volume, sample number, and PCR replicates. Increasing sample volume yields the greatest increase in sensitivity. It is recommended that investigators estimate and communicate the sensitivity of eDNA surveys to help facilitate interpretation of eDNA survey results. In the absence of such information, it is difficult to evaluate the results of surveys in which no water samples test positive for the target marker. It is also recommended that invasive species managers articulate concentration

  9. Modeling the Sensitivity of Field Surveys for Detection of Environmental DNA (eDNA)

    PubMed Central

    Schultz, Martin T.; Lance, Richard F.

    2015-01-01

    The environmental DNA (eDNA) method is the practice of collecting environmental samples and analyzing them for the presence of a genetic marker specific to a target species. Little is known about the sensitivity of the eDNA method. Sensitivity is the probability that the target marker will be detected if it is present in the water body. Methods and tools are needed to assess the sensitivity of sampling protocols, design eDNA surveys, and interpret survey results. In this study, the sensitivity of the eDNA method is modeled as a function of ambient target marker concentration. The model accounts for five steps of sample collection and analysis, including: 1) collection of a filtered water sample from the source; 2) extraction of DNA from the filter and isolation in a purified elution; 3) removal of aliquots from the elution for use in the polymerase chain reaction (PCR) assay; 4) PCR; and 5) genetic sequencing. The model is applicable to any target species. For demonstration purposes, the model is parameterized for bighead carp (Hypophthalmichthys nobilis) and silver carp (H. molitrix) assuming sampling protocols used in the Chicago Area Waterway System (CAWS). Simulation results show that eDNA surveys have a high false negative rate at low concentrations of the genetic marker. This is attributed to processing of water samples and division of the extraction elution in preparation for the PCR assay. Increases in field survey sensitivity can be achieved by increasing sample volume, sample number, and PCR replicates. Increasing sample volume yields the greatest increase in sensitivity. It is recommended that investigators estimate and communicate the sensitivity of eDNA surveys to help facilitate interpretation of eDNA survey results. In the absence of such information, it is difficult to evaluate the results of surveys in which no water samples test positive for the target marker. It is also recommended that invasive species managers articulate concentration

  10. The effect of novel rhenium compounds on lymphosarcoma, PC-3 prostate and myeloid leukemia cancer cell lines and an investigation on the DNA binding properties of one of these compounds through electronic spectroscopy

    PubMed Central

    Parson, Carl; Smith, Valerie; Krauss, Christopher; Banerjee, Hirendra N.; Reilly, Christopher; Krause, Jeanette A.; Wachira, James M.; Giri, Dipak; Winstead, Angela; Mandal, Santosh K.

    2014-01-01

    Despite the tremendous success of cisplatin and other platinum-based anticancer drugs, severe toxicity and resistance to tumors limit their applications. It is believed that the coordination (formation of covalent bond) of the metal (platinum) to the nitrogen bases of DNA cause the ruptures of the cancer as well as normal cells. A search for anticancer drugs with different modes of action resulted in the synthesis of variety of novel compounds. Many of them are in clinical trials now. Recently we synthesized a series of novel rhenium pentylcarbonato compounds (PC1–PC6). The rhenium atom in each compound is coordinated (bonded) to a planar polypyridyl aromatic ligand, thereby forcing each compound to intercalate between the DNA bases. We have investigated the DNA binding properties of one of the PC-series of compounds (PC6) using electronic spectroscopy. The UV absorption titration of PC6 with DNA shows hypochromic effect with concomitant bathochromic shift of the charge transfer band at 290 nm. These results suggest that the compound PC6 binds to DNA through intercalation. It is therefore likely that the other PC-series of compounds will behave in a similar manner. Thus it is expected that these compounds will exhibit negligible or no side effect. We have observed that the PC-series of compounds are strong cytotoxic agents against lymphosarcoma (average GI50 ≈ 2±2.6 µM), PC-3 prostate (average GI50 ≈ 3±2.8 µM) and myeloid leukemia (average GI50 ≈ 3±2.8 µM) cancer cell lines. The average GI50 values of the PC-series of compounds are 2–3 less than the corresponding GI50 values of cisplatin. Also each of the PC-series of compounds exhibits less toxicity than cisplatin in the glomerular mesangial cells. PMID:25221731

  11. Model for compound formation during ion-beam mixing

    SciTech Connect

    Desimoni, J.; Traverse, A. )

    1993-11-01

    We propose an ion-beam-mixing model that accounts for compound formation at a boundary between two materials during ion irradiation. It is based on Fick's law together with a chemical driving force in order to simulate the chemical reaction at the boundary. The behavior of the squared thickness of the mixed layer, [ital X][sup 2], with the irradiation fluence, [Phi], has been found in several mixing experiments to be either quadratic ([ital X][sup 2][alpha][Phi][sup 2]) or linear ([ital X][sup 2][alpha][Phi]), a result which is qualitatively reproduced. Depending on the fluence range, compound formation or diffusion is the limiting process of mixing kinetics. A criterion is established in terms of the ratio of the diffusion coefficient [ital D] due to irradiation to the chemical reaction rate squared which allows us to predict quadratic or linear behavior. When diffusion is the limiting process, [ital D] is enhanced by a factor which accounts for the formation of a compound in the mixed layer. Good agreement is found between the calculated mixing rates and the data taken from mixing experiments in metal/Si bilayers.

  12. A COMPOUND MODEL FOR THE ORIGIN OF EARTH'S WATER

    SciTech Connect

    Izidoro, A.; Winter, O. C.; De Souza Torres, K.; Haghighipour, N.

    2013-04-10

    One of the most important subjects of debate in the formation of the solar system is the origin of Earth's water. Comets have long been considered as the most likely source of the delivery of water to Earth. However, elemental and isotopic arguments suggest a very small contribution from these objects. Other sources have also been proposed, among which local adsorption of water vapor onto dust grains in the primordial nebula and delivery through planetesimals and planetary embryos have become more prominent. However, no sole source of water provides a satisfactory explanation for Earth's water as a whole. In view of that, using numerical simulations, we have developed a compound model incorporating both the principal endogenous and exogenous theories, and investigating their implications for terrestrial planet formation and water delivery. Comets are also considered in the final analysis, as it is likely that at least some of Earth's water has cometary origin. We analyze our results comparing two different water distribution models, and complement our study using the D/H ratio, finding possible relative contributions from each source and focusing on planets formed in the habitable zone. We find that the compound model plays an important role by showing greater advantage in the amount and time of water delivery in Earth-like planets.

  13. Cytotoxic Hydrophilic Iminophosphorane Coordination Compounds of d8 Metals. Studies of their Interactions with DNA and HSA

    PubMed Central

    Carreira, Monica; Calvo-Sanjuán, Rubén; Sanaú, Mercedes; Zhao, Xiangbo; Magliozzo, Richard S.; Marzo, Isabel; Contel, María

    2012-01-01

    The synthesis and characterization of a new water-soluble N,N-chelating iminophosphorane ligand TPA=N-C(O)-2-NC5H4 (N,N-IM) (1) and its d8 (AuIII, PdII and PtII) coordination complexes are reported. The structures of cationic [AuCl2(N,N-IM)] ClO4 (2) and neutral [MCl2(N,N-IM)] M = Pd (3), Pt(4) complexes were determined by X-ray diffraction studies or by means of density-functional calculations. While the Pd and Pt compounds are stable in mixtures of DMSO/H2O over 4 days, the gold derivative (2) decomposes quickly to TPA=O and previously reported neutral gold(III) compound [AuCl2(N,N-H)] 5 (containing the chelating N,N- fragment HN-C(O)-2-NC5H4). The cytotoxicities of complexes 2–5 were evaluated in vitro against human Jurkat-T acute lymphoblastic leukemia cells and DU-145 human prostate cancer cells. Pt (4) and Au compounds (2 and 5) are more cytotoxic than cisplatin to these cell lines and to cisplatin-resistant Jurkat sh-Bak cell lines and their cell death mechanism is different from that of cisplatin. All the compounds show higher toxicity against leukemia cells when compared to normal human T-lymphocytes (PBMC). The interaction of the Pd and Pt compounds with calf thymus and plasmid (pBR322) DNA is different from that of cisplatin. All compounds bind to human serum albumin (HSA) faster than cisplatin (measured by fluorescence spectroscopy). Weak and stronger binding interactions were found for the Pd (3) and Pt (4) derivatives by isothermal titration calorimetry. Importantly, for the Pt (4) compounds the binding to HSA was reversed by addition of a chelating agent (citric acid) and by a decrease in pH. PMID:23063789

  14. Modeling photoionization of aqueous DNA and its components.

    PubMed

    Pluhařová, Eva; Slavíček, Petr; Jungwirth, Pavel

    2015-05-19

    Radiation damage to DNA is usually considered in terms of UVA and UVB radiation. These ultraviolet rays, which are part of the solar spectrum, can indeed cause chemical lesions in DNA, triggered by photoexcitation particularly in the UVB range. Damage can, however, be also caused by higher energy radiation, which can ionize directly the DNA or its immediate surroundings, leading to indirect damage. Thanks to absorption in the atmosphere, the intensity of such ionizing radiation is negligible in the solar spectrum at the surface of Earth. Nevertheless, such an ionizing scenario can become dangerously plausible for astronauts or flight personnel, as well as for persons present at nuclear power plant accidents. On the beneficial side, ionizing radiation is employed as means for destroying the DNA of cancer cells during radiation therapy. Quantitative information about ionization of DNA and its components is important not only for DNA radiation damage, but also for understanding redox properties of DNA in redox sensing or labeling, as well as charge migration along the double helix in nanoelectronics applications. Until recently, the vast majority of experimental and computational data on DNA ionization was pertinent to its components in the gas phase, which is far from its native aqueous environment. The situation has, however, changed for the better due to the advent of photoelectron spectroscopy in liquid microjets and its most recent application to photoionization of aqueous nucleosides, nucleotides, and larger DNA fragments. Here, we present a consistent and efficient computational methodology, which allows to accurately evaluate ionization energies and model photoelectron spectra of aqueous DNA and its individual components. After careful benchmarking, the method based on density functional theory and its time-dependent variant with properly chosen hybrid functionals and polarizable continuum solvent model provides ionization energies with accuracy of 0.2-0.3 e

  15. Modeling photoionization of aqueous DNA and its components.

    PubMed

    Pluhařová, Eva; Slavíček, Petr; Jungwirth, Pavel

    2015-05-19

    Radiation damage to DNA is usually considered in terms of UVA and UVB radiation. These ultraviolet rays, which are part of the solar spectrum, can indeed cause chemical lesions in DNA, triggered by photoexcitation particularly in the UVB range. Damage can, however, be also caused by higher energy radiation, which can ionize directly the DNA or its immediate surroundings, leading to indirect damage. Thanks to absorption in the atmosphere, the intensity of such ionizing radiation is negligible in the solar spectrum at the surface of Earth. Nevertheless, such an ionizing scenario can become dangerously plausible for astronauts or flight personnel, as well as for persons present at nuclear power plant accidents. On the beneficial side, ionizing radiation is employed as means for destroying the DNA of cancer cells during radiation therapy. Quantitative information about ionization of DNA and its components is important not only for DNA radiation damage, but also for understanding redox properties of DNA in redox sensing or labeling, as well as charge migration along the double helix in nanoelectronics applications. Until recently, the vast majority of experimental and computational data on DNA ionization was pertinent to its components in the gas phase, which is far from its native aqueous environment. The situation has, however, changed for the better due to the advent of photoelectron spectroscopy in liquid microjets and its most recent application to photoionization of aqueous nucleosides, nucleotides, and larger DNA fragments. Here, we present a consistent and efficient computational methodology, which allows to accurately evaluate ionization energies and model photoelectron spectra of aqueous DNA and its individual components. After careful benchmarking, the method based on density functional theory and its time-dependent variant with properly chosen hybrid functionals and polarizable continuum solvent model provides ionization energies with accuracy of 0.2-0.3 e

  16. Furry pet allergens, fungal DNA and microbial volatile organic compounds (MVOCs) in the commercial aircraft cabin environment.

    PubMed

    Fu, Xi; Lindgren, Torsten; Guo, Moran; Cai, Gui-Hong; Lundgren, Håkan; Norbäck, Dan

    2013-06-01

    There has been concern about the cabin environment in commercial aircraft. We measured cat, dog and horse allergens and fungal DNA in cabin dust and microbial volatile organic compounds (MVOCs) in cabin air. Samples were collected from two European airline companies, one with cabins having textile seats (TSC) and the other with cabins having leather seats (LSC), 9 airplanes from each company. Dust was vacuumed from seats and floors in the flight deck and different parts of the cabin. Cat (Fel d1), dog (Can f1) and horse allergens (Equ cx) were analyzed by ELISA. Five sequences of fungal DNA were analyzed by quantitative PCR. MVOCs were sampled on charcoal tubes in 42 TSC flights, and 17 compounds were analyzed by gas chromatography mass spectrometry (GC-MS) with selective ion monitoring (SIM). MVOC levels were compared with levels in homes from Nordic countries. The weight of dust was 1.8 times larger in TSC cabins as compared to LSC cabins (p < 0.001). In cabins with textile seats, the geometric mean (GM) concentrations of Fel d1, Can f1 and Equ cx were 5359 ng g(-1), 6067 ng g(-1), and 13 703 ng g(-1) (GM) respectively. Levels of Fel d1, Can f1 and Equ cx were 50 times, 27 times and 75 times higher respectively, in TSC cabins as compared to LSC cabins (p < 0.001). GM levels of Aspergillus/Penicillium DNA, Aspergillus versicolor DNA, Stachybotrys chartarum DNA and Streptomyces DNA were all higher in TSC as compared to LSC (p < 0.05). The sum of MVOCs in cabin air (excluding butanols) was 3192 ng m(-3) (GM), 3.7 times higher than in homes (p < 0.001) and 2-methyl-1-butanol and 3-methyl-1-butanol concentrations were 15-17 times higher as compared to homes (p < 0.001). Concentrations of isobutanol, 1-butanol, dimethyldisulfide, 2-hexanone, 2-heptanone, 3-octanone, isobutyl acetate and ethyl-2-methylbutyrate were lower in cabin air as compared to homes (p < 0.05). In conclusion, textile seats are much more contaminated by pet allergens and fungal DNA than leather

  17. Furry pet allergens, fungal DNA and microbial volatile organic compounds (MVOCs) in the commercial aircraft cabin environment.

    PubMed

    Fu, Xi; Lindgren, Torsten; Guo, Moran; Cai, Gui-Hong; Lundgren, Håkan; Norbäck, Dan

    2013-06-01

    There has been concern about the cabin environment in commercial aircraft. We measured cat, dog and horse allergens and fungal DNA in cabin dust and microbial volatile organic compounds (MVOCs) in cabin air. Samples were collected from two European airline companies, one with cabins having textile seats (TSC) and the other with cabins having leather seats (LSC), 9 airplanes from each company. Dust was vacuumed from seats and floors in the flight deck and different parts of the cabin. Cat (Fel d1), dog (Can f1) and horse allergens (Equ cx) were analyzed by ELISA. Five sequences of fungal DNA were analyzed by quantitative PCR. MVOCs were sampled on charcoal tubes in 42 TSC flights, and 17 compounds were analyzed by gas chromatography mass spectrometry (GC-MS) with selective ion monitoring (SIM). MVOC levels were compared with levels in homes from Nordic countries. The weight of dust was 1.8 times larger in TSC cabins as compared to LSC cabins (p < 0.001). In cabins with textile seats, the geometric mean (GM) concentrations of Fel d1, Can f1 and Equ cx were 5359 ng g(-1), 6067 ng g(-1), and 13 703 ng g(-1) (GM) respectively. Levels of Fel d1, Can f1 and Equ cx were 50 times, 27 times and 75 times higher respectively, in TSC cabins as compared to LSC cabins (p < 0.001). GM levels of Aspergillus/Penicillium DNA, Aspergillus versicolor DNA, Stachybotrys chartarum DNA and Streptomyces DNA were all higher in TSC as compared to LSC (p < 0.05). The sum of MVOCs in cabin air (excluding butanols) was 3192 ng m(-3) (GM), 3.7 times higher than in homes (p < 0.001) and 2-methyl-1-butanol and 3-methyl-1-butanol concentrations were 15-17 times higher as compared to homes (p < 0.001). Concentrations of isobutanol, 1-butanol, dimethyldisulfide, 2-hexanone, 2-heptanone, 3-octanone, isobutyl acetate and ethyl-2-methylbutyrate were lower in cabin air as compared to homes (p < 0.05). In conclusion, textile seats are much more contaminated by pet allergens and fungal DNA than leather

  18. Aquatic pathways model to predict the fate of phenolic compounds

    SciTech Connect

    Aaberg, R.L.; Peloquin, R.A.; Strenge, D.L.; Mellinger, P.J.

    1983-04-01

    Organic materials released from energy-related activities could affect human health and the environment. To better assess possible impacts, we developed a model to predict the fate of spills or discharges of pollutants into flowing or static bodies of fresh water. A computer code, Aquatic Pathways Model (APM), was written to implement the model. The computer programs use compartmental analysis to simulate aquatic ecosystems. The APM estimates the concentrations of chemicals in fish tissue, water and sediment, and is therefore useful for assessing exposure to humans through aquatic pathways. The APM will consider any aquatic pathway for which the user has transport data. Additionally, APM will estimate transport rates from physical and chemical properties of chemicals between several key compartments. The major pathways considered are biodegradation, fish and sediment uptake, photolysis, and evaporation. The model has been implemented with parameters for distribution of phenols, an important class of compounds found in the water-soluble fractions of coal liquids. Current modeling efforts show that, in comparison with many pesticides and polyaromatic hydrocarbons (PAH), the lighter phenolics (the cresols) are not persistent in the environment. The properties of heavier molecular weight phenolics (indanols, naphthols) are not well enough understood at this time to make similar judgements. For the twelve phenolics studied, biodegradation appears to be the major pathway for elimination from aquatic environments. A pond system simulation (using APM) of a spill of solvent refined coal (SRC-II) materials indicates that phenol, cresols, and other single cyclic phenolics are degraded to 16 to 25 percent of their original concentrations within 30 hours. Adsorption of these compounds into sediments and accumulation by fish was minor.

  19. Synthesis of model compounds for coal liquefaction research

    SciTech Connect

    Not Available

    1991-11-01

    Coal liquefaction investigations required the availability of model compounds for mechanistic investigations. Towards this end, IITRI was funded to develop an approach for the synthesis of one of the target compound. This study was carried out in several phases as outlined here. Initial synthetic investigations on obtaining 2-tetrolol was carried out using high pressure and temperature reduction with Raney nickel catalyst. The next step consisted in incorporation of a hydroxymethyelene group at the C-3 position. This was successfully carried out utilizing 2-tetrolol, formaldehyde, and calcium oxide. An alternate improved method was developed using 3-carboxyl-2-naphthol. This required less time, gave a cheer product in higher yield. Efforts at the introduction of a chloromethylene group only yielded polymeric material or starting material in spite of protection the phenolic group by various groups. They synthesis of 3, 5-dimethyl-6- bromobenzyl chloride was successfully carried out by performing the Blank reaction of 2, 4-dimethyl bromobenzene. The product was characterized by GC/MS. Purification was not possible, as it was a complex mixture. Efforts at converting it to the acetate followed by separation to was not feasible. Unlike in the case of 2- hydroxyteralol, hydroxymetylation by established procedure yielded only the starting materials. Commercially available 4-methoxy-1- maphthaldehyde was protected as the ethylene acetal. The Wittig reagent 3-chlorobenzyl phosphonium bromide was prepared and condensed with 4-methoxy-1-napthaldehyde successfully and proved that the overall synthetic approach was proceeding in the desired direction. All the necessary intermediates have been synthesized,and we have demonstrated using model compounds, that the synthetic objective can be attained.

  20. Application of the underscreened Kondo lattice model to neptunium compounds

    NASA Astrophysics Data System (ADS)

    Thomas, Christopher; da Rosa Simoes, Acirete S.; Iglesias, J. R.; Lacroix, C.; Coqublin, B.

    2012-12-01

    The coexistence of Kondo effect and ferromagnetic order has been observed in many uranium and neptunium compounds such as UTe or Np2PdGa3. This coexistence can be described within the underscreened Anderson lattice model with two f-electrons and S = 1 spins on each site. After performing the Schrieffer-Wolff transformation on this model, we have obtained an effective Hamiltonian with a f-band term in addition to the Kondo interaction for S = 1 spins. The results indicate a coexistence of Kondo effect and ferromagnetic order, with different relative values of the Kondo TK and Curie TC temperatures. We emphasize here especially the case TK < TC where there is a Kondo behavior below TC and a clear decrease of the magnetization below TK. Such a behavior has been observed in the magnetization curves of NpNiSi2 at low temperatures.

  1. Enzymology of repair of DNA adducts produced by N-nitroso compounds

    SciTech Connect

    Setlow, R.B.; Cao, E.H.; Delihas, N.C.

    1983-01-01

    The biological effects of DNA adducts depend on their nature, and on their half-lives relative to the rates of DNA replication and transcription. Their half-lives are determined by the rates of spontaneous decay, such as depurination, and the rates of enzymatic repair of the adducts or their decay products. The principle modes of repair of methylating and ethylating agents are by glycosylase catalyzed depurination of 7-alkylguanine and 3-alkyladenine and by the dealkalation of O/sup 6/-alkylguanine. Repair by dealkylation cannot be detected by the standard methods used to measure DNA repair, but it is easy to estimate the acceptor activity in cell extracts by measuring the transfer of radioactive O/sup 6/-alkyl groups in an exogenous DNA to protein. In extracts of cells treated with alkylating agents the activity is depressed because the endogenous DNA is rapidly dealkylated, using up the acceptor activity. In many cell types the decrease in activity is followed by an increase to the normal constitutive level. In other cells there is no such adaptive response. Differences in constitutive levels of methyl accepting activity in extracts of human lymphocytes and on the acceptor activity in lung macrophages from smokers (low activity) and non-smokers (high activity) have been observed. 46 references.

  2. Model of elongation of short DNA sequence by thermophilic DNA polymerase under isothermal conditions.

    PubMed

    Kato, Tomohiro; Liang, Xingguo; Asanuma, Hiroyuki

    2012-10-01

    Short DNA sequences, especially those that are repetitive or palindromic, can be used as the seeds for synthesis of long DNA by some DNA polymerases in an unusual manner. Although several elongation mechanisms have been proposed, there is no well-established model that explains highly efficient elongation under isothermal conditions. In the present study, we analyzed the elongation of nonrepetitive sequences with distinct hairpins at each end. These DNAs were elongated efficiently under isothermal conditions by thermophilic Vent (exo(-)) DNA polymerase, and the products were longer than 10 kb within 10 min of the reaction. A 20-nucleotide DNA with only one hairpin was also elongated. Sequence analysis revealed that the long products are mainly tandem repeats of the short seed sequences. The thermal melting temperatures of the products were much higher than the reaction temperature, indicating that most DNAs form duplexes during the reaction. Accordingly, a terminal hairpin formation and self-priming extension model was proposed in detail, and the efficient elongation was explained. Formation of the hairpin at the 5' end plays an important role during the elongation.

  3. A ROS-Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds.

    PubMed

    Thowfeik, Fathima Shazna; AbdulSalam, Safnas F; Wunderlich, Mark; Wyder, Michael; Greis, Kenneth D; Kadekaro, Ana L; Mulloy, James C; Merino, Edward J

    2015-11-01

    We designed ROS-activated cytotoxic agents (RACs) that are active against AML cancer cells. In this study, the mechanism of action and synergistic effects against cells coexpressing the AML oncogenes MLL-AF9 fusion and FLT3-ITD were investigated. One RAC (RAC1) had an IC50 value of 1.8±0.3 μm, with ninefold greater selectivity for transformed cells compared to untransformed cells. Treatment induced DNA strand breaks, apoptosis, and cell cycle arrest. Proteomics and transcriptomics revealed enhanced expression of the pentose phosphate pathway, DNA repair, and pathways common to cell stress. Western blotting confirmed repair by homologous recombination. Importantly, RAC1 treatment was synergistic in combination with multiple pathway-targeting therapies in AML cells but less so in untransformed cells. Together, these results demonstrate that RAC1 can selectively target poor prognosis AML and that it does so by creating DNA double-strand breaks that require homologous recombination.

  4. A ROS-Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds

    PubMed Central

    Thowfeik, Fathima Shazna; AbdulSalam, Safnas F.; Wunderlich, Mark; Wyder, Michael; Greis, Kenneth D.; Kadekaro, Ana L.; Mulloy, James C.

    2016-01-01

    We designed ROS-activated cytotoxic agents (RACs) that are active against AML cancer cells. In this study, the mechanism of action and synergistic effects against cells coexpressing the AML oncogenes MLL-AF9 fusion and FLT3-ITD were investigated. One RAC (RAC1) had an IC50 value of 1.8 ± 0.3 µm, with ninefold greater selectivity for transformed cells compared to untransformed cells. Treatment induced DNA strand breaks, apoptosis, and cell cycle arrest. Proteomics and transcriptomics revealed enhanced expression of the pentose phosphate pathway, DNA repair, and pathways common to cell stress. Western blotting confirmed repair by homologous recombination. Importantly, RAC1 treatment was synergistic in combination with multiple pathway-targeting therapies in AML cells but less so in untransformed cells. Together, these results demonstrate that RAC1 can selectively target poor prognosis AML and that it does so by creating DNA double-strand breaks that require homologous recombination. PMID:26419938

  5. Dynamic frailty models based on compound birth-death processes.

    PubMed

    Putter, Hein; van Houwelingen, Hans C

    2015-07-01

    Frailty models are used in survival analysis to model unobserved heterogeneity. They accommodate such heterogeneity by the inclusion of a random term, the frailty, which is assumed to multiply the hazard of a subject (individual frailty) or the hazards of all subjects in a cluster (shared frailty). Typically, the frailty term is assumed to be constant over time. This is a restrictive assumption and extensions to allow for time-varying or dynamic frailties are of interest. In this paper, we extend the auto-correlated frailty models of Henderson and Shimakura and of Fiocco, Putter and van Houwelingen, developed for longitudinal count data and discrete survival data, to continuous survival data. We present a rigorous construction of the frailty processes in continuous time based on compound birth-death processes. When the frailty processes are used as mixtures in models for survival data, we derive the marginal hazards and survival functions and the marginal bivariate survival functions and cross-ratio function. We derive distributional properties of the processes, conditional on observed data, and show how to obtain the maximum likelihood estimators of the parameters of the model using a (stochastic) expectation-maximization algorithm. The methods are applied to a publicly available data set.

  6. Transport of organic compounds in thermoplastic geomembranes. 1: Mathematical model

    SciTech Connect

    Park, J.K.; Hoopes, J.A.; Sakti, J.P.

    1996-09-01

    A quasi-two-dimensional partition-diffusion transport model was developed to determine the diffusion coefficient and partition coefficient for various types of geomembranes from measurements of aqueous organic compound concentrations in a confined, double-compartment apparatus with a geomembrane separating the two compartments. The geomembranes tested were high-density polyethylene (HDPE), very low-density polyethylene (VLDPE), and polyvinyl chloride (PVC) and the permeants were mixtures of methylene chloride, toluene, trichloroethylene (TCE), and m-xylene at 10--100 mg/L. The diffusion coefficient increased exponentially was unaffected by compound concentration and membrane thickness. As HDPE geomembranes had stretched by 5% of their original length, the partition coefficient increased by 0.15--0.6 times. VLDPE had 1.8--3.3 times greater partition coefficients and 1.6--2.8 times greater diffusion coefficients than HDPE, while PVC had 6.2--8.3 times greater partition coefficients and 1--1.8 times greater diffusion coefficients than HDPE.

  7. An approach to accidents modeling based on compounds road environments.

    PubMed

    Fernandes, Ana; Neves, Jose

    2013-04-01

    The most common approach to study the influence of certain road features on accidents has been the consideration of uniform road segments characterized by a unique feature. However, when an accident is related to the road infrastructure, its cause is usually not a single characteristic but rather a complex combination of several characteristics. The main objective of this paper is to describe a methodology developed in order to consider the road as a complete environment by using compound road environments, overcoming the limitations inherented in considering only uniform road segments. The methodology consists of: dividing a sample of roads into segments; grouping them into quite homogeneous road environments using cluster analysis; and identifying the influence of skid resistance and texture depth on road accidents in each environment by using generalized linear models. The application of this methodology is demonstrated for eight roads. Based on real data from accidents and road characteristics, three compound road environments were established where the pavement surface properties significantly influence the occurrence of accidents. Results have showed clearly that road environments where braking maneuvers are more common or those with small radii of curvature and high speeds require higher skid resistance and texture depth as an important contribution to the accident prevention. PMID:23376544

  8. High-temperature pyrolysis mechanisms of coal model compounds

    SciTech Connect

    Penn, J.H.; Owens, W.H.

    1991-01-01

    The degradation of the carboxylic acid group has been examined with respect to potential pretreatment strategies for fossil fuel conversion processes. In one potential pretreatment strategy involving cation exchange of the carboxylic acid group, a series of benzoic acid and stearic acid salts have been chosen to model the tight'' carboxylic acids of immature fossil fuel feedstocks and have been pyrolyzed with an entrained flow reactor. Our preliminary results indicate that Group I and II salts yield primarily the parent acid. Benzoate salts also yield small amounts of benzene while the stearic acid salts give no other detectable products. In two alternative treatment strategies, esterification and anhydride preparation have also been accomplished with these compounds being subjected to the entrained flow reactor conditions. The benzoate esters give a number of products, such as benzaldehyde, benzene, and low MW gases. The formation of these compounds is extremely dependent on pyrolysis conditions and alkoxy chain length. A xenon flashlamp and an entrained flow reactor have been used to heat organic substrates to varying temperatures using different heating rates. Ultrarapid flashlamp pyrolysis (heating rate>10{sup 50}C/s) has been performed. Since the ultrarapid pyrolysis products differ from those observed with traditional heating techniques and differ from the products formed photochemically, the flashlamp pyrolysis products are attributed to high temperature thermal activation.

  9. Apples: content of phenolic compounds vs. variety, part of apple and cultivation model, extraction of phenolic compounds, biological properties.

    PubMed

    Kalinowska, Monika; Bielawska, Aleksandra; Lewandowska-Siwkiewicz, Hanna; Priebe, Waldemar; Lewandowski, Włodzimierz

    2014-11-01

    Apples are among the most popular fruits in the world. They are rich in phenolic compounds, pectin, sugar, macro- and microelements. Applying different extraction techniques it is possible to isolate a particular group of compounds or individual chemicals and then test their biological properties. Many reports point to the antioxidant, antimicrobial, anticancer and many other beneficial effects of apple components that may have potential applications in food, pharmaceutical and cosmetic industries. This paper summarizes and compiles information about apple phenolic compounds, their biological properties with particular emphasis on health-related aspects. The data are reviewed with regard to different apple varieties, part of apple, cultivation model and methods of extraction. PMID:25282014

  10. Apples: content of phenolic compounds vs. variety, part of apple and cultivation model, extraction of phenolic compounds, biological properties.

    PubMed

    Kalinowska, Monika; Bielawska, Aleksandra; Lewandowska-Siwkiewicz, Hanna; Priebe, Waldemar; Lewandowski, Włodzimierz

    2014-11-01

    Apples are among the most popular fruits in the world. They are rich in phenolic compounds, pectin, sugar, macro- and microelements. Applying different extraction techniques it is possible to isolate a particular group of compounds or individual chemicals and then test their biological properties. Many reports point to the antioxidant, antimicrobial, anticancer and many other beneficial effects of apple components that may have potential applications in food, pharmaceutical and cosmetic industries. This paper summarizes and compiles information about apple phenolic compounds, their biological properties with particular emphasis on health-related aspects. The data are reviewed with regard to different apple varieties, part of apple, cultivation model and methods of extraction.

  11. Modeling of flap endonuclease interactions with DNA substrate.

    PubMed

    Allawi, Hatim T; Kaiser, Michael W; Onufriev, Alexey V; Ma, Wu-Po; Brogaard, Andrew E; Case, David A; Neri, Bruce P; Lyamichev, Victor I

    2003-05-01

    Structure-specific 5' nucleases play an important role in DNA replication and repair uniquely recognizing an overlap flap DNA substrate and processing it into a DNA nick. However, in the absence of a high-resolution structure of the enzyme/DNA complex, the mechanism underlying this recognition and substrate specificity, which is key to the enzyme's function, remains unclear. Here, we propose a three-dimensional model of the structure-specific 5' flap endonuclease from Pyrococcus furiosus in its complex with DNA. The model is based on the known X-ray structure of the enzyme and a variety of biochemical and molecular dynamics (MD) data utilized in the form of distance restraints between the enzyme and the DNA. Contacts between the 5' flap endonuclease and the sugar-phosphate backbone of the overlap flap substrate were identified using enzyme activity assays on substrates with methylphosphonate or 2'-O-methyl substitutions. The enzyme footprint extends two to four base-pairs upstream and eight to nine base-pairs downstream of the cleavage site, thus covering 10-13 base-pairs of duplex DNA. The footprint data are consistent with a model in which the substrate is bound in the DNA-binding groove such that the downstream duplex interacts with the helix-hairpin-helix motif of the enzyme. MD simulations to identify the substrate orientation in this model are consistent with the results of the enzyme activity assays on the methylphosphonate and 2'-O-methyl-modified substrates. To further refine the model, 5' flap endonuclease variants with alanine point substitutions at amino acid residues expected to contact phosphates in the substrate and one deletion mutant were tested in enzyme activity assays on the methylphosphonate-modified substrates. Changes in the enzyme footprint observed for two point mutants, R64A and R94A, and for the deletion mutant in the enzyme's beta(A)/beta(B) region, were interpreted as being the result of specific interactions in the enzyme/DNA complex

  12. Bond-deformation model for rocksalt-structure compounds

    NASA Astrophysics Data System (ADS)

    Dragoo, A. L.

    1984-03-01

    The bond-deformation model is developed for compounds having the rocksalt structure-namely, the alkali halides and the alkaline-earth oxides. The full set of nearest-neighbor bond-deformation parameters is presented, and the parameters are related to the Lagrangian and internal strains and to the atomic displacements. The next-nearest-neighbor bond-stretching parameters are shown to be reducible to the nearest-neighbor parameters. A variety of central-force and non-central-force interactions is identified in the expansion of the short-range portion of the strain energy. By a transformation of variables the short-range contributions to the dynamical matrix are obtained. Expressions are derived for the elastic constants and for the force constant associated with the homogeneous polarization of the lattice.

  13. Sliding of proteins non-specifically bound to DNA: Brownian dynamics studies with coarse-grained protein and DNA models.

    PubMed

    Ando, Tadashi; Skolnick, Jeffrey

    2014-12-01

    DNA binding proteins efficiently search for their cognitive sites on long genomic DNA by combining 3D diffusion and 1D diffusion (sliding) along the DNA. Recent experimental results and theoretical analyses revealed that the proteins show a rotation-coupled sliding along DNA helical pitch. Here, we performed Brownian dynamics simulations using newly developed coarse-grained protein and DNA models for evaluating how hydrodynamic interactions between the protein and DNA molecules, binding affinity of the protein to DNA, and DNA fluctuations affect the one dimensional diffusion of the protein on the DNA. Our results indicate that intermolecular hydrodynamic interactions reduce 1D diffusivity by 30%. On the other hand, structural fluctuations of DNA give rise to steric collisions between the CG-proteins and DNA, resulting in faster 1D sliding of the protein. Proteins with low binding affinities consistent with experimental estimates of non-specific DNA binding show hopping along the CG-DNA. This hopping significantly increases sliding speed. These simulation studies provide additional insights into the mechanism of how DNA binding proteins find their target sites on the genome.

  14. Antioxidative Dietary Compounds Modulate Gene Expression Associated with Apoptosis, DNA Repair, Inhibition of Cell Proliferation and Migration

    PubMed Central

    Wang, Likui; Gao, Shijuan; Jiang, Wei; Luo, Cheng; Xu, Maonian; Bohlin, Lars; Rosendahl, Markus; Huang, Wenlin

    2014-01-01

    Many dietary compounds are known to have health benefits owing to their antioxidative and anti-inflammatory properties. To determine the molecular mechanism of these food-derived compounds, we analyzed their effect on various genes related to cell apoptosis, DNA damage and repair, oxidation and inflammation using in vitro cell culture assays. This review further tests the hypothesis proposed previously that downstream products of COX-2 (cyclooxygenase-2) called electrophilic oxo-derivatives induce antioxidant responsive elements (ARE), which leads to cell proliferation under antioxidative conditions. Our findings support this hypothesis and show that cell proliferation was inhibited when COX-2 was down-regulated by polyphenols and polysaccharides. Flattened macrophage morphology was also observed following the induction of cytokine production by polysaccharides extracted from viili, a traditional Nordic fermented dairy product. Coix lacryma-jobi (coix) polysaccharides were found to reduce mitochondrial membrane potential and induce caspase-3- and 9-mediated apoptosis. In contrast, polyphenols from blueberries were involved in the ultraviolet-activated p53/Gadd45/MDM2 DNA repair system by restoring the cell membrane potential. Inhibition of hypoxia-inducible factor-1 by saponin extracts of ginsenoside (Ginsen) and Gynostemma and inhibition of S100A4 by coix polysaccharides inhibited cancer cell migration and invasion. These observations suggest that antioxidants and changes in cell membrane potential are the major driving forces that transfer signals through the cell membrane into the cytosol and nucleus, triggering gene expression, changes in cell proliferation and the induction of apoptosis or DNA repair. PMID:25226533

  15. Entropy-driven hysteresis in a model of DNA overstretching

    NASA Astrophysics Data System (ADS)

    Whitelam, Stephen; Pronk, Sander; Geissler, Phillip

    2008-03-01

    When pulled along its axis, double-stranded DNA elongates abruptly at a force of about 65 pN. Two physical pictures have been developed to describe this overstretched state. The first proposes that strong forces induce a phase transition to a molten state consisting of unhybridized single strands. The second picture instead introduces an elongated hybridized phase, called S-DNA, structurally and thermodynamically distinct from standard B-DNA. Little thermodynamic evidence exists to discriminate directly between these competing pictures. Here we show that within a microscopic model of DNA we can distinguish between the dynamics associated with each. In experiment, considerable hysteresis in a cycle of stretching and shortening develops as temperature is increased. Since there are few possible causes of hysteresis in a system whose extent is appreciable in only one dimension, such behavior offers a discriminating test of the two pictures of overstretching. Most experiments are performed upon nicked DNA, permitting the detachment (`unpeeling') of strands. We show that the long-wavelength motion accompanying strand separation generates hysteresis, the character of which agrees with experiment only if we assume the existence of S-DNA.

  16. Generalized Levy-walk model for DNA nucleotide sequences

    NASA Technical Reports Server (NTRS)

    Buldyrev, S. V.; Goldberger, A. L.; Havlin, S.; Simons, M.; Stanley, H. E.

    1993-01-01

    We propose a generalized Levy walk to model fractal landscapes observed in noncoding DNA sequences. We find that this model provides a very close approximation to the empirical data and explains a number of statistical properties of genomic DNA sequences such as the distribution of strand-biased regions (those with an excess of one type of nucleotide) as well as local changes in the slope of the correlation exponent alpha. The generalized Levy-walk model simultaneously accounts for the long-range correlations in noncoding DNA sequences and for the apparently paradoxical finding of long subregions of biased random walks (length lj) within these correlated sequences. In the generalized Levy-walk model, the lj are chosen from a power-law distribution P(lj) varies as lj(-mu). The correlation exponent alpha is related to mu through alpha = 2-mu/2 if 2 < mu < 3. The model is consistent with the finding of "repetitive elements" of variable length interspersed within noncoding DNA.

  17. Gaps and forks in DNA replication: Rediscovering old models.

    PubMed

    Lehmann, Alan R; Fuchs, Robert P

    2006-12-01

    Most current models for replication past damaged lesions envisage that translesion synthesis occurs at the replication fork. However older models suggested that gaps were left opposite lesions to allow the replication fork to proceed, and these gaps were subsequently sealed behind the replication fork. Two recent articles lend support to the idea that bypass of the damage occurs behind the fork. In the first paper, electron micrographs of DNA replicated in UV-irradiated yeast cells show regions of single-stranded DNA both at the replication forks and behind the fork, the latter being consistent with the presence of gaps in the daughter-strands opposite lesions. The second paper describes an in vitro DNA replication system reconstituted from purified bacterial proteins. Repriming of synthesis downstream from a blocked fork occurred not only on the lagging strand as expected, but also on the leading strand, demonstrating that contrary to widely accepted beliefs, leading strand synthesis does not need to be continuous.

  18. Synthesis, characterization, crystal structure and theoretical study of a compound with benzodiazole ring: Antimicrobial activity and DNA binding

    NASA Astrophysics Data System (ADS)

    Latha, P.; Kodisundaram, P.; Sundararajan, M. L.; Jeyakumar, T.

    2014-08-01

    2-(Thiophen-2-yl)-1-((thiophen-2-yl)methyl)-1H-1,3-benzodiazole (HL) is synthesized and characterized by elemental analysis, UV-Vis, FT-IR, 1H, 13C NMR, mass spectra, scanning electron microscope (SEM) and single crystal X-ray diffraction. The crystal structure is stabilized by intermolecular Csbnd H⋯N and Csbnd H⋯π interactions. The molecular structure is also optimized at the B3LYP/6-31G level using density functional theory (DFT). The structural parameters from the theory are nearer to those of crystal, the calculated total energy of coordination is -1522.814 a.u. The energy of HOMO-LUMO and the energy gap are -0.20718, -0.04314, 0.16404 a.u, respectively. All data obtained from the spectral studies support the structural properties of the compound HL. The benzimidazole ring is essentially planar. The in vitro biological screening effects of the synthesized compound is tested against four bacterial and four fungal strains by well diffusion method. Antioxidant property and DNA binding behaviour of the compound has been investigated using spectrophotometric method.

  19. Computational and analytical modeling of cationic lipid-DNA complexes.

    PubMed

    Farago, Oded; Grønbech-Jensen, Niels

    2007-05-01

    We present a theoretical study of the physical properties of cationic lipid-DNA (CL-DNA) complexes--a promising synthetically based nonviral carrier of DNA for gene therapy. The study is based on a coarse-grained molecular model, which is used in Monte Carlo simulations of mesoscopically large systems over timescales long enough to address experimental reality. In the present work, we focus on the statistical-mechanical behavior of lamellar complexes, which in Monte Carlo simulations self-assemble spontaneously from a disordered random initial state. We measure the DNA-interaxial spacing, d(DNA), and the local cationic area charge density, sigma(M), for a wide range of values of the parameter (c) representing the fraction of cationic lipids. For weakly charged complexes (low values of (c)), we find that d(DNA) has a linear dependence on (c)(-1), which is in excellent agreement with x-ray diffraction experimental data. We also observe, in qualitative agreement with previous Poisson-Boltzmann calculations of the system, large fluctuations in the local area charge density with a pronounced minimum of sigma(M) halfway between adjacent DNA molecules. For highly-charged complexes (large (c)), we find moderate charge density fluctuations and observe deviations from linear dependence of d(DNA) on (c)(-1). This last result, together with other findings such as the decrease in the effective stretching modulus of the complex and the increased rate at which pores are formed in the complex membranes, are indicative of the gradual loss of mechanical stability of the complex, which occurs when (c) becomes large. We suggest that this may be the origin of the recently observed enhanced transfection efficiency of lamellar CL-DNA complexes at high charge densities, because the completion of the transfection process requires the disassembly of the complex and the release of the DNA into the cytoplasm. Some of the structural properties of the system are also predicted by a continuum

  20. Measuring and Modeling the Interactions Between DNA-Functionalized Colloids

    NASA Astrophysics Data System (ADS)

    Rogers, William; Crocker, John

    2011-03-01

    DNA hybridization is an ideal tool to direct ``bottom-up'' assembly of complex materials and has been used to form crystalline assemblies of quantum dots, polymer microspheres and other materials made exclusively of DNA. In order to fully realize the potential of DNA-directed self-assembly, one must be able to quantitatively predict the binding energies and interaction potentials between the relevant ``building blocks.'' In this work, we use a scanning-line optical tweezers instrument to measure DNA-induced interactions between colloidal microspheres. We then use well-known concepts in statistical mechanics to model the pair-potentials, whose functional form and energetics of binding are intimately related to the equilibrium configurations of grafted polymers and polymer bridges. By measuring and modeling the pair interaction energies as a function of the essential system parameters (solution hybridization free energies, DNA concentrations, temperature, interparticle separation, etc.), we are able to develop simple, numerical tools that can be used to guide both experiment and simulation.

  1. Oxidations of alkenes and lignin model compounds in aqueous dispersions

    SciTech Connect

    Zhu, Weiming.

    1991-01-01

    The objective was to develop methods to oxidize water-immiscible alkenes and lignin model compounds with polymer colloid supported transition metal catalysts. The oxidations of organic compounds were carried out in aqueous phase with several water-soluble oxidants and dioxygen. Cationic polymer latexes were prepared by the emulsion copolymerization of vinylbenzyl chloride, divinylbenzene, and vinyl octadecyl ether, or styrene, or n-decyl methacrylate, and the subsequent quaternization of copolymers with trimethylamine. The latex particles were 44 nm to 71 nm in diameter. The latex bound Mn porphyrin catalysts were formed with MnTSPP [TSPP = meso-tetrakis(2,6-dichloro-3-sulfonatophenyl)porphyrin], which catalyzed the oxidation of cyclohexene, cycloocetene, allylbenzene, and 1-octene by sodium hypochlorite (NaOCl) and potassium peroxymonosulfate (KHSO[sub 5]). The latex bound porphyrin catalysts showed higher activity than MnTSPP in solution. Oxidations of 3,4-dimethoxybenzyl alcohol (DMBA), 4-hydroxy-3-methoxytoluene (HMT), and 3,4-dimethoxytoluene (DMT) were performed with either dioxygen or hydrogen peroxide and CoPcTS (PcTS = tetrasulfonatophthalocyanine), FePcTS, CuPcTS, NiPcTS, FeTCPP [TCPP = meso-tetrakis(4-carboxyphenyl)porphyrin], and MnTSPP. CoPcTS catalyzed the autoxidation of DMBA and HMT at 70-85[degrees]C and pH [ge] 8. All catalysts were active for the oxidation of DMBA, HMT, and DMT with H[sub 2]O[sub 2]. Aqueous solutions of KHSO[sub 5] oxidized water-immiscible alkenes at room temperature in the absence of organic solvent. The acidic pH [le] 1.7 solutions of commercial 2KHSO[sub 5][center dot]K[sub 2]SO[sub 4] in water produced diols from all reactive alkenes except cyclooctene. Adjustment of initial pH to [ge]6.7 with NaHCO[sub 3] enabled selective epoxidations.

  2. Multistage carcinogenesis modeling including cell cycle and DNA damage states

    NASA Astrophysics Data System (ADS)

    Hazelton, W.; Moolgavkar, S.

    The multistage clonal expansion model of carcinogenesis is generalized to include cell cycle states and corresponding DNA damage states with imperfect repair for normal and initiated stem cells. Initiated cells may undergo transformation to a malignant state, eventually leading to cancer incidence or death. The model allows oxidative or radiation induced DNA damage, checkpoint delay, DNA repair, apoptosis, and transformation rates to depend on the cell cycle state or DNA damage state of normal and initiated cells. A probability generating function approach is used to represent the time dependent probability distribution for cells in all states. The continuous time coupled Markov system representing this joint distribution satisfies a partial differential equation (pde). Time dependent survival and hazard functions are found through numerical solution of the characteristic equations for the pde. Although the hazard and survival can be calculated numerically, number and size distributions of pre-malignant lesions from models that are developed will be approximated through simulation. We use the model to explore predictions for hazard and survival as parameters representing cell cycle regulation and arrest are modified. Modification of these parameters may influence rates for cell division, apoptosis and malignant transformation that are important in carcinogenesis. We also explore enhanced repair that may be important for low-dose hypersensitivity and adaptive response, and degradation of repair processes or loss of checkpoint control that may drive genetic instability.

  3. Analysing DNA structural parameters using a mesoscopic model

    NASA Astrophysics Data System (ADS)

    Amarante, Tauanne D.; Weber, Gerald

    2014-03-01

    The Peyrard-Bishop model is a mesoscopic approximation to model DNA and RNA molecules. Several variants of this model exists, from 3D Hamiltonians, including torsional angles, to simpler 2D versions. Currently, we are able to parametrize the 2D variants of the model which allows us to extract important information about the molecule. For example, with this technique we were able recently to obtain the hydrogen bonds of RNA from melting temperatures, which previously were obtainable only from NMR measurements. Here, we take the 3D torsional Hamiltonian and set the angles to zero. Curiously, in doing this we do not recover the traditional 2D Hamiltonians. Instead, we obtain a different 2D Hamiltonian which now includes a base pair step distance, commonly known as rise. A detailed knowledge of the rise distance is important as it determines the overall length of the DNA molecule. This 2D Hamiltonian provides us with the exciting prospect of obtaining DNA structural parameters from melting temperatures. Our results of the rise distance at low salt concentration are in good qualitative agreement with those from several published x-ray measurements. We also found an important dependence of the rise distance with salt concentration. In contrast to our previous calculations, the elastic constants now show little dependence with salt concentrations which appears to be closer to what is seen experimentally in DNA flexibility experiments.

  4. A Mesoscale Model of DNA and Its Renaturation

    PubMed Central

    Sambriski, E.J.; Schwartz, D.C.; de Pablo, J.J.

    2009-01-01

    A mesoscale model of DNA is presented (3SPN.1), extending the scheme previously developed by our group. Each nucleotide is mapped onto three interaction sites. Solvent is accounted for implicitly through a medium-effective dielectric constant and electrostatic interactions are treated at the level of Debye-Hückel theory. The force field includes a weak, solvent-induced attraction, which helps mediate the renaturation of DNA. Model parameterization is accomplished through replica exchange molecular dynamics simulations of short oligonucleotide sequences over a range of composition and chain length. The model describes the melting temperature of DNA as a function of composition as well as ionic strength, and is consistent with heat capacity profiles from experiments. The dependence of persistence length on ionic strength is also captured by the force field. The proposed model is used to examine the renaturation of DNA. It is found that a typical renaturation event occurs through a nucleation step, whereby an interplay between repulsive electrostatic interactions and colloidal-like attractions allows the system to undergo a series of rearrangements before complete molecular reassociation occurs. PMID:19254530

  5. Theory and modeling of particles with DNA-mediated interactions

    NASA Astrophysics Data System (ADS)

    Licata, Nicholas A.

    In recent years significant attention has been attracted to proposals which utilize DNA for nanotechnological applications. Potential applications of these ideas range from the programmable self-assembly of colloidal crystals, to biosensors and nanoparticle based drug delivery platforms. In Chapter I we introduce the system, which generically consists of colloidal particles functionalized with specially designed DNA markers. The sequence of bases on the DNA markers determines the particle type. Due to the hybridization between complementary single-stranded DNA, specific, type-dependent interactions can be introduced between particles by choosing the appropriate DNA marker sequences. In Chapter II we develop a statistical mechanical description of the aggregation and melting behavior of particles with DNA-mediated interactions. A quantitative comparison between the theory and experiments is made by calculating the experimentally observed melting profile. In Chapter III a model is proposed to describe the dynamical departure and diffusion of particles which form reversible key-lock connections. The model predicts a crossover from localized to diffusive behavior. The random walk statistics for the particles' in plane diffusion is discussed. The lateral motion is analogous to dispersive transport in disordered semiconductors, ranging from standard diffusion with a renormalized diffusion coefficient to anomalous, subdiffusive behavior. In Chapter IV we propose a method to self-assemble nanoparticle clusters using DNA scaffolds. An optimal concentration ratio is determined for the experimental implementation of our self-assembly proposal. A natural extension is discussed in Chapter V, the programmable self-assembly of nanoparticle clusters where the desired cluster geometry is encoded using DNA-mediated interactions. We determine the probability that the system self-assembles the desired cluster geometry, and discuss the connections to jamming in granular and colloidal

  6. Maternal exposure to anti-androgenic compounds, vinclozolin, flutamide and procymidone, has no effects on spermatogenesis and DNA methylation in male rats of subsequent generations

    SciTech Connect

    Inawaka, Kunifumi Kawabe, Mayumi; Takahashi, Satoru; Doi, Yuko; Tomigahara, Yoshitaka; Tarui, Hirokazu; Abe, Jun; Kawamura, Satoshi; Shirai, Tomoyuki

    2009-06-01

    To verify whether anti-androgens cause transgenerational effects on spermatogenesis and DNA methylation in rats, gravid Crl:CD(SD) female rats (4 or 5/group, gestational day (GD) 0 = day sperm detected) were intraperitoneally treated with anti-androgenic compounds, such as vinclozolin (100 mg/kg/day), procymidone (100 mg/kg/day), or flutamide (10 mg/kg/day), from GD 8 to GD 15. Testes were collected from F1 male pups at postnatal day (PND) 6 for DNA methylation analysis of the region (210 bp including 7 CpG sites) within the lysophospholipase gene by bisulfite DNA sequencing method. F0 and F1 males underwent the sperm analysis (count, motility and morphology), followed by DNA methylation analysis of the sperm. Remaining F1 males were cohabited with untreated-females to obtain F2 male pups for subsequent DNA methylation analysis of the testes at PND 6. These analyses showed no effects on spermatogenesis and fertility in F1 males of any treatment group. DNA methylation status in testes (F1 and F2 pups at PND 6) or sperms (F1 males at 13 weeks old) of the treatment groups were comparable to the control at all observation points, although DNA methylation rates in testes were slightly lower than those in sperm. In F0 males, no abnormalities in the spermatogenesis, fertility and DNA methylation status of sperm were observed. No transgenerational abnormalities of spermatogenesis and DNA methylation status caused by anti-androgenic compounds were observed.

  7. Mechanistic Study of the Acid Degradation of Lignin Model Compounds

    SciTech Connect

    Sturgeon, M.; Kim, S.; Chmely, S. C.; Foust, T. D.; Beckham, G. T.

    2012-01-01

    Lignin is a major constituent of biomass, which remains underutilized in selective biomass conversion strategies to renewable fuels and chemicals. Here we are interested in understanding the mechanisms related to the acid deconstruction of lignin with a combined theoretical and experimental approach. Two model dimers with a b-O-4 aryl ether linkage (2-phenoxy-1-phenethanol and 2-phenoxy-1-phenyl-1,3 propanediol) and model dimmers with an a-O-4 aryl ether linkage were synthesized and deconstructed in H2SO4. The major products of the acidolysis of the b-O-4 compounds consisted of phenol and two aldehydes, phenylacetaldehyde and benzaldehyde. Quantum mechanical calculations were employed to elucidate possible deconstruction mechanisms with transition state theory. To confirm proposed mechanisms several possible intermediates were studied under similar acidolysis conditions. Although the resonance time for cleavage was on the order several hours, we have shown that the cleavage of the aryl ether linkage affords phenol and aldehydes. We would next like to utilize our mechanism of aryl ether cleavage in actual lignin.

  8. Modeling 3D facial shape from DNA.

    PubMed

    Claes, Peter; Liberton, Denise K; Daniels, Katleen; Rosana, Kerri Matthes; Quillen, Ellen E; Pearson, Laurel N; McEvoy, Brian; Bauchet, Marc; Zaidi, Arslan A; Yao, Wei; Tang, Hua; Barsh, Gregory S; Absher, Devin M; Puts, David A; Rocha, Jorge; Beleza, Sandra; Pereira, Rinaldo W; Baynam, Gareth; Suetens, Paul; Vandermeulen, Dirk; Wagner, Jennifer K; Boster, James S; Shriver, Mark D

    2014-03-01

    Human facial diversity is substantial, complex, and largely scientifically unexplained. We used spatially dense quasi-landmarks to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). Using bootstrapped response-based imputation modeling (BRIM), we uncover the relationships between facial variation and the effects of sex, genomic ancestry, and a subset of craniofacial candidate genes. The facial effects of these variables are summarized as response-based imputed predictor (RIP) variables, which are validated using self-reported sex, genomic ancestry, and observer-based facial ratings (femininity and proportional ancestry) and judgments (sex and population group). By jointly modeling sex, genomic ancestry, and genotype, the independent effects of particular alleles on facial features can be uncovered. Results on a set of 20 genes showing significant effects on facial features provide support for this approach as a novel means to identify genes affecting normal-range facial features and for approximating the appearance of a face from genetic markers. PMID:24651127

  9. Modeling 3D Facial Shape from DNA

    PubMed Central

    Claes, Peter; Liberton, Denise K.; Daniels, Katleen; Rosana, Kerri Matthes; Quillen, Ellen E.; Pearson, Laurel N.; McEvoy, Brian; Bauchet, Marc; Zaidi, Arslan A.; Yao, Wei; Tang, Hua; Barsh, Gregory S.; Absher, Devin M.; Puts, David A.; Rocha, Jorge; Beleza, Sandra; Pereira, Rinaldo W.; Baynam, Gareth; Suetens, Paul; Vandermeulen, Dirk; Wagner, Jennifer K.; Boster, James S.; Shriver, Mark D.

    2014-01-01

    Human facial diversity is substantial, complex, and largely scientifically unexplained. We used spatially dense quasi-landmarks to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). Using bootstrapped response-based imputation modeling (BRIM), we uncover the relationships between facial variation and the effects of sex, genomic ancestry, and a subset of craniofacial candidate genes. The facial effects of these variables are summarized as response-based imputed predictor (RIP) variables, which are validated using self-reported sex, genomic ancestry, and observer-based facial ratings (femininity and proportional ancestry) and judgments (sex and population group). By jointly modeling sex, genomic ancestry, and genotype, the independent effects of particular alleles on facial features can be uncovered. Results on a set of 20 genes showing significant effects on facial features provide support for this approach as a novel means to identify genes affecting normal-range facial features and for approximating the appearance of a face from genetic markers. PMID:24651127

  10. Modeling the relaxation time of DNA confined in a nanochannel

    PubMed Central

    Tree, Douglas R.; Wang, Yanwei; Dorfman, Kevin D.

    2013-01-01

    Using a mapping between a Rouse dumbbell model and fine-grained Monte Carlo simulations, we have computed the relaxation time of λ-DNA in a high ionic strength buffer confined in a nanochannel. The relaxation time thus obtained agrees quantitatively with experimental data [Reisner et al., Phys. Rev. Lett. 94, 196101 (2005)] using only a single O(1) fitting parameter to account for the uncertainty in model parameters. In addition to validating our mapping, this agreement supports our previous estimates of the friction coefficient of DNA confined in a nanochannel [Tree et al., Phys. Rev. Lett. 108, 228105 (2012)], which have been difficult to validate due to the lack of direct experimental data. Furthermore, the model calculation shows that as the channel size passes below approximately 100 nm (or roughly the Kuhn length of DNA) there is a dramatic drop in the relaxation time. Inasmuch as the chain friction rises with decreasing channel size, the reduction in the relaxation time can be solely attributed to the sharp decline in the fluctuations of the chain extension. Practically, the low variance in the observed DNA extension in such small channels has important implications for genome mapping. PMID:24309551

  11. Minimalist Model for Force-Dependent DNA Replication

    PubMed Central

    Nong, Eva X.; DeVience, Stephen J.; Herschbach, Dudley

    2012-01-01

    In experiments using optical or magnetic tweezers, investigators have monitored the rate at which polymerase enzymes catalyze DNA replication when the template strand is subjected to a stretching force. For T7, Klenow, and Sequenase polymerases, the replication rate increases modestly at low tension and then decreases markedly at higher tension. Molecular-dynamics (MD) simulations using x-ray structure data for the open and closed complexes of the Taq enzyme with DNA revealed that the dependence of replication rate on tension could be accounted for in terms of the induced enthalpy changes for the two DNA segments adjacent to the site of the added nucleotide. Here, we present a simple, minimalist two-segment local model (M2L) derived from some striking features seen in the MD simulations. The model predicts the tension dependence of the replication rate using only structural data and a critical tension, f∗, without recourse to MD simulations. At f∗, the outermost DNA segment undergoes a large angular reorientation in the open conformation of the enzyme. We give a generic plot for the M2L model, apply it to family A and B polymerases and HIV reverse transcriptase, and discuss factors that may govern the f∗ flip parameter. PMID:22385852

  12. Modeling the Control of DNA Replication in Fission Yeast

    NASA Astrophysics Data System (ADS)

    Novak, Bela; Tyson, John J.

    1997-08-01

    A central event in the eukaryotic cell cycle is the decision to commence DNA replication (S phase). Strict controls normally operate to prevent repeated rounds of DNA replication without intervening mitoses (``endoreplication'') or initiation of mitosis before DNA is fully replicated (``mitotic catastrophe''). Some of the genetic interactions involved in these controls have recently been identified in yeast. From this evidence we propose a molecular mechanism of ``Start'' control in Schizosaccharomyces pombe. Using established principles of biochemical kinetics, we compare the properties of this model in detail with the observed behavior of various mutant strains of fission yeast: wee1- (size control at Start), cdc13Δ and rum1OP (endoreplication), and wee1- rum1Δ (rapid division cycles of diminishing cell size). We discuss essential features of the mechanism that are responsible for characteristic properties of Start control in fission yeast, to expose our proposal to crucial experimental tests.

  13. An atomistic geometrical model of the B-DNA configuration for DNA-radiation interaction simulations

    NASA Astrophysics Data System (ADS)

    Bernal, M. A.; Sikansi, D.; Cavalcante, F.; Incerti, S.; Champion, C.; Ivanchenko, V.; Francis, Z.

    2013-12-01

    In this paper, an atomistic geometrical model for the B-DNA configuration is explained. This model accounts for five organization levels of the DNA, up to the 30 nm chromatin fiber. However, fragments of this fiber can be used to construct the whole genome. The algorithm developed in this work is capable to determine which is the closest atom with respect to an arbitrary point in space. It can be used in any application in which a DNA geometrical model is needed, for instance, in investigations related to the effects of ionizing radiations on the human genetic material. Successful consistency checks were carried out to test the proposed model. Catalogue identifier: AEPZ_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEPZ_v1_0.html Program obtainable from: CPC Program Library, Queen’s University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 1245 No. of bytes in distributed program, including test data, etc.: 6574 Distribution format: tar.gz Programming language: FORTRAN. Computer: Any. Operating system: Multi-platform. RAM: 2 Gb Classification: 3. Nature of problem: The Monte Carlo method is used to simulate the interaction of ionizing radiation with the human genetic material in order to determine DNA damage yields per unit absorbed dose. To accomplish this task, an algorithm to determine if a given energy deposition lies within a given target is needed. This target can be an atom or any other structure of the genetic material. Solution method: This is a stand-alone subroutine describing an atomic-resolution geometrical model of the B-DNA configuration. It is able to determine the closest atom to an arbitrary point in space. This model accounts for five organization levels of the human genetic material, from the nucleotide pair up to the 30 nm chromatin fiber. This subroutine carries out a series of coordinate transformations

  14. Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage

    PubMed Central

    McMahon, Stephen J.; Schuemann, Jan; Paganetti, Harald; Prise, Kevin M.

    2016-01-01

    Characterising and predicting the effects of ionising radiation on cells remains challenging, with the lack of robust models of the underlying mechanism of radiation responses providing a significant limitation to the development of personalised radiotherapy. In this paper we present a mechanistic model of cellular response to radiation that incorporates the kinetics of different DNA repair processes, the spatial distribution of double strand breaks and the resulting probability and severity of misrepair. This model enables predictions to be made of a range of key biological endpoints (DNA repair kinetics, chromosome aberration and mutation formation, survival) across a range of cell types based on a set of 11 mechanistic fitting parameters that are common across all cells. Applying this model to cellular survival showed its capacity to stratify the radiosensitivity of cells based on aspects of their phenotype and experimental conditions such as cell cycle phase and plating delay (correlation between modelled and observed Mean Inactivation Doses R2 > 0.9). By explicitly incorporating underlying mechanistic factors, this model can integrate knowledge from a wide range of biological studies to provide robust predictions and may act as a foundation for future calculations of individualised radiosensitivity. PMID:27624453

  15. Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage.

    PubMed

    McMahon, Stephen J; Schuemann, Jan; Paganetti, Harald; Prise, Kevin M

    2016-01-01

    Characterising and predicting the effects of ionising radiation on cells remains challenging, with the lack of robust models of the underlying mechanism of radiation responses providing a significant limitation to the development of personalised radiotherapy. In this paper we present a mechanistic model of cellular response to radiation that incorporates the kinetics of different DNA repair processes, the spatial distribution of double strand breaks and the resulting probability and severity of misrepair. This model enables predictions to be made of a range of key biological endpoints (DNA repair kinetics, chromosome aberration and mutation formation, survival) across a range of cell types based on a set of 11 mechanistic fitting parameters that are common across all cells. Applying this model to cellular survival showed its capacity to stratify the radiosensitivity of cells based on aspects of their phenotype and experimental conditions such as cell cycle phase and plating delay (correlation between modelled and observed Mean Inactivation Doses R(2) > 0.9). By explicitly incorporating underlying mechanistic factors, this model can integrate knowledge from a wide range of biological studies to provide robust predictions and may act as a foundation for future calculations of individualised radiosensitivity. PMID:27624453

  16. Prevention of DNA photodamage by vitamin E compounds and sunscreens: roles of ultraviolet absorbance and cellular uptake.

    PubMed

    McVean, M; Liebler, D C

    1999-03-01

    Topical application of alpha-tocopherol (alphaTH), the most prominent naturally occurring form of vitamin E, inhibits ultraviolet (UV) B-induced photocarcinogenesis and DNA photodamage in C3H mice in vivo. In this study, we compared alphaTH with other vitamin E compounds and with three commercial sunscreen compounds for their ability to inhibit DNA photodamage in C3H mouse skin in vivo. When applied in a 5% dispersion in a neutral cream vehicle, alpha-tocopherol (alphaTH), gamma-tocopherol (gammaTH), and delta-tocopherol (deltaTH) each produced a statistically significant inhibition of thymine dimer formation, whereas alpha-tocopherol acetate (alphaTAc) and alpha-tocopherol methyl ether (alphaTOMe) did not. Application of 5% dispersions of the commercial sunscreen agent octylmethoxycinnamate also inhibited dimer formation, whereas ethylhexyl salicylate and oxybenzone did not, despite their considerably greater UVB absorbances than alphaTH. To test the hypothesis that cellular uptake and distribution are necessary for optimal photoprotection by tocopherols, photoprotection was studied in mouse 308 keratinocyte cells in vitro. Preincubation of 308 cells with 1 microM alphaTH for at least 2 h before exposure to 2.5 J/m2/s UVB for 10 min significantly (P < 0.05) attenuated thymine dimer formation. Pre-incubation with 1 microM gammaTH, deltaTH, alphaTAc, or alphaTOMe for 2 h did not inhibit thymine dimer formation significantly. Uptake of alphaTH was measured after incubation with 1 microM [2H3]alphaTH (d3-alphaTH) and resulted in a time-dependent increase in alphaTH levels. Use of d3-alphaTH allowed separate, simultaneous measurement of added d3-alphaTH and unlabeled endogenous alphaTH by gas chromatography-mass spectrometry. Accumulation of 167 +/- 62 pmol d3-alphaTH/mg protein was measured within 1 h in whole-cell fractions. d3-AlphaTH in the nuclear fraction reached levels of 15 +/- 4 pmol d3-alphaTH/mg protein at 2 h. Accumulation of alphaTH in the whole cell and

  17. Prevention of DNA photodamage by vitamin E compounds and sunscreens: roles of ultraviolet absorbance and cellular uptake.

    PubMed

    McVean, M; Liebler, D C

    1999-03-01

    Topical application of alpha-tocopherol (alphaTH), the most prominent naturally occurring form of vitamin E, inhibits ultraviolet (UV) B-induced photocarcinogenesis and DNA photodamage in C3H mice in vivo. In this study, we compared alphaTH with other vitamin E compounds and with three commercial sunscreen compounds for their ability to inhibit DNA photodamage in C3H mouse skin in vivo. When applied in a 5% dispersion in a neutral cream vehicle, alpha-tocopherol (alphaTH), gamma-tocopherol (gammaTH), and delta-tocopherol (deltaTH) each produced a statistically significant inhibition of thymine dimer formation, whereas alpha-tocopherol acetate (alphaTAc) and alpha-tocopherol methyl ether (alphaTOMe) did not. Application of 5% dispersions of the commercial sunscreen agent octylmethoxycinnamate also inhibited dimer formation, whereas ethylhexyl salicylate and oxybenzone did not, despite their considerably greater UVB absorbances than alphaTH. To test the hypothesis that cellular uptake and distribution are necessary for optimal photoprotection by tocopherols, photoprotection was studied in mouse 308 keratinocyte cells in vitro. Preincubation of 308 cells with 1 microM alphaTH for at least 2 h before exposure to 2.5 J/m2/s UVB for 10 min significantly (P < 0.05) attenuated thymine dimer formation. Pre-incubation with 1 microM gammaTH, deltaTH, alphaTAc, or alphaTOMe for 2 h did not inhibit thymine dimer formation significantly. Uptake of alphaTH was measured after incubation with 1 microM [2H3]alphaTH (d3-alphaTH) and resulted in a time-dependent increase in alphaTH levels. Use of d3-alphaTH allowed separate, simultaneous measurement of added d3-alphaTH and unlabeled endogenous alphaTH by gas chromatography-mass spectrometry. Accumulation of 167 +/- 62 pmol d3-alphaTH/mg protein was measured within 1 h in whole-cell fractions. d3-AlphaTH in the nuclear fraction reached levels of 15 +/- 4 pmol d3-alphaTH/mg protein at 2 h. Accumulation of alphaTH in the whole cell and

  18. The extended version of restriction analysis approach for the examination of the ability of low-molecular-weight compounds to modify DNA in a cell-free system.

    PubMed

    Kołodziejski, Dominik; Brillowska-Dąbrowska, Anna; Bartoszek, Agnieszka

    2015-01-01

    One of the primary requirements in toxicology is the assessment of ability of chemicals to induce DNA covalent modification. There are several well-established methods used for this purpose such as (32)P-Postlabeling or HPLC-MS. However, all of these approaches have difficult to overcome limitations, which prevents their use in genotoxin screening. Here, we describe the simple protocol exploiting specificity of restriction enzymes for the detection of DNA modification. It uses a specifically designed DNA amplicon, which contains two restriction sites recognized by Tru1I or MspI/HapII endonucleases. Modification of a restriction site abolishes its recognition and thus cleavage by the corresponding enzyme. The inhibition of cleavage indicates the occurrence of DNA modification of the restriction site(s), simultaneously pointing at the kind of base pairs (AT or GC) involved in DNA adduct formation. Previously, the application of this method was demonstrated for two antitumor compounds. Current study shows the extended version, that includes different ways of activation of tested compounds. Moreover, we propose an array of applications being of interest in toxicological research such as monitoring the kinetics of DNA adduct formation, detection of oxidative DNA damage, as well as assessment of the ability of antioxidative phytochemicals to prevent the latter DNA lesions.

  19. Generation of aroma compounds in a fermented sausage meat model system by Debaryomyces hansenii strains.

    PubMed

    Cano-García, Liliana; Rivera-Jiménez, Silvia; Belloch, Carmela; Flores, Mónica

    2014-05-15

    The ability of seven Debaryomyces hansenii strains to generate aroma compounds in a fermented sausage model system was evaluated. The presence of the yeast, in the inoculated models, was confirmed by PCR amplification of M13 minisatellite. Volatile compounds production was analysed using Solid Phase Micro-Extraction and gas chromatography/mass spectrometry. Forty volatile compounds were detected, quantified and their odour activity values (OAVs) calculated. All volatile compounds increased during time in the inoculated models although significant differences were found amongst them. Ester and sulphur production was strongly dependent on the strain inoculated. D. hansenii P2 and M6 strains were the highest producers of sulphur compounds where dimethyl disulphide and dimethyl trisulfide were the most prominent aroma components identified by their OAVs whereas, M4 showed the highest OAVs for ester compounds followed by the P2 strain. The meat model system has been useful to show the real ability of yeast strains to produce aroma compounds. PMID:24423545

  20. Generation of aroma compounds in a fermented sausage meat model system by Debaryomyces hansenii strains.

    PubMed

    Cano-García, Liliana; Rivera-Jiménez, Silvia; Belloch, Carmela; Flores, Mónica

    2014-05-15

    The ability of seven Debaryomyces hansenii strains to generate aroma compounds in a fermented sausage model system was evaluated. The presence of the yeast, in the inoculated models, was confirmed by PCR amplification of M13 minisatellite. Volatile compounds production was analysed using Solid Phase Micro-Extraction and gas chromatography/mass spectrometry. Forty volatile compounds were detected, quantified and their odour activity values (OAVs) calculated. All volatile compounds increased during time in the inoculated models although significant differences were found amongst them. Ester and sulphur production was strongly dependent on the strain inoculated. D. hansenii P2 and M6 strains were the highest producers of sulphur compounds where dimethyl disulphide and dimethyl trisulfide were the most prominent aroma components identified by their OAVs whereas, M4 showed the highest OAVs for ester compounds followed by the P2 strain. The meat model system has been useful to show the real ability of yeast strains to produce aroma compounds.

  1. Modeling the Biodegradability of Chemical Compounds Using the Online CHEmical Modeling Environment (OCHEM).

    PubMed

    Vorberg, Susann; Tetko, Igor V

    2014-01-01

    Biodegradability describes the capacity of substances to be mineralized by free-living bacteria. It is a crucial property in estimating a compound's long-term impact on the environment. The ability to reliably predict biodegradability would reduce the need for laborious experimental testing. However, this endpoint is difficult to model due to unavailability or inconsistency of experimental data. Our approach makes use of the Online Chemical Modeling Environment (OCHEM) and its rich supply of machine learning methods and descriptor sets to build classification models for ready biodegradability. These models were analyzed to determine the relationship between characteristic structural properties and biodegradation activity. The distinguishing feature of the developed models is their ability to estimate the accuracy of prediction for each individual compound. The models developed using seven individual descriptor sets were combined in a consensus model, which provided the highest accuracy. The identified overrepresented structural fragments can be used by chemists to improve the biodegradability of new chemical compounds. The consensus model, the datasets used, and the calculated structural fragments are publicly available at http://ochem.eu/article/31660.

  2. Source apportionment modeling of volatile organic compounds in streams.

    PubMed

    Pankow, James F; Asher, William E; Zogorski, John S

    2006-04-01

    It often is of interest to understand the relative importance of the different sources contributing to the concentration c(w) of a contaminant in a stream; the portions related to sources 1, 2, 3, etc. are denoted c(w,1), c(w2), c(w3), etc. Like c(w), the fractions alpha1 = c(w,1)/c(w), alpha2 = c(w,2)/c(w), alpha3 = c(w,3)/c(w), etc. depend on location and time. Volatile organic compounds (VOCs) can undergo absorption from the atmosphere into stream water or loss from stream water to the atmosphere, causing complexities affecting the source apportionment (SA) of VOCs in streams. Two SA rules are elaborated. Rule 1: VOC entering a stream across the air/water interface exclusively is assigned to the atmospheric portion of c(w). Rule 2: VOC loss by volatilization, flow loss to groundwater, in-stream degradation, etc. is distributed over c(w,1), c(w,2), c(w3), etc. in proportion to their corresponding alpha values. How the two SA rules are applied, as well as the nature of the SA output for a given case, will depend on whether transport across the air/water interface is handled using the net flux F convention or using the individual fluxes J convention. Four hypothetical stream cases involving acetone, methyl-tert-butyl ether (MTBE), benzene, chloroform, and perchloroethylene (PCE) are considered. Acetone and MTBE are sufficiently water soluble from air for a domestic atmospheric source to be capable of yielding c(w) values approaching the common water quality guideline range of 1 to 10 microg/L. For most other VOCs, such levels cause net outgassing (F > 0). When F > 0 in a given section of stream, in the net flux convention, all of the alpha(j) for the compound remain unchanged over that section while c(w) decreases. A characteristic time tau(d) can be calculated to predict when there will be differences between SA results obtained by the net flux convention versus the individual fluxes convention. Source apportionment modeling provides the framework necessary for

  3. Source apportionment modeling of volatile organic compounds in streams

    USGS Publications Warehouse

    Pankow, J.F.; Asher, W.E.; Zogorski, J.S.

    2006-01-01

    It often is of interest to understand the relative importance of the different sources contributing to the concentration cw of a contaminant in a stream; the portions related to sources 1, 2, 3, etc. are denoted cw,1, cw,2, cw,3, etc. Like c w, 'he fractions ??1, = cw,1/c w, ??2 = cw,2/cw, ??3 = cw,3/cw, etc. depend on location and time. Volatile organic compounds (VOCs) can undergo absorption from the atmosphere into stream water or loss from stream water to the atmosphere, causing complexities affecting the source apportionment (SA) of VOCs in streams. Two SA rules are elaborated. Rule 1: VOC entering a stream across the air/water interface exclusively is assigned to the atmospheric portion of cw. Rule 2: VOC loss by volatilization, flow loss to groundwater, in-stream degradation, etc. is distributed over cw,1 cw,2, c w,3, etc. in proportion to their corresponding ?? values. How the two SA rules are applied, as well as the nature of the SA output for a given case, will depend on whether transport across the air/water interface is handled using the net flux F convention or using the individual fluxes J convention. Four hypothetical stream cases involving acetone, methyl-tert-butyl ether (MTBE), benzene, chloroform, and perchloroethylene (PCE) are considered. Acetone and MTBE are sufficiently water soluble from air for a domestic atmospheric source to be capable of yielding cw values approaching the common water quality guideline range of 1 to 10 ??g/L. For most other VOCs, such levels cause net outgassing (F > 0). When F > 0 in a given section of stream, in the net flux convention, all of the ??j, for the compound remain unchanged over that section while cw decreases. A characteristic time ??d can be calculated to predict when there will be differences between SA results obtained by the net flux convention versus the individual fluxes convention. Source apportionment modeling provides the framework necessary for comparing different strategies for mitigating

  4. Modeling the Relaxation Time of DNA Confined in a Nanochannel

    NASA Astrophysics Data System (ADS)

    Wang, Yanwei; Tree, Douglas R.; Dorfman, Kevin D.

    2014-03-01

    Using a mapping between a dumbbell model and fine-grained Monte Carlo simulations, we have computed the relaxation time of λ-DNA in a high ionic strength buffer confined in a nanochannel (Tree et al., Biomicrofluidics 2013, 7, 054118). The relaxation time thus obtained agrees quantitatively with experimental data (Reisner et al., PRL 2005, 94, 196101) using only a single O(1) fitting parameter to account for the uncertainty in model parameters. In addition to validating our mapping, this agreement supports our previous estimates of the friction coefficient of DNA confined in a nanochannel (Tree et al., PRL 2012, 108, 228105), which have been difficult to validate due to the lack of direct experimental data. Furthermore, our calculation shows that as the channel size passes below ~100 nm (or roughly the Kuhn length of DNA) there is a dramatic drop in the relaxation time. Inasmuch as the chain friction rises with decreasing channel size, the reduction in the relaxation time can be solely attributed to the sharp decline in the fluctuations of the chain extension. Practically, the low variance in the observed DNA extension in such small channels has important implications for genome mapping. This work was supported by the NIH (R01-HG005216 and R01-HG006851) and the NSFC (21204061) and was carried out in part using computing resources at the University of Minnesota Supercomputing Institute.

  5. Modeling the Study of DNA Damage Responses in Mice

    PubMed Central

    Specks, Julia; Nieto-Soler, Maria; Lopez-Contreras, Andres J; Fernandez-Capetillo, Oscar

    2016-01-01

    Summary Damaged DNA has a profound impact on mammalian health and overall survival. In addition to being the source of mutations that initiate cancer, the accumulation of toxic amounts of DNA damage can cause severe developmental diseases and accelerate ageing. Therefore, understanding how cells respond to DNA damage has become one of the most intense areas of biomedical research in the recent years. However, whereas most mechanistic studies derive from in vitro or in cellulo work, the impact of a given mutation on a living organism is largely unpredictable. For instance, why BRCA1 mutations preferentially lead to breast cancer whereas mutations compromising mismatch repair drive colon cancer is still not understood. In this context, evaluating the specific physiological impact of mutations that compromise genome integrity has become crucial for a better dimensioning of our knowledge. We here describe the various technologies that can be used for modeling mutations in mice, and provide a review of the genes and pathways that have been modeled so far in the context of DNA damage responses. PMID:25636482

  6. Clusters of DNA induced by ionizing radiation: formation of short DNA fragments. I. Theoretical modeling

    NASA Technical Reports Server (NTRS)

    Holley, W. R.; Chatterjee, A.

    1996-01-01

    We have developed a general theoretical model for the interaction of ionizing radiation with chromatin. Chromatin is modeled as a 30-nm-diameter solenoidal fiber comprised of 20 turns of nucleosomes, 6 nucleosomes per turn. Charged-particle tracks are modeled by partitioning the energy deposition between primary track core, resulting from glancing collisions with 100 eV or less per event, and delta rays due to knock-on collisions involving energy transfers >100 eV. A Monte Carlo simulation incorporates damages due to the following molecular mechanisms: (1) ionization of water molecules leading to the formation of OH, H, eaq, etc.; (2) OH attack on sugar molecules leading to strand breaks: (3) OH attack on bases; (4) direct ionization of the sugar molecules leading to strand breaks; (5) direct ionization of the bases. Our calculations predict significant clustering of damage both locally, over regions up to 40 bp and over regions extending to several kilobase pairs. A characteristic feature of the regional damage predicted by our model is the production of short fragments of DNA associated with multiple nearby strand breaks. The shapes of the spectra of DNA fragment lengths depend on the symmetries or approximate symmetries of the chromatin structure. Such fragments have subsequently been detected experimentally and are reported in an accompanying paper (B. Rydberg, Radiat, Res. 145, 200-209, 1996) after exposure to both high- and low-LET radiation. The overall measured yields agree well quantitatively with the theoretical predictions. Our theoretical results predict the existence of a strong peak at about 85 bp, which represents the revolution period about the nucleosome. Other peaks at multiples of about 1,000 bp correspond to the periodicity of the particular solenoid model of chromatin used in these calculations. Theoretical results in combination with experimental data on fragmentation spectra may help determine the consensus or average structure of the

  7. Clusters of DNA induced by ionizing radiation: formation of short DNA fragments. I. Theoretical modeling.

    PubMed

    Holley, W R; Chatterjee, A

    1996-02-01

    We have developed a general theoretical model for the interaction of ionizing radiation with chromatin. Chromatin is modeled as a 30-nm-diameter solenoidal fiber comprised of 20 turns of nucleosomes, 6 nucleosomes per turn. Charged-particle tracks are modeled by partitioning the energy deposition between primary track core, resulting from glancing collisions with 100 eV or less per event, and delta rays due to knock-on collisions involving energy transfers >100 eV. A Monte Carlo simulation incorporates damages due to the following molecular mechanisms: (1) ionization of water molecules leading to the formation of OH, H, eaq, etc.; (2) OH attack on sugar molecules leading to strand breaks: (3) OH attack on bases; (4) direct ionization of the sugar molecules leading to strand breaks; (5) direct ionization of the bases. Our calculations predict significant clustering of damage both locally, over regions up to 40 bp and over regions extending to several kilobase pairs. A characteristic feature of the regional damage predicted by our model is the production of short fragments of DNA associated with multiple nearby strand breaks. The shapes of the spectra of DNA fragment lengths depend on the symmetries or approximate symmetries of the chromatin structure. Such fragments have subsequently been detected experimentally and are reported in an accompanying paper (B. Rydberg, Radiat, Res. 145, 200-209, 1996) after exposure to both high- and low-LET radiation. The overall measured yields agree well quantitatively with the theoretical predictions. Our theoretical results predict the existence of a strong peak at about 85 bp, which represents the revolution period about the nucleosome. Other peaks at multiples of about 1,000 bp correspond to the periodicity of the particular solenoid model of chromatin used in these calculations. Theoretical results in combination with experimental data on fragmentation spectra may help determine the consensus or average structure of the

  8. Differentiation of yeasts growing on dry-cured Iberian ham by mitochondrial DNA restriction analysis, RAPD-PCR and their volatile compounds production.

    PubMed

    Andrade, M J; Rodríguez, M; Casado, E M; Bermúdez, E; Córdoba, J J

    2009-09-01

    The efficiency of mitochondrial DNA (mtDNA) restriction analysis, RAPD-PCR and volatile compounds analysis to differentiate yeast biotypes involved in flavour development of dry-cured Iberian ham throughout the ripening process is evaluated. For this purpose, 86 yeasts isolated from Iberian hams in the main ripening stages at different industries of the four Protected Designations of Origin of this product, were used. The combination of mtDNA restriction analysis and RAPD-PCR using the primer (GACA)4 showed a higher variability in the yeast species detected than obtained using only mtDNA restriction analysis. Only two species, Debaryomyces hansenii and Candida zeylanoides, were identified throughout the whole ripening process and a wide diversity of biotypes was found in these two species, with those of D. hansenii predominating. Clear differences between biotypes were detected in the generation of volatile compounds, with the biotype C2-2 of D. hansenii showing the highest concentrations of volatiles. The combined use of mtDNA restriction analysis and RAPD-PCR distinguishes yeast biotypes with different production of volatile compounds. In addition, analysis of the production profile of volatile compounds is needed to differentiate yeast strains of the same biotype recovered at different stages of ripening. Thus, the combination of these three methods could be very useful to select or monitor yeasts as starter cultures in dry-cured meat products. PMID:19527832

  9. Differentiation of yeasts growing on dry-cured Iberian ham by mitochondrial DNA restriction analysis, RAPD-PCR and their volatile compounds production.

    PubMed

    Andrade, M J; Rodríguez, M; Casado, E M; Bermúdez, E; Córdoba, J J

    2009-09-01

    The efficiency of mitochondrial DNA (mtDNA) restriction analysis, RAPD-PCR and volatile compounds analysis to differentiate yeast biotypes involved in flavour development of dry-cured Iberian ham throughout the ripening process is evaluated. For this purpose, 86 yeasts isolated from Iberian hams in the main ripening stages at different industries of the four Protected Designations of Origin of this product, were used. The combination of mtDNA restriction analysis and RAPD-PCR using the primer (GACA)4 showed a higher variability in the yeast species detected than obtained using only mtDNA restriction analysis. Only two species, Debaryomyces hansenii and Candida zeylanoides, were identified throughout the whole ripening process and a wide diversity of biotypes was found in these two species, with those of D. hansenii predominating. Clear differences between biotypes were detected in the generation of volatile compounds, with the biotype C2-2 of D. hansenii showing the highest concentrations of volatiles. The combined use of mtDNA restriction analysis and RAPD-PCR distinguishes yeast biotypes with different production of volatile compounds. In addition, analysis of the production profile of volatile compounds is needed to differentiate yeast strains of the same biotype recovered at different stages of ripening. Thus, the combination of these three methods could be very useful to select or monitor yeasts as starter cultures in dry-cured meat products.

  10. A 3D Model of Double-Helical DNA Showing Variable Chemical Details

    ERIC Educational Resources Information Center

    Cady, Susan G.

    2005-01-01

    Since the first DNA model was created approximately 50 years ago using molecular models, students and teachers have been building simplified DNA models from various practical materials. A 3D double-helical DNA model, made by placing beads on a wire and stringing beads through holes in plastic canvas, is described. Suggestions are given to enhance…

  11. New Quantitative Structure-Activity Relationship Models Improve Predictability of Ames Mutagenicity for Aromatic Azo Compounds.

    PubMed

    Manganelli, Serena; Benfenati, Emilio; Manganaro, Alberto; Kulkarni, Sunil; Barton-Maclaren, Tara S; Honma, Masamitsu

    2016-10-01

    Existing Quantitative Structure-Activity Relationship (QSAR) models have limited predictive capabilities for aromatic azo compounds. In this study, 2 new models were built to predict Ames mutagenicity of this class of compounds. The first one made use of descriptors based on simplified molecular input-line entry system (SMILES), calculated with the CORAL software. The second model was based on the k-nearest neighbors algorithm. The statistical quality of the predictions from single models was satisfactory. The performance further improved when the predictions from these models were combined. The prediction results from other QSAR models for mutagenicity were also evaluated. Most of the existing models were found to be good at finding toxic compounds but resulted in many false positive predictions. The 2 new models specific for this class of compounds avoid this problem thanks to a larger set of related compounds as training set and improved algorithms.

  12. New Quantitative Structure-Activity Relationship Models Improve Predictability of Ames Mutagenicity for Aromatic Azo Compounds.

    PubMed

    Manganelli, Serena; Benfenati, Emilio; Manganaro, Alberto; Kulkarni, Sunil; Barton-Maclaren, Tara S; Honma, Masamitsu

    2016-10-01

    Existing Quantitative Structure-Activity Relationship (QSAR) models have limited predictive capabilities for aromatic azo compounds. In this study, 2 new models were built to predict Ames mutagenicity of this class of compounds. The first one made use of descriptors based on simplified molecular input-line entry system (SMILES), calculated with the CORAL software. The second model was based on the k-nearest neighbors algorithm. The statistical quality of the predictions from single models was satisfactory. The performance further improved when the predictions from these models were combined. The prediction results from other QSAR models for mutagenicity were also evaluated. Most of the existing models were found to be good at finding toxic compounds but resulted in many false positive predictions. The 2 new models specific for this class of compounds avoid this problem thanks to a larger set of related compounds as training set and improved algorithms. PMID:27413112

  13. DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy.

    PubMed

    Fayzullina, Saniya; Martin, Lee J

    2016-09-01

    We studied DNA damage response (DDR) and DNA repair capacities of skeletal muscle cells from a mouse model of infantile spinal muscular atrophy (SMA) caused by loss-of-function mutation of survival of motor neuron (Smn). Primary myocyte cultures derived from skeletal muscle satellite cells of neonatal control and mutant SMN mice had similar myotube length, myonuclei, satellite cell marker Pax7 and differentiated myotube marker myosin, and acetylcholine receptor clustering. DNA damage was induced in differentiated skeletal myotubes by γ-irradiation, etoposide, and methyl methanesulfonate (MMS). Unexposed control and SMA myotubes had stable genome integrity. After γ-irradiation and etoposide, myotubes repaired most DNA damage equally. Control and mutant myotubes exposed to MMS exhibited equivalent DNA damage without repair. Control and SMA myotube nuclei contained DDR proteins phospho-p53 and phospho-H2AX foci that, with DNA damage, dispersed and then re-formed similarly after recovery. We conclude that mouse primary satellite cell-derived myotubes effectively respond to and repair DNA strand-breaks, while DNA alkylation repair is underrepresented. Morphological differentiation, genome stability, genome sensor, and DNA strand-break repair potential are preserved in mouse SMA myocytes; thus, reduced SMN does not interfere with myocyte differentiation, genome integrity, and DNA repair, and faulty DNA repair is unlikely pathogenic in SMA. PMID:27452406

  14. Microbial extraction of sulfur from model coal organosulfur compounds

    SciTech Connect

    Purdy, R.F.; Ward, B.; Lepo, J.E.

    1991-12-31

    Several hundred bacterial cultures isolated from a variety of natural sites were screened for their ability to desulfurize the model coal organosulfur compounds, dibenzothiophene (DBT) and DBT-sulfone. A sulfur-stress assay, in which DBT-sulfone was the only bioavailable source of sulfur, was used to screen and select for organisms that selectively desulfurized the organic-sulfur substrate. Only two new isolates, UMX9 and UMX3, and strain IGTS-8, a Rhodococcus rhodochrous provided by the Institute for Gas Technology (Chicago, USA.) as a reference culture, would grow on DBT or DBT-sulfone as a sole source of sulfur. Under sulfur-stress conditions, a desulfurized product identified as 2-hydroxybiphenyl (2-phenylphenol) was detected only for UMX9 and IGTS-8. Biodesulfurization activity for all three organisms occurred only for growing cultures, and was depressed by free sulfate, although more so for UMX3 and IGTS-8 than for UMX9. None of the three cultures exhibited good growth on DBT, DBT-sulfone, or 2-phenylphenol as sole sources of carbon. Taxonomic studies revealed UMX3 to be similar to IGTS-8, whereas UMX9 only exhibited Rhodococcus-like features. Comparative tests for carbohydrate utilization revealed that only UMX9 would grow on glucose, and that only IGTS-8 would grow on L-arabinose. Assays of biodesulfurization activity as a function of temperature or pH revealed further differences between UMX9 and UMX3/IGTS-8. Under optimized assay conditions for each organism, UMX9 exhibited up to 30% greater biodesulfurization activity than did IGTS-8 and UMX3, which were similar in activity.

  15. Mathematical modeling of DNA's transcription process for the cancer study

    NASA Astrophysics Data System (ADS)

    Morales-Peñaloza, A.; Meza-López, C. D.; Godina-Nava, J. J.

    2012-10-01

    The cancer is a phenomenon caused by an anomaly in the DNA's transcription process, therefore it is necessary to known how such anomaly is generated in order to implement alternative therapies to combat it. We propose to use mathematical modeling to treat the problem. Is implemented a simulation of the process of transcription and are studied the transport properties in the heterogeneous case using nonlinear dynamics.

  16. A Kronig-Penney model of salts of DNA.

    PubMed

    Rosen, P

    1968-04-01

    A one dimensional Kronig-Penney model for a salt like Na DNA is given. The helical periodicity is treated in a manner suggested by Tinoco and Woody. Using data on the semiconductor band gap, we estimate the strength of the potential barrier. The energy limits of the ten bands filled by 20pi electrons per unit cell are calculated and exhibited in Table I.

  17. CRISPR-Cas9-based target validation for p53-reactivating model compounds

    PubMed Central

    Wanzel, Michael; Vischedyk, Jonas B; Gittler, Miriam P; Gremke, Niklas; Seiz, Julia R; Hefter, Mirjam; Noack, Magdalena; Savai, Rajkumar; Mernberger, Marco; Charles, Joël P; Schneikert, Jean; Bretz, Anne Catherine; Nist, Andrea; Stiewe, Thorsten

    2015-01-01

    Inactivation of the p53 tumor suppressor by Mdm2 is one of the most frequent events in cancer, so compounds targeting the p53-Mdm2 interaction are promising for cancer therapy. Mechanisms conferring resistance to p53-reactivating compounds are largely unknown. Here we show using CRISPR-Cas9–based target validation in lung and colorectal cancer that the activity of nutlin, which blocks the p53-binding pocket of Mdm2, strictly depends on functional p53. In contrast, sensitivity to the drug RITA, which binds the Mdm2-interacting N terminus of p53, correlates with induction of DNA damage. Cells with primary or acquired RITA resistance display cross-resistance to DNA crosslinking compounds such as cisplatin and show increased DNA cross-link repair. Inhibition of FancD2 by RNA interference or pharmacological mTOR inhibitors restores RITA sensitivity. The therapeutic response to p53-reactivating compounds is therefore limited by compound-specific resistance mechanisms that can be resolved by CRISPR-Cas9-based target validation and should be considered when allocating patients to p53-reactivating treatments. PMID:26595461

  18. Modeling DNA structure and processes through animation and kinesthetic visualizations

    NASA Astrophysics Data System (ADS)

    Hager, Christine

    There have been many studies regarding the effectiveness of visual aids that go beyond that of static illustrations. Many of these have been concentrated on the effectiveness of visual aids such as animations and models or even non-traditional visual aid activities like role-playing activities. This study focuses on the effectiveness of three different types of visual aids: models, animation, and a role-playing activity. Students used a modeling kit made of Styrofoam balls and toothpicks to construct nucleotides and then bond nucleotides together to form DNA. Next, students created their own animation to depict the processes of DNA replication, transcription, and translation. Finally, students worked in teams to build proteins while acting out the process of translation. Students were given a pre- and post-test that measured their knowledge and comprehension of the four topics mentioned above. Results show that there was a significant gain in the post-test scores when compared to the pre-test scores. This indicates that the incorporated visual aids were effective methods for teaching DNA structure and processes.

  19. Emerging models for DNA repair: Dictyostelium discoideum as a model for nonhomologous end-joining.

    PubMed

    Pears, Catherine J; Lakin, Nicholas D

    2014-05-01

    DNA double strand breaks (DSBs) are a particularly cytotoxic variety of DNA lesion that can be repaired by homologous recombination (HR) or nonhomologous end-joining (NHEJ). HR utilises sequences homologous to the damage DNA template to facilitate repair. In contrast, NHEJ does not require homologous sequences for repair but instead functions by directly re-joining DNA ends. These pathways are critical to resolve DSBs generated intentionally during processes such as meiotic and site-specific recombination. However, they are also utilised to resolve potentially pathological DSBs generated by mutagens and errors during DNA replication. The importance of DSB repair is underscored by the findings that defects in these pathways results in chromosome instability that contributes to a variety of disease states including malignancy. The general principles of NHEJ are conserved in eukaryotes. As such, relatively simple model organisms have been instrumental in identifying components of these pathways and providing a mechanistic understanding of repair that has subsequently been applied to vertebrates. However, certain components of the NHEJ pathway are absent or show limited conservation in the most commonly used invertebrate models exploited to study DNA repair. Recently, however, it has become apparent that vertebrate DNA repair pathway components, including those involved in NHEJ, are unusually conserved in the amoeba Dictyostelium discoideum. Traditionally, this genetically tractable organism has been exploited to study the molecular basis of cell type specification, cell motility and chemotaxis. Here we discuss the use of this organism as an additional model to study DNA repair, with specific reference to NHEJ.

  20. DNA.

    ERIC Educational Resources Information Center

    Felsenfeld, Gary

    1985-01-01

    Structural form, bonding scheme, and chromatin structure of and gene-modification experiments with deoxyribonucleic acid (DNA) are described. Indicates that DNA's double helix is variable and also flexible as it interacts with regulatory and other molecules to transfer hereditary messages. (DH)

  1. A one-dimensional model of Nucleosome distribution in DNA

    NASA Astrophysics Data System (ADS)

    Osberg, Brendan; Moebius, Wolfram; Nguyen, Kien; Gerland, Ulrich

    2012-02-01

    Nucleosome positioning along DNA is neither random nor precisely regular. Genome-wide maps of nucleosome positions in various eukaryotes have revealed a common pattern around transcription start sites, involving a nucleosome-free region flanked by a periodic pattern in the average nucleosome density. We take a quantitative mathematical description of the nucleosome pattern, and incorporate specifically bound transcription factors. Our model assumes a dense, one-dimensional gas of particles, however, instead of previous work which assumes fixed-size particles interacting only by exclusion, our model explicitly accounts for transient unwrapping of short segments of nucleosomal DNA. Hence, such particles no longer have a fixed size, but interact by an effective repulsive potential. This model has been succesfully used, by us, to provide a unified description of 12 Hemiascomycota yeast species with a single unified set of model parameters. We incorporate into this model, specifically bound particles, or transcription factors (TF), which serve an important role in gene regulation. Nucleosome distribution patterns have an important influence on TF binding, and can even mediate interactions between transcription factors at a distance. This interaction can account for cooperative or competitive binding between these proteins, and we will discuss the implications this can have on gene regulation.

  2. Encapsulation of a model compound in pectin delays its release from a biobased polymeric material

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A model compound was encapsulated in pectin and then extruded with thermoplastic starch to form a composite. The intended product was a food-contact tray made of biobased polymers infused with an anti-microbial agent; however, caffeine was used as the model compound in the preliminary work. The mode...

  3. DNA Cleavage, Cytotoxic Activities, and Antimicrobial Studies of Ternary Copper(II) Complexes of Isoxazole Schiff Base and Heterocyclic Compounds

    PubMed Central

    Chityala, Vijay Kumar; Sathish Kumar, K.; Macha, Ramesh; Tigulla, Parthasarathy; Shivaraj

    2014-01-01

    Novel mixed ligand bivalent copper complexes [Cu. L. A. ClO4] and [Cu. L. A] where “L” is Schiff bases, namely 2-((3,4-dimethylisoxazol-5-ylimino)methyl)-4-bromophenol (DMIIMBP)/2-((3,4-dimethylisoxazol-5-ylimino)methyl)-4-chlorophenol (DMIIMCP), and “A” is heterocyclic compound, such as 1,10-phenanthroline (phen)/2,21-bipyridyl (bipy)/8-hydroxyquinoline (oxine)/5-chloro-8-hydroxyquinoline (5-Cl-oxine), have been synthesized. These complexes have been characterized by IR, UV-Vis, ESR, elemental analysis, magnetic moments, TG, and DTA. On the basis of spectral studies and analytical data, five-coordinated square pyramidal/four-coordinated square planar geometry is assigned to all complexes. The ligands and their ternary complexes with Cu(II) have been screened for antimicrobial activity against bacteria and fungi by paper disc method. The antimicrobial studies of Schiff bases and their metal complexes showed significant activity and further it is observed that the metal complexes showed more activity than corresponding Schiff bases. In vitro antitumor activity of Cu(II) complexes was assayed against human cervical carcinoma (HeLa) cancer cells and it was observed that few complexes exhibit good antitumor activity on HeLa cell lines. The DNA cleavage studies have also been carried out on pBR 322 and it is observed that these Cu(II) complexes are capable of cleaving supercoiled plasmid DNA in the presence of H2O2 and UV light. PMID:24895493

  4. Phi29 Connector-DNA Interactions Govern DNA Crunching and Rotation, Supporting the Check-Valve Model.

    PubMed

    Kumar, Rajendra; Grubmüller, Helmut

    2016-01-19

    During replication of the ϕ29 bacteriophage inside a bacterial host cell, a DNA packaging motor transports the viral DNA into the procapsid against a pressure difference of up to 40 ± 20 atm. Several models have been proposed for the underlying molecular mechanism. Here we have used molecular dynamics simulations to examine the role of the connector part of the motor, and specifically the one-way revolution and the push-roll model. We have focused at the structure and intermolecular interactions between the DNA and the connector, for which a near-complete structure is available. The connector is found to induce considerable DNA deformations with respect to its canonical B-form. We further assessed by force-probe simulations to which extent the connector is able to prevent DNA leakage and found that the connector can act as a partial one-way valve by a check-valve mechanism via its mobile loops. Analysis of the geometry, flexibility, and energetics of channel lysine residues suggested that this arrangement of residues is incompatible with the observed DNA packaging step-size of ∼2.5 bp, such that the step-size is probably determined by the other components of the motor. Previously proposed DNA revolution and rolling motions inside the connector channel are both found implausible due to structural entanglement between the DNA and connector loops that have not been resolved in the crystal structure. Rather, in the simulations, the connector facilitates minor DNA rotation during the packaging process compatible with recent optical-tweezers experiments. Combined with the available experimental data, our simulation results suggest that the connector acts as a check-valve that prevents DNA leakage and induces DNA compression and rotation during DNA packaging. PMID:26789768

  5. Phi29 Connector-DNA Interactions Govern DNA Crunching and Rotation, Supporting the Check-Valve Model.

    PubMed

    Kumar, Rajendra; Grubmüller, Helmut

    2016-01-19

    During replication of the ϕ29 bacteriophage inside a bacterial host cell, a DNA packaging motor transports the viral DNA into the procapsid against a pressure difference of up to 40 ± 20 atm. Several models have been proposed for the underlying molecular mechanism. Here we have used molecular dynamics simulations to examine the role of the connector part of the motor, and specifically the one-way revolution and the push-roll model. We have focused at the structure and intermolecular interactions between the DNA and the connector, for which a near-complete structure is available. The connector is found to induce considerable DNA deformations with respect to its canonical B-form. We further assessed by force-probe simulations to which extent the connector is able to prevent DNA leakage and found that the connector can act as a partial one-way valve by a check-valve mechanism via its mobile loops. Analysis of the geometry, flexibility, and energetics of channel lysine residues suggested that this arrangement of residues is incompatible with the observed DNA packaging step-size of ∼2.5 bp, such that the step-size is probably determined by the other components of the motor. Previously proposed DNA revolution and rolling motions inside the connector channel are both found implausible due to structural entanglement between the DNA and connector loops that have not been resolved in the crystal structure. Rather, in the simulations, the connector facilitates minor DNA rotation during the packaging process compatible with recent optical-tweezers experiments. Combined with the available experimental data, our simulation results suggest that the connector acts as a check-valve that prevents DNA leakage and induces DNA compression and rotation during DNA packaging.

  6. Modeling emissions of volatile organic compounds from silage

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Photochemical smog is a major air pollution problem and a significant cause of premature death in the U.S. Smog forms in the presence of volatile organic compounds (VOCs), which are emitted primarily from industry and motor vehicles in the U.S. However, dairy farms may be an important source in so...

  7. MICROBIAL VOLATILE ORGANIC COMPOUND EMISSION RATES AND EXPOSURE MODEL

    EPA Science Inventory

    This paper presents the results from a study that examined microbial volatile organic compound (MVOC) emissions from six fungi and one bacterial species (Streptomyces spp.) commonly found in indoor environments. Data are presented on peak emission rates from inoculated agar plate...

  8. Modelling DNA origami self-assembly at the domain level

    SciTech Connect

    Dannenberg, Frits; Kwiatkowska, Marta; Dunn, Katherine E.; Bath, Jonathan; Turberfield, Andrew J.; Ouldridge, Thomas E.

    2015-10-28

    We present a modelling framework, and basic model parameterization, for the study of DNA origami folding at the level of DNA domains. Our approach is explicitly kinetic and does not assume a specific folding pathway. The binding of each staple is associated with a free-energy change that depends on staple sequence, the possibility of coaxial stacking with neighbouring domains, and the entropic cost of constraining the scaffold by inserting staple crossovers. A rigorous thermodynamic model is difficult to implement as a result of the complex, multiply connected geometry of the scaffold: we present a solution to this problem for planar origami. Coaxial stacking of helices and entropic terms, particularly when loop closure exponents are taken to be larger than those for ideal chains, introduce interactions between staples. These cooperative interactions lead to the prediction of sharp assembly transitions with notable hysteresis that are consistent with experimental observations. We show that the model reproduces the experimentally observed consequences of reducing staple concentration, accelerated cooling, and absent staples. We also present a simpler methodology that gives consistent results and can be used to study a wider range of systems including non-planar origami.

  9. DNA Duplex Formation with a Coarse-Grained Model

    PubMed Central

    2015-01-01

    A middle-resolution coarse-grained model of DNA is proposed. The DNA chain is built of spherical and planar rigid bodies connected by elastic virtual bonds. The bonded part of the potential energy function is fit to potentials of mean force of model systems. The rigid bodies are sets of neutral, charged, and dipolar beads. Electrostatic and van der Waals interactions are parametrized by our recently developed procedure [Maciejczyk, M.; Spasic, A.; Liwo, A.; Scheraga, H.A. J. Comp. Chem.2010, 31, 1644]. Interactions with the solvent and an ionic cloud are approximated by a multipole–multipole Debye–Hückel model. A very efficient R-RATTLE algorithm, for integrating the movement of rigid bodies, is implemented. It is the first coarse-grained model, in which both bonded and nonbonded interactions were parametrized ab initio and which folds stable double helices from separated complementary strands, with the final conformation close to the geometry of experimentally determined structures. PMID:25400520

  10. Long-range electron transfer in a model for DNA

    NASA Astrophysics Data System (ADS)

    Endres, R. G.; Cox, D. L.

    2001-03-01

    Long-range electron transfer (ET) between well separated donor (D) and acceptor (A) sites through quantum mechanical tunneling is essential to many biological processes like respiration, photosynthesis and possibly DNA repair and damage. We are investigating the distance dependence of the electronic transition matrix element H_DA and hence of the electron transfer rate in a model for DNA. Fluorescence quenching in DNA at D-A distances of 40 Åand more suggests ET with an unusually high decay length β-1 of order 10 Å (S.O.Kelley and J.K.Barton, in:Metal Ions in Biological Systems), A.Sigel and H.Sigel, Eds., Marcel Dekker, New York, Vol.36, 1999. Assuming strong electron interactions on the D complex and suitable energetics, this could be explained by formation of a many electron Kondo boundstate. We obtain H_DA from the splitting between the two lowest adiabatic electronic eigenenergies, which constitute the potential energy surfaces (PES) of the nuclear motion in lowest order Born-Oppenheimer approximation. The PES are constructed by coupling D and A to local breathing modes and by making a semi-analytical variational ansatz for the adiabatic eigenstates. The results from the PES are compared with results from the Mulliken-Hush algorithm.

  11. Advanced steady-state model for the fate of hydrophobic and volatile compounds in activated sludge

    SciTech Connect

    Lee, K.C.; Rittmann, B.E.; Shi, J.; McAvoy, D.

    1998-09-01

    A steady-state, advanced, general fate model developed to study the fate of organic compounds in primary and activated-sludge systems. This model considers adsorption, biodegradation from the dissolved and adsorbed phases, bubble volatilization, and surface volatilization as removal mechanisms. A series of modeling experiments was performed to identify the key trends of these removal mechanisms for compounds with a range of molecular properties. With typical municipal wastewater treatment conditions, the results from the modeling experiments show that co-metabolic and primary utilization mechanisms give very different trends in biodegradation for the compounds tested. For co-metabolism, the effluent concentration increases when the influent concentration increases, while the effluent concentration remains unchanged when primary utilization occurs. For a highly hydrophobic compound, the fraction of compound removed from adsorption onto primary sludge can be very important, and the direct biodegradation of compound sorbed to the activated sludge greatly increases its biodegradation and reduces its discharge with the waste activated sludge. Volatilization from the surface of the primary and secondary systems is important for compounds with moderate to high volatilities, especially when these compounds are not biodegradable. Finally, bubble volatilization can be a major removal mechanism for highly volatile compounds even when they are highly biodegradable.

  12. Misfit layer compounds and ferecrystals: Model systems for thermoelectric nanocomposites

    DOE PAGES

    Merrill, Devin R.; Moore, Daniel B.; Bauers, Sage R.; Falmbigl, Matthias; Johnson, David C.

    2015-04-22

    A basic summary of thermoelectric principles is presented in a historical context, following the evolution of the field from initial discovery to modern day high-zT materials. A specific focus is placed on nanocomposite materials as a means to solve the challenges presented by the contradictory material requirements necessary for efficient thermal energy harvest. Misfit layer compounds are highlighted as an example of a highly ordered anisotropic nanocomposite system. Their layered structure provides the opportunity to use multiple constituents for improved thermoelectric performance, through both enhanced phonon scattering at interfaces and through electronic interactions between the constituents. Recently, a class ofmore » metastable, turbostratically-disordered misfit layer compounds has been synthesized using a kinetically controlled approach with low reaction temperatures. The kinetically stabilized structures can be prepared with a variety of constituent ratios and layering schemes, providing an avenue to systematically understand structure-function relationships not possible in the thermodynamic compounds. We summarize the work that has been done to date on these materials. The observed turbostratic disorder has been shown to result in extremely low cross plane thermal conductivity and in plane thermal conductivities that are also very small, suggesting the structural motif could be attractive as thermoelectric materials if the power factor could be improved. The first 10 compounds in the [(PbSe)1+δ]m(TiSe₂)n family (m, n ≤ 3) are reported as a case study. As n increases, the magnitude of the Seebeck coefficient is significantly increased without a simultaneous decrease in the in-plane electrical conductivity, resulting in an improved thermoelectric power factor.« less

  13. Misfit layer compounds and ferecrystals: Model systems for thermoelectric nanocomposites

    SciTech Connect

    Merrill, Devin R.; Moore, Daniel B.; Bauers, Sage R.; Falmbigl, Matthias; Johnson, David C.

    2015-04-22

    A basic summary of thermoelectric principles is presented in a historical context, following the evolution of the field from initial discovery to modern day high-zT materials. A specific focus is placed on nanocomposite materials as a means to solve the challenges presented by the contradictory material requirements necessary for efficient thermal energy harvest. Misfit layer compounds are highlighted as an example of a highly ordered anisotropic nanocomposite system. Their layered structure provides the opportunity to use multiple constituents for improved thermoelectric performance, through both enhanced phonon scattering at interfaces and through electronic interactions between the constituents. Recently, a class of metastable, turbostratically-disordered misfit layer compounds has been synthesized using a kinetically controlled approach with low reaction temperatures. The kinetically stabilized structures can be prepared with a variety of constituent ratios and layering schemes, providing an avenue to systematically understand structure-function relationships not possible in the thermodynamic compounds. We summarize the work that has been done to date on these materials. The observed turbostratic disorder has been shown to result in extremely low cross plane thermal conductivity and in plane thermal conductivities that are also very small, suggesting the structural motif could be attractive as thermoelectric materials if the power factor could be improved. The first 10 compounds in the [(PbSe)1+δ]m(TiSe₂)n family (m, n ≤ 3) are reported as a case study. As n increases, the magnitude of the Seebeck coefficient is significantly increased without a simultaneous decrease in the in-plane electrical conductivity, resulting in an improved thermoelectric power factor.

  14. Homology Modeling of NAD+-Dependent DNA Ligase of the Wolbachia Endosymbiont of Brugia malayi and Its Drug Target Potential Using Dispiro-Cycloalkanones

    PubMed Central

    Shrivastava, Nidhi; Nag, Jeetendra K.; Pandey, Jyoti; Tripathi, Rama Pati; Shah, Priyanka; Siddiqi, Mohammad Imran

    2015-01-01

    Lymphatic filarial nematodes maintain a mutualistic relationship with the endosymbiont Wolbachia. Depletion of Wolbachia produces profound defects in nematode development, fertility, and viability and thus has great promise as a novel approach for treating filarial diseases. NAD+-dependent DNA ligase is an essential enzyme of DNA replication, repair, and recombination. Therefore, in the present study, the antifilarial drug target potential of the NAD+-dependent DNA ligase of the Wolbachia symbiont of Brugia malayi (wBm-LigA) was investigated using dispiro-cycloalkanone compounds. Dispiro-cycloalkanone specifically inhibited the nick-closing and cohesive-end ligation activities of the enzyme without inhibiting human or T4 DNA ligase. The mode of inhibition was competitive with the NAD+ cofactor. Docking studies also revealed the interaction of these compounds with the active site of the target enzyme. The adverse effects of these inhibitors were observed on adult and microfilarial stages of B. malayi in vitro, and the most active compounds were further monitored in vivo in jirds and mastomys rodent models. Compounds 1, 2, and 5 had severe adverse effects in vitro on the motility of both adult worms and microfilariae at low concentrations. Compound 2 was the best inhibitor, with the lowest 50% inhibitory concentration (IC50) (1.02 μM), followed by compound 5 (IC50, 2.3 μM) and compound 1 (IC50, 2.9 μM). These compounds also exhibited the same adverse effect on adult worms and microfilariae in vivo (P < 0.05). These compounds also tremendously reduced the wolbachial load, as evident by quantitative real-time PCR (P < 0.05). wBm-LigA thus shows great promise as an antifilarial drug target, and dispiro-cycloalkanone compounds show great promise as antifilarial lead candidates. PMID:25845868

  15. Insights into DNA-mediated interparticle interactions from a coarse-grained model

    NASA Astrophysics Data System (ADS)

    Ding, Yajun; Mittal, Jeetain

    2014-11-01

    DNA-functionalized particles have great potential for the design of complex self-assembled materials. The major hurdle in realizing crystal structures from DNA-functionalized particles is expected to be kinetic barriers that trap the system in metastable amorphous states. Therefore, it is vital to explore the molecular details of particle assembly processes in order to understand the underlying mechanisms. Molecular simulations based on coarse-grained models can provide a convenient route to explore these details. Most of the currently available coarse-grained models of DNA-functionalized particles ignore key chemical and structural details of DNA behavior. These models therefore are limited in scope for studying experimental phenomena. In this paper, we present a new coarse-grained model of DNA-functionalized particles which incorporates some of the desired features of DNA behavior. The coarse-grained DNA model used here provides explicit DNA representation (at the nucleotide level) and complementary interactions between Watson-Crick base pairs, which lead to the formation of single-stranded hairpin and double-stranded DNA. Aggregation between multiple complementary strands is also prevented in our model. We study interactions between two DNA-functionalized particles as a function of DNA grafting density, lengths of the hybridizing and non-hybridizing parts of DNA, and temperature. The calculated free energies as a function of pair distance between particles qualitatively resemble experimental measurements of DNA-mediated pair interactions.

  16. Nonlinear Model of the Specificity of DNA-Protein Interactions and Its Stability

    NASA Astrophysics Data System (ADS)

    Dwiputra, D.; Hidayat, W.; Khairani, R.; Zen, F. P.

    2016-08-01

    Specific DNA-protein interactions are fundamental processes of living cells. We propose a new model of DNA-protein interactions to explain the site specificity of the interactions. The hydrogen bonds between DNA base pairs and between DNA-protein peptide groups play a significant role in determination of the specific binding site. We adopt the Morse potential with coupling terms to construct the Hamiltonian of coupled oscillators representing the hydrogen bonds in which the depth of the potentials vary in the DNA chain. In this paper we investigate the stability of the model to determine the conditions satisfying the biological circumstances of the DNA-protein interactions.

  17. Hands on Group Work Paper Model for Teaching DNA Structure, Central Dogma and Recombinant DNA

    ERIC Educational Resources Information Center

    Altiparmak, Melek; Nakiboglu Tezer, Mahmure

    2009-01-01

    Understanding life on a molecular level is greatly enhanced when students are given the opportunity to visualize the molecules. Especially understanding DNA structure and function is essential for understanding key concepts of molecular biology such as DNA, central dogma and the manipulation of DNA. Researches have shown that undergraduate…

  18. Compound prioritization methods increase rates of chemical probe discovery in model organisms

    PubMed Central

    Wallace, Iain M; Urbanus, Malene L; Luciani, Genna M; Burns, Andrew R; Han, Mitchell KL; Wang, Hao; Arora, Kriti; Heisler, Lawrence E; Proctor, Michael; St. Onge, Robert P; Roemer, Terry; Roy, Peter J; Cummins, Carolyn L; Bader, Gary D; Nislow, Corey; Giaever, Guri

    2011-01-01

    SUMMARY Pre-selection of compounds that are more likely to induce a phenotype can increase the efficiency and reduce the costs for model organism screening. To identify such molecules, we screened ~81,000 compounds in S. cerevisiae and identified ~7,500 that inhibit cell growth. Screening these growth-inhibitory molecules across a diverse panel of model organisms resulted in an increased phenotypic hit-rate. This data was used to build a model to predict compounds that inhibit yeast growth. Empirical and in silico application of the model enriched the discovery of bioactive compounds in diverse model organisms. To demonstrate the potential of these molecules as lead chemical probes we used chemogenomic profiling in yeast and identified specific inhibitors of lanosterol synthase and of stearoyl-CoA 9-desaturase. As community resources, the ~7,500 growth-inhibitory molecules has been made commercially available and the computational model and filter used are provided. PMID:22035796

  19. Compound prioritization methods increase rates of chemical probe discovery in model organisms.

    PubMed

    Wallace, Iain M; Urbanus, Malene L; Luciani, Genna M; Burns, Andrew R; Han, Mitchell K L; Wang, Hao; Arora, Kriti; Heisler, Lawrence E; Proctor, Michael; St Onge, Robert P; Roemer, Terry; Roy, Peter J; Cummins, Carolyn L; Bader, Gary D; Nislow, Corey; Giaever, Guri

    2011-10-28

    Preselection of compounds that are more likely to induce a phenotype can increase the efficiency and reduce the costs for model organism screening. To identify such molecules, we screened ~81,000 compounds in Saccharomyces cerevisiae and identified ~7500 that inhibit cell growth. Screening these growth-inhibitory molecules across a diverse panel of model organisms resulted in an increased phenotypic hit-rate. These data were used to build a model to predict compounds that inhibit yeast growth. Empirical and in silico application of the model enriched the discovery of bioactive compounds in diverse model organisms. To demonstrate the potential of these molecules as lead chemical probes, we used chemogenomic profiling in yeast and identified specific inhibitors of lanosterol synthase and of stearoyl-CoA 9-desaturase. As community resources, the ~7500 growth-inhibitory molecules have been made commercially available and the computational model and filter used are provided.

  20. Double-stranded DNA organization in bacteriophage heads: An alternative toroid-based model

    SciTech Connect

    Hud, N.V.

    1995-10-01

    Studies of the organization of double-stranded DNA within bacteriophage heads during the past four decades have produced a wealth of data. However, despite the presentation of numerous models, the true organization of DNA within phage heads remains unresolved. The observations of toroidal DNA structures in electron micrographs of phage lysates have long been cited as support for the organization of DNA in a spool-like fashion. This particular model, like all other models, has not been found to be consistent with all available data. Recently, the authors proposed that DNA within toroidal condensates produced in vitro is organized in a manner significantly different from that suggested by the spool model. This new toroid model has allowed the development of an alternative model for DNA organization within bacteriophage heads that is consistent with a wide range of biophysical data. Here the authors propose that bacteriophage DNA is packaged in a toroid that is folded into a highly compact structure.

  1. DNA damage response and DNA repair – dog as a model?

    PubMed Central

    2014-01-01

    Background Companion animals like dogs frequently develop tumors with age and similarly to human malignancies, display interpatient tumoral heterogeneity. Tumors are frequently characterized with regard to their mutation spectra, changes in gene expression or protein levels. Among others, these changes affect proteins involved in the DNA damage response (DDR), which served as a basis for the development of numerous clinically relevant cancer therapies. Even though the effects of different DNA damaging agents, as well as DDR kinetics, have been well characterized in mammalian cells in vitro, very little is so far known about the kinetics of DDR in tumor and normal tissues in vivo. Discussion Due to (i) the similarities between human and canine genomes, (ii) the course of spontaneous tumor development, as well as (iii) common exposure to environmental agents, canine tumors are potentially an excellent model to study DDR in vivo. This is further supported by the fact that dogs show approximately the same rate of tumor development with age as humans. Though similarities between human and dog osteosarcoma, as well as mammary tumors have been well established, only few studies using canine tumor samples addressed the importance of affected DDR pathways in tumor progression, thus leaving many questions unanswered. Summary Studies in humans showed that misregulated DDR pathways play an important role during tumor development, as well as in treatment response. Since dogs are proposed to be a good tumor model in many aspects of cancer research, we herein critically investigate the current knowledge of canine DDR and discuss (i) its future potential for studies on the in vivo level, as well as (ii) its possible translation to veterinary and human medicine. PMID:24641873

  2. The S=1 Underscreened Anderson Lattice model for Uranium compounds

    NASA Astrophysics Data System (ADS)

    Thomas, C.; Simões, A. S. R.; Iglesias, J. R.; Lacroix, C.; Perkins, N. B.; Coqblin, B.

    2011-01-01

    Magnetic properties of uranium and neptunium compounds showing coexistence of the Kondo effect and ferromagnetic order are investigated within the degenerate Anderson Lattice Hamiltonian, describing a 5f2 electronic configuration with S = 1 spins. Through the Schrieffer-Wolff transformation, both an exchange Kondo interaction for the S = 1 f-spins and an effective f-band term are obtained, allowing to describe the coexistence of Kondo effect and ferromagnetic ordering and a weak delocalization of the 5f-electrons. We calculate the Kondo and Curie temperatures and we can account for the pressure dependence of the Curie temperature of UTe.

  3. Deep eutectic solvents as novel extraction media for phenolic compounds from model oil.

    PubMed

    Gu, Tongnian; Zhang, Mingliang; Tan, Ting; Chen, Jia; Li, Zhan; Zhang, Qinghua; Qiu, Hongdeng

    2014-10-11

    Deep eutectic solvents (DES) as a new kind of green solvent were used for the first time to excellently extract phenolic compounds from model oil. It was also proved that DES could be used to extract other polar compounds from non-polar or weakly-polar solvents by liquid-phase microextraction.

  4. Selecting a Response in Task Switching: Testing a Model of Compound Cue Retrieval

    ERIC Educational Resources Information Center

    Schneider, Darryl W.; Logan, Gordon D.

    2009-01-01

    How can a task-appropriate response be selected for an ambiguous target stimulus in task-switching situations? One answer is to use compound cue retrieval, whereby stimuli serve as joint retrieval cues to select a response from long-term memory. In the present study, the authors tested how well a model of compound cue retrieval could account for a…

  5. ESTIMATING TRANSPORT AND DEPOSITION OF A SEMI-VOLATILE COMPOUND WITH A REGIONAL PHOTOCHEMICAL MODEL

    EPA Science Inventory

    To simulate the fate of compounds that are considered semi-volatile and toxic, we have modified a model for regional particulate matter. Our changes introduce a semi-volatile compound into the atmosphere as gaseous emissions from an area source. Once emitted, the gas can transf...

  6. Deep eutectic solvents as novel extraction media for phenolic compounds from model oil.

    PubMed

    Gu, Tongnian; Zhang, Mingliang; Tan, Ting; Chen, Jia; Li, Zhan; Zhang, Qinghua; Qiu, Hongdeng

    2014-10-11

    Deep eutectic solvents (DES) as a new kind of green solvent were used for the first time to excellently extract phenolic compounds from model oil. It was also proved that DES could be used to extract other polar compounds from non-polar or weakly-polar solvents by liquid-phase microextraction. PMID:25144155

  7. DNA

    ERIC Educational Resources Information Center

    Stent, Gunther S.

    1970-01-01

    This history for molecular genetics and its explanation of DNA begins with an analysis of the Golden Jubilee essay papers, 1955. The paper ends stating that the higher nervous system is the one major frontier of biological inquiry which still offers some romance of research. (Author/VW)

  8. Elucidating the reactivity of Pt(II) complexes with (O,S) bidentate ligands towards DNA model systems.

    PubMed

    Mügge, Carolin; Musumeci, Domenica; Michelucci, Elena; Porru, Francesca; Marzo, Tiziano; Massai, Lara; Messori, Luigi; Weigand, Wolfgang; Montesarchio, Daniela

    2016-07-01

    In the search for novel platinum-based anticancer therapeutic agents, we have recently established a structural motif of (O,S) bidentate ligands bound to a Pt(II) metal center which is effective against various cancer cell lines. Aiming at further enhancing the cytotoxicity of metal-based drugs, the identification of potential biological targets and elucidation of the mode of action of selected lead compounds is of utmost importance. Here we report our studies on the DNA interaction of three representative Pt(II) complexes of the investigated series, using various model systems and analytical techniques. In detail, CD spectroscopy as well as ESI-MS and MS(2) techniques were applied to gain an overall picture of the binding properties of this class of (O,S) bidentate Pt(II) compounds with defined oligonucleotide sequences in single strand, duplex or G-quadruplex form, as well as with the nucleobase 9-methylguanine. On the whole, it was demonstrated that the tested compounds interact with DNA and produce conformational changes of different extents depending on the sequence and structure of the examined oligonucleotide. Guanine was established as the preferential target within the DNA sequence, but in the absence or unavailability of guanines, alternative binding sites can be addressed. The implications of these results are thoroughly discussed. PMID:26921982

  9. A New Fractal Model of Chromosome and DNA Processes

    NASA Astrophysics Data System (ADS)

    Bouallegue, K.

    Dynamic chromosome structure remains unknown. Can fractals and chaos be used as new tools to model, identify and generate a structure of chromosomes?Fractals and chaos offer a rich environment for exploring and modeling the complexity of nature. In a sense, fractal geometry is used to describe, model, and analyze the complex forms found in nature. Fractals have also been widely not only in biology but also in medicine. To this effect, a fractal is considered an object that displays self-similarity under magnification and can be constructed using a simple motif (an image repeated on ever-reduced scales).It is worth noting that the problem of identifying a chromosome has become a challenge to find out which one of the models it belongs to. Nevertheless, the several different models (a hierarchical coiling, a folded fiber, and radial loop) have been proposed for mitotic chromosome but have not reached a dynamic model yet.This paper is an attempt to solve topological problems involved in the model of chromosome and DNA processes. By combining the fractal Julia process and the numerical dynamical system, we have finally found out four main points. First, we have developed not only a model of chromosome but also a model of mitosis and one of meiosis. Equally important, we have identified the centromere position through the numerical model captured below. More importantly, in this paper, we have discovered the processes of the cell divisions of both mitosis and meiosis. All in all, the results show that this work could have a strong impact on the welfare of humanity and can lead to a cure of genetic diseases.

  10. Potential of the NBP method for the study of alkylation mechanisms: NBP as a DNA-model.

    PubMed

    Gómez-Bombarelli, Rafael; González-Pérez, Marina; Calle, Emilio; Casado, Julio

    2012-06-18

    Alkylating agents are considered to be archetypal carcinogens. One suitable technique to evaluate the activity of alkylating compounds is the NBP assay. This method is based on the formation of a chromophore in the reaction between the alkylating agent and the nucleophile 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to those of DNA bases. NBP is known to react with strong and weak alkylating agents, and much insight into such alkylation mechanisms in vivo can be gained from kinetic study of some alkylation reactions in vitro. Since 1925, the NBP assay has evolved from being a qualitative, analytical tool to becoming a useful physicochemical method that not only allows the rules of chemical reactivity that govern electrophilicity and nucleophilicity to be applied to the reaction of DNA with alkylating agents but also helps to understand some significant relationships between the structure of many alkylation substrates (including DNA) and their chemical and biological responses. Given that advances in this area have the potential to yield both fundamental and practical advances in chemistry, biology, predictive toxicology, and anticancer drug development, this review is designed to provide an overview of the evolution of the NBP method from its early inception until its recent kinetic-mechanistic approach, which allows the pros and cons of NBP as a DNA-model to be analyzed. The validity of NBP as a nucleophilicity model for DNA in general and the position of guanosine at N7 in particular are discussed. PMID:22480281

  11. Energetics of hydrogen bonding in proteins: a model compound study.

    PubMed Central

    Habermann, S. M.; Murphy, K. P.

    1996-01-01

    Differences in the energetics of amide-amide and amide-hydroxyl hydrogen bonds in proteins have been explored from the effect of hydroxyl groups on the structure and dissolution energetics of a series of crystalline cyclic dipeptides. The calorimetrically determined energetics are interpreted in light of the crystal structures of the studied compounds. Our results indicate that the amide-amide and amide-hydroxyl hydrogen bonds both provide considerable enthalpic stability, but that the amide-amide hydrogen bond is about twice that of the amide-hydroxyl. Additionally, the interaction of the hydroxyl group with water is seen most readily in its contributions to entropy and heat capacity changes. Surprisingly, the hydroxyl group shows weakly hydrophobic behavior in terms of these contributions. These results can be used to understand the effects of mutations on the stability of globular proteins. PMID:8819156

  12. Synthesis of model compounds for coal liquefaction research

    SciTech Connect

    Asaro, M.F.; Bottaro, J.C.; Hirschon, A.S.

    1991-05-01

    The objective of this project are to develop feasible synthetic routes to produce (1) 4(4{prime}-hydroxy-5{prime},6{prime},7{prime},8{prime}-tetrahydro-1{prime}-naphthylmethyl)-6-methyldibenzothiophene, and (2) a 1-hydroxynaphthalene-dibenzothiophene polymer. These compounds are thought to be representative of sulfur containing molecules in coal. The program is divided into three tasks, the first of which is a project work plan that we have already submitted. Tasks 2 and 3 are as follows: Synthesis of 4(4-hydroxy-5{prime},6{prime},7{prime},8{prime}-tetrahydro-1{prime}-naphthylmethyl)-6-methyldibenzothiophene and synthesis of 1-hydroxynaphthalene-dibenzothiophene polymer linked by methylene bonds. 14 refs.

  13. [Emission model of volatile organic compounds from materials used indoors].

    PubMed

    Han, K

    1998-11-30

    Various materials, such as wall-paper, floor-wax, paint, multicolor wall-coat, air freshener and mothball were experimented in a simulated test chamber under constant selected temperature, humidity and air exchange rate. The relation between the total VOCs concentration and time was regressed by four emission models and the surface emission rate was calculated. The regressed results indicated the similarity among four emission models for the liquid materials with volatile-solvent such as paint and multicolor wall-coat. But for low volatile solid materials, such as wall-paper, floor-wax, mothball, the sink model and the empirical model were better than the dilution model and vapor pressure model. Only for air freshener, it was improper to the total VOCs concentration as a parameter.

  14. MODELING VOLATILE ORGANIC COMPOUND PHARMACOKINETICS IN RAT PUPS

    EPA Science Inventory

    PBPK model predictions of internal dosimetry in young rats were compared to adult animals for benzene, chloroform (CHL), methylene chloride, methyl ethly ketone (MEK), perchloroethylene, and trichloroethylene.

  15. Ecological Niche Modelling and nDNA Sequencing Support a New, Morphologically Cryptic Beetle Species Unveiled by DNA Barcoding

    PubMed Central

    Hawlitschek, Oliver; Porch, Nick; Hendrich, Lars; Balke, Michael

    2011-01-01

    Background DNA sequencing techniques used to estimate biodiversity, such as DNA barcoding, may reveal cryptic species. However, disagreements between barcoding and morphological data have already led to controversy. Species delimitation should therefore not be based on mtDNA alone. Here, we explore the use of nDNA and bioclimatic modelling in a new species of aquatic beetle revealed by mtDNA sequence data. Methodology/Principal Findings The aquatic beetle fauna of Australia is characterised by high degrees of endemism, including local radiations such as the genus Antiporus. Antiporus femoralis was previously considered to exist in two disjunct, but morphologically indistinguishable populations in south-western and south-eastern Australia. We constructed a phylogeny of Antiporus and detected a deep split between these populations. Diagnostic characters from the highly variable nuclear protein encoding arginine kinase gene confirmed the presence of two isolated populations. We then used ecological niche modelling to examine the climatic niche characteristics of the two populations. All results support the status of the two populations as distinct species. We describe the south-western species as Antiporus occidentalis sp.n. Conclusion/Significance In addition to nDNA sequence data and extended use of mitochondrial sequences, ecological niche modelling has great potential for delineating morphologically cryptic species. PMID:21347370

  16. Identifying developmental vascular disruptor compounds using a predictive signature and alternative toxicity models

    EPA Science Inventory

    Identifying Developmental Vascular Disruptor Compounds Using a Predictive Signature and Alternative Toxicity Models Presenting Author: Tamara Tal Affiliation: U.S. EPA/ORD/ISTD, RTP, NC, USA Chemically induced vascular toxicity during embryonic development can result in a wide...

  17. Indoor Residence Times of Semivolatile Organic Compounds: Model Estimation and Field Evaluation

    EPA Science Inventory

    Indoor residence times of semivolatile organic compounds (SVOCs) are a major and mostly unavailable input for residential exposure assessment. We calculated residence times for a suite of SVOCs using a fugacity model applied to residential environments. Residence times depend on...

  18. Porphyrin-quinone compounds as synthetic models of the reaction centre in photosynthesis

    NASA Astrophysics Data System (ADS)

    Borovkov, V. V.; Evstigneeva, Rima P.; Strekova, L. N.; Filippovich, E. I.

    1989-06-01

    Data on the synthesis, steric structure, and photochemical properties of porphyrin-quinone compounds as synthetic models of the reaction centre in photosynthesis are examined and described systematically. The bibliography includes 113 references.

  19. Computational method and system for modeling, analyzing, and optimizing DNA amplification and synthesis

    DOEpatents

    Vandersall, Jennifer A.; Gardner, Shea N.; Clague, David S.

    2010-05-04

    A computational method and computer-based system of modeling DNA synthesis for the design and interpretation of PCR amplification, parallel DNA synthesis, and microarray chip analysis. The method and system include modules that address the bioinformatics, kinetics, and thermodynamics of DNA amplification and synthesis. Specifically, the steps of DNA selection, as well as the kinetics and thermodynamics of DNA hybridization and extensions, are addressed, which enable the optimization of the processing and the prediction of the products as a function of DNA sequence, mixing protocol, time, temperature and concentration of species.

  20. DNA repair in reduced genome: the Mycoplasma model.

    PubMed

    Carvalho, Fabíola Marques; Fonseca, Marbella Maria; Batistuzzo De Medeiros, Sílvia; Scortecci, Kátia Castanho; Blaha, Carlos Alfredo Galindo; Agnez-Lima, Lucymara Fassarella

    2005-11-01

    The occurrence of bacteria with a reduced genome, such as that found in Mycoplasmas, raises the question as to which genes should be enough to guarantee the genomic stability indispensable for the maintenance of life. The aim of this work was to compare nine Mycoplasma genomes in regard to DNA repair genes. An in silico analysis was done using six Mycoplasma species, whose genomes are accessible at GenBank, and M. synoviae, and two strains of M. hyopneumoniae, whose genomes were recently sequenced by The Brazilian National Genome Project Consortium and Southern Genome Investigation Program (Brazil) respectively. Considering this reduced genome model, our comparative analysis suggests that the DNA integrity necessary for life can be primarily maintained by nucleotide excision repair (NER), which is the only complete repair pathway. Furthermore, some enzymes involved with base excision repair (BER) and recombination are also present and can complement the NER activity. The absence of RecR and RecO-like ORFs was observed only in M. genitalium and M. pneumoniae, which can be involved with the conservation of gene order observed between these two species. We also obtained phylogenetic evidence for the recent acquisition of the ogt gene in M. pulmonis and M. penetrans by a lateral transference event. In general, the presence or nonexistence of repair genes is shared by all species analyzed, suggesting that the loss of the majority of repair genes was an ancestral event, which occurred before the divergence of the Mycoplasma species. PMID:16153783

  1. Recombinant DNA Paper Model Simulation: The Genetic Engineer.

    ERIC Educational Resources Information Center

    Wagner, Joan

    1998-01-01

    Describes a course for talented high school students that focuses on DNA science and technology. Employs Cold Spring Harbor's DNA Science laboratory manual. Engages students in performing sickle-cell anemia and thalassemia tests in rabbits. (DDR)

  2. Genotoxicity of a variety of azobenzene and aminoazobenzene compounds in the hepatocyte/DNA repair test and the Salmonella/mutagenicity test.

    PubMed

    Mori, H; Mori, Y; Sugie, S; Yoshimi, N; Takahashi, M; Ni-i, H; Yamazaki, H; Toyoshi, K; Williams, G M

    1986-04-01

    Genotoxicity of 39 azo dye compounds of azobenzenes, aminoazobenzenes, and diaminoazobenzenes was examined in the hepatocyte primary culture/DNA repair test. Azobenzene (AzB) and 3,3'- or 4,4'-substituted azobenzenes such as (CH3)2AzB, (CH2OH)2AzB, (CH2OCOCH3)2AzB, and (CH2Cl)2AzB did not generate DNA repair, indicating lack of genotoxicity of these compounds. In contrast, all of 24 aminoazobenzenes, including those of unknown carcinogenicity, i.e., 3'-methyl-4-aminoazobenzene, 3'-CH2OH-aminoazobenzene, 3'-hydroxymethyl-N-methyl-4-aminoazobenzene, 3'-COOH-methylaminoazobenzene, 4'-formyl-N,N-dimethyl-4-aminoazobenzene, 3'-CH2Cl-dimethylaminoazobenzene, 4'-CH2Cl-dimethylaminoazobenzene, and 2'-, 3'-, or 4'-CH2OCOCH3-dimethylaminoazobenzene, elicited DNA repair synthesis. A positive DNA repair response was obtained for the 3 of 6 tested diaminoazobenzenes, i.e., N'-acetyl-N'-methyl-4-amino-dimethylaminoazobenzene, N'-acetyl-N'-methyl-4-amino-methylaminoazobenzene, and N'-acetyl-N'-methyl-4-amino-N-acetyl-methylaminoazobenzene, which are known to be carcinogenic. These results indicate that the amino group is functional for the expression of genotoxicity of azobenzene compounds. Twenty-one azobenzenes of these 3 classes were also examined for their mutagenicity in the Salmonella/mutagenicity assay. These results were almost identical with those of the DNA repair test except for several azo dyes such as AzB and 4,4'-(CH2Oacetyl)2AzB of the azobenzenes and N'-acetyl-4-amino-dimethylaminoazobenzene and N'-acetyl-N-methyl-4-amino-N-acetyl methylaminoazobenzene of the diaminoazobenzenes.

  3. Distributed feedback laser action from polymeric waveguides doped with oligo phenylene vinylene model compounds

    NASA Astrophysics Data System (ADS)

    Kretsch, Kevin P.; Blau, Werner J.; Dumarcher, Vincent; Rocha, Licinio; Fiorini, Celine; Nunzi, Jean-Michel; Pfeiffer, Steffen; Tillmann, Hartwig; Hörhold, Hans-Heinrich

    2000-04-01

    We report lasing studies of poly(styrene) waveguides doped with amino- and cyano-substituted oligo phenylene vinylene (distyryl benzene) model compounds under picosecond excitation. Optical feedback is provided by distributed Bragg gratings formed in the film by interference patterns in the pump beam. We demonstrate broad tunability of laser emission in these materials and simultaneous lasing at two wavelengths separated by 23 nm. Tuning ranges of the model compounds are compared with previous experiments.

  4. Quantification of Cooperativity in Heterodimer-DNA Binding Improves the Accuracy of Binding Specificity Models*

    PubMed Central

    Isakova, Alina; Berset, Yves; Hatzimanikatis, Vassily; Deplancke, Bart

    2016-01-01

    Many transcription factors (TFs) have the ability to cooperate on DNA elements as heterodimers. Despite the significance of TF heterodimerization for gene regulation, a quantitative understanding of cooperativity between various TF dimer partners and its impact on heterodimer DNA binding specificity models is still lacking. Here, we used a novel integrative approach, combining microfluidics-steered measurements of dimer-DNA assembly with mechanistic modeling of the implicated protein-protein-DNA interactions to quantitatively interrogate the cooperative DNA binding behavior of the adipogenic peroxisome proliferator-activated receptor γ (PPARγ):retinoid X receptor α (RXRα) heterodimer. Using the high throughput MITOMI (mechanically induced trapping of molecular interactions) platform, we derived equilibrium DNA binding data for PPARγ, RXRα, as well as the PPARγ:RXRα heterodimer to more than 300 target DNA sites and variants thereof. We then quantified cooperativity underlying heterodimer-DNA binding and derived an integrative heterodimer DNA binding constant. Using this cooperativity-inclusive constant, we were able to build a heterodimer-DNA binding specificity model that has superior predictive power than the one based on a regular one-site equilibrium. Our data further revealed that individual nucleotide substitutions within the target site affect the extent of cooperativity in PPARγ:RXRα-DNA binding. Our study therefore emphasizes the importance of assessing cooperativity when generating DNA binding specificity models for heterodimers. PMID:26912662

  5. Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability

    PubMed Central

    Hendriks, Delilah F. G.; Fredriksson Puigvert, Lisa; Messner, Simon; Mortiz, Wolfgang; Ingelman-Sundberg, Magnus

    2016-01-01

    Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound’s potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days. In contrast, no such synergism was observed after both 8 and 14 days of exposure to the BA mixture for compounds that cause non-cholestatic hepatotoxicity. Mechanisms behind the toxicity of the cholestatic compound chlorpromazine were accurately detected in both spheroid models, including intracellular BA accumulation, inhibition of ABCB11 expression and disruption of the F-actin cytoskeleton. Furthermore, the observed synergistic toxicity of chlorpromazine and BA was associated with increased oxidative stress and modulation of death receptor signalling. Combined, our results demonstrate that the hepatic spheroid models presented here can be used to detect and study compounds with cholestatic liability. PMID:27759057

  6. The Dynamic Character of the BCL2 Promoter i-Motif Provides a Mechanism for Modulation of Gene Expression by Compounds That Bind Selectively to the Alternative DNA Hairpin Structure

    PubMed Central

    2015-01-01

    It is generally accepted that DNA predominantly exists in duplex form in cells. However, under torsional stress imposed by active transcription, DNA can assume nonduplex structures. The BCL2 promoter region forms two different secondary DNA structures on opposite strands called the G-quadruplex and the i-motif. The i-motif is a highly dynamic structure that exists in equilibrium with a flexible hairpin species. Here we identify a pregnanol derivative and a class of piperidine derivatives that differentially modulate gene expression by stabilizing either the i-motif or the flexible hairpin species. Stabilization of the i-motif structure results in significant upregulation of the BCL2 gene and associated protein expression; in contrast, stabilization of the flexible hairpin species lowers BCL2 levels. The BCL2 levels reduced by the hairpin-binding compound led to chemosensitization to etoposide in both in vitro and in vivo models. Furthermore, we show antagonism between the two classes of compounds in solution and in cells. For the first time, our results demonstrate the principle of small molecule targeting of i-motif structures in vitro and in vivo to modulate gene expression. PMID:24559410

  7. Acute elevation by short-term dietary restriction or food deprivation of type I I-compound levels in rat liver DNA.

    PubMed

    Zhou, G D; Hernandez, N S; Randerath, E; Randerath, K

    1999-01-01

    Type I I-compounds are bulky endogenous DNA modifications detectable by 32P postlabeling that exhibit age, species, tissue, genotype, gender, and diet dependence. Their formation appears unrelated to oxidative stress. In fact, several lines of indirect evidence suggest that many type I I-compounds may represent normal functional DNA modifications. For example, long-term dietary restriction (DR), which retards the development of age-related diseases including cancer and extends median and maximum life spans, unexpectedly elicits significant increases rather than decreases in the levels of many I-compounds in different rodent tissues. Positive linear correlations have been observed between such levels and median life spans of the animals. In the present work we have investigated 1) whether elevation of I-compound levels does not depend on chronic DR, i.e., occurs after a short period of DR or fasting, and 2) whether I-compound levels return to control values after the animals are returned to unrestricted feeding after food deprivation. Female Fischer 344 rats (approx 140 g each) were randomized into three groups. Group I was fed a natural ingredient (Purina 5001) diet ad libitum (AL) throughout the study, Group 2 was switched to 60% of the AL amount (40% DR) at 0 hour, and Group 3 was given no food for up to 72 hours and then returned to AL feeding until the end of the experiment. Liver DNA of individual rats (n = 4) was isolated for I-compound analysis at 24, 72, and 240 hours. Restricted and food-deprived rats showed elevated levels of hepatic I-compounds, with fasting eliciting the highest levels. These effects were seen as early as the 24-hour time point. Refeeding after 72 hours of food deprivation restored the levels to control values, measured at 240 hours. Our observations are discussed in relation to carcinogenesis and tumor promotion. The almost instantaneous changes of endogenous DNA modifications showed their exquisite sensitivity to nutritional factors

  8. Investigation of membrane fouling in ultrafiltration using model organic compounds.

    PubMed

    Kweon, J H; Lawler, D F

    2005-01-01

    Natural organic matter (NOM) is known to be the worst foulant in the membrane processes, but the complexities of NOM make it difficult to determine its effects on membrane fouling. Therefore, simple organic compounds (surrogates for NOM) were used in this research to investigate the fouling mechanisms in ultrafiltration. Previous research on NOM components in membrane processes indicated that polysaccharides formed an important part of the fouling cake. Three polysaccharides (dextran, alginic acid, and polygalacturonic acid) and a smaller carbohydrate (tannic acid) were evaluated for their removal in softening (the treatment process in the City of Austin). Two polysaccharides (dextran and alginic acid) were selected and further investigated for their effects on membrane fouling. The two raw organic waters (4 mg/L C) showed quite different patterns of flux decline indicating different fouling mechanisms. Softening pretreatment was effective to reduce flux decline of both waters. The SEM images of the fouled membrane clearly showed the shapes of deposited foulants. The high resolution results of the XPS spectra showed substantially different spectra of carbon, C(1s), in the membrane fouled by two raw organic waters. The XPS was beneficial in determining the relative composition of each fouling material on the membrane surface.

  9. Investigation of membrane fouling in ultrafiltration using model organic compounds.

    PubMed

    Kweon, J H; Lawler, D F

    2005-01-01

    Natural organic matter (NOM) is known to be the worst foulant in the membrane processes, but the complexities of NOM make it difficult to determine its effects on membrane fouling. Therefore, simple organic compounds (surrogates for NOM) were used in this research to investigate the fouling mechanisms in ultrafiltration. Previous research on NOM components in membrane processes indicated that polysaccharides formed an important part of the fouling cake. Three polysaccharides (dextran, alginic acid, and polygalacturonic acid) and a smaller carbohydrate (tannic acid) were evaluated for their removal in softening (the treatment process in the City of Austin). Two polysaccharides (dextran and alginic acid) were selected and further investigated for their effects on membrane fouling. The two raw organic waters (4 mg/L C) showed quite different patterns of flux decline indicating different fouling mechanisms. Softening pretreatment was effective to reduce flux decline of both waters. The SEM images of the fouled membrane clearly showed the shapes of deposited foulants. The high resolution results of the XPS spectra showed substantially different spectra of carbon, C(1s), in the membrane fouled by two raw organic waters. The XPS was beneficial in determining the relative composition of each fouling material on the membrane surface. PMID:16003967

  10. A modeling approach for compounds affecting body composition.

    PubMed

    Gennemark, Peter; Jansson-Löfmark, Rasmus; Hyberg, Gina; Wigstrand, Maria; Kakol-Palm, Dorota; Håkansson, Pernilla; Hovdal, Daniel; Brodin, Peter; Fritsch-Fredin, Maria; Antonsson, Madeleine; Ploj, Karolina; Gabrielsson, Johan

    2013-12-01

    Body composition and body mass are pivotal clinical endpoints in studies of welfare diseases. We present a combined effort of established and new mathematical models based on rigorous monitoring of energy intake (EI) and body mass in mice. Specifically, we parameterize a mechanistic turnover model based on the law of energy conservation coupled to a drug mechanism model. Key model variables are fat-free mass (FFM) and fat mass (FM), governed by EI and energy expenditure (EE). An empirical Forbes curve relating FFM to FM was derived experimentally for female C57BL/6 mice. The Forbes curve differs from a previously reported curve for male C57BL/6 mice, and we thoroughly analyse how the choice of Forbes curve impacts model predictions. The drug mechanism function acts on EI or EE, or both. Drug mechanism parameters (two to three parameters) and system parameters (up to six free parameters) could be estimated with good precision (coefficients of variation typically <20 % and not greater than 40 % in our analyses). Model simulations were done to predict the EE and FM change at different drug provocations in mice. In addition, we simulated body mass and FM changes at different drug provocations using a similar model for man. Surprisingly, model simulations indicate that an increase in EI (e.g. 10 %) was more efficient than an equal lowering of EI. Also, the relative change in body mass and FM is greater in man than in mouse at the same relative change in either EI or EE. We acknowledge that this assumes the same drug mechanism impact across the two species. A set of recommendations regarding the Forbes curve, vehicle control groups, dual action on EI and loss, and translational aspects are discussed. This quantitative approach significantly improves data interpretation, disease system understanding, safety assessment and translation across species.

  11. A segmentation model using compound Markov random fields based on a boundary model.

    PubMed

    Wu, Jue; Chung, Albert C S

    2007-01-01

    Markov random field (MRF) theory has been widely applied to the challenging problem of image segmentation. In this paper, we propose a new nontexture segmentation model using compound MRFs, in which the original label MRF is coupled with a new boundary MRF to help improve the segmentation performance. The boundary model is relatively general and does not need prior training on boundary patterns. Unlike some existing related work, the proposed method offers a more compact interaction between label and boundary MRFs. Furthermore, our boundary model systematically takes into account all the possible scenarios of a single edge existing in a 3 x 3 neighborhood and, thus, incorporates sophisticated prior information about the relation between label and boundary. It is experimentally shown that the proposed model can segment objects with complex boundaries and at the same time is able to work under noise corruption. The new method has been applied to medical image segmentation. Experiments on synthetic images and real clinical datasets show that the proposed model is able to produce more accurate segmentation results and satisfactorily keep the delicate boundary. It is also less sensitive to noise in both high and low signal-to-noise ratio regions than some of the existing models in common use.

  12. Modeling and predicting competitive sorption of organic compounds in soil.

    PubMed

    Faria, Isabel R; Young, Thomas M

    2010-12-01

    Binary systems consisting of 1,2-dichlorobenzene (12DCB) + competitor were investigated over a range of concentrations of competitor in three natural sorbents with distinct characteristics. Two models, the ideal adsorbed solution theory (IAST) and the potential theory (Polanyi-based multisolute model), widely used in the prediction of multisolute sorption equilibrium from single-solute data, were used to simulate competitive sorption in our systems. The goal was to determine which multisolute model best represented the experimentally obtained multisolute data in natural sorbents of varied properties. Results suggested that for the sorbents and sorbates studied, the IAST model provided much better results. On average, the IAST model provided lower errors (23%) than the potential model (45%). The effect of competitor structure on the degree of competition was also investigated to identify any relationships between competition and structure using molecular descriptors. The competitors chlorobenzene, naphthalene, 1,4-dichlorobenzene, 1,2,4-trichlorobenzene all showed very similar degrees of competition, while benzene, phenanthrene, and pyrene were the least effective competitors toward 12DCB across all sorbents. Different sorption sites or sorption mechanisms might be involved in the sorption of these molecules leading to a lack of competitive behavior. A significant relationship between competitor structure and the degree of competition was observed at environmentally relevant sorbed competitor concentrations for the soil containing the highest fraction of hard carbon (Forbes soil).

  13. Modeling Scalable Pattern Generation in DNA Reaction Networks

    PubMed Central

    Allen, Peter B.; Chen, Xi; Simpson, Zack B.; Ellington, Andrew D.

    2013-01-01

    We have developed a theoretical framework for developing patterns in multiple dimensions using controllable diffusion and designed reactions implemented in DNA. This includes so-called strand displacement reactions in which one single-stranded DNA hybridizes to a hemi-duplex DNA and displaces another single-stranded DNA, reversibly or irreversibly. These reactions can be designed to proceed with designed rate and molecular specificity. By also controlling diffusion by partial complementarity to a stationary, cross-linked DNA, we can generate predictable patterns. We demonstrate this with several simulations showing deterministic, predictable shapes in space. PMID:25506295

  14. Modeling emissions of volatile organic compounds from silage storages and feed lanes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An initial volatile organic compound (VOC) emission model for silage sources, developed using experimental data from previous studies, was incorporated into the Integrated Farm System Model (IFSM), a whole-farm simulation model used to assess the performance, environmental impacts, and economics of ...

  15. Modeling of Intermetallic Compounds Growth Between Dissimilar Metals

    NASA Astrophysics Data System (ADS)

    Wang, Li; Wang, Yin; Prangnell, Philip; Robson, Joseph

    2015-09-01

    A model has been developed to predict growth kinetics of the intermetallic phases (IMCs) formed in a reactive diffusion couple between two metals for the case where multiple IMC phases are observed. The model explicitly accounts for the effect of grain boundary diffusion through the IMC layer, and can thus be used to explore the effect of IMC grain size on the thickening of the reaction layer. The model has been applied to the industrially important case of aluminum to magnesium alloy diffusion couples in which several different IMC phases are possible. It is demonstrated that there is a transition from grain boundary-dominated diffusion to lattice-dominated diffusion at a critical grain size, which is different for each IMC phase. The varying contribution of grain boundary diffusion to the overall thickening kinetics with changing grain size helps explain the large scatter in thickening kinetics reported for diffusion couples produced under different conditions.

  16. Synthesis of a naphthalene-hydroxynaphthalene polymer model compound. Final report, June 13, 1990--September 12, 1991

    SciTech Connect

    Not Available

    1991-10-02

    The objective of this project was the synthesis of one pound of a new naphthalene-hydroxynaphthalene polymer model compound for use in coal combustion studies. Since this compound was an unreported compound, this effort also required the development of a synthetic route to this compound (including routes to the unique and unreported intermediates leading to its synthesis).

  17. Chalcogen bonding interactions between reducible sulfur and selenium compounds and models of zinc finger proteins.

    PubMed

    Lutz, Patricia B; Bayse, Craig A

    2016-04-01

    Reducible sulfur and selenium (r-S/Se) compounds, defined as sulfur and selenium compounds not in the lowest -2 oxidation state (e.g., -1 to +6), release Zn(2+) from zinc-sulfur proteins such as zinc fingers (ZFs) and metallothionein. A series of density functional theory calculations was performed on donor-acceptor complexes between r-S/Se compounds and models of the Cys2His2, Cys3His and Cys4 ZF sites. These S⋯S/Se chalcogen bonding interactions consist of the donation of electron density from a S lone pair on the ZF model to a S/Se-X antibonding molecular orbital of the r-S/Se compound. The strength of the interaction was shown to be dependent upon the Lewis basicity of the ZF model (Cys4>Cys3His>Cys2His2) and the Lewis acidity of the r-S/Se compound as measured by the energy of the S/Se-X antibonding orbital. Interactions with the softer r-Se compounds were stronger than the r-S compounds, consistent with the greater reactivity of the former with ZF proteins.

  18. Five-descriptor model to predict the chromatographic sequence of natural compounds.

    PubMed

    Hou, Shuying; Wang, Jinhua; Li, Zhangming; Wang, Yang; Wang, Ying; Yang, Songling; Xu, Jia; Zhu, Wenliang

    2016-03-01

    Despite the recent introduction of mass detection techniques, ultraviolet detection is still widely applied in the field of the chromatographic analysis of natural medicines. Here, a neural network cascade model consisting of nine small artificial neural network units was innovatively developed to predict the chromatographic sequence of natural compounds by integrating five molecular descriptors as the input. A total of 117 compounds of known structure were collected for model building. The order of appearance of each compound was determined in gradient chromatography. Strong linear correlation was found between the predicted and actual chromatographic position orders (Spearman's rho = 0.883, p < 0.0001). Application of the model to the external validation set of nine natural compounds was shown to dramatically increase the prediction accuracy of the real chromatographic order of multiple compounds. A case study shows that chromatographic sequence prediction based on a neural network cascade facilitated compound identification in the chromatographic fingerprint of Radix Salvia miltiorrhiza. For natural medicines of known compound composition, our method provides a feasible means for identifying the constituents of interest when only ultraviolet detection is available.

  19. Percutaneous absorption of explosives and related compounds: an empirical model of bioavailability of organic nitro compounds from soil.

    PubMed

    Reifenrath, William G; Kammen, Harold O; Palmer, Winifred G; Major, Michael M; Leach, Glenn J

    2002-07-15

    The percutaneous absorption potentials of (14)C-labeled 2,4,6-trinitrotoluene (TNT), trinitrobenzene, 2,4-dinitrotoluene (2,4-DNT), 2,6-dinitrotoluene (2,6-DNT), 2-amino-4,6-dinitrotoluene, 4-amino-2,6-dinitrotoluene, 2,4-diamino-6-nitrotoluene, 2,6-diamino-4-nitrotoluene, N-methyl-N,2,4,6-tetranitrobenzamine, hexahydro-1,3,5-trinitro-1,3,5-triazine, octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine, and 2,2-thiobis(ethanol) were determined from two soil types, Yolo having 1.9% carbon and Tinker having 9.5% carbon. TNT skin absorption from another low-carbon soil (Umatilla) was also determined. Approximately 10 microg/cm(2) of radiolabeled compound was applied in 5 microl of acetone or 10 mg/cm(2) of soil to excised pigskin mounted in skin penetration-evaporation chambers. Absorption from acetone served as a control. Radiolabel recovered from the dermis and tissue culture media (receptor fluid) was summed to determine the percentage of absorption from the soils. For each compound, percentage absorptions of radiolabel were highest from acetone solution and lowest from Tinker soil, with the results from Yolo soil being intermediate. Skin absorptions of TNT from Yolo and Umatilla soils were similar. For TNT in all vehicles, the penetration rate of radiolabel into the receptor fluid was highest during the 1- to 2-h interval after dosing. HPLC analysis of TNT radiolabel in receptor fluid at maximum flux indicated extensive conversion to monoamino derivatives and other metabolites. For 2,4-DNT and 2,6-DNT applications in Yolo soil, percentage absorptions approached those obtained from acetone applications. After 2,4-DNT and 2,6-DNT applications (acetone and soils), HPLC analysis of radiolabel in receptor fluid during the period of maximum flux revealed no significant metabolites. Skin absorption of the nitro compounds from soils was found to correlate with the compound's water solubility and vapor pressure. These findings formed the basis of an empirical model to predict

  20. Solubility Prediction of Active Pharmaceutical Compounds with the UNIFAC Model

    NASA Astrophysics Data System (ADS)

    Nouar, Abderrahim; Benmessaoud, Ibtissem; Koutchoukali, Ouahiba; Koutchoukali, Mohamed Salah

    2016-03-01

    The crystallization from solution of an active pharmaceutical ingredient requires the knowledge of the solubility in the entire temperature range investigated during the process. However, during the development of a new active ingredient, these data are missing. Its experimental determination is possible, but tedious. UNIFAC Group contribution method Fredenslund et al. (Vapor-liquid equilibria using UNIFAC: a group contribution method, 1977; AIChE J 21:1086, 1975) can be used to predict this physical property. Several modifications on this model have been proposed since its development in 1977, modified UNIFAC of Dortmund Weidlich et al. (Ind Eng Chem Res 26:1372, 1987), Gmehling et al. (Ind Eng Chem Res 32:178, 1993), Pharma-modified UNIFAC Diedrichs et al. (Evaluation und Erweiterung thermodynamischer Modelle zur Vorhersage von Wirkstofflöslichkeiten, PhD Thesis, 2010), KT-UNIFAC Kang et al. (Ind Eng Chem Res 41:3260, 2002), ldots In this study, we used UNIFAC model by considering the linear temperature dependence of interaction parameters as in Pharma-modified UNIFAC and structural groups as defined by KT-UNIFAC first-order model. More than 100 binary datasets were involved in the estimation of interaction parameters. These new parameters were then used to calculate activity coefficient and solubility of some molecules in various solvents at different temperatures. The model gives better results than those from the original UNIFAC and shows good agreement between the experimental solubility and the calculated one.

  1. Diffusion-controlled reactions modeling in Geant4-DNA

    SciTech Connect

    Karamitros, M.; Luan, S.; Bernal, M.A.; Allison, J.; Baldacchino, G.; Davidkova, M.; Francis, Z.; Friedland, W.; Ivantchenko, V.; Ivantchenko, A.; Mantero, A.; Nieminem, P.; Santin, G.; Tran, H.N.; Stepan, V.; Incerti, S.

    2014-10-01

    Context Under irradiation, a biological system undergoes a cascade of chemical reactions that can lead to an alteration of its normal operation. There are different types of radiation and many competing reactions. As a result the kinetics of chemical species is extremely complex. The simulation becomes then a powerful tool which, by describing the basic principles of chemical reactions, can reveal the dynamics of the macroscopic system. To understand the dynamics of biological systems under radiation, since the 80s there have been on-going efforts carried out by several research groups to establish a mechanistic model that consists in describing all the physical, chemical and biological phenomena following the irradiation of single cells. This approach is generally divided into a succession of stages that follow each other in time: (1) the physical stage, where the ionizing particles interact directly with the biological material; (2) the physico-chemical stage, where the targeted molecules release their energy by dissociating, creating new chemical species; (3) the chemical stage, where the new chemical species interact with each other or with the biomolecules; (4) the biological stage, where the repairing mechanisms of the cell come into play. This article focuses on the modeling of the chemical stage. Method This article presents a general method of speeding-up chemical reaction simulations in fluids based on the Smoluchowski equation and Monte-Carlo methods, where all molecules are explicitly simulated and the solvent is treated as a continuum. The model describes diffusion-controlled reactions. This method has been implemented in Geant4-DNA. The keys to the new algorithm include: (1) the combination of a method to compute time steps dynamically with a Brownian bridge process to account for chemical reactions, which avoids costly fixed time step simulations; (2) a k–d tree data structure for quickly locating, for a given molecule, its closest reactants. The

  2. Diffusion-controlled reactions modeling in Geant4-DNA

    NASA Astrophysics Data System (ADS)

    Karamitros, M.; Luan, S.; Bernal, M. A.; Allison, J.; Baldacchino, G.; Davidkova, M.; Francis, Z.; Friedland, W.; Ivantchenko, V.; Ivantchenko, A.; Mantero, A.; Nieminem, P.; Santin, G.; Tran, H. N.; Stepan, V.; Incerti, S.

    2014-10-01

    Context Under irradiation, a biological system undergoes a cascade of chemical reactions that can lead to an alteration of its normal operation. There are different types of radiation and many competing reactions. As a result the kinetics of chemical species is extremely complex. The simulation becomes then a powerful tool which, by describing the basic principles of chemical reactions, can reveal the dynamics of the macroscopic system. To understand the dynamics of biological systems under radiation, since the 80s there have been on-going efforts carried out by several research groups to establish a mechanistic model that consists in describing all the physical, chemical and biological phenomena following the irradiation of single cells. This approach is generally divided into a succession of stages that follow each other in time: (1) the physical stage, where the ionizing particles interact directly with the biological material; (2) the physico-chemical stage, where the targeted molecules release their energy by dissociating, creating new chemical species; (3) the chemical stage, where the new chemical species interact with each other or with the biomolecules; (4) the biological stage, where the repairing mechanisms of the cell come into play. This article focuses on the modeling of the chemical stage. Method This article presents a general method of speeding-up chemical reaction simulations in fluids based on the Smoluchowski equation and Monte-Carlo methods, where all molecules are explicitly simulated and the solvent is treated as a continuum. The model describes diffusion-controlled reactions. This method has been implemented in Geant4-DNA. The keys to the new algorithm include: (1) the combination of a method to compute time steps dynamically with a Brownian bridge process to account for chemical reactions, which avoids costly fixed time step simulations; (2) a k-d tree data structure for quickly locating, for a given molecule, its closest reactants. The

  3. Space Radiation Effects on Human Cells: Modeling DNA Breakage, DNA Damage Foci Distribution, Chromosomal Aberrations and Tissue Effects

    NASA Technical Reports Server (NTRS)

    Ponomarev, A. L.; Huff, J. L.; Cucinotta, F. A.

    2011-01-01

    Future long-tem space travel will face challenges from radiation concerns as the space environment poses health risk to humans in space from radiations with high biological efficiency and adverse post-flight long-term effects. Solar particles events may dramatically affect the crew performance, while Galactic Cosmic Rays will induce a chronic exposure to high-linear-energy-transfer (LET) particles. These types of radiation, not present on the ground level, can increase the probability of a fatal cancer later in astronaut life. No feasible shielding is possible from radiation in space, especially for the heavy ion component, as suggested solutions will require a dramatic increase in the mass of the mission. Our research group focuses on fundamental research and strategic analysis leading to better shielding design and to better understanding of the biological mechanisms of radiation damage. We present our recent effort to model DNA damage and tissue damage using computational models based on the physics of heavy ion radiation, DNA structure and DNA damage and repair in human cells. Our particular area of expertise include the clustered DNA damage from high-LET radiation, the visualization of DSBs (DNA double strand breaks) via DNA damage foci, image analysis and the statistics of the foci for different experimental situations, chromosomal aberration formation through DSB misrepair, the kinetics of DSB repair leading to a model-derived spectrum of chromosomal aberrations, and, finally, the simulation of human tissue and the pattern of apoptotic cell damage. This compendium of theoretical and experimental data sheds light on the complex nature of radiation interacting with human DNA, cells and tissues, which can lead to mutagenesis and carcinogenesis later in human life after the space mission.

  4. Global emissions and models of photochemically active compounds

    SciTech Connect

    Penner, J.E.; Atherton, C.S.; Graedel, T.E.

    1993-05-20

    Anthropogenic emissions from industrial activity, fossil fuel combustion, and biomass burning are now known to be large enough (relative to natural sources) to perturb the chemistry of vast regions of the troposphere. A goal of the IGAC Global Emissions Inventory Activity (GEIA) is to provide authoritative and reliable emissions inventories on a 1{degree} {times} 1{degree} grid. When combined with atmospheric photochemical models, these high quality emissions inventories may be used to predict the concentrations of major photochemical products. Comparison of model results with measurements of pertinent species allows us to understand whether there are major shortcomings in our understanding of tropospheric photochemistry, the budgets and transport of trace species, and their effects in the atmosphere. Through this activity, we are building the capability to make confident predictions of the future consequences of anthropogenic emissions. This paper compares IGAC recommended emissions inventories for reactive nitrogen and sulfur dioxide to those that have been in use previously. We also present results from the three-dimensional LLNL atmospheric chemistry model that show how emissions of anthropogenic nitrogen oxides might potentially affect tropospheric ozone and OH concentrations and how emissions of anthropogenic sulfur increase sulfate aerosol loadings.

  5. Sources of DNA Double-Strand Breaks and Models of Recombinational DNA Repair

    PubMed Central

    Mehta, Anuja; Haber, James E.

    2014-01-01

    DNA is subject to many endogenous and exogenous insults that impair DNA replication and proper chromosome segregation. DNA double-strand breaks (DSBs) are one of the most toxic of these lesions and must be repaired to preserve chromosomal integrity. Eukaryotes are equipped with several different, but related, repair mechanisms involving homologous recombination, including single-strand annealing, gene conversion, and break-induced replication. In this review, we highlight the chief sources of DSBs and crucial requirements for each of these repair processes, as well as the methods to identify and study intermediate steps in DSB repair by homologous recombination. PMID:25104768

  6. Titanocene-phosphine derivatives as precursors to cytotoxic heterometallic TiAu2 and TiM (M = Pd, Pt) compounds. Studies of their interactions with DNA.

    PubMed

    González-Pantoja, Jose F; Stern, Michael; Jarzecki, Andrzej A; Royo, Eva; Robles-Escajeda, Elisa; Varela-Ramírez, Armando; Aguilera, Renato J; Contel, María

    2011-11-01

    A series of tri- and bimetallic titanium-gold, titanium-palladium, and titanium-platinum derivatives of the general formulas [Ti{η(5)-C(5)H(4)(CH(2))(n)PPh(2)(AuCl)}(2)]·2THF [n = 0 (1); n = 2 (2); n = 3 (3)] and [TiCl(2){η(5)-C(5)H(4)κ-(CH(2))(n)PPh(2)}(2)(MCl(2))]·2THF [M = Pd, n = 0 (4); n = 2 (5); n = 3 (6) ; M = Pt, n = 0 (7); n = 2 (8); n = 3 (9)] have been synthesized and characterized by different spectroscopic techniques and mass spectrometry. The molecular structures of compounds 1-9 have been investigated by means of density functional theory calculations. The calculated IR spectra of the optimized structures fit well with the experimental IR data obtained for 1-9. The stability of the heterometallic compounds in deuterated solvents [CDCl(3), dimethyl sulfoxide (DMSO)-d(6), and mixtures 50:50 DMSO-d(6)/D(2)O and 1:99 DMSO-d(6)/D(2)O at acidic and neutral pH] has been evaluated by (31)P and (1)H NMR spectroscopy showing a higher stability for these compounds than for Cp(2)TiCl(2) or precursors [Ti{η(5)-C(5)H(4)(CH(2))(n)PPh(2)}(2)]. The new compounds display a lower acidity (1-2 units) than Cp(2)TiCl(2). The decomposition products have been identified over time. Complexes 1-9 have been tested as potential anticancer agents, and their cytotoxicity properties were evaluated in vitro against HeLa human cervical carcinoma and DU-145 human prostate cancer cells. TiAu(2) and TiPd compounds were highly cytotoxic for these two cell lines. The interactions of the compounds with calf thymus DNA have been evaluated by thermal denaturation (1-9) and by circular dichroism (1, 3, 4, and 7) spectroscopic methods. All of these complexes show a stronger interaction with DNA than that displayed by Cp(2)TiCl(2) at neutral pH. The data are consistent with electrostatic interactions with DNA for TiAu(2) compounds and for a covalent binding mode for TiM (M = Pd, Pt) complexes.

  7. Neutral and ionic platinum compounds containing a cyclometallated chiral primary amine: synthesis, antitumor activity, DNA interaction and topoisomerase I-cathepsin B inhibition.

    PubMed

    Albert, Joan; Bosque, Ramon; Crespo, Margarita; Granell, Jaume; López, Concepción; Martín, Raquel; González, Asensio; Jayaraman, Anusha; Quirante, Josefina; Calvis, Carme; Badía, Josefa; Baldomà, Laura; Font-Bardia, Mercè; Cascante, Marta; Messeguer, Ramon

    2015-08-14

    The synthesis and preliminary biological evaluation of neutral and cationic platinum derivatives of chiral 1-(1-naphthyl)ethylamine are reported, namely cycloplatinated neutral complexes [PtCl{(R or S)-NH(2)CH(CH(3))C(10)H(6)}(L)] [L = SOMe(2) ( 1-R or 1-S ), L = PPh(3) (2-R or 2-S), L = P(4-FC(6)H(4))(3) (3-R), L = P(CH(2))(3)N(3)(CH(2))(3) (4-R)], cycloplatinated cationic complexes [Pt{(R)-NH(2)CH(CH(3))C(10)H(6)}{L}]Cl [L = Ph(2)PCH(2)CH(2)PPh(2) (5-R), L = (C(6)F(5))(2)PCH(2)CH(2)P(C(6)F(5))(2) (6-R)] and the Pt(ii) coordination compound trans-[PtCl(2){(R)-NH(2)CH(CH(3))C(10)H(6)}(2)] (7-R). The X-ray molecular structure of 7-R is reported. The cytotoxic activity against a panel of human adenocarcinoma cell lines (A-549 lung, MDA-MB-231 and MCF-7 breast, and HCT-116 colon), cell cycle arrest and apoptosis, DNA interaction, topoisomerase I and cathepsin B inhibition, and Pt cell uptake of the studied compounds are presented. Remarkable cytotoxicity was observed for most of the synthesized Pt(ii) compounds regardless of (i) the absolute configuration R or S, and (ii) the coordinated/cyclometallated (neutral or cationic) nature of the complexes. The most potent compound 2-R (IC(50) = 270 nM) showed a 148-fold increase in potency with regard to cisplatin in HCT-116 colon cancer cells. Preliminary biological results point out to different biomolecular targets for the investigated compounds. Neutral cyclometallated complexes 1-R and 2-R, modify the DNA migration as cisplatin, cationic platinacycle 5-R was able to inhibit topoisomerase I-promoted DNA supercoiling, and Pt(ii) coordination compound 7-R turned out to be the most potent inhibitor of cathepsin B. Induction of G-1 phase ( 2-R and 5-R ), and S and G-2 phases (6-R) arrests are related to the antiproliferative activity of some representative compounds upon A-549 cells. Induction of apoptosis is also observed for 2-R and 6-R.

  8. PH- and salt-dependent molecular combing of DNA: experiments and phenomenological model

    NASA Astrophysics Data System (ADS)

    Benke, Annegret; Mertig, Michael; Pompe, Wolfgang

    2011-01-01

    λ-DNA as well as plasmids can be successfully deposited by molecular combing on hydrophobic surfaces, for pH values ranging from 4 to 10. On polydimethylsiloxane (PDMS) substrates, the deposited DNA molecules are overstretched by about 60-100%. There is a significant influence of sodium ions (NaCl) on the surface density of the deposited DNA, with a maximum near to 100 mM NaCl for a DNA solution (28 ng µl - 1) at pH 8. The combing process can be described by a micromechanical model including: (i) the adsorption of free moving coiled DNA at the substrate; (ii) the stretching of the coiled DNA by the preceding meniscus; (iii) the relaxation of the deposited DNA to the final length. The sticky ends of λ-DNA cause an adhesion force in the range of about 400 pN which allows a stable overstretching of the DNA by the preceding meniscus. The exposing of hidden hydrophobic bonds of the overstretched DNA leads to a stable deposition on the hydrophobic substrate. The pH-dependent density of deposited DNA as well as the observed influence of sodium ions can be explained by their screening of the negatively charged DNA backbone and sticky ends, respectively. The final DNA length can be derived from a balance of the stored elastic energy of the overstretched molecules and the energy of adhesion.

  9. Inelastic quantum transport in a ladder model: Implications for DNA conduction and comparison to experiments on suspended DNA oligomers

    NASA Astrophysics Data System (ADS)

    Gutiérrez, R.; Mohapatra, S.; Cohen, H.; Porath, D.; Cuniberti, G.

    2006-12-01

    We investigate quantum transport characteristics of a ladder model, which effectively mimics the topology of a double-stranded DNA molecule. We consider the interaction of tunneling charges with a selected internal vibrational degree of freedom and discuss its influence on the structure of the current-voltage characteristics. Further, molecule-electrode contact effects are shown to dramatically affect the orders of magnitude of the current. Recent electrical transport measurements on suspended DNA oligomers with a complex base-pair sequence, revealing strikingly high currents, are also presented and used as a reference point for the theoretical modeling. A semiquantitative description of the measured I-V curves is achieved, suggesting that the coupling to vibrational excitations plays an important role in DNA conduction.

  10. Transalkylation reactions in fossil fuels and related model compounds

    SciTech Connect

    Farcasiu, M.; Forbus, T.R.; LaPierre, R.B.

    1983-02-01

    The alkyl substituents of high molecular weight polycyclic aromatic constituents of petroleum residues are transferable to exogenous monocyclic aromatics (benzene, toluene, o-xylene, etc.) by acid catalyzed (CF/sub 3/SO/sub 3/H) Friedel Crafts transalkylation. Analysis (GC-MS) of the volatile alkylated monocyclic aromatic products provides a method for the determination of the alkyl group content/structure of the starting fossil fuel mixture. Both model systems, using alkylated naphthalenes, phenanthrenes, pyrenes and dibenzothiophenes and demineralized shale oil or petroleum resid were studied. The model studies (alkyl chain length 2-10 carbons) revealed the following reaction pathways to predominate: (1) transalkylation rates/equilibria are independent of chain length; (2) n-alkyl groups are transfered without rearrangement or fragmentation; (3) reaction rate depends upon the aromatic moiety; (4) formation of dixylylmethanes via benzyl carbenium ions is significant (12 to 25% of product; and (5) significant minor products at longer reaction times are alkyl tetralins, tetralins, napthalenes and alkylated acceptors having a chain length reduced by (-CH/sub 2/-)/sub 4/.

  11. Recent advances in small organic molecules as DNA intercalating agents: synthesis, activity, and modeling.

    PubMed

    Rescifina, Antonio; Zagni, Chiara; Varrica, Maria Giulia; Pistarà, Venerando; Corsaro, Antonino

    2014-03-01

    The interaction of small molecules with DNA plays an essential role in many biological processes. As DNA is often the target for majority of anticancer and antibiotic drugs, study about the interaction of drug and DNA has a key role in pharmacology. Moreover, understanding the interactions of small molecules with DNA is of prime significance in the rational design of more powerful and selective anticancer agents. Two of the most important and promising targets in cancer chemotherapy include DNA alkylating agents and DNA intercalators. For these last the DNA recognition is a critical step in their anti-tumor action and the intercalation is not only one kind of the interactions in DNA recognition but also a pivotal step of several clinically used anti-tumor drugs such as anthracyclines, acridines and anthraquinones. To push clinical cancer therapy, the discovery of new DNA intercalators has been considered a practical approach and a number of intercalators have been recently reported. The intercalative binding properties of such molecules can also be harnessed as diagnostic probes for DNA structure in addition to DNA-directed therapeutics. Moreover, the problem of intercalation site formation in the undistorted B-DNA of different length and sequence is matter of tremendous importance in molecular modeling studies and, nowadays, three models of DNA intercalation targets have been proposed that account for the binding features of intercalators. Finally, despite DNA being an important target for several drugs, most of the docking programs are validated only for proteins and their ligands. Therefore, a default protocol to identify DNA binding modes which uses a modified canonical DNA as receptor is needed.

  12. Structure of an XPF endonuclease with and without DNA suggests a model for substrate recognition.

    PubMed

    Newman, Matthew; Murray-Rust, Judith; Lally, John; Rudolf, Jana; Fadden, Andrew; Knowles, Philip P; White, Malcolm F; McDonald, Neil Q

    2005-03-01

    The XPF/Mus81 structure-specific endonucleases cleave double-stranded DNA (dsDNA) within asymmetric branched DNA substrates and play an essential role in nucleotide excision repair, recombination and genome integrity. We report the structure of an archaeal XPF homodimer alone and bound to dsDNA. Superposition of these structures reveals a large domain movement upon binding DNA, indicating how the (HhH)(2) domain and the nuclease domain are coupled to allow the recognition of double-stranded/single-stranded DNA junctions. We identify two nonequivalent DNA-binding sites and propose a model in which XPF distorts the 3' flap substrate in order to engage both binding sites and promote strand cleavage. The model rationalises published biochemical data and implies a novel role for the ERCC1 subunit of eukaryotic XPF complexes. PMID:15719018

  13. Numerical modeling of DNA-chip hybridization with chaotic advection

    PubMed Central

    Raynal, Florence; Beuf, Aurélien; Carrière, Philippe

    2013-01-01

    We present numerical simulations of DNA-chip hybridization, both in the “static” and “dynamical” cases. In the static case, transport of free targets is limited by molecular diffusion; in the dynamical case, an efficient mixing is achieved by chaotic advection, with a periodic protocol using pumps in a rectangular chamber. This protocol has been shown to achieve rapid and homogeneous mixing. We suppose in our model that all free targets are identical; the chip has different spots on which the probes are fixed, also all identical, and complementary to the targets. The reaction model is an infinite sink potential of width dh, i.e., a target is captured as soon as it comes close enough to a probe, at a distance lower than dh. Our results prove that mixing with chaotic advection enables much more rapid hybridization than the static case. We show and explain why the potential width dh does not play an important role in the final results, and we discuss the role of molecular diffusion. We also recover realistic reaction rates in the static case. PMID:24404027

  14. Modeling the surface chemistry of biomass model compounds on oxygen-covered Rh(100).

    PubMed

    Caglar, B; Niemantsverdriet, J W Hans; Weststrate, C J Kees-Jan

    2016-08-24

    Rhodium-based catalysts are potential candidates to process biomass and serve as a representation of the class of noble metal catalysts for biomass-related processes. Biomass can be processed in aqueous media (hydrolysis and aqueous phase reforming), and in this case the surface chemistry involves hydroxyl (OH) species. In our study this was modelled by the presence of pre-adsorbed oxygen. Ethylene glycol, with a hydroxyl group on every carbon atom, serves as a model compound to understand the conversion of biomass derived molecules into desirable chemicals on catalytically active metal surfaces. Ethanol (containing one OH group) serves as a reference molecule for ethylene glycol (containing two OH groups) to understand the interaction of C-OH functionalities with a Rh(100) surface. The surface chemistry of ethylene glycol and ethanol in the presence of pre-adsorbed oxygen on a Rh(100) surface has been studied via temperature programmed reaction spectroscopy (TPRS) and reflection absorption infrared spectroscopy (RAIRS) using various coverages of O(ad) and ethylene glycol and ethanol. Pre-adsorbed oxygen alters the decomposition chemistry of both compounds, thereby affecting the product distribution. Under an oxygen-lean condition, the selectivity to produce methane from ethanol is enhanced significantly (4.5-fold with respect to that obtained on the oxygen-free surface). For ethylene glycol, oxygen-lean conditions promote the formation of formaldehyde, with 10-15% selectivity. In addition, with Oad present the fraction of molecules that decompose on the surface increases 2-fold for ethanol and 1.5-fold for ethylene glycol, due to fast O-H bond activation by pre-adsorbed oxygen. Under oxygen-rich conditions, the decomposition products are mainly oxidized to carbon dioxide and water for both molecules. In this condition, the promotion effect provided by adsorbed oxygen for the dissociative adsorption of ethanol and ethylene glycol is reduced due to the site blocking

  15. Mixtures of compound Poisson processes as models of tick-by-tick financial data

    NASA Astrophysics Data System (ADS)

    Scalas, Enrico

    2007-10-01

    A model for the phenomenological description of tick-by-tick share prices in a stock exchange is introduced. It is based on mixtures of compound Poisson processes. Preliminary results based on Monte Carlo simulation show that this model can reproduce various stylized facts.

  16. The Effect of Leonurus sibiricus Plant Extracts on Stimulating Repair and Protective Activity against Oxidative DNA Damage in CHO Cells and Content of Phenolic Compounds

    PubMed Central

    Sitarek, Przemysław; Skała, Ewa; Wysokińska, Halina; Wielanek, Marzena; Szemraj, Janusz; Toma, Monika; Śliwiński, Tomasz

    2016-01-01

    Leonurus sibiricus L. has been used as a traditional and medicinal herb for many years in Asia and Europe. This species is known to have antibacterial, anti-inflammatory, and antioxidant activity and has demonstrated a reduction of intracellular reactive oxygen species. All tested extracts of L. sibiricus showed protective and DNA repair stimulating effects in Chinese hamster ovary (CHO) cells exposed to H2O2. Preincubation of the CHO cells with 0.5 mg/mL of plant extracts showed increased expression level of antioxidant genes (SOD2, CAT, and GPx). LC-MS/MS and HPLC analyses revealed the presence of nine phenolic compounds in L. sibiricus plant extracts: catechin, verbascoside, two flavonoids (quercetin and rutin), and five phenolic acids (4-hydroxybenzoic acid, chlorogenic acid, caffeic acid, p-coumaric acid, and ferulic acid). The roots and aerial parts of in vitro L. sibiricus plant extracts, which had the strongest antioxidant properties, may be responsible for stimulating CHO cells to repair oxidatively induced DNA damage, as well as protecting DNA via enhanced activation of the antioxidant genes (SOD2, CAT, and GPx) regulating intracellular antioxidant capacity. The content of phenolic compounds in in vitro raised plants was greater than the levels found in plants propagated from seeds. PMID:26788249

  17. The Effect of Leonurus sibiricus Plant Extracts on Stimulating Repair and Protective Activity against Oxidative DNA Damage in CHO Cells and Content of Phenolic Compounds.

    PubMed

    Sitarek, Przemysław; Skała, Ewa; Wysokińska, Halina; Wielanek, Marzena; Szemraj, Janusz; Toma, Monika; Śliwiński, Tomasz

    2016-01-01

    Leonurus sibiricus L. has been used as a traditional and medicinal herb for many years in Asia and Europe. This species is known to have antibacterial, anti-inflammatory, and antioxidant activity and has demonstrated a reduction of intracellular reactive oxygen species. All tested extracts of L. sibiricus showed protective and DNA repair stimulating effects in Chinese hamster ovary (CHO) cells exposed to H2O2. Preincubation of the CHO cells with 0.5 mg/mL of plant extracts showed increased expression level of antioxidant genes (SOD2, CAT, and GPx). LC-MS/MS and HPLC analyses revealed the presence of nine phenolic compounds in L. sibiricus plant extracts: catechin, verbascoside, two flavonoids (quercetin and rutin), and five phenolic acids (4-hydroxybenzoic acid, chlorogenic acid, caffeic acid, p-coumaric acid, and ferulic acid). The roots and aerial parts of in vitro L. sibiricus plant extracts, which had the strongest antioxidant properties, may be responsible for stimulating CHO cells to repair oxidatively induced DNA damage, as well as protecting DNA via enhanced activation of the antioxidant genes (SOD2, CAT, and GPx) regulating intracellular antioxidant capacity. The content of phenolic compounds in in vitro raised plants was greater than the levels found in plants propagated from seeds.

  18. DNA sensor model based on a carbon nanotube network in the degenerate limit

    NASA Astrophysics Data System (ADS)

    Abadi, H. Karimi Feiz; Webb, J. F.; Ahmadi, M. T.; Rahmani, M.; Saeidmanesh, M.; Khalid, M.; Ismail, R.

    2012-11-01

    An analytical model of a possible DNA sensor based on a carbon nanotube network that functions as a selective detector of DNA molecules is presented. The ability to implement label-free electronic detection using a DNA sensor based on a carbon nanotube network constitutes an important step towards low-cost, highly sensitive, simple and accurate molecular diagnostics. In particular, there is an urgent need for a simple method of detection of DNA molecules as this will provided a new and efficient way to diagnosis genetic or pathogenic diseases. Bio-compatibility and high sensitivity towards environmental perturbations make graphene nanomaterials a good choice for a sensing layer in an electronic DNA sensor. In this study, a conductance model of a DNA sensor based on a carbon nanotube network is suggested and the performance of the model is evaluated by calculating current-voltage characteristics.

  19. Effects of structure on the interactions between five natural antimicrobial compounds and phospholipids of bacterial cell membrane on model monolayers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Monolayers composed of bacterial phospholipids were used as model membranes to study interactions of naturally occurring phenolic compounds 2,5-dihydroxybenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde and the plant essential oil compounds carvacrol, cinnamaldehyde, and geraniol, previously found to be...

  20. Topoisomerase inhibition, nucleolytic and electrolytic contribution on DNA binding activity exerted by biological active analogue of coordination compounds.

    PubMed

    Patel, Mohan N; Bhatt, Bhupesh S; Dosi, Promise A

    2012-04-01

    The neutral mononuclear copper complexes with the quinolone antibacterial drug ciprofloxacin and bipyridine derivatives have been synthesized and characterized. Complexes were screened for their antibacterial activity against three Gram((-)) and two Gram((+)) bacteria, and study suggests inhibition of gyrase activity by metal complexes as the possible mechanism. The nucleolytic activity of adducts was carried out on double stranded pUC19 DNA using gel electrophoresis in the presence of radical scavenging agents that suggest hydrolytic cleavage mechanism for plasmid DNA.

  1. Modeling the early stage of DNA sequence recognition within RecA nucleoprotein filaments.

    PubMed

    Saladin, Adrien; Amourda, Christopher; Poulain, Pierre; Férey, Nicolas; Baaden, Marc; Zacharias, Martin; Delalande, Olivier; Prévost, Chantal

    2010-10-01

    Homologous recombination is a fundamental process enabling the repair of double-strand breaks with a high degree of fidelity. In prokaryotes, it is carried out by RecA nucleofilaments formed on single-stranded DNA (ssDNA). These filaments incorporate genomic sequences that are homologous to the ssDNA and exchange the homologous strands. Due to the highly dynamic character of this process and its rapid propagation along the filament, the sequence recognition and strand exchange mechanism remains unknown at the structural level. The recently published structure of the RecA/DNA filament active for recombination (Chen et al., Mechanism of homologous recombination from the RecA-ssDNA/dsDNA structure, Nature 2008, 453, 489) provides a starting point for new exploration of the system. Here, we investigate the possible geometries of association of the early encounter complex between RecA/ssDNA filament and double-stranded DNA (dsDNA). Due to the huge size of the system and its dense packing, we use a reduced representation for protein and DNA together with state-of-the-art molecular modeling methods, including systematic docking and virtual reality simulations. The results indicate that it is possible for the double-stranded DNA to access the RecA-bound ssDNA while initially retaining its Watson-Crick pairing. They emphasize the importance of RecA L2 loop mobility for both recognition and strand exchange.

  2. Interaction of zanamivir with DNA and RNA: Models for drug DNA and drug RNA bindings

    NASA Astrophysics Data System (ADS)

    Nafisi, Shohreh; Kahangi, Fatemeh Ghoreyshi; Azizi, Ebrahim; Zebarjad, Nader; Tajmir-Riahi, Heidar-Ali

    2007-03-01

    Zanamivir (ZAN) is the first of a new generation of influenza virus-specific drugs known as neuraminidase inhibitors, which acts by interfering with life cycles of influenza viruses A and B. It prevents the virus spreading infection to other cells by blocking the neuraminidase enzyme present on the surface of the virus. The aim of this study was to examine the stability and structural features of calf thymus DNA and yeast RNA complexes with zanamivir in aqueous solution, using constant DNA or RNA concentration (12.5 mM) and various zanamivir/polynucleotide ( P) ratios of 1/20, 1/10, 1/4, and 1/2. FTIR and UV-visible spectroscopy are used to determine the drug external binding modes, the binding constant and the stability of zanamivir-DNA and RNA complexes in aqueous solution. Structural analysis showed major interaction of zanamivir with G-C (major groove) and A-T (minor groove) base pairs and minor perturbations of the backbone PO 2 group with overall binding constants of Kzanamivir-DNA = 1.30 × 10 4 M -1 and Kzanamivir-RNA = 1.38 × 10 4 M -1. The drug interaction induces a partial B to A-DNA transition, while RNA remains in A-conformation.

  3. The reciprocal relationship between compounding awareness and vocabulary knowledge in Chinese: a latent growth model study

    PubMed Central

    Cheng, Yahua; Li, Liping; Wu, Xinchun

    2015-01-01

    The aim of this study is to examine the developmental relationship between compounding awareness and vocabulary knowledge from grades 1 to 2 in Chinese children. In this study, 149 Chinese children were tested on compounding awareness and vocabulary knowledge from Time 1 to Time 4, with non-verbal IQ, working memory, phonological awareness, orthographical awareness, and rapid automatized naming at Time 1 as control variables. Latent growth modeling was conducted to analyze the data. Univariate models separately calculated children's initial levels and growth rates in compounding awareness and vocabulary knowledge. Bivariate model was used to examine the direction of the developmental relationships between the two variables with other cognitive and linguistic variables and the autoregression controlled. The results demonstrated that the initial level of compounding awareness predicted the growth rate of vocabulary knowledge, and the reverse relation was also found, after controlling for other cognitive and linguistic variables and the autoregression. The results suggested a reciprocal developmental relationship between children's compounding awareness and vocabulary knowledge for Chinese children, a finding that informs current models of the relationship between morphological awareness and vocabulary knowledge. PMID:25926807

  4. An exploratory approach to modeling explosive compound persistence and flux using dissolution kinetics.

    PubMed

    Lynch, Jason C; Brannon, James M; Hatfield, Kirk; Delfino, Joseph J

    2003-11-01

    Recent advances in the description of aqueous dissolution rates for explosive compounds enhance the ability to describe these compounds as a contaminant source term and to model the behavior of these compounds in a field environment. The objective of this study is to make predictions concerning the persistence of 2,4,6-trinitrotoluene (TNT) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) in solid form both as individual explosive compounds and components of octol, and the resultant concentrations of explosives in water as a result of dissolution using three exploratory modeling approaches. The selection of dissolution model and rate greatly affect not only the predicted persistence of explosive compound sources but also their resulting concentrations in solution. This study identifies the wide range in possible predictions using existing information and these modeling approaches to highlight the need for further research to ensure that risk assessment, remediation and predicted fate and transport are appropriately presented and interpreted.

  5. Determination of the n-octanol/water partition coefficients of weakly ionizable basic compounds by reversed-phase high-performance liquid chromatography with neutral model compounds.

    PubMed

    Liang, Chao; Han, Shu-ying; Qiao, Jun-qin; Lian, Hong-zhen; Ge, Xin

    2014-11-01

    A strategy to utilize neutral model compounds for lipophilicity measurement of ionizable basic compounds by reversed-phase high-performance liquid chromatography is proposed in this paper. The applicability of the novel protocol was justified by theoretical derivation. Meanwhile, the linear relationships between logarithm of apparent n-octanol/water partition coefficients (logKow '') and logarithm of retention factors corresponding to the 100% aqueous fraction of mobile phase (logkw ) were established for a basic training set, a neutral training set and a mixed training set of these two. As proved in theory, the good linearity and external validation results indicated that the logKow ''-logkw relationships obtained from a neutral model training set were always reliable regardless of mobile phase pH. Afterwards, the above relationships were adopted to determine the logKow of harmaline, a weakly dissociable alkaloid. As far as we know, this is the first report on experimental logKow data for harmaline (logKow = 2.28 ± 0.08). Introducing neutral compounds into a basic model training set or using neutral model compounds alone is recommended to measure the lipophilicity of weakly ionizable basic compounds especially those with high hydrophobicity for the advantages of more suitable model compound choices and convenient mobile phase pH control.

  6. Pyrolysis reaction networks for lignin model compounds: unraveling thermal deconstruction of β-O-4 and α-O-4 compounds

    SciTech Connect

    Choi, Yong S.; Singh, Rahul; Zhang, Jing; Balasubramanian, Ganesh; Sturgeon, Matthew R.; Katahira, Rui; Chupka, Gina; Beckham, Gregg T.; Shanks, Brent H.

    2016-01-01

    Although lignin is one of the main components of biomass, its pyrolysis chemistry is not well understood due to complex heterogeneity. To gain insights into this chemistry, the pyrolysis of seven lignin model compounds (five ..beta..-O-4 and two ..alpha..-O-4 linked molecules) was investigated in a micropyrolyzer connected to GC-MS/FID. According to quantitative product mole balance for the reaction networks, concerted retro-ene fragmentation and homolytic dissociation were strongly suggested as the initial reaction step for ..beta..-O-4 compounds and ..alpha..-O-4 compounds, respectively. The difference in reaction pathway between compounds with different linkages was believed to result from thermodynamics of the radical initiation. The rate constants for the different reaction pathways were predicted from ab initio density functional theory calculations and pre-exponential literature values. The computational findings were consistent with the experiment results, further supporting the different pyrolysis mechanisms for the ..beta..-ether linked and ..alpha..-ether linked compounds. A combination of the two pathways from the dimeric model compounds was able to describe qualitatively the pyrolysis of a trimeric lignin model compound containing both ..beta..-O-4 and ..alpha..-O-4 linkages.

  7. Chemopreventive activity of compounds extracted from Casearia sylvestris (Salicaceae) Sw against DNA damage induced by particulate matter emitted by sugarcane burning near Araraquara, Brazil

    SciTech Connect

    Prieto, A.M.; Santos, A.G.; Csipak, A.R.; Caliri, C.M.; Silva, I.C.; Arbex, M.A.; Silva, F.S.; Marchi, M.R.R.

    2012-12-15

    Ethanolic extract of Casearia sylvestris is thought to be antimutagenic. In this study, we attempted to determine whether this extract and casearin X (a clerodane diterpene from C. sylvestris) are protective against the harmful effects of airborne pollutants from sugarcane burning. To that end, we used the Tradescantia micronucleus test in meiotic pollen cells of Tradescantia pallida, the micronucleus test in mouse bone marrow cells, and the comet assay in mouse blood cells. The mutagenic compound was total suspended particulate (TSP) from air. For the Tradescantia micronucleus test, T. pallida cuttings were treated with the extract at 0.13, 0.25, or 0.50 mg/ml. Subsequently, TSP was added at 0.3 mg/ml, and tetrads from the inflorescences were examined for micronuclei. For the micronucleus test in mouse bone marrow cells and the comet assay in mouse blood cells, Balb/c mice were treated for 15 days with the extract—3.9, 7.5, or 15.0 mg/kg body weight (BW)—or with casearin X—0.3, 0.25, or 1.2 mg/kg BW—after which they received TSP (3.75 mg/kg BW). In T. pallida and mouse bone marrow cells, the extract was antimutagenic at all concentrations tested. In mouse blood cells, the extract was antigenotoxic at all concentrations, whereas casearin X was not antimutagenic but was antigenotoxic at all concentrations. We conclude that C. sylvestris ethanolic extract and casearin X protect DNA from damage induced by airborne pollutants from sugarcane burning. -- Highlights: ► We assessed DNA protection of C. sylvestris ethanolic extract. ► We assessed DNA protection of casearin X. ► We used Tradescantia pallida micronucleus test as screening. ► We used comet assay and micronucleus test in mice. ► The compounds protected DNA against sugar cane burning pollutants.

  8. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease

    PubMed Central

    Gulsuner, Suleyman; Stapleton, Gail A.; Walsh, Tom; Lee, Ming K.; Mandell, Jessica B.; Morales, Augusto; Klevit, Rachel E.; King, Mary-Claire; Rogers, R. Curtis

    2016-01-01

    Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder. PMID:27551684

  9. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease.

    PubMed

    Pierce, Sarah B; Gulsuner, Suleyman; Stapleton, Gail A; Walsh, Tom; Lee, Ming K; Mandell, Jessica B; Morales, Augusto; Klevit, Rachel E; King, Mary-Claire; Rogers, R Curtis

    2016-07-01

    Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder. PMID:27551684

  10. A compound memristive synapse model for statistical learning through STDP in spiking neural networks

    PubMed Central

    Bill, Johannes; Legenstein, Robert

    2014-01-01

    Memristors have recently emerged as promising circuit elements to mimic the function of biological synapses in neuromorphic computing. The fabrication of reliable nanoscale memristive synapses, that feature continuous conductance changes based on the timing of pre- and postsynaptic spikes, has however turned out to be challenging. In this article, we propose an alternative approach, the compound memristive synapse, that circumvents this problem by the use of memristors with binary memristive states. A compound memristive synapse employs multiple bistable memristors in parallel to jointly form one synapse, thereby providing a spectrum of synaptic efficacies. We investigate the computational implications of synaptic plasticity in the compound synapse by integrating the recently observed phenomenon of stochastic filament formation into an abstract model of stochastic switching. Using this abstract model, we first show how standard pulsing schemes give rise to spike-timing dependent plasticity (STDP) with a stabilizing weight dependence in compound synapses. In a next step, we study unsupervised learning with compound synapses in networks of spiking neurons organized in a winner-take-all architecture. Our theoretical analysis reveals that compound-synapse STDP implements generalized Expectation-Maximization in the spiking network. Specifically, the emergent synapse configuration represents the most salient features of the input distribution in a Mixture-of-Gaussians generative model. Furthermore, the network's spike response to spiking input streams approximates a well-defined Bayesian posterior distribution. We show in computer simulations how such networks learn to represent high-dimensional distributions over images of handwritten digits with high fidelity even in presence of substantial device variations and under severe noise conditions. Therefore, the compound memristive synapse may provide a synaptic design principle for future neuromorphic architectures. PMID

  11. Investigation on mechanism of coal liquefaction-hydrocracking of model compounds

    SciTech Connect

    Wu, J.Z.; Gao, J.S.; Hang, Y.Z.; Oelert, H.H.

    1997-12-31

    There is strong evidence for the existence of -O-CH{sub 2}- and -CH{sub 2}-CH{sub 2}-bridge linkages in coal, especially in low rank coals, so there is a close relationship between hydrocracking kinetic of model compounds and coal liquefaction. In a tube autoclave with the volume of 17 ml the hydrocracking experiments of six model compounds are carried out in the presence of tetralin. The results show that the stability order of six model compounds in hydrocracking is as follows: Ph-Ch{sub 2}-Ph > Ph-O-Ph > Ph-Ch{sub 2}-Ch{sub 2}-Ph > Ph-O-CH{sub 2}-Ph > Ph-CH{sub 2}-S-CH{sub 2}-Ph > Ph-CH{sub 2}-S-S-CH{sub 2}-Ph. Introducing 10% (in weight) of benzyl phenyl ether can increase the decomposition ratios of diphenyl methane and diphenyl ether from 4.3% to 12.6% and 18.3% to 31.5% respectively. From the hydrocracking kinetic experiments for both benzyl phenyl ether (BPE) and dibenzyl (DB), the reaction corresponds to first order. The apparent activation (DE) is 83.9 kJ/mol for BPE and 150 kJ/mol for DB in the range of temperature 330--450 C, that is, the same as coal liquefaction. The influence of initial hydrogen pressure on hydrocracking of model compounds is also described in this paper. Under the conditions of the experiments the decomposition ratios (DR) of model compounds increase linearly with the increase of initial hydrogen pressure, e.g., DR is only 34.3% under 3.0 MPa (420 C), but 56.8% can be obtained when the initial hydrogen pressure reaches 8.5 MPa. Moreover, changing the initial pressure can influence not only DR of model compounds but also their hydrocracking mechanisms. Applying Mo-Ni, Y- and 5A-sieves to hydrocracking of model compounds are all effective. For more stable compounds such as dibenzyl methane and diphenyl ether the Y-sieve is better than the Mo-Ni catalyst, but it is just contrary to crack for benzyl phenyl ether.

  12. Spermidine-condensed phi X174 DNA cleavage by micrococcal nuclease: torus cleavage model and evidence for unidirectional circumferential DNA wrapping.

    PubMed Central

    Marx, K A; Reynolds, T C

    1982-01-01

    Spermidine-condensed phi X174 replicative form (RF) II DNA was digested with micrococcal nuclease to yield seven identifiable DNA bands forming an arithmetic fragment-length series. The DNA monomer unit length was found to be 780 +/- 80 base pairs. This result is most consistent with a proposed model for micrococcal nuclease cleavage of a DNA torus organized by the unidirectional, circumferential wrapping of B-geometry DNA. By a topological consideration, the blunt-end-rod-fusion model for torus formation [Eickbush, T. H. & Moudrianakis, E. N. (1978) Cell 13, 295-306] is shown to be inconsistent with our empirical solution results. We propose a continuous, circumferential DNA wrapping model in which a significant fraction of the collapsed circular phi X174 RFII DNA molecules form regular toruses comprised of seven complete, unidirectional double-helical wraps. Images PMID:6216482

  13. Hydrodynamic radius fluctuations in model DNA-grafted nanoparticles

    NASA Astrophysics Data System (ADS)

    Vargas-Lara, Fernando; Starr, Francis W.; Douglas, Jack F.

    2016-05-01

    We utilize molecular dynamics simulations (MD) and the path-integration program ZENO to quantify hydrodynamic radius (Rh) fluctuations of spherical symmetric gold nanoparticles (NPs) decorated with single-stranded DNA chains (ssDNA). These results are relevant to understanding fluctuation-induced interactions among these NPs and macromolecules such as proteins. In particular, we explore the effect of varying the ssDNA-grafted NPs structural parameters, such as the chain length (L), chain persistence length (lp), NP core size (R), and the number of chains (N) attached to the nanoparticle core. We determine Rh fluctuations by calculating its standard deviation (σRh) of an ensemble of ssDNA-grafted NPs configurations generated by MD. For the parameter space explored in this manuscript, σR h shows a peak value as a function of N, the amplitude of which depends on L, lp and R, while the broadness depends on R.

  14. A DNA-hairpin model for repeat-addition processivity in telomere synthesis.

    PubMed

    Yang, Wei; Lee, Young-Sam

    2015-11-01

    We propose a DNA-hairpin model for the processivity of telomeric-repeat addition. Concomitantly with template-RNA translocation after each repeat synthesis, the complementary DNA repeat, for example, AGGGTT, loops out in a noncanonical base-paired hairpin, thus freeing the RNA template for the next round of repeat synthesis. The DNA hairpin is temporarily stabilized by telomerase and the incoming dGTP but becomes realigned for processive telomere synthesis.

  15. Physical modeling of chromosome segregation in escherichia coli reveals impact of force and DNA relaxation.

    PubMed

    Lampo, Thomas J; Kuwada, Nathan J; Wiggins, Paul A; Spakowitz, Andrew J

    2015-01-01

    The physical mechanism by which Escherichia coli segregates copies of its chromosome for partitioning into daughter cells is unknown, partly due to the difficulty in interpreting the complex dynamic behavior during segregation. Analysis of previous chromosome segregation measurements in E. coli demonstrates that the origin of replication exhibits processive motion with a mean displacement that scales as t(0.32). In this work, we develop a model for segregation of chromosomal DNA as a Rouse polymer in a viscoelastic medium with a force applied to a single monomer. Our model demonstrates that the observed power-law scaling of the mean displacement and the behavior of the velocity autocorrelation function is captured by accounting for the relaxation of the polymer chain and the viscoelastic environment. We show that the ratio of the mean displacement to the variance of the displacement during segregation events is a critical metric that eliminates the compounding effects of polymer and medium dynamics and provides the segregation force. We calculate the force of oriC segregation in E. coli to be ∼0.49 pN.

  16. Detection of pesticide model compounds in ethanolic and aqueous microdroplets by nonlinear Raman spectroscopy.

    PubMed

    Schlücker, S; Roman, V; Kiefer, W; Popp, J

    2001-07-01

    Pesticide model compounds are detected in microdroplets by means of in situ nonlinear Raman spectroscopy. The chloro- and nitro-substituted aromatics are dissolved in ethanol as well as in water. Their vibrational spectroscopic fingerprint, that is, Raman bands characteristic of the functional groups attached to the aromatic system, is determined in bulk medium by linear Raman spectroscopy. As a result of the concept of group vibrations, the chosen compounds can be regarded as representatives for a whole class of pesticides containing these residues. External seeding of stimulated Raman scattering (SRS) is applied for the detection of these group vibrations of the pesticide model compounds. This technique can be utilized for in situ diagnostics and a noninvasive vibrational spectroscopic analysis of the chemical composition of microdroplets with natural or anthropogenic origin.

  17. Molecular modeling and snake venom phospholipase A2 inhibition by phenolic compounds: Structure-activity relationship.

    PubMed

    Alam, Md Iqbal; Alam, Mohammed A; Alam, Ozair; Nargotra, Amit; Taneja, Subhash Chandra; Koul, Surrinder

    2016-05-23

    In our earlier study, we have reported that a phenolic compound 2-hydroxy-4-methoxybenzaldehyde from Janakia arayalpatra root extract was active against Viper and Cobra envenomations. Based on the structure of this natural product, libraries of synthetic structurally variant phenolic compounds were studied through molecular docking on the venom protein. To validate the activity of eight selected compounds, we have tested them in in vivo and in vitro models. The compound 21 (2-hydroxy-3-methoxy benzaldehyde), 22 (2-hydroxy-4-methoxybenzaldehyde) and 35 (2-hydroxy-3-methoxybenzylalcohol) were found to be active against venom-induced pathophysiological changes. The compounds 20, 15 and 35 displayed maximum anti-hemorrhagic, anti-lethal and PLA2 inhibitory activity respectively. In terms of SAR, the presence of a formyl group in conjunction with a phenolic group was seen as a significant contributor towards increasing the antivenom activity. The above observations confirmed the anti-venom activity of the phenolic compounds which needs to be further investigated for the development of new anti-snake venom leads. PMID:26986086

  18. Introducing improved structural properties and salt dependence into a coarse-grained model of DNA

    SciTech Connect

    Snodin, Benedict E. K. Mosayebi, Majid; Schreck, John S.; Romano, Flavio; Doye, Jonathan P. K.; Randisi, Ferdinando; Šulc, Petr; Ouldridge, Thomas E.; Tsukanov, Roman; Nir, Eyal; Louis, Ard A.

    2015-06-21

    We introduce an extended version of oxDNA, a coarse-grained model of deoxyribonucleic acid (DNA) designed to capture the thermodynamic, structural, and mechanical properties of single- and double-stranded DNA. By including explicit major and minor grooves and by slightly modifying the coaxial stacking and backbone-backbone interactions, we improve the ability of the model to treat large (kilobase-pair) structures, such as DNA origami, which are sensitive to these geometric features. Further, we extend the model, which was previously parameterised to just one salt concentration ([Na{sup +}] = 0.5M), so that it can be used for a range of salt concentrations including those corresponding to physiological conditions. Finally, we use new experimental data to parameterise the oxDNA potential so that consecutive adenine bases stack with a different strength to consecutive thymine bases, a feature which allows a more accurate treatment of systems where the flexibility of single-stranded regions is important. We illustrate the new possibilities opened up by the updated model, oxDNA2, by presenting results from simulations of the structure of large DNA objects and by using the model to investigate some salt-dependent properties of DNA.

  19. Use of standardized SCID-hu Thy/Liv mouse model for preclinical efficacy testing of anti-human immunodeficiency virus type 1 compounds.

    PubMed Central

    Rabin, L; Hincenbergs, M; Moreno, M B; Warren, S; Linquist, V; Datema, R; Charpiot, B; Seifert, J; Kaneshima, H; McCune, J M

    1996-01-01

    We have developed standardized procedures and practices for infection of SCID-hu Thy/Liv mice with human immunodeficiency virus type 1 for the prophylactic administration of antiviral compounds and for evaluation of the antiviral effect in vivo. Endpoint analyses included quantitation of viral load by intracellular p24 enzyme-linked immunosorbent assay, DNA PCR for the presence of proviral genomes, flow cytometry to measure the representation of CD4+ and CD8+ cells, and cocultivation for the isolation of virus. Efficacy tests in this model are demonstrated with the nucleoside analogs zidovudine and dideoxyinosine and with the nonnucleoside reverse transcriptase inhibitor nevirapine. This small-animal model should be particularly useful in the preclinical prioritization of lead compounds within a common chemical class, in the evaluation of alternative in vivo dosing regimens, and in the determination of appropriate combination therapy in vivo. PMID:8851606

  20. Use of standardized SCID-hu Thy/Liv mouse model for preclinical efficacy testing of anti-human immunodeficiency virus type 1 compounds.

    PubMed

    Rabin, L; Hincenbergs, M; Moreno, M B; Warren, S; Linquist, V; Datema, R; Charpiot, B; Seifert, J; Kaneshima, H; McCune, J M

    1996-03-01

    We have developed standardized procedures and practices for infection of SCID-hu Thy/Liv mice with human immunodeficiency virus type 1 for the prophylactic administration of antiviral compounds and for evaluation of the antiviral effect in vivo. Endpoint analyses included quantitation of viral load by intracellular p24 enzyme-linked immunosorbent assay, DNA PCR for the presence of proviral genomes, flow cytometry to measure the representation of CD4+ and CD8+ cells, and cocultivation for the isolation of virus. Efficacy tests in this model are demonstrated with the nucleoside analogs zidovudine and dideoxyinosine and with the nonnucleoside reverse transcriptase inhibitor nevirapine. This small-animal model should be particularly useful in the preclinical prioritization of lead compounds within a common chemical class, in the evaluation of alternative in vivo dosing regimens, and in the determination of appropriate combination therapy in vivo.

  1. Mathematical modeling of the role of mitochondrial fusion and fission in mitochondrial DNA maintenance.

    PubMed

    Tam, Zhi Yang; Gruber, Jan; Halliwell, Barry; Gunawan, Rudiyanto

    2013-01-01

    Accumulation of mitochondrial DNA (mtDNA) mutations has been implicated in a wide range of human pathologies, including neurodegenerative diseases, sarcopenia, and the aging process itself. In cells, mtDNA molecules are constantly turned over (i.e. replicated and degraded) and are also exchanged among mitochondria during the fusion and fission of these organelles. While the expansion of a mutant mtDNA population is believed to occur by random segregation of these molecules during turnover, the role of mitochondrial fusion-fission in this context is currently not well understood. In this study, an in silico modeling approach is taken to investigate the effects of mitochondrial fusion and fission dynamics on mutant mtDNA accumulation. Here we report model simulations suggesting that when mitochondrial fusion-fission rate is low, the slow mtDNA mixing can lead to an uneven distribution of mutant mtDNA among mitochondria in between two mitochondrial autophagic events leading to more stochasticity in the outcomes from a single random autophagic event. Consequently, slower mitochondrial fusion-fission results in higher variability in the mtDNA mutation burden among cells in a tissue over time, and mtDNA mutations have a higher propensity to clonally expand due to the increased stochasticity. When these mutations affect cellular energetics, nuclear retrograde signalling can upregulate mtDNA replication, which is expected to slow clonal expansion of these mutant mtDNA. However, our simulations suggest that the protective ability of retrograde signalling depends on the efficiency of fusion-fission process. Our results thus shed light on the interplay between mitochondrial fusion-fission and mtDNA turnover and may explain the mechanism underlying the experimentally observed increase in the accumulation of mtDNA mutations when either mitochondrial fusion or fission is inhibited.

  2. Rapid screening and identification of compounds with DNA-binding activity from Folium Citri Reticulatae using on-line HPLC-DAD-MS(n) coupled with a post column fluorescence detection system.

    PubMed

    Fu, Qingrong; Zhang, Cangman; Lin, Zongtao; Sun, Hongyang; Liang, Yi; Jiang, Haixiu; Song, Zhiling; Wang, Hong; Chen, Shizhong

    2016-02-01

    To study the interactions between natural compounds and deoxyribonucleic acid (DNA), a method has been established combining a high-performance liquid chromatography-diode array detector-multi-stage mass spectrometer with a fluorescence detector (HPLC-DAD-MS(n)-FLD). The FLD was used to monitor fluorescence intensity of the ethidium bromide-DNA (EB-DNA) complex when a compound separated by HPLC was introduced. This novel method was used to simultaneously obtain the HPLC fingerprint, UV spectra, MS(n) fragments and DNA-binding activity profile of various components in Folium Citri Reticulatae. As a result, 35 compounds were identified, of which 25 were found in the extract of Folium Citri Reticulatae for the first time, and 33 compounds showed DNA-binding activities, with the most active being feruloylhexaric and p-coumaroylhexaric acids. In addition, the precision, stability and reproducibility of this method were validated by two positive controls, quercetin and hesperidin. This new on-line method is accurate, precise and reliable for further high-throughput screening of DNA-binding compounds from food samples and other complex matrices.

  3. Adsorption of selected pharmaceuticals and an endocrine disrupting compound by granular activated carbon. 2. Model prediction

    SciTech Connect

    Yu, Z.; Peldszus, S.; Huck, P.M.

    2009-03-01

    The adsorption of two representative pharmaceutically active compounds (PhACs) naproxen and carbamazepine and one endocrine disrupting compound (EDC) nonylphenol was studied in pilot-scale granular activated carbon (GAC) adsorbers using post-sedimentation (PS) water from a full-scale drinking water treatment plant. The GAC adsorbents were coal-based Calgon Filtrasorb 400 and coconut shell-based PICA CTIF TE. Acidic naproxen broke through fastest while nonylphenol was removed best, which was consistent with the degree to which fouling affected compound removals. Model predictions and experimental data were generally in good agreement for all three compounds, which demonstrated the effectiveness and robustness of the pore and surface diffusion model (PSDM) used in combination with the time-variable parameter approach for predicting removals at environmentally relevant concentrations (i.e., ng/L range). Sensitivity analyses suggested that accurate determination of film diffusion coefficients was critical for predicting breakthrough for naproxen and carbamazepine, in particular when high removals are targeted. Model simulations demonstrated that GAC carbon usage rates (CURs) for naproxen were substantially influenced by the empty bed contact time (EBCT) at the investigated conditions. Model-based comparisons between GAC CURs and minimum CURs for powdered activated carbon (PAC) applications suggested that PAC would be most appropriate for achieving 90% removal of naproxen, whereas GAC would be more suitable for nonylphenol. 25 refs., 4 figs., 1 tab.

  4. Adsorption of selected pharmaceuticals and an endocrine disrupting compound by granular activated carbon. 2. Model prediction.

    PubMed

    Yu, Zirui; Peldszus, Sigrid; Huck, Peter M

    2009-03-01

    The adsorption of two representative pharmaceutically active compounds (PhACs)-naproxen and carbamazepine and one endocrine disrupting compound (EDC)-nonylphenol was studied in pilot-scale granular activated carbon (GAC) adsorbers using post-sedimentation (PS) water from a full-scale drinking water treatment plant. Acidic naproxen broke through fastest while nonylphenol was removed best, which was consistent with the degree to which fouling affected compound removals. Model predictions and experimental data were generally in good agreement for all three compounds, which demonstrated the effectiveness and robustness of the pore and surface diffusion model (PSDM) used in combination with the time-variable parameter approach for predicting removals at environmentally relevant concentrations (i.e., ng/L range). Sensitivity analyses suggested that accurate determination of film diffusion coefficients was critical for predicting breakthrough for naproxen and carbamazepine, in particular when high removals are targeted. Model simulations demonstrated that GAC carbon usage rates (CURs) for naproxen were substantially influenced by the empty bed contact time (EBCT) at the investigated conditions. Model-based comparisons between GAC CURs and minimum CURs for powdered activated carbon (PAC) applications suggested that PAC would be most appropriate for achieving 90% removal of naproxen, whereas GAC would be more suitable for nonylphenol. PMID:19350922

  5. Using Molecular Modeling in Teaching Group Theory Analysis of the Infrared Spectra of Organometallic Compounds

    ERIC Educational Resources Information Center

    Wang, Lihua

    2012-01-01

    A new method is introduced for teaching group theory analysis of the infrared spectra of organometallic compounds using molecular modeling. The main focus of this method is to enhance student understanding of the symmetry properties of vibrational modes and of the group theory analysis of infrared (IR) spectra by using visual aids provided by…

  6. MODELING OF MULTICOMPONENT PERVAPORATION FOR REMOVAL OF VOLATILE ORGANIC COMPOUNDS FROM WATER

    EPA Science Inventory

    A resistance-in-series model was used to study the pervaporation of multiple volatile organic compounds (VOCs)-water mixtures. Permeation experiments were carried out for four membranes: poly(dimethylsiloxane) (PDMS), polyether-block-polyamides (PEBA), polyurethane (PUR) and sil...

  7. A Connectionist Model of Stimulus Class Formation with a Yes/No Procedure and Compound Stimuli

    ERIC Educational Resources Information Center

    Tovar, Angel E.; Chavez, Alvaro Torres

    2012-01-01

    We analyzed stimulus class formation in a human study and in a connectionist model (CM) with a yes/no procedure, using compound stimuli. In the human study, the participants were six female undergraduate students; the CM was a feed-forward back-propagation network. Two 3-member stimulus classes were trained with a similar procedure in both the…

  8. Standard Model for Superconductivity in Graphite Intercalation Compounds: Prediction of Optimum Tc

    NASA Astrophysics Data System (ADS)

    Takada, Yasutami

    2009-03-01

    Based on the model that was successfully applied to the explanation of superconductivity with the transition temperature Tc of about 0.1K or less in the alkali- intercalated graphite compounds such as KC8, RbC8, and CsC8 in 1982 [Y. Takada, J. Phys. Soc. Jpn. 51, 63 (1982) ], we have calculated Tc for the alkaline-earth- intercalated graphite compounds including CaC6, YbC6, and SrC6 with Tc of about 10K or less to find that the same model reproduces the observed Tc in those compounds as well, indicating that it is a standard model for superconductivity in the graphite intercalation compounds with Tc ranging over three orders of magnitude. The difference in Tc by two orders between KC8 and CaC6 can be accounted for by (i) doubling Z the valency of the metal ions, which enhances Tc by one order, and (ii) tripling m^* the effective mass of the superconducting three-dimensional electrons in the interlayer band, which also enhances Tc by one order. Enhancement of Tc well beyond 10 K is also predicted in this model, if intercalant metals are judiciously chosen so that both Z and m^* are increased further.

  9. Reactions of coal model compounds in tetralin using microwave energy: Effects of catalysts

    SciTech Connect

    Eray, E.; Yagmur, E.; Simsek, E.H.; Alibeyli, R.; Togrul, T.

    2006-10-01

    Reaction mechanisms of model compounds of coal in tetralin by microwave energy were investigated. Diphenylmethane (DFM), phenyl-methyl ether (anisole), and phenyl-methyl ketone (acetophenon) were chosen as model compounds. Experiments were carried out for 10 minutes of microwave energy and different catalysts were used (pyratol, zeolite, BaCl{sub 2}, AlNiMo) to find out the distribution of reaction products of the model compounds. GC and GC/MS are used to analyze the reaction products. The main reaction products from DFM and tetralin under microwave radiation with catalysts were ethyl benzene, naphthalene, 2-methyl naphthalene, 3,4-dihydronaphthaleneone, 1-1'-ethyldene 1-benzene, and 1-methyl 4-phenyl methyl benzene. The main reaction products from anisole and tetralin under microwave radiation were ethyl benzene, phenol, methyl phenol, decahydronaphthalene, and tetrahydronaphthalenol. The main reaction products from acetophenon and tetralin under microwave radiation with catalysts were ethyl benzene, methoxy benzene, decahydronaphthalene, naphthalene, tetrahydronaphthalenol, 3,4-dihydronaphthalenone and 2-butene-1-one-1,3 diphenyl. The estimated mechanism of the model compounds with tetralin is compared with the results taken from GC/MS analysis. It is obtained that the results suggested theoretically were similar with the GC/MS results.

  10. Pulsed-field electrophoresis: application of a computer model to the separation of large DNA molecules.

    PubMed Central

    Lalande, M; Noolandi, J; Turmel, C; Rousseau, J; Slater, G W

    1987-01-01

    The biased reptation theory has been applied to the pulsed-field electrophoresis of DNA in agarose gels. A computer simulation of the theoretical model that calculates the mobility of large DNA molecules as a function of agarose pore size, DNA chain properties, and electric field conditions has been used to generate mobility curves for DNA molecules in the size range of the larger yeast chromosomes. Pulsed-field electrophoresis experiments resulting in the establishment of an electrophoretic karyotype for yeast, where the mobility of the DNA fragments is a monotonic function of molecular size for the entire size range that is resolved (200-2200 kilobase pairs), has been compared to the theoretical mobility curves generated by the computer model. The various physical mechanisms and experimental conditions responsible for band inversion and improved electrophoretic separation are identified and discussed in the framework of the model. Images PMID:3317398

  11. Comparisons of Non-Gaussian Statistical Models in DNA Methylation Analysis

    PubMed Central

    Ma, Zhanyu; Teschendorff, Andrew E.; Yu, Hong; Taghia, Jalil; Guo, Jun

    2014-01-01

    As a key regulatory mechanism of gene expression, DNA methylation patterns are widely altered in many complex genetic diseases, including cancer. DNA methylation is naturally quantified by bounded support data; therefore, it is non-Gaussian distributed. In order to capture such properties, we introduce some non-Gaussian statistical models to perform dimension reduction on DNA methylation data. Afterwards, non-Gaussian statistical model-based unsupervised clustering strategies are applied to cluster the data. Comparisons and analysis of different dimension reduction strategies and unsupervised clustering methods are presented. Experimental results show that the non-Gaussian statistical model-based methods are superior to the conventional Gaussian distribution-based method. They are meaningful tools for DNA methylation analysis. Moreover, among several non-Gaussian methods, the one that captures the bounded nature of DNA methylation data reveals the best clustering performance. PMID:24937687

  12. Stochastic model of homogeneous coding and latent periodicity in DNA sequences.

    PubMed

    Chaley, Maria; Kutyrkin, Vladimir

    2016-02-01

    The concept of latent triplet periodicity in coding DNA sequences which has been earlier extensively discussed is confirmed in the result of analysis of a number of eukaryotic genomes, where latent periodicity of a new type, called profile periodicity, is recognized in the CDSs. Original model of Stochastic Homogeneous Organization of Coding (SHOC-model) in textual string is proposed. This model explains the existence of latent profile periodicity and regularity in DNA sequences. PMID:26656186

  13. Comparison of empirical models for predicting lethal body burdens of neutral, organic compounds

    SciTech Connect

    Kubitz, J.A.; Lauren, D.J.; Barber, T.R. |

    1995-12-31

    Three empirical models that predict lethal body burdens (LBBs) for neutral organic compounds were evaluated by using a probabilistic modeling technique. The models had the general form: log LBB = [(m log K{sub ow} + b) + (log K{sub ow} + log lipid content)]. The median and 95% predictive intervals from the model were compared to 14 independently-developed, residue-effect values from the literature for seven compounds and five aquatic species. One model, which was developed by calculating mean slopes (m) and intercepts (b) from thirteen published linear quantitative structure-activity relationships (QSARs), consistently overestimated the LBBs reported in the literature. A second model, which was developed by fitting Pimephales promelas toxicity data to a one compartment, first-order kinetic model, accurately predicted 7 of 14 (50%) reported LBBs. A third model was developed by fitting toxicity test data from three species (Cyprinodon variegatus, Mysidopsis bahia, and P. promelas) to a linear QSAR, and correctly predicted 13 of 14 (93%) reported LBBs. This study demonstrated that LBBs were accurately predicted on the basis of the toxicant`s octanol-water partition coefficient (K{sub ow}) and the lipid content of the exposed organism. The multi-species model was more accurate than the single-species model for predicting LBBs. An accurate multi-species model could not be estimated by calculating the mean slope and intercept of several single-species QSARs; the original data were required. These results verify that empirical, structure-based models are a valid approach for predicting the toxicity of neutral, organic compounds to a variety of species. This modeling approach has applications for assessing ecological risks, especially for species that have not been used in laboratory toxicity tests.

  14. Two-dimensional discrete model for DNA dynamics: Longitudinal wave propagation and denaturation

    NASA Astrophysics Data System (ADS)

    Muto, V.; Lomdahl, P. S.; Christiansen, P. L.

    1990-12-01

    In this paper, a simple, two-dimensional model of the deoxyribonucleic acid (DNA) is presented. In the model the two polynucleotide strands are linked together through the hydrogen bonds. The phosphodiester bridges in the backbone are described by the anharmonic potential of Toda kind, while the hydrogen bonds are described by the Lennard-Jones potential. Longitudinal wave propagation on ring-shaped DNA molecules is investigated. The model predicts a significant increase in the lifetime of the open states of the hydrogen bonds at physiological temperatures. Thus anharmonicity may play a role in DNA denaturation.

  15. Ising-model description of long-range correlations in DNA sequences

    NASA Astrophysics Data System (ADS)

    Colliva, A.; Pellegrini, R.; Testori, A.; Caselle, M.

    2015-05-01

    We model long-range correlations of nucleotides in the human DNA sequence using the long-range one-dimensional (1D) Ising model. We show that, for distances between 103 and 106 bp, the correlations show a universal behavior and may be described by the non-mean-field limit of the long-range 1D Ising model. This allows us to make some testable hypothesis on the nature of the interaction between distant portions of the DNA chain which led to the DNA structure that we observe today in higher eukaryotes.

  16. Modeling reactive transport of organic compounds in groundwater using a partial redox disequilibrium approach

    NASA Astrophysics Data System (ADS)

    McNab, W. W.; Narasimhan, T. N.

    1994-09-01

    The chemical transformation of organic contaminants in natural groundwater systems is clearly dependent upon local geochemistry which determines the thermodynamically favorable degradation reactions and the nature of local microbial populations. Conversely, groundwater geochemistry may be impacted significantly in terms of pH and redox couple speciation by the chemical transformation of sufficient quantities of organic compounds. Therefore an understanding of the coupling between degradation reactions, local geochemistry, and chemical transport is essential in predicting the chemical evolution of contaminated aquifers. Equilibrium-based reactive chemical transport models are usually not utilized for problems involving the transport of degradable organic compounds due to slow reaction kinetics and the persistence of intermediate degradation products. In this study we propose a reactive geochemical transport model which considers these types of degradation reactions. An expert system approach is used to postulate a set of sequential, first-order degradation reactions for the organic compounds based upon thermodynamic considerations and user-defined rules. Redox disequilibrium provides the driving force for the abiotic or microbially mediated transformation of the organic compounds as well as the associated response of groundwater geochemistry. Coupling between local inorganic geochemistry and reacting organic compounds is achieved by assuring conservation of operational valence and mass balance. The composite geochemical model is in turn coupled with an integral finite difference transport algorithm using a two-step sequential solution approach. The transport equation is solved separately for each inorganic aqueous species, complex, and dissolved organic species, allowing a high degree of flexibility in problem definition. We apply the model to an illustrative example problem concerning the introduction of aromatic hydrocarbons and chlorinated ethenes into an

  17. Mitochondrial DNA content of mature spermatozoa and oocytes in the genetic model Drosophila.

    PubMed

    Wolff, Jonci Nikolai; Sutovsky, Peter; Ballard, John William Oman

    2013-07-01

    Although crucial to the success of fertilization and embryogenesis, little is known about the mitochondrial DNA (mtDNA) content of mature spermatozoa and oocytes across taxa and across different fertilization systems. Oocytes are assumed to hold a large population of mtDNAs that populate emerging cells during early embryogenesis, whereas spermatozoa harbor only a limited pool of mtDNAs that is believed to sustain functionality but fails to contribute paternal mtDNA to the zygote. Recent work suggests that mature sperm of the genetic model Drosophila melanogaster lack mtDNA, questioning the significance of zygotic mechanisms for the selective elimination of paternal mtDNA and their necessity for fertilization success. This finding further contradicts previous observations of the inheritance of paternal mtDNA in drosophilids. Using quantitative polymerase chain reaction, we estimate the mtDNA content of several laboratory strains of D. melanogaster and D. simulans to shed light on this discrepancy and to describe the mitochondrial/mtDNA load of gametes within this system. These measurements led to an average estimate of 22.91±4.61 mtDNA molecules/copies per spermatozoon across both species and to 1.07E+07±2.71E+06 molecules/copies per oocyte for D. simulans. As a consequence, the ratio of paternal and maternal mtDNA in the zygote was estimated at 1:4.65E+05.

  18. Cleavage of C-O bonds in lignin model compounds catalyzed by methyldioxorhenium in homogeneous phase.

    PubMed

    Harms, Reentje G; Markovits, Iulius I E; Drees, Markus; Herrmann, H C Mult Wolfgang A; Cokoja, Mirza; Kühn, Fritz E

    2014-02-01

    Methyldioxorhenium (MDO)-catalyzed C-O bond cleavage of a variety of lignin β-O-4-model compounds yields phenolic and aldehydic compounds in homogeneous phase under mild reaction conditions. MDO is in situ generated by reduction of methyltrioxorhenium (MTO) and is remarkably stable under the applied reaction conditions allowing its reuse for least five times without significant activity loss. Based on the observed and isolated intermediates, 17 O- and 2 H-isotope labeling experiments, DFT calculations, and several spectroscopic studies, a reaction mechanism is proposed.

  19. Modeling of DNA thermophoresis in dilute solutions using the non-equilibrium thermodynamics approach

    NASA Astrophysics Data System (ADS)

    Eslamian, Morteza; Saghir, M. Ziad

    2012-03-01

    Our previous approach on thermodiffusion modeling of dilute polymer solutions is extended to dilute DNA solutions. The model is based on linear non-equilibrium thermodynamics and the concept of Eyring's activation energy of viscous flow to estimate the Soret coefficient in thermophoresis of macromolecules that are not in liquid phase. The net heat of transport of single- and double-stranded DNA molecules, which are in solid state, are replaced by the activation energy of viscous flow of liquid alkanes with comparable molecular weights. The proposed formula is tested against available experimental data and qualitative agreement is observed. For double-stranded DNA molecules, the experimental data are scattered and the model can qualitatively predict the data, whereas for single-stranded DNA experiments in the infinite dilution model, for which the model is prescribed, a very good agreement is observed.

  20. Ribonuclease H/DNA Polymerase HIV-1 Reverse Transcriptase Dual Inhibitor: Mechanistic Studies on the Allosteric Mode of Action of Isatin-Based Compound RMNC6

    PubMed Central

    Corona, Angela; Meleddu, Rita; Esposito, Francesca; Distinto, Simona; Bianco, Giulia; Masaoka, Takashi; Maccioni, Elias; Menéndez-Arias, Luis; Alcaro, Stefano; Le Grice, Stuart F. J.; Tramontano, Enzo

    2016-01-01

    The DNA polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) are needed for the replication of the viral genome and are validated drug targets. However, there are no approved drugs inhibiting RNase H and the efficiency of DNA polymerase inhibitors can be diminished by the presence of drug resistance mutations. In this context, drugs inhibiting both activities could represent a significant advance towards better anti-HIV therapies. We report on the mechanisms of allosteric inhibition of a newly synthesized isatin-based compound designated as RMNC6 that showed IC50 values of 1.4 and 9.8 μM on HIV-1 RT-associated RNase H and polymerase activities, respectively. Blind docking studies predict that RMNC6 could bind two different pockets in the RT: one in the DNA polymerase domain (partially overlapping the non-nucleoside RT inhibitor [NNRTI] binding pocket), and a second one close to the RNase H active site. Enzymatic studies showed that RMNC6 interferes with efavirenz (an approved NNRTI) in its binding to the RT polymerase domain, although NNRTI resistance-associated mutations such as K103N, Y181C and Y188L had a minor impact on RT susceptibility to RMNC6. In addition, despite being naturally resistant to NNRTIs, the polymerase activity of HIV-1 group O RT was efficiently inhibited by RMNC6. The compound was also an inhibitor of the RNase H activity of wild-type HIV-1 group O RT, although we observed a 6.5-fold increase in the IC50 in comparison with the prototypic HIV-1 group M subtype B enzyme. Mutagenesis studies showed that RT RNase H domain residues Asn474 and Tyr501, and in a lesser extent Ala502 and Ala508, are critical for RMNC6 inhibition of the endonuclease activity of the RT, without affecting its DNA polymerization activity. Our results show that RMNC6 acts as a dual inhibitor with allosteric sites in the DNA polymerase and the RNase H domains of HIV-1 RT. PMID:26800261

  1. Detection of gamma-irradiation induced DNA damage and radioprotection of compounds in yeast using comet assay.

    PubMed

    Nemavarkar, P S; Chourasia, B K; Pasupathy, K

    2004-06-01

    The single cell gel electrophoresis assay (SCGE), a very rapid and sensitive method, has been applied to follow gamma-irradiation induced DNA damage in budding yeast, Saccharomyces cerevisiae. Spheroplasting the gamma-irradiated yeast cells by enzyme glusulase, before subjecting them to electrophoresis, resulted in a well-defined appearance of comets. Yeast comets look quite different from mammalian comets. A linear relationship was observed between the doses of irradiation and the tail moments of comets. These studies were extended to follow the action of known radio-protectors, i.e., caffeine and disulfiram. The results revealed the usefulness SCGE as applied to yeast in studies of the gamma-irradiation-induced DNA breaks and also radio-protection by chemicals at doses that are not feasible with other eukaryotes. PMID:15304956

  2. Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound.

    PubMed

    Merle, Patrick; Gueugneau, Marine; Teulade-Fichou, Marie-Paule; Müller-Barthélémy, Mélanie; Amiard, Simon; Chautard, Emmanuel; Guetta, Corinne; Dedieu, Véronique; Communal, Yves; Mergny, Jean-Louis; Gallego, Maria; White, Charles; Verrelle, Pierre; Tchirkov, Andreï

    2015-11-06

    Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them from nucleotidic degradation and end-to-end fusions. The G-rich telomeric single-stranded DNA overhang can adopt a four-stranded G-quadruplex DNA structure (G4). Stabilization of the G4 structure by binding of small molecule ligands enhances radiosensitivity of tumor cells, and this combined treatment represents a novel anticancer approach. We studied the effect of the platinum-derived G4-ligand, Pt-ctpy, in association with radiation on human glioblastoma (SF763 and SF767) and non-small cell lung cancer (A549 and H1299) cells in vitro and in vivo. Treatments with submicromolar concentrations of Pt-ctpy inhibited tumor proliferation in vitro with cell cycle alterations and induction of apoptosis. Non-toxic concentrations of the ligand were then combined with ionizing radiation. Pt-ctpy radiosensitized all cell lines with dose-enhancement factors between 1.32 and 1.77. The combined treatment led to increased DNA breaks. Furthermore, a significant radiosensitizing effect of Pt-ctpy in mice xenografted with glioblastoma SF763 cells was shown by delayed tumor growth and improved survival. Pt-ctpy can act in synergy with radiation for efficient killing of cancer cells at concentrations at which it has no obvious toxicity per se, opening perspectives for future therapeutic applications.

  3. Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound

    PubMed Central

    Merle, Patrick; Gueugneau, Marine; Teulade-Fichou, Marie-Paule; Müller-Barthélémy, Mélanie; Amiard, Simon; Chautard, Emmanuel; Guetta, Corinne; Dedieu, Véronique; Communal, Yves; Mergny, Jean-Louis; Gallego, Maria; White, Charles; Verrelle, Pierre; Tchirkov, Andreï

    2015-01-01

    Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them from nucleotidic degradation and end-to-end fusions. The G-rich telomeric single-stranded DNA overhang can adopt a four-stranded G-quadruplex DNA structure (G4). Stabilization of the G4 structure by binding of small molecule ligands enhances radiosensitivity of tumor cells, and this combined treatment represents a novel anticancer approach. We studied the effect of the platinum-derived G4-ligand, Pt-ctpy, in association with radiation on human glioblastoma (SF763 and SF767) and non-small cell lung cancer (A549 and H1299) cells in vitro and in vivo. Treatments with submicromolar concentrations of Pt-ctpy inhibited tumor proliferation in vitro with cell cycle alterations and induction of apoptosis. Non-toxic concentrations of the ligand were then combined with ionizing radiation. Pt-ctpy radiosensitized all cell lines with dose-enhancement factors between 1.32 and 1.77. The combined treatment led to increased DNA breaks. Furthermore, a significant radiosensitizing effect of Pt-ctpy in mice xenografted with glioblastoma SF763 cells was shown by delayed tumor growth and improved survival. Pt-ctpy can act in synergy with radiation for efficient killing of cancer cells at concentrations at which it has no obvious toxicity per se, opening perspectives for future therapeutic applications. PMID:26542881

  4. Melting behavior and different bound states in three-stranded DNA models.

    PubMed

    Maji, Jaya; Bhattacharjee, Somendra M; Seno, Flavio; Trovato, Antonio

    2014-01-01

    Thermal denaturation of DNA is often studied with coarse-grained models in which native sequential base pairing is mimicked by the existence of attractive interactions only between monomers at the same position along strands (Poland and Scheraga models). Within this framework, the existence of a three-stranded DNA bound state in conditions where a duplex DNA would be in the denaturated state was recently predicted from a study of three directed polymer models on simplified hierarchical lattices (d>2) and in 1+1 dimensions. Such a phenomenon which is similar to the Efimov effect in nuclear physics was named Efimov-DNA. In this paper we study the melting of the three-stranded DNA on a Sierpinski gasket of dimensions d<2 by assigning extra weight factors to fork openings and closings, to induce a two-strand DNA melting. In such a context we can find again the existence of the Efimov-DNA-like state but quite surprisingly we discover also the presence of a different phase, to be called a mixed state, where the strands are pair-wise bound but without three chain contacts. Whereas the Efimov DNA turns out to be a crossover near melting, the mixed phase is a thermodynamic phase. PMID:24580186

  5. Melting behavior and different bound states in three-stranded DNA models.

    PubMed

    Maji, Jaya; Bhattacharjee, Somendra M; Seno, Flavio; Trovato, Antonio

    2014-01-01

    Thermal denaturation of DNA is often studied with coarse-grained models in which native sequential base pairing is mimicked by the existence of attractive interactions only between monomers at the same position along strands (Poland and Scheraga models). Within this framework, the existence of a three-stranded DNA bound state in conditions where a duplex DNA would be in the denaturated state was recently predicted from a study of three directed polymer models on simplified hierarchical lattices (d>2) and in 1+1 dimensions. Such a phenomenon which is similar to the Efimov effect in nuclear physics was named Efimov-DNA. In this paper we study the melting of the three-stranded DNA on a Sierpinski gasket of dimensions d<2 by assigning extra weight factors to fork openings and closings, to induce a two-strand DNA melting. In such a context we can find again the existence of the Efimov-DNA-like state but quite surprisingly we discover also the presence of a different phase, to be called a mixed state, where the strands are pair-wise bound but without three chain contacts. Whereas the Efimov DNA turns out to be a crossover near melting, the mixed phase is a thermodynamic phase.

  6. Key intermediates in nitrogen transformation during microwave pyrolysis of sewage sludge: a protein model compound study.

    PubMed

    Zhang, Jun; Tian, Yu; Cui, Yanni; Zuo, Wei; Tan, Tao

    2013-03-01

    The nitrogen transformations with attention to NH3 and HCN were investigated at temperatures of 300-800°C during microwave pyrolysis of a protein model compound. The evolution of nitrogenated compounds in the char, tar and gas products were conducted. The amine-N, heterocyclic-N and nitrile-N compounds were identified as three important intermediates during the pyrolysis. NH3 and HCN were formed with comparable activation energies competed to consume the same reactive substances at temperatures of 300-800°C. The deamination and dehydrogenation of amine-N compounds from protein cracking contributed to the formation of NH3 (about 8.9% of Soy-N) and HCN (6.6%) from 300 to 500°C. The cracking of nitrile-N and heterocyclic-N compounds from the dehydrogenation and polymerization of amine-N generated HCN (13.4%) and NH3 (31.3%) between 500 and 800°C. It might be able to reduce the HCN and NH3 emissions through controlling the intermediates production at temperatures of 500-800°C.

  7. Molecular Modeling and Experimental Investigations of Nonlinear Optical Compounds Monosubstituted Derivatives of Dicyanovinylbenzene

    NASA Technical Reports Server (NTRS)

    Timofeeva, Tatiana V.; Nesterov, Vladimir N.; Antipin, Mikhail Yu.; Clark, Ronald D.; Sanghadasa, Mohan; Cardelino, Beatriz H.; Moore, Craig E.; Frazier, Donald O.

    1999-01-01

    A search for potential nonlinear optical compounds was performed using the Cambridge Structure Database and molecular modeling. We investigated a series of monosubstituted derivatives of dicyanovinylbenzene, since the nonlinear optical (NLO) properties of such derivatives (o-methoxy-dicyanovinylbenzene, DIVA) were studied earlier. The molecular geometry of these compounds was investigated with x-ray analysis and discussed along with the results of molecular mechanics and ab initio quantum chemical calculations. The influence of crystal packing on the planarity of the molecules of this series has been revealed. Two new compounds from the series studied, ortho-F and para-Cl-dicyanovinylbenzene, according to powder measurements, were found to be NLO compounds in the crystal state about 10 times more active than urea. The peculiarities of crystal structure formation in the framework of balance between van der Waals and electrostatic interactions have been discussed. The crystal shape of DIVA and two new NLO compounds have been calculated on the basis of the known crystal structure.

  8. DNA Bending and Wrapping around RNA Polymerase: a “Revolutionary” Model Describing Transcriptional Mechanisms

    PubMed Central

    Coulombe, Benoit; Burton, Zachary F.

    1999-01-01

    A model is proposed in which bending and wrapping of DNA around RNA polymerase causes untwisting of the DNA helix at the RNA polymerase catalytic center to stimulate strand separation prior to initiation. During elongation, DNA bending through the RNA polymerase active site is proposed to lower the energetic barrier to the advance of the transcription bubble. Recent experiments with mammalian RNA polymerase II along with accumulating evidence from studies of Escherichia coli RNA polymerase indicate the importance of DNA bending and wrapping in transcriptional mechanisms. The DNA-wrapping model describes specific roles for general RNA polymerase II transcription factors (TATA-binding protein [TBP], TFIIB, TFIIF, TFIIE, and TFIIH), provides a plausible explanation for preinitiation complex isomerization, suggests mechanisms underlying the synergy between transcriptional activators, and suggests an unforseen role for TBP-associating factors in transcription. PMID:10357858

  9. Correct assessment of new compounds using in vivo screening models can reduce false positives.

    PubMed

    Bueters, Tjerk J H; Hoogstraate, Janet; Visser, Sandra A G

    2009-01-01

    During early drug discovery the initial in vivo efficacy testing is often performed in rodent models optimized to screen and select lead compounds rapidly, before progressing them to in vivo models that reflect the human form of the disease more closely. The way such models are frequently run can risk overestimating the efficacy of new compounds when using pre- and co-administration, as shown in three examples from different central nervous system research areas. This is undesirable for reasons ranging from good decision-making, cost efficiency and time management to the ethics of animal use. Abandoning the use of pre-treatment, monitoring crucial physiological parameters in (satellite) animals and systematically applying simple pharmacokinetic-pharmacodynamic analysis could reduce the number of false positive results.

  10. Kinetics of model high molecular weight organic compounds biodegradation in soil aquifer treatment.

    PubMed

    Fox, Peter; Makam, Roshan

    2011-10-01

    Soil Aquifer Treatment (SAT) is a process where treated wastewater is purified during transport through unsaturated and saturated zones. Easily biodegradable compounds are rapidly removed in the unsaturated zone and the residual organic carbon is comprised of primarily high molecular weight compounds. This research focuses on flow in the saturated zone where flow conditions are predictable and high molecular weight compounds are degraded. Flow through the saturated zone was investigated with 4 reactors packed with 2 different particle sizes and operated at 4 different flow rates. The objective was to evaluate the kinetics of transformation for high molecular weight organics during SAT. Dextran was used as a model compound to eliminate the complexity associated with studying a mixture of high molecular weight organics. The hydrolysis products of dextran are easily degradable sugars. Batch experiments with media taken from the reactors were used to determine the distribution of microbial activity in the reactors. Zero-order kinetics were observed for the removal of dextran in batch experiments which is consistent with hydrolysis of high molecular weight organics where extracellular enzymes limit the substrate utilization rate. Biomass and microbial activity measurements demonstrated that the biomass was independent of position in the reactors. A Monod based substrate/biomass growth kinetic model predicted the performance of dextran removal in the reactors. The rate limiting step appears to be hydrolysis and the overall rate was not affected by surface area even though greater biomass accumulation occurred as the surface area decreased. PMID:21723581

  11. Kinetics of model high molecular weight organic compounds biodegradation in soil aquifer treatment.

    PubMed

    Fox, Peter; Makam, Roshan

    2011-10-01

    Soil Aquifer Treatment (SAT) is a process where treated wastewater is purified during transport through unsaturated and saturated zones. Easily biodegradable compounds are rapidly removed in the unsaturated zone and the residual organic carbon is comprised of primarily high molecular weight compounds. This research focuses on flow in the saturated zone where flow conditions are predictable and high molecular weight compounds are degraded. Flow through the saturated zone was investigated with 4 reactors packed with 2 different particle sizes and operated at 4 different flow rates. The objective was to evaluate the kinetics of transformation for high molecular weight organics during SAT. Dextran was used as a model compound to eliminate the complexity associated with studying a mixture of high molecular weight organics. The hydrolysis products of dextran are easily degradable sugars. Batch experiments with media taken from the reactors were used to determine the distribution of microbial activity in the reactors. Zero-order kinetics were observed for the removal of dextran in batch experiments which is consistent with hydrolysis of high molecular weight organics where extracellular enzymes limit the substrate utilization rate. Biomass and microbial activity measurements demonstrated that the biomass was independent of position in the reactors. A Monod based substrate/biomass growth kinetic model predicted the performance of dextran removal in the reactors. The rate limiting step appears to be hydrolysis and the overall rate was not affected by surface area even though greater biomass accumulation occurred as the surface area decreased.

  12. A unified approach to the transition matrices of DNA substitution models.

    PubMed

    Yap, Von Bing

    2013-04-01

    For a reversible finite-state continuous-time Markov chain containing similar states, the computation of the transition matrix can be expressed quite elegantly in terms of the transition matrix of an associated lumped Markov chain. This result is immensely useful for obtaining explicit transition matrices for many DNA substitution models, without diagonalizing a matrix or solving a differential equation. Furthermore, the technique works for the analogous problem in the discrete-time DNA substitution models.

  13. Tissue specific response to DNA damage: C. elegans as role model.

    PubMed

    Lans, Hannes; Vermeulen, Wim

    2015-08-01

    The various symptoms associated with hereditary defects in the DNA damage response (DDR), which range from developmental and neurological abnormalities and immunodeficiency to tissue-specific cancers and accelerated aging, suggest that DNA damage affects tissues differently. Mechanistic DDR studies are, however, mostly performed in vitro, in unicellular model systems or cultured cells, precluding a clear and comprehensive view of the DNA damage response of multicellular organisms. Studies performed in intact, multicellular animals models suggest that DDR can vary according to the type, proliferation and differentiation status of a cell. The nematode Caenorhabditis elegans has become an important DDR model and appears to be especially well suited to understand in vivo tissue-specific responses to DNA damage as well as the impact of DNA damage on development, reproduction and health of an entire multicellular organism. C. elegans germ cells are highly sensitive to DNA damage induction and respond via classical, evolutionary conserved DDR pathways aimed at efficient and error-free maintenance of the entire genome. Somatic tissues, however, respond differently to DNA damage and prioritize DDR mechanisms that promote growth and function. In this mini-review, we describe tissue-specific differences in DDR mechanisms that have been uncovered utilizing C. elegans as role model. PMID:25957488

  14. Modeling reactive transport of organic compounds in groundwater using a partial redox disequilibrium approach

    SciTech Connect

    McNab, W.W. Jr.; Narasimhan, T.N. )

    1994-09-01

    The chemical transformation of organic contaminants in natural groundwater systems is clearly dependent upon local geochemistry which determines the thermodynamically favorable degradation reactions and the nature of local microbial populations. Conversely, groundwater geochemistry may be impacted significantly in terms of pH and redox couple speciation by the chemical transformation of sufficient quantities of organic compounds. Therefore an understanding of the coupling between degradation reactions, local geochemistry, and chemical transport is essential in predicting the chemical evolution of contaminated aquifers. Equilibrium-based reactive chemical transport models are usually not utilized for problems involving the transport of degradable organic compounds due to slow reaction kinetics and the persistence of intermediate degradation products. In this study we propose a reactive geochemical transport model which considers these types of degradation reactions. An expert system approach is used to postulate a set of sequential, first-order degradation reactions for the organic compounds based upon thermodynamic considerations and user-defined rules. Redox disequilibrium provides the driving force for the abiotic or microbially mediated transformation of the organic compounds as well as the associated response of groundwater geochemistry. Coupling between local inorganic geochemistry and reacting organic compounds is achieved by assuring conservation of operation valence and mass balance. The composite geochemical model is in turn coupled with an integral finite difference transport algorithm using a two-step sequential solution approach. The transport equation is solved separately for each inorganic aqueous species, complex, and dissolved organic species, allowing degree of flexibility in problem definition. 58 refs., 18 figs., 2 tabs.

  15. The Murine Intravaginal HSV-2 Challenge Model for Investigation of DNA Vaccines

    PubMed Central

    Marshak, Joshua O.; Dong, Lichun; Koelle, David M.

    2014-01-01

    DNA vaccines have been licensed in veterinary medicine and have promise for humans. This format is relatively immunogenic in mice and guinea pigs, the two principle HSV-2 animal models, permitting rapid assessment of vectors, antigens, adjuvants, and delivery systems. Limitations include the relatively poor immunogenicity of naked DNA in humans and the profound differences in HSV-2 pathogenesis between host species. Herein, we detail lessons learned over the last few years investigating candidate DNA vaccines in the progesterone-primed female mouse vaginal model of HSV-2 infection as a guide to investigators in the field. PMID:24671693

  16. Cleavage of a model DNA replication fork by a methyl-specific endonuclease.

    PubMed

    Ishikawa, Ken; Handa, Naofumi; Sears, Lauren; Raleigh, Elisabeth A; Kobayashi, Ichizo

    2011-07-01

    Epigenetic DNA methylation is involved in many biological processes. An epigenetic status can be altered by gain or loss of a DNA methyltransferase gene or its activity. Repair of DNA damage can also remove DNA methylation. In response to such alterations, DNA endonucleases that sense DNA methylation can act and may cause cell death. Here, we explored the possibility that McrBC, a methylation-dependent DNase of Escherichia coli, cleaves DNA at a replication fork. First, we found that in vivo restriction by McrBC of bacteriophage carrying a foreign DNA methyltransferase gene is increased in the absence of homologous recombination. This suggests that some cleavage events are repaired by recombination and must take place during or after replication. Next, we demonstrated that the enzyme can cleave a model DNA replication fork in vitro. Cleavage of a fork required methylation on both arms and removed one, the other or both of the arms. Most cleavage events removed the methylated sites from the fork. This result suggests that acquisition of even rarely occurring modification patterns will be recognized and rejected efficiently by modification-dependent restriction systems that recognize two sites. This process might serve to maintain an epigenetic status along the genome through programmed cell death.

  17. Variation in rDNA locus number and position among legume species and detection of 2 linked rDNA loci in the model Medicago truncatula by FISH.

    PubMed

    Abirached-Darmency, Mona; Prado-Vivant, Emilce; Chelysheva, Liudmila; Pouthier, Thomas

    2005-06-01

    Within Fabaceae, legume species have a variable genome size, chromosome number, and ploidy level. The genome distribution of ribosomal genes, easily detectable by fluorescent in situ hybridization (FISH), is a good tool for anchoring physical and genetic comparative maps. The organisation of 45S rDNA and 5S loci was analysed by FISH in the 4 closely related species: Pisum sativum, Medicago truncatula, Medicago sativa (2 diploid taxa), and Lathyrus sativus. The 2 types of rDNA arrays displayed interspecific variation in locus number and location, but little intraspecific variation was detected. In the model legume, M. truncatula, the presence of 2 adjacent 45S rDNA loci was demonstrated, and the location of the rDNA loci was independent of the general evolution of the genome DNA. The different parameters relative to clustering of the rDNA loci in specific chromosome regions and the possible basis of rDNA instability are discussed. PMID:16121252

  18. Some new nano-structure zinc(II) coordination compounds of an imidazolidine Schiff base: Spectral, thermal, antimicrobial properties and DNA interaction

    NASA Astrophysics Data System (ADS)

    Montazerozohori, Morteza; Musavi, Sayed Alireza; Naghiha, Asghar; Zohour, Mostafa Montazer

    2014-08-01

    Some novel nano-sized structure zinc complexes of a new Schiff base ligand entitled as (3-nitro-benzylidene)-{2-[2-(3-nitro-phenyl)-imidazolidine-1-yl]-ethyl}-amine(L) with general formula of ZnLX2 wherein X = Cl-, Br-, I-, SCN- and N3- have been synthesized under ultrasonic conditions. The ligand and its complexes have been characterized by elemental analysis, molar conductance measurements, FT-IR, 1H and 13C NMR and UV-Visible spectroscopy. The resulting data from spectral investigation especially 1H and 13C NMR well confirmed formation of an imidazolidine ring in the ligand structure. Transmission electron microscopy (TEM) showed nano-size structures with average particle sizes of 21.80-78.10 nm for the zinc(II) Schiff base complexes. The free Schiff base and its Zn(II) complexes have been screened in vitro both for antibacterial activity against some gram-positive and gram-negative bacteria and also for antifungal activity. The metal complexes were found to be more active than the free Schiff base ligand. The results showed that ZnL(N3)2 is the most effective inhibitor against Escherichia coli, Pseudomonas aereuguinosa, Staphylococcus aureus and Candida albicans while ZnLBr2 was found to be more effective against Bacillus subtillis than other compounds. Moreover, DNA cleavage potential of all compounds with plasmid DNA was investigated. The results showed that the ligand and ZnLCl2 complex cleave DNA more efficiently than others. In final, thermal analysis of ligand and its complexes revealed that they are decomposed via 2-3 thermal steps in the range of room temperature to 1000 °C. Furthermore some activation kinetic parameters such as A, E*, ΔH*, ΔS* and ΔG* were calculated based on TG/DTA plots by use of coats - Redfern relation. Positive values of activation energy evaluated for the compounds confirmed the thermal stability of them. In addition to, the positive ΔH*, and ΔG* values suggested endothermic character for the thermal decomposition steps.

  19. Phosphorus-nitrogen compounds: Part 28. Syntheses, structural characterizations, antimicrobial and cytotoxic activities, and DNA interactions of new phosphazenes bearing vanillinato and pendant ferrocenyl groups

    NASA Astrophysics Data System (ADS)

    Tümer, Yasemin; Asmafiliz, Nuran; Kılıç, Zeynel; Hökelek, Tuncer; Yasemin Koç, L.; Açık, Leyla; Yola, Mehmet Lütfi; Solak, Ali Osman; Öner, Yağmur; Dündar, Devrim; Yavuz, Makbule

    2013-10-01

    The gradually Cl replacement reactions of spirocyclic mono (1 and 2) and bisferrocenyl cyclotriphosphazenes (3-5) with the potassium salt of 4-hydroxy-3-methoxybenzaldehyde (potassium vanillinate) gave mono (1a-5a), geminal (gem-1b-5b), non-geminal (cis-1b, cis-5b and trans-2b-5b), tri (1c-5c) and tetra-substituted phosphazenes (1d-5d). Some phosphazenes have stereogenic P-center(s). The chirality of 4c was verified using chiral HPLC column. Electrochemical behaviors were influenced only by the number of ferrocene groups, but not the length of the amine chains and the substituent(s). The structures of the new phosphazenes were determined by FTIR, MS, 1H, 13C and 31P NMR, HSQC and HMBC spectral data. The solid-state structures of cis-1b and 4d were examined by single crystal X-ray diffraction techniques. The twelve phosphazene derivatives were screened for antimicrobial activity and the compounds 5a, cis-1b and 2c exhibited the highest antibacterial activity against G(+) and G(-) bacteria. In addition, it was found that overall gem-1b inhibited the growth of Mycobacterium tuberculosis. The compounds 1d, 2d and 4d were tested in HeLa cancer cell lines. Among these compounds, 2d had cytotoxic effect on HeLa cell in the first 48 h. Moreover, interactions between compounds 2a, gem-1b, gem-2b, cis-1b, 2c, 3c, 4c, 5c, 1d, 2d and 4d, and pBR322 plasmid DNA were investigated.

  20. Equilibrium and kinetics of DNA overstretching modeled with a quartic energy landscape.

    PubMed

    Argudo, David; Purohit, Prashant K

    2014-11-01

    It is well known that the dsDNA molecule undergoes a phase transition from B-DNA into an overstretched state at high forces. For some time, the structure of the overstretched state remained unknown and highly debated, but recent advances in experimental techniques have presented evidence of more than one possible phase (or even a mixed phase) depending on ionic conditions, temperature, and basepair sequence. Here, we present a theoretical model to study the overstretching transition with the possibility that the overstretched state is a mixture of two phases: a structure with portions of inner strand separation (melted or M-DNA), and an extended phase that retains the basepair structure (S-DNA). We model the double-stranded DNA as a chain composed of n segments of length l, where the transition is studied by means of a Landau quartic potential with statistical fluctuations. The length l is a measure of cooperativity of the transition and is key to characterizing the overstretched phase. By analyzing the different values of l corresponding to a wide spectrum of experiments, we find that for a range of temperatures and ionic conditions, the overstretched form is likely to be a mix of M-DNA and S-DNA. For a transition close to a pure S-DNA state, where the change in extension is close to 1.7 times the original B-DNA length, we find l ? 25 basepairs regardless of temperature and ionic concentration. Our model is fully analytical, yet it accurately reproduces the force-extension curves, as well as the transient kinetic behavior, seen in DNA overstretching experiments.

  1. How nanochannel confinement affects the DNA melting transition within the Poland-Scheraga model

    NASA Astrophysics Data System (ADS)

    Reiter-Schad, Michaela; Werner, Erik; Tegenfeldt, Jonas O.; Mehlig, Bernhard; Ambjörnsson, Tobias

    2015-09-01

    When double-stranded DNA molecules are heated, or exposed to denaturing agents, the two strands are separated. The statistical physics of this process has a long history and is commonly described in terms of the Poland-Scheraga (PS) model. Crucial to this model is the configurational entropy for a melted region (compared to the entropy of an intact region of the same size), quantified by the loop factor. In this study, we investigate how confinement affects the DNA melting transition, by using the loop factor for an ideal Gaussian chain. By subsequent numerical solutions of the PS model, we demonstrate that the melting temperature depends on the persistence lengths of single-stranded and double-stranded DNA. For realistic values of the persistence lengths, the melting temperature is predicted to decrease with decreasing channel diameter. We also demonstrate that confinement broadens the melting transition. These general findings hold for the three scenarios investigated: 1. homo-DNA, i.e., identical basepairs along the DNA molecule, 2. random sequence DNA, and 3. "real" DNA, here T4 phage DNA. We show that cases 2 and 3 in general give rise to broader transitions than case 1. Case 3 exhibits a similar phase transition as case 2 provided the random sequence DNA has the same ratio of AT to GC basepairs (A - adenine, T - thymine, G - guanine, C - cytosine). A simple analytical estimate for the shift in melting temperature is provided as a function of nanochannel diameter. For homo-DNA, we also present an analytical prediction of the melting probability as a function of temperature.

  2. DEVELOPMENT AND VALIDATION OF AN AIR-TO-BEEF FOOD CHAIN MODEL FOR DIOXIN-LIKE COMPOUNDS

    EPA Science Inventory

    A model for predicting concentrations of dioxin-like compounds in beef is developed and tested. The key premise of the model is that concentrations of these compounds in air are the source term, or starting point, for estimating beef concentrations. Vapor-phase concentrations t...

  3. Stereoregularity of poly (lactic acid) and their model compounds as studied by NMR and quantum chemical calculations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In order to understand the origin of the tacticity splitting in the NMR spectrum of poly(lactic acid), monomer model compound and dimer model compounds (both isotactic and syndiotactic) were synthesized and their 1H and 13C NMR chemical shifts observed. Two energetically stable conformations were o...

  4. Probing Complex Free-Radical Reaction Pathways of Fuel Model Compounds

    SciTech Connect

    Buchanan III, A C; Kidder, Michelle; Beste, Ariana; Britt, Phillip F

    2012-01-01

    Fossil (e.g. coal) and renewable (e.g. woody biomass) organic energy resources have received considerable attention as possible sources of liquid transportation fuels and commodity chemicals. Knowledge of the reactivity of these complex materials has been advanced through fundamental studies of organic compounds that model constituent substructures. In particular, an improved understanding of thermochemical reaction pathways involving free-radical intermediates has arisen from detailed experimental kinetic studies and, more recently, advanced computational investigations. In this presentation, we will discuss our recent investigations of the fundamental pyrolysis pathways of model compounds that represent key substructures in the lignin component of woody biomass with a focus on molecules representative of the dominant beta-O-4 aryl ether linkages. Additional mechanistic insights gleaned from DFT calculations on the kinetics of key elementary reaction steps will also be presented, as well as a few thoughts on the significant contributions of Jim Franz to this area of free radical chemistry.

  5. Reaction of nitric oxide with heme proteins and model compounds of hemoglobin

    SciTech Connect

    Sharma, V.S.; Traylor, T.G.; Gardiner, R.; Mizukami, H.

    1987-06-30

    Rates for the reaction of nitric oxide with several ferric heme proteins and model compounds have been measured. The NO combination rates are markedly affected by the presence or absence of distal histidine. Elephant myoglobin in which the E7 distal histidine has been replaced by glutamine reacts with NO 500-1000 times faster than do the native hemoglobins or myoglobins. By contrast, there is not difference in the CO combination rate constants of sperm whale and elephant myoglobins. Studies on ferric model compounds for the R and T states of hemoglobin indicate that their NO combination rate constants are similar to those observed for the combination of CO with the corresponding ferro derivatives. The last observation suggests that the presence of an axial water molecule at the ligand binding site of ferric hemoglobin A prevents it from exhibiting significant cooperativity in its reactions with NO.

  6. Tannin structural elucidation and quantitative ³¹P NMR analysis. 1. Model compounds.

    PubMed

    Melone, Federica; Saladino, Raffaele; Lange, Heiko; Crestini, Claudia

    2013-10-01

    Tannins and flavonoids are secondary metabolites of plants that display a wide array of biological activities. This peculiarity is related to the inhibition of extracellular enzymes that occurs through the complexation of peptides by tannins. Not only the nature of these interactions, but more fundamentally also the structure of these heterogeneous polyphenolic molecules are not completely clear. This first paper describes the development of a new analytical method for the structural characterization of tannins on the basis of tannin model compounds employing an in situ labeling of all labile H groups (aliphatic OH, phenolic OH, and carboxylic acids) with a phosphorus reagent. The ³¹P NMR analysis of ³¹P-labeled samples allowed the unprecedented quantitative and qualitative structural characterization of hydrolyzable tannins, proanthocyanidins, and catechin tannin model compounds, forming the foundations for the quantitative structural elucidation of a variety of actual tannin samples described in part 2 of this series. PMID:24059814

  7. Chapter 8: Pyrolysis Mechanisms of Lignin Model Compounds Using a Heated Micro-Reactor

    SciTech Connect

    Robichaud, David J.; Nimlos, Mark R.; Ellison, G. Barney

    2015-10-03

    Lignin is an important component of biomass, and the decomposition of its thermal deconstruction products is important in pyrolysis and gasification. In this chapter, we investigate the unimolecular pyrolysis chemistry through the use of singly and doubly substituted benzene molecules that are model compounds representative of lignin and its primary pyrolysis products. These model compounds are decomposed in a heated micro-reactor, and the products, including radicals and unstable intermediates, are measured using photoionization mass spectrometry and matrix isolation infrared spectroscopy. We show that the unimolecular chemistry can yield insight into the initial decomposition of these species. At pyrolysis and gasification severities, singly substituted benzenes typically undergo bond scission and elimination reactions to form radicals. Some require radical-driven chain reactions. For doubly substituted benzenes, proximity effects of the substituents can change the reaction pathways.

  8. Random aggregation models for the formation and evolution of coding and non-coding DNA

    NASA Astrophysics Data System (ADS)

    Provata, A.

    A random aggregation model with influx is proposed for the formation of the non-coding DNA regions via random co-aggregation and influx of biological macromolecules such as viruses, parasite DNA, and replication segments. The constant mixing (transpositions) and influx drives the system in an out-of-equilibrium steady state characterised by a power law size distribution. The model predicts the long range distributions found in the noncoding eucaryotic DNA and explains the observed correlations. For the formation of coding DNA a random closed aggregation model is proposed which predicts short range coding size distributions. The closed aggregation process drives the system in an almost “frozen” stable state which is robust to external perturbations and which is characterised by well defined space and time scales, as observed in coding sequences.

  9. Estimation of the environmental properties of compounds from chromatographic measurements and the solvation parameter model.

    PubMed

    Poole, Colin F; Ariyasena, Thiloka C; Lenca, Nicole

    2013-11-22

    This article provides an overview of chromatographic methods as surrogate models for environmental processes and for the determination of descriptors for compounds of environmental interest. The solvation parameter model is the link to the identification of suitable chromatographic models for the estimation of environmental properties using a set of tools that allow screening of chromatographic databases for the selection of candidate systems. As an alternative approach, many transport and distribution properties of environmental interest can be described directly by the solvation parameter model. Environmental properties for compounds with known descriptors can then be predicted through these models. The central role chromatographic methods, together with liquid-liquid partition coefficients, occupy in the determination of the six descriptors used in the solvation parameter model is detailed. There is a current need to accelerate efforts to expand the coverage of environmental process models by incorporating more complex molecules of contemporary environmental interest. For many of these molecules descriptor values are unavailable and their determination should be prioritized.

  10. Mesoscale Computer Modeling of Lipid-DNA Complexes for Gene Therapy

    NASA Astrophysics Data System (ADS)

    Farago, Oded; Grønbech-Jensen, Niels; Pincus, Philip

    2006-01-01

    We report on a molecular simulation method, which captures the self-assembly of cationic lipid-DNA (CL-DNA) gene delivery complexes. Computational efficiency required for large length- and time-scale simulations is achieved through a coarse-grained representation of the intramolecular details and via intermolecular potentials, which effectively mimic the hydrophobic effect without an explicit solvent. The broad utility of the model is illustrated by demonstrating excellent agreement with x-ray diffraction experimental data for the dependence of the spacing between DNA chains on the concentration of CLs. At high concentrations, the large electrostatic pressure induces the formation of pores in the membranes through which the DNA molecules may escape the complex. We relate this observation to the origin of recently observed enhanced transfection efficiency of lamellar CL-DNA complexes at high charge densities.

  11. Animal models that best reproduce the clinical manifestations of human intoxication with organophosphorus compounds.

    PubMed

    Pereira, Edna F R; Aracava, Yasco; DeTolla, Louis J; Beecham, E Jeffrey; Basinger, G William; Wakayama, Edgar J; Albuquerque, Edson X

    2014-08-01

    The translational capacity of data generated in preclinical toxicological studies is contingent upon several factors, including the appropriateness of the animal model. The primary objectives of this article are: 1) to analyze the natural history of acute and delayed signs and symptoms that develop following an acute exposure of humans to organophosphorus (OP) compounds, with an emphasis on nerve agents; 2) to identify animal models of the clinical manifestations of human exposure to OPs; and 3) to review the mechanisms that contribute to the immediate and delayed OP neurotoxicity. As discussed in this study, clinical manifestations of an acute exposure of humans to OP compounds can be faithfully reproduced in rodents and nonhuman primates. These manifestations include an acute cholinergic crisis in addition to signs of neurotoxicity that develop long after the OP exposure, particularly chronic neurologic deficits consisting of anxiety-related behavior and cognitive deficits, structural brain damage, and increased slow electroencephalographic frequencies. Because guinea pigs and nonhuman primates, like humans, have low levels of circulating carboxylesterases-the enzymes that metabolize and inactivate OP compounds-they stand out as appropriate animal models for studies of OP intoxication. These are critical points for the development of safe and effective therapeutic interventions against OP poisoning because approval of such therapies by the Food and Drug Administration is likely to rely on the Animal Efficacy Rule, which allows exclusive use of animal data as evidence of the effectiveness of a drug against pathologic conditions that cannot be ethically or feasibly tested in humans.

  12. Track structure based modelling of light ion radiation effects on nuclear and mitochondrial DNA

    NASA Astrophysics Data System (ADS)

    Schmitt, Elke; Ottolenghi, Andrea; Dingfelder, Michael; Friedland, Werner; Kundrat, Pavel; Baiocco, Giorgio

    2016-07-01

    Space radiation risk assessment is of great importance for manned spaceflights in order to estimate risks and to develop counter-measures to reduce them. Biophysical simulations with PARTRAC can help greatly to improve the understanding of initial biological response to ionizing radiation. Results from modelling radiation quality dependent DNA damage and repair mechanisms up to chromosomal aberrations (e.g. dicentrics) can be used to predict radiation effects depending on the kind of mixed radiation field exposure. Especially dicentric yields can serve as a biomarker for an increased risk due to radiation and hence as an indicator for the effectiveness of the used shielding. PARTRAC [1] is a multi-scale biophysical research MC code for track structure based initial DNA damage and damage response modelling. It integrates physics, radiochemistry, detailed nuclear DNA structure and molecular biology of DNA repair by NHEJ-pathway to assess radiation effects on cellular level [2]. Ongoing experiments with quasi-homogeneously distributed compared to sub-micrometre focused bunches of protons, lithium and carbon ions allow a separation of effects due to DNA damage complexity on nanometre scale from damage clustering on (sub-) micrometre scale [3, 4]. These data provide an unprecedented benchmark for the DNA damage response model in PARTRAC and help understand the mechanisms leading to cell killing and chromosomal aberrations (e.g. dicentrics) induction. A large part of space radiation is due to a mixed ion field of high energy protons and few heavier ions that can be only partly absorbed by the shielding. Radiation damage induced by low-energy ions significantly contributes to the high relative biological efficiency (RBE) of ion beams around Bragg peak regions. For slow light ions the physical cross section data basis in PARTRAC has been extended to investigate radiation quality effects in the Bragg peak region [5]. The resulting range and LET values agree with ICRU data

  13. Molecular Modeling and Experimental Study of Nonlinear Optical Compounds: Mono-Substituted Derivatives of Dicyanovinylbenzene

    NASA Technical Reports Server (NTRS)

    Timofeeva, Tatyana V.; Nesterov, Vladimir N.; Antipin, Mikhael Y.; Clark, R. D.; Sanghadasa, M.; Cardelino, B. H.; Moore, C. E.; Frazier, Donald O.

    2000-01-01

    A search for potential nonlinear optical (NLO) compounds has been performed using the Cambridge Structural Database and molecular modeling. We have studied a series of mono-substituted derivatives of dicyanovinylbenzene as the NLO properties of one of its derivatives (o-methoxy-dicyanovinylbenzene, DIVA) were described earlier. The molecular geometry in the series of the compounds studied was investigated with an X- ray analysis and discussed along with results of molecular mechanics and ab initio quantum chemical calculations. The influence of crystal packing on the molecular planarity has been revealed. Two new compounds from the series studied were found to be active for second harmonic generation (SHG) in the powder. The measurements of SHG efficiency have shown that the o-F- and p-Cl-derivatives of dicyanovinylbenzene are about 10 and 20- times more active than urea, respectively. The peculiarities of crystal structure formation in the framework of balance between the van der Waals and electrostatic interactions have been discussed. The crystal morphology of DIVA and two new SHG-active compounds have been calculated on the basis of their known crystal structures.

  14. A model for integration of DNA into the genome during transformation of Fusarium graminearum.

    PubMed

    Watson, R J; Burchat, S; Bosley, J

    2008-10-01

    Transformants of Fusarium graminearum were derived using linearized DNA of plasmids designed to replace the trichodiene synthase gene, a cutinase gene or a xylanase gene with a hygromycin-resistance marker cassette by homologous recombination between 1-kbp segments of flanking DNA. Most transformants did not exhibit the DNA structure expected of integration by classical double recombination. Instead, they contained linearized plasmid joined end-to-end and variably incorporated into the genome. Transformant types included ectopic integrations and integrations at the target site with or without removal of the targeted gene. We have analyzed a large number of transformants using cloning, PCR and DNA sequencing to determine the structures of their integrated DNA, and describe a model to explain their derivations. The data indicate that 1-3 copies of input DNA are first joined end-to-end to produce either linear or circular structures, probably mediated by the non-homologous end-joining (NHEJ) system. The end-joins typically have 1-5 nucleotides in common and are near or within the original cleavage site of the plasmid. Ectopic integrations occur by attaching linear DNA to two ends of genomic DNA via the same joining mechanism. Integration at the target site is consistent with replication around circularized input DNA, beginning and ending within the flanking homologous DNA, resulting in the integration of multiple copies of the entire structure. This results in deletion or duplication of the target site, or leaves one copy at either end of the integrated multimer. Reiterated DNA in the more complex structures is unstable due to homologous recombination, such that conversion to simpler forms is detected. PMID:18722542

  15. DNA studies are necessary for accurate patient diagnosis in compound heterozygosity for Hb Adana (HBA2:c.179>A) with deletional or nondeletional α-thalassaemia.

    PubMed

    Tan, Jin Ai Mary Anne; Kho, Siew Leng; Ngim, Chin Fang; Chua, Kek Heng; Goh, Ai Sim; Yeoh, Seoh Leng; George, Elizabeth

    2016-01-01

    Haemoglobin (Hb) Adana (HBA2:c.179>A) interacts with deletional and nondeletional α-thalassaemia mutations to produce HbH disorders with varying clinical manifestations from asymptomatic to severe anaemia with significant hepatosplenomegaly. Hb Adana carriers are generally asymptomatic and haemoglobin subtyping is unable to detect this highly unstable α-haemoglobin variant. This study identified 13 patients with compound heterozygosity for Hb Adana with either the 3.7 kb gene deletion (-α(3.7)), Hb Constant Spring (HbCS) (HBA2:c.427T>C) or Hb Paksé (HBA2:429A>T). Multiplex Amplification Refractory Mutation System was used for the detection of five deletional and six nondeletional α-thalassaemia mutations. Duplex-PCR was used to confirm Hb Paksé and HbCS. Results showed 84.6% of the Hb Adana patients were Malays. Using DNA studies, compound heterozygosity for Hb Adana and HbCS (α(codon 59)α/α(CS)α) was confirmed in 11 patients. A novel point in this investigation was that DNA studies confirmed Hb Paksé for the first time in a Malaysian patient (α(codon 59)α/α(Paksé)α) after nine years of being misdiagnosis with Hb Adana and HbCS (α(codon 59)α/α(CS)α). Thus, the reliance on haematology studies and Hb subtyping to detect Hb variants is inadequate in countries where thalassaemia is prevalent and caused by a wide spectrum of mutations. PMID:27271331

  16. DNA studies are necessary for accurate patient diagnosis in compound heterozygosity for Hb Adana (HBA2:c.179>A) with deletional or nondeletional α-thalassaemia

    PubMed Central

    Tan, Jin Ai Mary Anne; Kho, Siew Leng; Ngim, Chin Fang; Chua, Kek Heng; Goh, Ai Sim; Yeoh, Seoh Leng; George, Elizabeth

    2016-01-01

    Haemoglobin (Hb) Adana (HBA2:c.179>A) interacts with deletional and nondeletional α-thalassaemia mutations to produce HbH disorders with varying clinical manifestations from asymptomatic to severe anaemia with significant hepatosplenomegaly. Hb Adana carriers are generally asymptomatic and haemoglobin subtyping is unable to detect this highly unstable α-haemoglobin variant. This study identified 13 patients with compound heterozygosity for Hb Adana with either the 3.7 kb gene deletion (-α3.7), Hb Constant Spring (HbCS) (HBA2:c.427T>C) or Hb Paksé (HBA2:429A>T). Multiplex Amplification Refractory Mutation System was used for the detection of five deletional and six nondeletional α-thalassaemia mutations. Duplex-PCR was used to confirm Hb Paksé and HbCS. Results showed 84.6% of the Hb Adana patients were Malays. Using DNA studies, compound heterozygosity for Hb Adana and HbCS (αcodon 59α/αCSα) was confirmed in 11 patients. A novel point in this investigation was that DNA studies confirmed Hb Paksé for the first time in a Malaysian patient (αcodon 59α/αPakséα) after nine years of being misdiagnosis with Hb Adana and HbCS (αcodon 59α/αCSα). Thus, the reliance on haematology studies and Hb subtyping to detect Hb variants is inadequate in countries where thalassaemia is prevalent and caused by a wide spectrum of mutations. PMID:27271331

  17. A Comparison Study for DNA Motif Modeling on Protein Binding Microarray.

    PubMed

    Wong, Ka-Chun; Li, Yue; Peng, Chengbin; Wong, Hau-San

    2016-01-01

    Transcription factor binding sites (TFBSs) are relatively short (5-15 bp) and degenerate. Identifying them is a computationally challenging task. In particular, protein binding microarray (PBM) is a high-throughput platform that can measure the DNA binding preference of a protein in a comprehensive and unbiased manner; for instance, a typical PBM experiment can measure binding signal intensities of a protein to all possible DNA k-mers (k = 8∼10). Since proteins can often bind to DNA with different binding intensities, one of the major challenges is to build TFBS (also known as DNA motif) models which can fully capture the quantitative binding affinity data. To learn DNA motif models from the non-convex objective function landscape, several optimization methods are compared and applied to the PBM motif model building problem. In particular, representative methods from different optimization paradigms have been chosen for modeling performance comparison on hundreds of PBM datasets. The results suggest that the multimodal optimization methods are very effective for capturing the binding preference information from PBM data. In particular, we observe a general performance improvement if choosing di-nucleotide modeling over mono-nucleotide modeling. In addition, the models learned by the best-performing method are applied to two independent applications: PBM probe rotation testing and ChIP-Seq peak sequence prediction, demonstrating its biological applicability.

  18. A case study of in silico modelling of ciprofloxacin hydrochloride/metallic compound interactions.

    PubMed

    Stojkovic, Aleksandra; Parojcic, Jelena; Djuric, Zorica; Corrigan, Owen I

    2014-04-01

    With the development of physiologically based absorption models, there is an increased scientific and regulatory interest in in silico modelling and simulation of drug-drug and drug-food interactions. Clinically significant interactions between ciprofloxacin and metallic compounds are widely documented. In the current study, a previously developed ciprofloxacin-specific in silico absorption model was employed in order to simulate ciprofloxacin/metallic compound interaction observed in vivo. Commercially available software GastroPlus™ (Simulations Plus Inc., USA) based on the ACAT model was used for gastrointestinal (GI) simulations. The required input parameters, relating to ciprofloxacin hydrochloride physicochemical and pharmacokinetic characteristics, were experimentally determined, taken from the literature or estimated by GastroPlus™. Parameter sensitivity analysis (PSA) was used to assess the importance of selected input parameters (solubility, permeability, stomach and small intestine transit time) in predicting percent drug absorbed. PSA identified solubility and permeability as critical parameters affecting the rate and extent of ciprofloxacin absorption. Using the selected input parameters, it was possible to generate a ciprofloxacin absorption model, without/with metal cation containing preparations co-administration, which matched well the in vivo data available. It was found that reduced ciprofloxacin absorption in the presence of aluminium hydroxide, calcium carbonate or multivitamins/zinc was accounted for by reduced drug solubility. The impact of solubility-permeability interplay on ciprofloxacin absorption can be observed in the ciprofloxacin-aluminium interaction, while in ciprofloxacin-calcium and ciprofloxacin-zinc interactions, effect of solubility was more pronounced. The results obtained indicate that in silico model developed can be successfully used to complement relevant in vitro studies in the simulation of physicochemical

  19. QSAR modeling and molecular interaction analysis of natural compounds as potent neuraminidase inhibitors.

    PubMed

    Sun, Jiaying; Mei, Hu

    2016-04-26

    Different QSAR models of 40 natural compounds as neuraminidase inhibitors (NIs) are developed to comprehend chemical-biological interactions and predict activities against neuraminidase (NA) from Clostridium perfringens. Based on the constitutional, topological and conformational descriptors, R(2) and Q(2) values of the obtained SRA model are 0.931 and 0.856. The R(2) and Q(2) values of the constructed HQSAR and almond models are 0.903 and 0.767, 0.904 and 0.511, respectively. Based on the pharmacophore alignment, R(2) and Q(2) values of the optimal CoMSIA model are 0.936 and 0.654. Moreover, Rtest(2) and Qext(2) of values of SRA, HQSAR, almond and CoMSIA models are 0.611 and 0.565, 0.753 and 0.750, 0.612 and 0.582, 0.582 and 0.571, respectively. So, QSAR models have good predictive capability. They can be further used to evaluate and screen new compounds. Moreover, hydrogen bonds and electrostatic factors have high contributions to activities. To understand molecular interactions between natural compounds and NA from Clostridium perfringens, molecular docking is investigated. The docking results elucidate that Arg266, Asp291, Asp328, Tyr485, Glu493, Arg555, Arg615 and Tyr655 are especially the key residues in the active site of 2bf6. Hydrogen bonds and electrostatics are key factors, which impact the interactions between NIs and NA. So, the influential factors of interactions between NIs and NA in the docking results are in agreement with the QSAR results. PMID:27008437

  20. Aquatic Pathways Model to predict the fate of phenolic compounds. Appendixes A through D

    SciTech Connect

    Aaberg, R.L.; Peloquin, R.A.; Strenge, D.L.; Mellinger, P.L.

    1983-04-01

    Organic materials released from energy-related activities could affect human health and the environment. We have developed a model to predict the fate of spills or discharges of pollutants into flowing or static bodies of fresh water. A computer code, Aquatic Pathways Model (APM), was written to implement the model. The APM estimates the concentrations of chemicals in fish tissue, water and sediment, and is therefore useful for assessing exposure to humans through aquatic pathways. The major pathways considered are biodegradation, fish and sediment uptake, photolysis, and evaporation. The model has been implemented with parameters for the distribution of phenols, an important class of compounds found in the water-soluble fractions of coal liquids. The model was developed to estimate the fate of liquids derived from coal. Current modeling efforts show that, in comparison with many pesticides and polyaromatic hydrocarbons (PAH), the lighter phenolics (the cresols) are not persistent in the environment. For the twelve phenolics studied, biodegradation appears to be the major pathway for elimination from aquatic environments. A pond system simulation of a spill of solvent-refined coal (SRC-II) materials indicates that phenol, cresols, and other single cyclic phenolics are degraded to 16 to 25 percent of their original concentrations within 30 hours. Adsorption of these compounds into sediments and accumulation by fish was minor. Results of a simulated spill of a coal liquid (SRC-II) into a pond show that APM predicted the allocation of 12 phenolic components among six compartments at 30 hours after a small spill. The simulation indicated that most of the introduced phenolic compounds were biodegraded. The phenolics remaining in the aquatic system partitioned according to their molecular weight and structure. A substantial amount was predicted to remain in the water, with less than 0.01% distributed in sediment or fish.

  1. Organic compounds present in airborne particles stimulate superoxide production and DNA fragmentation: role of NOX and xanthine oxidase in animal tissues.

    PubMed

    Busso, Iván Tavera; Silva, Guillermo Benjamín; Carreras, Hebe Alejandra

    2016-08-01

    Suspended particulate matter trigger the production of reactive oxygen species. However, most of the studies dealing with oxidative damage of airborne particles focus on the effects of individual compounds and not real mixtures. In order to study the enzymatic superoxide production resulting from the exposition to a complex mixture, we derived organic extracts from airborne particles collected daily in an urban area and exposed kidney, liver, and heart mammal tissues. After that, we measured DNA damage employing the comet assay. We observed that in every tissue, NADPH oxidase and xanthine oxidase were involved in O2 (-) production when they were exposed to the organic extracts, as the lucigenin's chemiluminescence decays when enzymes were inhibited. The same trend was observed with the percentage of cells with comets, since DNA damage was higher when they were exposed to same experimental conditions. Our data allow us to hypothesize that these enzymes play an important role in the oxidative stress produced by PAHs and that there is a mechanism involving them in the O2 (-)generation. PMID:27180836

  2. Organic compounds present in airborne particles stimulate superoxide production and DNA fragmentation: role of NOX and xanthine oxidase in animal tissues.

    PubMed

    Busso, Iván Tavera; Silva, Guillermo Benjamín; Carreras, Hebe Alejandra

    2016-08-01

    Suspended particulate matter trigger the production of reactive oxygen species. However, most of the studies dealing with oxidative damage of airborne particles focus on the effects of individual compounds and not real mixtures. In order to study the enzymatic superoxide production resulting from the exposition to a complex mixture, we derived organic extracts from airborne particles collected daily in an urban area and exposed kidney, liver, and heart mammal tissues. After that, we measured DNA damage employing the comet assay. We observed that in every tissue, NADPH oxidase and xanthine oxidase were involved in O2 (-) production when they were exposed to the organic extracts, as the lucigenin's chemiluminescence decays when enzymes were inhibited. The same trend was observed with the percentage of cells with comets, since DNA damage was higher when they were exposed to same experimental conditions. Our data allow us to hypothesize that these enzymes play an important role in the oxidative stress produced by PAHs and that there is a mechanism involving them in the O2 (-)generation.

  3. The traditional Chinese medical compound Rocaglamide protects nonmalignant primary cells from DNA damage-induced toxicity by inhibition of p53 expression

    PubMed Central

    Becker, M S; Schmezer, P; Breuer, R; Haas, S F; Essers, M A; Krammer, P H; Li-Weber, M

    2014-01-01

    One of the main obstacles of conventional anticancer therapy is the toxicity of chemotherapeutics to normal tissues. So far, clinical approaches that aim to specifically reduce chemotherapy-mediated toxicities are rare. Recently, a number of studies have demonstrated that herbal extracts derived from traditional Chinese medicine (TCM) may reduce chemotherapy-induced side effects. Thus, we screened a panel of published cancer-inhibiting TCM compounds for their chemoprotective potential and identified the phytochemical Rocaglamide (Roc-A) as a candidate. We show that Roc-A significantly reduces apoptotic cell death induced by DNA-damaging anticancer drugs in primary human and murine cells. Investigation of the molecular mechanism of Roc-A-mediated protection revealed that Roc-A specifically blocks DNA damage-induced upregulation of the transcription factor p53 by inhibiting its protein synthesis. The essential role of p53 in Roc-A-mediated protection was confirmed by siRNA knockdown of p53 and by comparison of the effects of Roc-A on chemoprotection of splenocytes isolated from wild-type and p53-deficient mice. Importantly, Roc-A did not protect p53-deficient or -mutated cancer cells. Our data suggest that Roc-A may be used as an adjuvant to reduce the side effects of chemotherapy in patients with p53-deficient or -mutated tumors. PMID:24434508

  4. Oxidative DNA damage background estimated by a system model of base excision repair

    SciTech Connect

    Sokhansanj, B A; Wilson, III, D M

    2004-05-13

    Human DNA can be damaged by natural metabolism through free radical production. It has been suggested that the equilibrium between innate damage and cellular DNA repair results in an oxidative DNA damage background that potentially contributes to disease and aging. Efforts to quantitatively characterize the human oxidative DNA damage background level based on measuring 8-oxoguanine lesions as a biomarker have led to estimates varying over 3-4 orders of magnitude, depending on the method of measurement. We applied a previously developed and validated quantitative pathway model of human DNA base excision repair, integrating experimentally determined endogenous damage rates and model parameters from multiple sources. Our estimates of at most 100 8-oxoguanine lesions per cell are consistent with the low end of data from biochemical and cell biology experiments, a result robust to model limitations and parameter variation. Our results show the power of quantitative system modeling to interpret composite experimental data and make biologically and physiologically relevant predictions for complex human DNA repair pathway mechanisms and capacity.

  5. DNA Minor Groove Induced Dimerization of Heterocyclic Cations: Compound Structure, Binding Affinity and Specificity for a TTAA Site

    PubMed Central

    Munde, Manoj; Kumar, Arvind; Nhili, Raja; Depauw, Sabine; David-Cordonnier, Marie-Hélène; Ismail, Mohamed A.; Stephens, Chad E.; Farahat, Abdelbasset A.; Batista-Parra, Adalgisa; Boykin, David W.; Wilson, W. David

    2010-01-01

    With the increasing number and variations of genome sequences available control of gene expression with synthetic, cell permeable molecules is within reach. The variety of sequence-specific-binding agents is, however, still quite limited. Many minor groove binding agents selectivity recognize AT over GC sequences but have less ability to distinguish among different AT sequences. The goal with this paper is to develop compounds that can bind selectively to different AT sequences. A number of studies indicate that AATT and TTAA sequences have significantly different physical and interaction properties and different requirements for minor groove recognition. Although it has been difficult to get minor groove binding at TTAA, DB293, a phenyl-furan-benzimidazole-diamidine, was found to bind as a strong, cooperative dimer at TTAA but with no selectivity over AATT. In order to improve selectivity, modifications were made to each unit of DB293. Binding affinities and stoichiometries obtained from biosensor-surface plasmon resonance experiments show that DB1003, a furan-furan-benzimidazole diamidine binds strongly to TTAA as a dimer and has selectivity (KTTAA/KAATT = 6). CD and DNAse I footprinting studies confirmed the preference of this compound for TTAA. In summary (i) a favorable stacking surface provided by the pi system, (ii) H-bond donors to interact with TA base pairs at the floor of the groove provided by a benzimidazole (or indole) –NH and amidines, and (iii) appropriate curvature of the dimer complex to match the curvature of the minor groove play important roles in differentiating the TTAA and AATT minor grooves. PMID:20713062

  6. [Relevance of animal models in the development of compounds targeting multidrug resistant cancer].

    PubMed

    Füredi, András; Tóth, Szilárd; Hámori, Lilla; Nagy, Veronika; Tóvári, József; Szakács, Gergely

    2015-12-01

    Anticancer compounds are typically identified in in vitro screens. Unfortunately, the in vitro drug sensitivity of cell lines does not reflect treatment efficiency in animal models, and neither show acceptable correlation to clinical results. While cell lines and laboratory animals can be readily "cured", the treatment of malignancies remains hampered by the multidrug resistance (MDR) of tumors. Genetically engineered mouse models (GEMMs) giving rise to spontaneous tumors offer a new possibility to characterize the evolution of drug resistance mechanisms and to target multidrug resistant cancer. PMID:26665195

  7. Thermal reaction studies of organic model compound-mineral matter interactions in solids

    SciTech Connect

    Buchanan, A.C. III; Britt, P.F.; Thomas, K.B.

    1995-07-01

    The solid-state chemistry of silica-immobilized phenethyl phenyl ethers is being investigated in the presence of interdispersed aluininosilicates at temperatures relevant to coal processing to gain a better understanding of the impact of mineral matter on pyrolysis and liquefaction mechanisms. Results demonstrate the dramatic effect that aluminosilicates can have in altering the normal thermal reaction pathways for these models of ether linkages in lignin and low rank coals. An investigation of the chemistry of these model compounds at low temperatures (ca. 150-200{degrees}C) in the presence of aluminosilicates, including montmorillonite, is currently being investigated to delineate the chemical transformations that can occur during lignin maturation.

  8. Characterizing DNA Star-Tile-Based Nanostructures Using a Coarse-Grained Model.

    PubMed

    Schreck, John S; Romano, Flavio; Zimmer, Matthew H; Louis, Ard A; Doye, Jonathan P K

    2016-04-26

    We use oxDNA, a coarse-grained model of DNA at the nucleotide level, to simulate large nanoprisms that are composed of multi-arm star tiles, in which the size of bulge loops that have been incorporated into the tile design is used to control the flexibility of the tiles. The oxDNA model predicts equilibrium structures for several different nanoprism designs that are in excellent agreement with the experimental structures as measured by cryoTEM. In particular we reproduce the chiral twisting of the top and bottom faces of the nanoprisms, as the bulge sizes in these structures are varied due to the greater flexibility of larger bulges. We are also able to follow how the properties of the star tiles evolve as the prisms are assembled. Individual star tiles are very flexible, but their structures become increasingly well-defined and rigid as they are incorporated into larger assemblies. oxDNA also finds that the experimentally observed prisms are more stable than their inverted counterparts, but interestingly this preference for the arms of the tiles to bend in a given direction only emerges after they are part of larger assemblies. These results show the potential for oxDNA to provide detailed structural insight as well as to predict the properties of DNA nanostructures and hence to aid rational design in DNA nanotechnology. PMID:27010928

  9. Characterizing DNA Star-Tile-Based Nanostructures Using a Coarse-Grained Model.

    PubMed

    Schreck, John S; Romano, Flavio; Zimmer, Matthew H; Louis, Ard A; Doye, Jonathan P K

    2016-04-26

    We use oxDNA, a coarse-grained model of DNA at the nucleotide level, to simulate large nanoprisms that are composed of multi-arm star tiles, in which the size of bulge loops that have been incorporated into the tile design is used to control the flexibility of the tiles. The oxDNA model predicts equilibrium structures for several different nanoprism designs that are in excellent agreement with the experimental structures as measured by cryoTEM. In particular we reproduce the chiral twisting of the top and bottom faces of the nanoprisms, as the bulge sizes in these structures are varied due to the greater flexibility of larger bulges. We are also able to follow how the properties of the star tiles evolve as the prisms are assembled. Individual star tiles are very flexible, but their structures become increasingly well-defined and rigid as they are incorporated into larger assemblies. oxDNA also finds that the experimentally observed prisms are more stable than their inverted counterparts, but interestingly this preference for the arms of the tiles to bend in a given direction only emerges after they are part of larger assemblies. These results show the potential for oxDNA to provide detailed structural insight as well as to predict the properties of DNA nanostructures and hence to aid rational design in DNA nanotechnology.

  10. In vitro determination of carcinogenicity of sixty-four compounds using a bovine papillomavirus DNA-carrying C3H/10T(1/2) cell line.

    PubMed

    Kowalski, L A; Laitinen, A M; Mortazavi-Asl, B; Wee, R K; Erb, H E; Assi, K P; Madden, Z

    2000-01-01

    A new in vitro test for predicting rodent carcinogenicity is evaluated against a testing database of 64 chemicals including both genotoxic and nongenotoxic carcinogens and carcinogens that normally require addition of an S-9 microsomal fraction for detection in the bacterial mutagenicity assay. The assay uses focus formation in a stable, bovine papillomavirus type 1 (BPV-1) DNA carrying C3H/10T(1/2) mouse embryo fibroblast cell line (T1) that does not require transfection, infection with virus, isolation of primary cells from animals, or addition of a microsomal fraction. Of a total database of 64 compounds, 92% of the carcinogens, promoters, or noncarcinogens were correctly predicted. Based on previously reported results, the test of bacterial mutagenicity would have correctly predicted 58% of carcinogens, promoters or noncarcinogens and the Syrian hamster embryo test would have correctly predicted 87% of carcinogens, promoters, or noncarcinogens of this database. Of carcinogens that normally require addition of an S-9 fraction, T1 cells correctly predicted rodent carcinogenicity of polyaromatic hydrocarbons, aflatoxins, azo-compounds, nitrosamines, and hydrazine without the addition of an S-9 fraction. Of nongenotoxic carcinogens, T1 cells correctly predicted diethylstilbestroel, diethylhexylphthalate, acetamides, alkyl halides, ethyl carbamate, and phorbol ester tumour promoters.

  11. Multifunctional receptor model for dioxin and related compound toxic action: possible thyroid hormone-responsive effector-linked site.

    PubMed Central

    McKinney, J D

    1989-01-01

    Molecular/theoretical modeling studies have revealed that thyroid hormones and toxic chlorinated aromatic hydrocarbons of environmental significance (for which dioxin or TCDD is the prototype) have similar structural properties that could be important in molecular recognition in biochemical systems. These molecular properties include a somewhat rigid, sterically accessible and polarizable aromatic ring and size-limited, hydrophobic lateral substituents, usually contained in opposite adjoining rings of a diphenyl compound. These molecular properties define the primary binding groups thought to be important in molecular recognition of both types of structures in biochemical systems. Similar molecular reactivities are supported by the demonstration of effective specific binding of thyroid hormones and chlorinated aromatic hydrocarbons with four different proteins, enzymes, or receptor preparations that are known or suspected to be involved in the expression of thyroid hormone activity. These binding interactions represent both aromatic-aromatic (stacking) and molecular cleft-type recognition processes. A multiple protein or multifunctional receptor-ligand binding mechanism model is proposed as a way of visualizing the details and possible role of both the stacking and cleft type molecular recognition factors in the expression of biological activity. The model suggests a means by which hormone-responsive effector-linked sites (possible protein-protein-DNA complexes) can maintain highly structurally specific control of hormone action. Finally, the model also provides a theoretical basis for the design and conduct of further biological experimentation on the molecular mechanism(s) of action of toxic chlorinated aromatic hydrocarbons and thyroid hormones. Images FIGURE 3. A FIGURE 3. B FIGURE 3. C FIGURE 3. D PMID:2551666

  12. Computational Model for DNA Organization Mediated by Protein Interaction in Prokaryotes

    NASA Astrophysics Data System (ADS)

    Garimella, Karthik; Kharel, Savan

    2016-03-01

    In Escherichia Coli, there are several mechanisms that drive chromosomal organization. We know through experiments that the E. Coli chromosome is condensed into highly structured regions known as macrodomains (MDs). One of the regions known as the Terminus undergoes DNA-bridging condensation that form loops between distant DNA sites and it is known to be mediated by a Terminus specific protein, which binds to specific markers within the Terminus region. In the absence of Terminus specific protein, however, the Terminus region is known to not condense nearly as much, which will likely impede several biological processes including DNA replication. In order to understand the molecular basis of protein mediation in vivo several models of Terminus specific segregation have been constructed in silico which model DNA as polymer chains.

  13. Binding properties of palmatine to DNA: spectroscopic and molecular modeling investigations.

    PubMed

    Mi, Ran; Tu, Bao; Bai, Xiao-Ting; Chen, Jun; Ouyang, Yu; Hu, Yan-Jun

    2015-12-01

    Palmatine, an isoquinoline alkaloid, is an important medicinal herbal extract with diverse pharmacological and biological properties. In this work, spectroscopic and molecular modeling approaches were employed to reveal the interaction between palmatine and DNA isolated from herring sperm. The absorption spectra and iodide quenching results indicated that groove binding was the main binding mode of palmatine to DNA. Fluorescence studies indicated that the binding constant (K) of palmatine and DNA was ~ 10(4)L·mol(-1). The associated thermodynamic parameters, ΔG, ΔH, and ΔS, indicated that hydrogen bonds and van der Waals forces played major roles in the interaction. The effects of chemical denaturant, thermal denaturation and pH on the interaction were investigated and provided further support for the groove binding mode. In addition to experimental approaches, molecular modeling was conducted to verify binding pattern of palmatine-DNA.

  14. DNA Nanostructures as Models for Evaluating the Role of Enthalpy and Entropy in Polyvalent Binding

    SciTech Connect

    Nangreave, Jeanette; Yan, Hao; Liu, Yan

    2011-03-30

    DNA nanotechnology allows the design and construction of nanoscale objects that have finely tuned dimensions, orientation, and structure with remarkable ease and convenience. Synthetic DNA nanostructures can be precisely engineered to model a variety of molecules and systems, providing the opportunity to probe very subtle biophysical phenomena. In this study, several such synthetic DNA nanostructures were designed to serve as models to study the binding behavior of polyvalent molecules and gain insight into how small changes to the ligand/receptor scaffolds, intended to vary their conformational flexibility, will affect their association equilibrium. This approach has yielded a quantitative identification of the roles of enthalpy and entropy in the affinity of polyvalent DNA nanostructure interactions, which exhibit an intriguing compensating effect.

  15. Investigation on the interaction of letrozole with herring sperm DNA through spectroscopic and modeling methods.

    PubMed

    Huang, Yan-Mei; Zheng, Shou-Jun; Yan, Jin; Yang, Hong-Qin; Wu, Di; Wang, Qing; Li, Hui

    2016-08-01

    The interaction of letrozole, an efficient and safe aromatase inhibitor, with herring sperm DNA (hsDNA) was investigated in vitro through spectroscopy analysis and molecular modeling to elucidate the binding mechanism of anticancer drugs and DNA. The binding constant and the number of binding sites were 2.13 × 10(4)  M(-1) and 1.09, respectively, at 298 K. Thermodynamic parameters (ΔG, ΔH and ΔS) exhibited negative values, which indicated that binding was spontaneous and Van der Waals forces and hydrogen bond were the main interaction forces. Fourier transform infrared spectroscopy and other spectroscopy analysis methods illustrated that letrozole could intercalate into the phosphate backbone of hsDNA and interact with the nitrogenous bases. Consistent with the experimental findings, molecular modeling results demonstrated that the interaction was dominated by intercalation and hydrogen bonding. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26669513

  16. A breathing wormlike chain model on DNA denaturation and bubble: effects of stacking interactions.

    PubMed

    Kim, Jae-Yeol; Jeon, Jae-Hyung; Sung, Wokyung

    2008-02-01

    DNA stably exists as a double-stranded structure due to hydrogen-bonding and stacking interactions between bases. The stacking interactions are strengthened when DNA is paired, which results in great enhancement of bending rigidity. We study the effects of this stacking-induced stiffness difference on DNA denaturation and bubble formations. To this end, we model double-stranded DNA as a duplex of two semiflexible chains whose persistence length varies depending on the base-pair distance. Using this model, we perform the Langevin dynamics simulation to examine the characteristics of the denaturation transition and the statistics of the bubbles. We find that the inclusion of the stacking interactions causes the denaturation transition to be much sharper than otherwise. At physiological temperature, the stacking interactions prohibit the initiation of bubble formation but promote bubbles, once grown, to retain the large size. PMID:18266461

  17. Modeling spin selectivity in charge transfer across the DNA/Gold interface

    NASA Astrophysics Data System (ADS)

    Behnia, S.; Fathizadeh, S.; Akhshani, A.

    2016-09-01

    Experimental results show that the photoelectrons emitted from the gold substrate due to laser radiation, passe through DNA nanowires with spin-polarized nature. This study proposes the use of chiral DNA molecule in spintronics and information processing. To investigate the spin transfer in DNA molecules, we established a theoretical model based on a combined spin-polaronic Peyrard-Bishop-Holstein model. Accordingly, a nearly pure spin current is appeared. The simultaneous effects of the incident radiation and external magnetic field create characteristic islands corresponding to the pure spin currents, which can be predicted and detected using the multifractal dimensions spectrum. We can verify the spin Hall effect on DNA oligomers through spin-orbit coupling. As such, we can proceed to our significant purpose, which is to create a nearly pure spin current for information transfer and determine the regions of parameter values from which the maximal polarization in spin current emerges.

  18. Investigation on the interaction of letrozole with herring sperm DNA through spectroscopic and modeling methods.

    PubMed

    Huang, Yan-Mei; Zheng, Shou-Jun; Yan, Jin; Yang, Hong-Qin; Wu, Di; Wang, Qing; Li, Hui

    2016-08-01

    The interaction of letrozole, an efficient and safe aromatase inhibitor, with herring sperm DNA (hsDNA) was investigated in vitro through spectroscopy analysis and molecular modeling to elucidate the binding mechanism of anticancer drugs and DNA. The binding constant and the number of binding sites were 2.13 × 10(4)  M(-1) and 1.09, respectively, at 298 K. Thermodynamic parameters (ΔG, ΔH and ΔS) exhibited negative values, which indicated that binding was spontaneous and Van der Waals forces and hydrogen bond were the main interaction forces. Fourier transform infrared spectroscopy and other spectroscopy analysis methods illustrated that letrozole could intercalate into the phosphate backbone of hsDNA and interact with the nitrogenous bases. Consistent with the experimental findings, molecular modeling results demonstrated that the interaction was dominated by intercalation and hydrogen bonding. Copyright © 2015 John Wiley & Sons, Ltd.

  19. DNA analysis servers: plot.it, bend.it, model.it and IS.

    PubMed

    Vlahovicek, Kristian; Kaján, László; Pongor, Sándor

    2003-07-01

    The WWW servers at http://www.icgeb.trieste.it/dna/ are dedicated to the analysis of user-submitted DNA sequences; plot.it creates parametric plots of 45 physicochemical, as well as statistical, parameters; bend.it calculates DNA curvature according to various methods. Both programs provide 1D as well as 2D plots that allow localisation of peculiar segments within the query. The server model.it creates 3D models of canonical or bent DNA starting from sequence data and presents the results in the form of a standard PDB file, directly viewable on the user's PC using any molecule manipulation program. The recently established introns server allows statistical evaluation of introns in various taxonomic groups and the comparison of taxonomic groups in terms of length, base composition, intron type etc. The options include the analysis of splice sites and a probability test for exon-shuffling. PMID:12824394

  20. Toxic volatile organic compounds in environmental tobacco smoke: Emission factors for modeling exposures of California populations

    SciTech Connect

    Daisey, J.M.; Mahanama, K.R.R.; Hodgson, A.T.

    1994-10-01

    The primary objective of this study was to measure emission factors for selected toxic air contaminants in environmental tobacco smoke (ETS) using a room-sized environmental chamber. The emissions of 23 volatile organic compounds (VOCs), including, 1,3-butadiene, three aldehydes and two vapor-phase N-nitrosamines were determined for six commercial brands of cigarettes and reference cigarette 1R4F. The commercial brands were selected to represent 62.5% of the cigarettes smoked in California. For each brand, three cigarettes were machine smoked in the chamber. The experiments were conducted over four hours to investigate the effects of aging. Emission factors of the target compounds were also determined for sidestream smoke (SS). For almost all target compounds, the ETS emission factors were significantly higher than the corresponding SS values probably due to less favorable combustion conditions and wall losses in the SS apparatus. Where valid comparisons could be made, the ETS emission factors were generally in good agreement with the literature. Therefore, the ETS emission factors, rather than the SS values, are recommended for use in models to estimate population exposures from this source. The variabilities in the emission factors ({mu}g/cigarette) of the selected toxic air contaminants among brands, expressed as coefficients of variation, were 16 to 29%. Therefore, emissions among brands were Generally similar. Differences among brands were related to the smoked lengths of the cigarettes and the masses of consumed tobacco. Mentholation and whether a cigarette was classified as light or regular did not significantly affect emissions. Aging was determined not to be a significant factor for the target compounds. There were, however, deposition losses of the less volatile compounds to chamber surfaces.

  1. Linear and nonlinear methods in modeling the aqueous solubility of organic compounds.

    PubMed

    Catana, Cornel; Gao, Hua; Orrenius, Christian; Stouten, Pieter F W

    2005-01-01

    Solubility data for 930 diverse compounds have been analyzed using linear Partial Least Square (PLS) and nonlinear PLS methods, Continuum Regression (CR), and Neural Networks (NN). 1D and 2D descriptors from MOE package in combination with E-state or ISIS keys have been used. The best model was obtained using linear PLS for a combination between 22 MOE descriptors and 65 ISIS keys. It has a correlation coefficient (r2) of 0.935 and a root-mean-square error (RMSE) of 0.468 log molar solubility (log S(w)). The model validated on a test set of 177 compounds not included in the training set has r2 0.911 and RMSE 0.475 log S(w). The descriptors were ranked according to their importance, and at the top of the list have been found the 22 MOE descriptors. The CR model produced results as good as PLS, and because of the way in which cross-validation has been done it is expected to be a valuable tool in prediction besides PLS model. The statistics obtained using nonlinear methods did not surpass those got with linear ones. The good statistic obtained for linear PLS and CR recommends these models to be used in prediction when it is difficult or impossible to make experimental measurements, for virtual screening, combinatorial library design, and efficient leads optimization.

  2. A potential impact of DNA repair on ageing and lifespan in the ageing model organism Podospora anserina: decrease in mitochondrial DNA repair activity during ageing.

    PubMed

    Soerensen, Mette; Gredilla, Ricardo; Müller-Ohldach, Mathis; Werner, Alexandra; Bohr, Vilhelm A; Osiewacz, Heinz D; Stevnsner, Tinna

    2009-08-01

    The free radical theory of ageing states that ROS play a key role in age-related decrease in mitochondrial function via the damage of mitochondrial DNA (mtDNA), proteins and lipids. In the sexually reproducing ascomycete Podospora anserina ageing is, as in other eukaryotes, associated with mtDNA instability and mitochondrial dysfunction. Part of the mtDNA instabilities may arise due to accumulation of ROS induced mtDNA lesions, which, as previously suggested for mammals, may be caused by an age-related decrease in base excision repair (BER). Alignments of known BER protein sequences with the P. anserina genome revealed high homology. We report for the first time the presence of BER activities in P. anserina mitochondrial extracts. DNA glycosylase activities decrease with age, suggesting that the increased mtDNA instability with age may be caused by decreased ability to repair mtDNA damage and hence contribute to ageing and lifespan control in this ageing model. Additionally, we find low DNA glycosylase activities in the long-lived mutants grisea and DeltaPaCox17::ble, which are characterized by low mitochondrial ROS generation. Overall, our data identify a potential role of mtDNA repair in controlling ageing and life span in P. anserina, a mechanism possibly regulated in response to ROS levels.

  3. A functional [NiFe]-hydrogenase model compound that undergoes biologically relevant reversible thiolate protonation.

    PubMed

    Weber, Katharina; Krämer, Tobias; Shafaat, Hannah S; Weyhermüller, Thomas; Bill, Eckhard; van Gastel, Maurice; Neese, Frank; Lubitz, Wolfgang

    2012-12-26

    Two model compounds of the active site of [NiFe]-hydrogenases with an unusual {S(2)Ni(μ-S)(μ-CO)Fe(CO)(2)S}-coordination environment around the metals are reported. The neutral compound [Ni(xbsms)(μ-CO)(μ-S)Fe(CO)(2)('S')], (1) (H(2)xbsms = 1,2-bis(4-mercapto-3,3-dimethyl-2-thiabutyl)benzene) is converted to [1H][BF(4)] by reversible protonation using HBF(4)·Et(2)O. The protonation takes place at the terminal thiolate sulfur atom that is coordinated to nickel. Catalytic intermediates with a protonated terminal cysteinate were suggested for the native protein but have not yet been confirmed experimentally. [1H][BF(4)] is the first dinuclear [NiFe] model compound for such a species. Both complexes have been synthesized and characterized by X-ray crystallography, NMR-, FTIR-, and (57)Fe-Mössbauer spectroscopy as well as by electronic absorption and resonance Raman spectroscopy. The experimental results clearly show that the protonation has a significant impact on the electronic structure of the iron center, although it takes place at the nickel site. DFT calculations support the interpretation of the spectroscopic data and indicate the presence of a bonding interaction between the metal ions, which is relevant for the enzyme as well. Electrochemical experiments show that both 1 and [1H][BF(4)] are active for electrocatalytic proton reduction in aprotic solvents.

  4. A functional [NiFe]-hydrogenase model compound that undergoes biologically relevant reversible thiolate protonation.

    PubMed

    Weber, Katharina; Krämer, Tobias; Shafaat, Hannah S; Weyhermüller, Thomas; Bill, Eckhard; van Gastel, Maurice; Neese, Frank; Lubitz, Wolfgang

    2012-12-26

    Two model compounds of the active site of [NiFe]-hydrogenases with an unusual {S(2)Ni(μ-S)(μ-CO)Fe(CO)(2)S}-coordination environment around the metals are reported. The neutral compound [Ni(xbsms)(μ-CO)(μ-S)Fe(CO)(2)('S')], (1) (H(2)xbsms = 1,2-bis(4-mercapto-3,3-dimethyl-2-thiabutyl)benzene) is converted to [1H][BF(4)] by reversible protonation using HBF(4)·Et(2)O. The protonation takes place at the terminal thiolate sulfur atom that is coordinated to nickel. Catalytic intermediates with a protonated terminal cysteinate were suggested for the native protein but have not yet been confirmed experimentally. [1H][BF(4)] is the first dinuclear [NiFe] model compound for such a species. Both complexes have been synthesized and characterized by X-ray crystallography, NMR-, FTIR-, and (57)Fe-Mössbauer spectroscopy as well as by electronic absorption and resonance Raman spectroscopy. The experimental results clearly show that the protonation has a significant impact on the electronic structure of the iron center, although it takes place at the nickel site. DFT calculations support the interpretation of the spectroscopic data and indicate the presence of a bonding interaction between the metal ions, which is relevant for the enzyme as well. Electrochemical experiments show that both 1 and [1H][BF(4)] are active for electrocatalytic proton reduction in aprotic solvents. PMID:23194246

  5. Etiology matters – Genomic DNA Methylation Patterns in Three Rat Models of Acquired Epilepsy

    PubMed Central

    Dębski, Konrad J.; Pitkanen, Asla; Puhakka, Noora; Bot, Anna M.; Khurana, Ishant; Harikrishnan, KN; Ziemann, Mark; Kaspi, Antony; El-Osta, Assam; Lukasiuk, Katarzyna; Kobow, Katja

    2016-01-01

    This study tested the hypothesis that acquired epileptogenesis is accompanied by DNA methylation changes independent of etiology. We investigated DNA methylation and gene expression in the hippocampal CA3/dentate gyrus fields at 3 months following epileptogenic injury in three experimental models of epilepsy: focal amygdala stimulation, systemic pilocarpine injection, or lateral fluid-percussion induced traumatic brain injury (TBI) in rats. In the models studies, DNA methylation and gene expression profiles distinguished controls from injured animals. We observed consistent increased methylation in gene bodies and hypomethylation at non-genic regions. We did not find a common methylation signature in all three different models and few regions common to any two models. Our data provide evidence that genome-wide alteration of DNA methylation signatures is a general pathomechanism associated with epileptogenesis and epilepsy in experimental animal models, but the broad pathophysiological differences between models (i.e. pilocarpine, amygdala stimulation, and post-TBI) are reflected in distinct etiology-dependent DNA methylation patterns. PMID:27157830

  6. A method for mutagenesis of mouse mtDNA and a resource of mouse mtDNA mutations for modeling human pathological conditions

    PubMed Central

    Fayzulin, Rafik Z.; Perez, Michael; Kozhukhar, Natalia; Spadafora, Domenico; Wilson, Glenn L.; Alexeyev, Mikhail F.

    2015-01-01

    Mutations in human mitochondrial DNA (mtDNA) can cause mitochondrial disease and have been associated with neurodegenerative disorders, cancer, diabetes and aging. Yet our progress toward delineating the precise contributions of mtDNA mutations to these conditions is impeded by the limited availability of faithful transmitochondrial animal models. Here, we report a method for the isolation of mutations in mouse mtDNA and its implementation for the generation of a collection of over 150 cell lines suitable for the production of transmitochondrial mice. This method is based on the limited mutagenesis of mtDNA by proofreading-deficient DNA-polymerase γ followed by segregation of the resulting highly heteroplasmic mtDNA population by means of intracellular cloning. Among generated cell lines, we identify nine which carry mutations affecting the same amino acid or nucleotide positions as in human disease, including a mutation in the ND4 gene responsible for 70% of Leber Hereditary Optic Neuropathies (LHON). Similar to their human counterparts, cybrids carrying the homoplasmic mouse LHON mutation demonstrated reduced respiration, reduced ATP content and elevated production of mitochondrial reactive oxygen species (ROS). The generated resource of mouse mtDNA mutants will be useful both in modeling human mitochondrial disease and in understanding the mechanisms of ROS production mediated by mutations in mtDNA. PMID:25820427

  7. Molecular modelling studies, synthesis and biological activity of a series of novel bisnaphthalimides and their development as new DNA topoisomerase II inhibitors.

    PubMed

    Filosa, Rosanna; Peduto, Antonella; Micco, Simone Di; Caprariis, Paolo de; Festa, Michela; Petrella, Antonello; Capranico, Giovanni; Bifulco, Giuseppe

    2009-01-01

    A series of bisnaphthalimide derivatives were synthesized and evaluated for growth-inhibitory property against HT-29 human colon carcinoma. The N,N'-bis[2-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benz[de]-isoquinolin-2-yl)]propane-2-ethanediamine (9) and the N,N'-Bis[2-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benz[de]-isoquinolin-2-yl)]butylaminoethyl]-2-propanediamine (12) derivatives emerged as the most potent compounds of this series. Molecular modelling studies indicated that the high potency of 12, the most cytotoxic compound of the whole series, could be due to larger number of intermolecular interactions and to the best position of the naphthalimido rings, which favours pi-pi stacking interactions with purine and pyrimidine bases in the DNA active site. Moreover, 12 was designed as a DNA topoisomerase II poison and biochemical studies showed its effect on human DNA topoisomerase II. We then selected the compounds with a significant cytotoxicity for apoptosis assay. Derivative 9 was able to induce significantly apoptosis (40%) at 0.1 microM concentration, and we demonstrated that the effect on apoptosis in HT-29 cells is mediated by caspases activation.

  8. Vanadium K-edge XANES in vanadium-bearing model compounds: a full multiple scattering study.

    PubMed

    Benzi, Federico; Giuli, Gabriele; Della Longa, Stefano; Paris, Eleonora

    2016-07-01

    A systematic study is presented on a set of vanadium-bearing model compounds, representative of the most common V coordination geometries and oxidation states, analysed by means of vanadium K-edge X-ray absorption near-edge spectroscopy calculations in the full multiple scattering (FMS) framework. Analysis and calibration of the free parameters of the theory under the muffin-tin approximation (muffin-tin overlap and interstitial potential) have been carried out by fitting the experimental spectra using the MXAN program. The analysis shows a correlation of the fit parameters with the V coordination geometry and oxidation state. By making use of this correlation it is possible to approach the study of unknown V-bearing compounds with useful preliminary information. PMID:27359143

  9. Spatial Arrangment of Organic Compounds on a Model Mineral Surface: Implications for Soil Organic Matter Stabilization

    SciTech Connect

    Petridis, Loukas; Ambaye, Haile Arena; Jagadamma, Sindhu; Kilbey, S. Michael; Lokitz, Bradley S; Lauter, Valeria; Mayes, Melanie

    2014-01-01

    The complexity of the mineral organic carbon interface may influence the extent of stabilization of organic carbon compounds in soils, which is important for global climate futures. The nanoscale structure of a model interface was examined here by depositing films of organic carbon compounds of contrasting chemical character, hydrophilic glucose and amphiphilic stearic acid, onto a soil mineral analogue (Al2O3). Neutron reflectometry, a technique which provides depth-sensitive insight into the organization of the thin films, indicates that glucose molecules reside in a layer between Al2O3 and stearic acid, a result that was verified by water contact angle measurements. Molecular dynamics simulations reveal the thermodynamic driving force behind glucose partitioning on the mineral interface: The entropic penalty of confining the less mobile glucose on the mineral surface is lower than for stearic acid. The fundamental information obtained here helps rationalize how complex arrangements of organic carbon on soil mineral surfaces may arise

  10. 1,4-Dihydropyridine Derivatives: Dihydronicotinamide Analogues—Model Compounds Targeting Oxidative Stress

    PubMed Central

    Velena, Astrida; Zarkovic, Neven; Gall Troselj, Koraljka; Bisenieks, Egils; Krauze, Aivars; Poikans, Janis; Duburs, Gunars

    2016-01-01

    Many 1,4-dihydropyridines (DHPs) possess redox properties. In this review DHPs are surveyed as protectors against oxidative stress (OS) and related disorders, considering the DHPs as specific group of potential antioxidants with bioprotective capacities. They have several peculiarities related to antioxidant activity (AOA). Several commercially available calcium antagonist, 1,4-DHP drugs, their metabolites, and calcium agonists were shown to express AOA. Synthesis, hydrogen donor properties, AOA, and methods and approaches used to reveal biological activities of various groups of 1,4-DHPs are presented. Examples of DHPs antioxidant activities and protective effects of DHPs against OS induced damage in low density lipoproteins (LDL), mitochondria, microsomes, isolated cells, and cell cultures are highlighted. Comparison of the AOA of different DHPs and other antioxidants is also given. According to the data presented, the DHPs might be considered as bellwether among synthetic compounds targeting OS and potential pharmacological model compounds targeting oxidative stress important for medicinal chemistry. PMID:26881016

  11. A physiologically based biodynamic (PBBD) model for estragole DNA binding in rat liver based on in vitro kinetic data and estragole DNA adduct formation in primary hepatocytes

    SciTech Connect

    Paini, Alicia; Punt, Ans; Viton, Florian; Scholz, Gabriele; Delatour, Thierry; Marin-Kuan, Maricel; Schilter, Benoit; Bladeren, Peter J. van; Rietjens, Ivonne M.C.M.

    2010-05-15

    Estragole has been shown to be hepatocarcinogenic in rodent species at high-dose levels. Translation of these results into the likelihood of formation of DNA adducts, mutation, and ultimately cancer upon more realistic low-dose exposures remains a challenge. Recently we have developed physiologically based biokinetic (PBBK) models for rat and human predicting bioactivation of estragole. These PBBK models, however, predict only kinetic characteristics. The present study describes the extension of the PBBK model to a so-called physiologically based biodynamic (PBBD) model predicting in vivo DNA adduct formation of estragole in rat liver. This PBBD model was developed using in vitro data on DNA adduct formation in rat primary hepatocytes exposed to 1'-hydroxyestragole. The model was extended by linking the area under the curve for 1'-hydroxyestragole formation predicted by the PBBK model to the area under the curve for 1'-hydroxyestragole in the in vitro experiments. The outcome of the PBBD model revealed a linear increase in DNA adduct formation with increasing estragole doses up to 100 mg/kg bw. Although DNA adduct formation of genotoxic carcinogens is generally seen as a biomarker of exposure rather than a biomarker of response, the PBBD model now developed is one step closer to the ultimate toxic effect of estragole than the PBBK model described previously. Comparison of the PBBD model outcome to available data showed that the model adequately predicts the dose-dependent level of DNA adduct formation. The PBBD model predicts DNA adduct formation at low levels of exposure up to a dose level showing to cause cancer in rodent bioassays, providing a proof of principle for modeling a toxicodynamic in vivo endpoint on the basis of solely in vitro experimental data.

  12. Understanding Karma Police: The Perceived Plausibility of Noun Compounds as Predicted by Distributional Models of Semantic Representation

    PubMed Central

    Günther, Fritz; Marelli, Marco

    2016-01-01

    Noun compounds, consisting of two nouns (the head and the modifier) that are combined into a single concept, differ in terms of their plausibility: school bus is a more plausible compound than saddle olive. The present study investigates which factors influence the plausibility of attested and novel noun compounds. Distributional Semantic Models (DSMs) are used to obtain formal (vector) representations of word meanings, and compositional methods in DSMs are employed to obtain such representations for noun compounds. From these representations, different plausibility measures are computed. Three of those measures contribute in predicting the plausibility of noun compounds: The relatedness between the meaning of the head noun and the compound (Head Proximity), the relatedness between the meaning of modifier noun and the compound (Modifier Proximity), and the similarity between the head noun and the modifier noun (Constituent Similarity). We find non-linear interactions between Head Proximity and Modifier Proximity, as well as between Modifier Proximity and Constituent Similarity. Furthermore, Constituent Similarity interacts non-linearly with the familiarity with the compound. These results suggest that a compound is perceived as more plausible if it can be categorized as an instance of the category denoted by the head noun, if the contribution of the modifier to the compound meaning is clear but not redundant, and if the constituents are sufficiently similar in cases where this contribution is not clear. Furthermore, compounds are perceived to be more plausible if they are more familiar, but mostly for cases where the relation between the constituents is less clear. PMID:27732599

  13. Food borne bacterial models for detection of benzo[a]pyrene-DNA adducts formation using RAPD-PCR.

    PubMed

    Lanzone, Valentina; Tofalo, Rosanna; Fasoli, Giuseppe; Perpetuini, Giorgia; Suzzi, Giovanna; Sergi, Manuel; Corrado, Federica; Compagnone, Dario

    2016-05-01

    Random amplified polymorphic DNA (RAPD) PCR is a feasible method to evaluate genotoxin-induced DNA damage and mutations. In this study, Lactobacillus plantarum ATCC 14917T, Enterococcus faecium DSMZ 20477T, Escherichia coli PQ37 and Saccharomyces cerevisiae S441 were screened for DNA genetic alterations by DNA fingerprinting using M13 and LA1 primers after treatment with three compounds forming covalent adducts with DNA [benzo[a]pyrenediol epoxide (BPDE), methyl methanesulfonate and 1,2,3,4-diepoxybutane (DEB)]. M13 RAPD fingerprinting revealed that the total number of bands decreased in all treated DNA compared to control samples and generally the lost bands were characterized by high molecular weight. Some extra bands were detected for L. plantarum and E. faecium, while in E. coli and S. cerevisiae DNAs BPDE and DEB treatments did not result in new extra bands. Besides qualitatively analysis, cluster analysis based on Unweighted Pair-Group Method with Average algorithm was performed to compare DNA fingerprints before and after treatments. This analysis confirmed the absence of significant differences between negative controls and treated DNA in S. cerevisiae and E. coli however the disappearance of some bands can be detected. The data indicate that this approach can be used for DNA damage detection and mutations induced by genotoxic compounds and highlighted the possible use of L. plantarum and E. faecium M13 based fingerprinting as reference for hazard identification in risk assessment.

  14. Food borne bacterial models for detection of benzo[a]pyrene-DNA adducts formation using RAPD-PCR.

    PubMed

    Lanzone, Valentina; Tofalo, Rosanna; Fasoli, Giuseppe; Perpetuini, Giorgia; Suzzi, Giovanna; Sergi, Manuel; Corrado, Federica; Compagnone, Dario

    2016-05-01

    Random amplified polymorphic DNA (RAPD) PCR is a feasible method to evaluate genotoxin-induced DNA damage and mutations. In this study, Lactobacillus plantarum ATCC 14917T, Enterococcus faecium DSMZ 20477T, Escherichia coli PQ37 and Saccharomyces cerevisiae S441 were screened for DNA genetic alterations by DNA fingerprinting using M13 and LA1 primers after treatment with three compounds forming covalent adducts with DNA [benzo[a]pyrenediol epoxide (BPDE), methyl methanesulfonate and 1,2,3,4-diepoxybutane (DEB)]. M13 RAPD fingerprinting revealed that the total number of bands decreased in all treated DNA compared to control samples and generally the lost bands were characterized by high molecular weight. Some extra bands were detected for L. plantarum and E. faecium, while in E. coli and S. cerevisiae DNAs BPDE and DEB treatments did not result in new extra bands. Besides qualitatively analysis, cluster analysis based on Unweighted Pair-Group Method with Average algorithm was performed to compare DNA fingerprints before and after treatments. This analysis confirmed the absence of significant differences between negative controls and treated DNA in S. cerevisiae and E. coli however the disappearance of some bands can be detected. The data indicate that this approach can be used for DNA damage detection and mutations induced by genotoxic compounds and highlighted the possible use of L. plantarum and E. faecium M13 based fingerprinting as reference for hazard identification in risk assessment. PMID:26991971

  15. Relaxed replication of mtDNA: A model with implications for the expression of disease.

    PubMed Central

    Chinnery, P F; Samuels, D C

    1999-01-01

    Heteroplasmic mtDNA defects are an important cause of human disease with clinical features that primarily involve nondividing (postmitotic) tissues. Within single cells the percentage level of mutated mtDNA must exceed a critical threshold level before the genetic defect is expressed. Although the level of mutated mtDNA may alter over time, the mechanism behind the change is not understood. It currently is not possible to directly measure the level of mutant mtDNA within living cells. We therefore developed a mathematical model of human mtDNA replication, based on a solid foundation of experimentally derived parameters, and studied the dynamics of intracellular heteroplasmy in postmitotic cells. Our simulations show that the level of intracellular heteroplasmy can vary greatly over a short period of time and that a high copy number of mtDNA molecules delays the time to fixation of an allele. We made the assumption that the optimal state for a cell is to contain 100% wild-type molecules. For cells that contain pathogenic mutations, the nonselective proliferation of mutant and wild-type mtDNA molecules further delays the fixation of both alleles, but this leads to a rapid increase in the mean percentage level of mutant mtDNA within a tissue. On its own, this mechanism will lead to the appearance of a critical threshold level of mutant mtDNA that must be exceeded before a cell expresses a biochemical defect. The hypothesis that we present is in accordance with the available data and may explain the late presentation and insidious progression of mtDNA diseases. PMID:10090901

  16. A Bayesian compound stochastic process for modeling nonstationary and nonhomogeneous sequence evolution.

    PubMed

    Blanquart, Samuel; Lartillot, Nicolas

    2006-11-01

    Variations of nucleotidic composition affect phylogenetic inference conducted under stationary models of evolution. In particular, they may cause unrelated taxa sharing similar base composition to be grouped together in the resulting phylogeny. To address this problem, we developed a nonstationary and nonhomogeneous model accounting for compositional biases. Unlike previous nonstationary models, which are branchwise, that is, assume that base composition only changes at the nodes of the tree, in our model, the process of compositional drift is totally uncoupled from the speciation events. In addition, the total number of events of compositional drift distributed across the tree is directly inferred from the data. We implemented the method in a Bayesian framework, relying on Markov Chain Monte Carlo algorithms, and applied it to several nucleotidic data sets. In most cases, the stationarity assumption was rejected in favor of our nonstationary model. In addition, we show that our method is able to resolve a well-known artifact. By Bayes factor evaluation, we compared our model with 2 previously developed nonstationary models. We show that the coupling between speciations and compositional shifts inherent to branchwise models may lead to an overparameterization, resulting in a lesser fit. In some cases, this leads to incorrect conclusions, concerning the nature of the compositional biases. In contrast, our compound model more flexibly adapts its effective number of parameters to the data sets under investigation. Altogether, our results show that accounting for nonstationary sequence evolution may require more elaborate and more flexible models than those currently used.

  17. Thermal Decomposition Mechanisms of Lignin Model Compounds: From Phenol to Vanillin

    NASA Astrophysics Data System (ADS)

    Scheer, Adam Michael

    Lignin is a complex, aromatic polymer abundant in cellulosic biomass (trees, switchgrass etc.). Thermochemical breakdown of lignin for liquid fuel production results in undesirable polycyclic aromatic hydrocarbons that lead to tar and soot byproducts. The fundamental chemistry governing these processes is not well understood. We have studied the unimolecular thermal decomposition mechanisms of aromatic lignin model compounds using a miniature SiC tubular reactor. Products are detected and characterized using time-of-flight mass spectrometry with both single photon (118.2 nm; 10.487 eV) and 1 + 1 resonance-enhanced multiphoton ionization (REMPI) as well as matrix isolation infrared spectroscopy. Gas exiting the heated reactor (300 K--1600 K) is subject to a free expansion after a residence time of approximately 100 micros. The expansion into vacuum rapidly cools the gas mixture and allows the detection of radicals and other highly reactive intermediates. By understanding the unimolecular fragmentation patterns of phenol (C6H5OH), anisole (C6H 5OCH3) and benzaldehyde (C6H5CHO), the more complicated thermocracking processes of the catechols (HO-C 6H4-OH), methoxyphenols (HO-C6H4-OCH 3) and hydroxybenzaldehydes (HO-C6H4-CHO) can be interpreted. These studies have resulted in a predictive model that allows the interpretation of vanillin, a complex phenolic ether containing methoxy, hydroxy and aldehyde functional groups. This model will serve as a guide for the pyrolyses of larger systems including lignin monomers such as coniferyl alcohol. The pyrolysis mechanisms of the dimethoxybenzenes (H3C-C 6H4-OCH3) and syringol, a hydroxydimethoxybenzene have also been studied. These results will aid in the understanding of the thermal fragmentation of sinapyl alcohol, the most complex lignin monomer. In addition to the model compound work, pyrolyisis of biomass has been studied via the pulsed laser ablation of poplar wood. With the REMPI scheme, aromatic lignin decomposition

  18. Application of the S=1 underscreened Anderson lattice model to Kondo uranium and neptunium compounds

    NASA Astrophysics Data System (ADS)

    Thomas, Christopher; da Rosa Simões, Acirete S.; Iglesias, J. R.; Lacroix, C.; Perkins, N. B.; Coqblin, B.

    2011-01-01

    Magnetic properties of uranium and neptunium compounds showing the coexistence of the Kondo screening effect and ferromagnetic order are investigated within the Anderson lattice Hamiltonian with a two-fold degenerate f level in each site, corresponding to 5f2 electronic configuration with S=1 spins. A derivation of the Schrieffer-Wolff transformation is presented and the resulting Hamiltonian has an effective f-band term, in addition to the regular exchange Kondo interaction between the S=1 f spins and the s=1/2 spins of the conduction electrons. The resulting effective Kondo lattice model can describe both the Kondo regime and a weak delocalization of the 5f electrons. Within this model we compute the Kondo and Curie temperatures as a function of model parameters, namely the Kondo exchange interaction constant JK, the magnetic intersite exchange interaction JH, and the effective f bandwidth. We deduce, therefore, a phase diagram of the model which yields the coexistence of the Kondo effect and ferromagnetic ordering and also accounts for the pressure dependence of the Curie temperature of uranium compounds such as UTe.

  19. Using QSAR to evaluate phenomenological models for sorption of organic compounds by soil

    SciTech Connect

    Brusseau, M.L. . Soil and Water Science Dept. and Hydrology and Water Resources Dept.)

    1993-10-01

    The functional dependencies of equilibrium and nonequilibrium sorption parameters on solute molecular descriptors were analyzed for 29 organic compounds and two soils. Similar correlation patterns were obtained with all three evaluated size/shape descriptors (molecular surface area, van der Waals volume, molecular connectivity). The functional dependencies of equilibrium distribution of coefficients on the solute molecular descriptors were analyzed for three systems used as phenomenological models of sorption by soil. The correlation patterns exhibited by the three models were compared to those reported for the soil systems. The correlation patterns exhibited by the soil data were similar to the patterns exhibited by the polymer systems and dissimilar to those exhibited by the octanol and RPLC systems. In addition, the correlation pattern between the sorption rate coefficient and molecular connectivity was similar to that between polymer-diffusion coefficients and molecular connectivity. Hence, it appears that the polymer analog may be the most appropriate of the three models for representing both equilibrium and nonequilibrium sorption by soil. Based on these results, the polymer analog is suggested as the phenomenological model of choice for investigating and evaluating the sorption dynamics of low-polarity organic compounds in soil systems.

  20. Curing chemistry of phenylethynyl-terminated imide oligomers: Model compounds, carbon-13 labeling and cure analysis

    NASA Astrophysics Data System (ADS)

    Roberts, Christopher Chad

    1998-11-01

    Phenylethynyl-terminated imide oligomers (PETI) are currently considered the state-of-the-art high performance resins for aerospace applications. The processing of these resins is more facile because of their low molecular weight, but PETI's cure to form a tough, solvent-resistant material. However, the final cure structure was a complete mystery. Hence, the present study was set forth with three essential goals. The determination of the final structure of the crosslinked polymer is of obvious importance. Second, the crosslinking mechanism and controlling factors is also of interest. Lastly, the final structure of the crosslinked polymers was correlated with mechanical and thermal properties, thereby helping to establish the structure-processing-properties relationships for PETI resins. These goals were accomplished by using a combination of synthesis of model compounds synthesis and proposed cure products, sp{13}C labeling of the ethynyl endgroup in PETI's, monitoring of the thermal cure using solid state sp{13}C NMR and ESR and molecular modeling techniques. Phenylethynyl endcapping agents, 4-(phenylethynyl)phthalic anhydride (PEPA) and 3-(phenylethynyl)aniline (3PEA), were synthesized via the palladium-catalyzed coupling of phenylacetylene with 4-bromophthalic anhydride or 3-iodonitrobenzene followed by reduction to 3PEA, respectively. Isolated yields of 41 and 86% for 3PEA and PEPA were obtained, respectively. Model compounds were synthesized from 3PEA and PEPA by reacting with them the appropriate aniline or phthalic anhydride derivative. Model compounds included N-pentafluorophenyl-4-(phenylethynyl)phthalimide (PEPA/F5An), N-(4-trifluoromethyl-phenyl)4-(phenylethynyl)phthalimide (PEPA/F3CAn), N-lbrack 3-(phenylethynyl)phenylrbrack\\ phthalimide (3PEA/PA), N-phenyl-4-(phenylethynyl)phthalimide (PEPA/An), N-(4-phenoxyphenyl)4-(phenylethynyl)phthalimide (PEPA/POAn), and N-(1-naphthyl)-4-(phenylethynyl)phthalimide (PEPA/Anaph). Proposed cure products such as

  1. Neuronal NOS and cyclooxygenase-2 contribute to DNA damage in a mouse model of Parkinson disease.

    PubMed

    Hoang, Tuan; Choi, Dong-Kug; Nagai, Makiko; Wu, Du-Chu; Nagata, Tetsuya; Prou, Delphine; Wilson, Glenn L; Vila, Miquel; Jackson-Lewis, Vernice; Dawson, Valina L; Dawson, Ted M; Chesselet, Marie-Françoise; Przedborski, Serge

    2009-10-01

    DNA damage is a proposed pathogenic factor in neurodegenerative disorders such as Parkinson disease. To probe the underpinning mechanism of such neuronal perturbation, we sought to produce an experimental model of DNA damage. We thus first assessed DNA damage by in situ nick translation and emulsion autoradiography in the mouse brain after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 x 20 mg/kg, ip, every 2 h), a neurotoxin known to produce a model of Parkinson disease. Here we show that DNA strand breaks occur in vivo in this mouse model of Parkinson disease with kinetics and a topography that parallel the degeneration of substantia nigra neurons, as assessed by FluoroJade labeling. Previously, nitric oxide synthase and cyclooxygenase-2 (Cox-2) were found to modulate MPTP-induced dopaminergic neuronal death. We thus assessed the contribution of these enzymes to DNA damage in mice lacking neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), or Cox-2. We found that the lack of Cox-2 and nNOS activities but not of iNOS activity attenuated MPTP-related DNA damage. We also found that not only nuclear, but also mitochondrial, DNA is a target for the MPTP insult. These results suggest that the loss of genomic integrity can be triggered by the concerted actions of nNOS and Cox-2 and provide further support to the view that DNA damage may contribute to the neurodegenerative process in Parkinson disease. PMID:19616617

  2. [Combined hopping-superexchange mechanism of charge transfer in DNA; a model with nearest interactions].

    PubMed

    Lakhno, V D; Sultanov, V B

    2007-01-01

    In the framework of the earlier developed combined hopping-superexchange mechanism of charge transfer in DNA, a model with all nearest interactions between nucleobases is proposed. It is shown that the transfer rates for various types of nucleotide sequences calculated within this model are in a good agreement with experimental data.

  3. Design of amphiphilic oligopeptides as models for fine tuning peptide assembly with plasmid DNA.

    PubMed

    Goparaju, Geetha N; Gupta, Pardeep K

    2014-08-01

    We discuss the design of novel amphiphilic oligopeptides with hydrophobic and cationic amino acids to serve as models to understand peptide-DNA assembly. Biophysical and thermodynamic characterization of interaction of these amphiphilic peptides with plasmid DNA is presented. Peptides with at least +4 charges favor stable complex formation. Surface potential is dependent on the type of hydrophobic amino acid for a certain charge. Thermodynamically it is a spontaneous interaction between most of the peptides and plasmid DNA. Lys(7) and Tyr peptides with +4/+5 charges indicate cooperative binding with pDNA without saturation of interaction while Val(2)-Gly-Lys(4), Val-Gly-Lys(5), and Phe-Gly-Lys(5) lead to saturation of interaction indicating condensed pDNA within the range of N/Ps studied. We show that the biophysical properties of DNA-peptide complexes could be modulated by design and the peptides presented here could be used as building blocks for creating DNA-peptide complexes for various biomedical applications, mainly nucleic acid delivery.

  4. Molecular aspects on the interaction of phenosafranine to deoxyribonucleic acid: Model for intercalative drug DNA binding

    NASA Astrophysics Data System (ADS)

    Das, Suman; Kumar, Gopinatha Suresh

    2008-01-01

    The mode, mechanism and energetics of interaction of phenosafranine, the planar, cationic and rigid phenazium dye to calf thymus DNA was investigated from absorption, fluorescence, circular dichroism, isothermal titration calorimetry, thermal melting, and viscosity. The study revealed non-cooperative binding of the dye to DNA with an affinity in the range (3.81-4.22) × 10 5 M -1 as observed from diverse techniques and obeying neighbor exclusion principle. The stoichiometry of binding was characterized to be one phenosafranine molecule per two base pairs. The binding was characterized by strong stabilization of DNA against thermal strand separation, large intrinsic circular dichroic changes of DNA by itself and the generation of induced circular dichroism for the optically inactive phenosafranine molecules. Hydrodynamic and fluorescence quenching studies revealed strong evidence that the phenosafranine molecules are intercalated between every alternate base pairs of calf thymus DNA. Isothermal titration calorimetry studies suggested that the binding was exothermic and favoured by both negative enthalpy and positive entropy changes. This study for the first time presents the complete molecular aspects and energetics of phenosafranine complexation to DNA as model for intercalative drug-DNA interaction.

  5. Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model.

    PubMed

    Cagnone, Gael; Tsai, Te-Sha; Srirattana, Kanokwan; Rossello, Fernando; Powell, David R; Rohrer, Gary; Cree, Lynsey; Trounce, Ian A; St John, Justin C

    2016-03-01

    The maternally inherited mitochondrial genome (mtDNA) is present in multimeric form within cells and harbors sequence variants (heteroplasmy). While a single mtDNA variant at high load can cause disease, naturally occurring variants likely persist at low levels across generations of healthy populations. To determine how naturally occurring variants are segregated and transmitted, we generated a mini-pig model, which originates from the same maternal ancestor. Following next-generation sequencing, we identified a series of low-level mtDNA variants in blood samples from the female founder and her daughters. Four variants, ranging from 3% to 20%, were selected for validation by high-resolution melting analysis in 12 tissues from 31 animals across three generations. All four variants were maintained in the offspring, but variant load fluctuated significantly across the generations in several tissues, with sex-specific differences in heart and liver. Moreover, variant load was persistently reduced in high-respiratory organs (heart, brain, diaphragm, and muscle), which correlated significantly with higher mtDNA copy number. However, oocytes showed increased heterogeneity in variant load, which correlated with increased mtDNA copy number during in vitro maturation. Altogether, these outcomes show that naturally occurring mtDNA variants segregate and are maintained in a tissue-specific manner across generations. This segregation likely involves the maintenance of selective mtDNA variants during organogenesis, which can be differentially regulated in oocytes and preimplantation embryos during maturation. PMID:26819245

  6. Priming of plant resistance by natural compounds. Hexanoic acid as a model

    PubMed Central

    Aranega-Bou, Paz; de la O Leyva, Maria; Finiti, Ivan; García-Agustín, Pilar; González-Bosch, Carmen

    2014-01-01

    Some alternative control strategies of currently emerging plant diseases are based on the use of resistance inducers. This review highlights the recent advances made in the characterization of natural compounds that induce resistance by a priming mechanism. These include vitamins, chitosans, oligogalacturonides, volatile organic compounds, azelaic and pipecolic acid, among others. Overall, other than providing novel disease control strategies that meet environmental regulations, natural priming agents are valuable tools to help unravel the complex mechanisms underlying the induced resistance (IR) phenomenon. The data presented in this review reflect the novel contributions made from studying these natural plant inducers, with special emphasis placed on hexanoic acid (Hx), proposed herein as a model tool for this research field. Hx is a potent natural priming agent of proven efficiency in a wide range of host plants and pathogens. It can early activate broad-spectrum defenses by inducing callose deposition and the salicylic acid (SA) and jasmonic acid (JA) pathways. Later it can prime pathogen-specific responses according to the pathogen’s lifestyle. Interestingly, Hx primes redox-related genes to produce an anti-oxidant protective effect, which might be critical for limiting the infection of necrotrophs. Our Hx-IR findings also strongly suggest that it is an attractive tool for the molecular characterization of the plant alarmed state, with the added advantage of it being a natural compound. PMID:25324848

  7. Exclusion of small terminase mediated DNA threading models for genome packaging in bacteriophage T4.

    PubMed

    Gao, Song; Zhang, Liang; Rao, Venigalla B

    2016-05-19

    Tailed bacteriophages and herpes viruses use powerful molecular machines to package their genomes. The packaging machine consists of three components: portal, motor (large terminase; TerL) and regulator (small terminase; TerS). Portal, a dodecamer, and motor, a pentamer, form two concentric rings at the special five-fold vertex of the icosahedral capsid. Powered by ATPase, the motor ratchets DNA into the capsid through the portal channel. TerS is essential for packaging, particularly for genome recognition, but its mechanism is unknown and controversial. Structures of gear-shaped TerS rings inspired models that invoke DNA threading through the central channel. Here, we report that mutations of basic residues that line phage T4 TerS (gp16) channel do not disrupt DNA binding. Even deletion of the entire channel helix retained DNA binding and produced progeny phage in vivo On the other hand, large oligomers of TerS (11-mers/12-mers), but not small oligomers (trimers to hexamers), bind DNA. These results suggest that TerS oligomerization creates a large outer surface, which, but not the interior of the channel, is critical for function, probably to wrap viral genome around the ring during packaging initiation. Hence, models involving TerS-mediated DNA threading may be excluded as an essential mechanism for viral genome packaging. PMID:26984529

  8. Exclusion of small terminase mediated DNA threading models for genome packaging in bacteriophage T4

    PubMed Central

    Gao, Song; Zhang, Liang; Rao, Venigalla B.

    2016-01-01

    Tailed bacteriophages and herpes viruses use powerful molecular machines to package their genomes. The packaging machine consists of three components: portal, motor (large terminase; TerL) and regulator (small terminase; TerS). Portal, a dodecamer, and motor, a pentamer, form two concentric rings at the special five-fold vertex of the icosahedral capsid. Powered by ATPase, the motor ratchets DNA into the capsid through the portal channel. TerS is essential for packaging, particularly for genome recognition, but its mechanism is unknown and controversial. Structures of gear-shaped TerS rings inspired models that invoke DNA threading through the central channel. Here, we report that mutations of basic residues that line phage T4 TerS (gp16) channel do not disrupt DNA binding. Even deletion of the entire channel helix retained DNA binding and produced progeny phage in vivo. On the other hand, large oligomers of TerS (11-mers/12-mers), but not small oligomers (trimers to hexamers), bind DNA. These results suggest that TerS oligomerization creates a large outer surface, which, but not the interior of the channel, is critical for function, probably to wrap viral genome around the ring during packaging initiation. Hence, models involving TerS-mediated DNA threading may be excluded as an essential mechanism for viral genome packaging. PMID:26984529

  9. Recent advances in hydrotreating of pyrolysis bio-oil and its oxygen-containing model compounds

    SciTech Connect

    Wang, Huamin; Male, Jonathan L.; Wang, Yong

    2013-05-01

    There is considerable world-wide interest in discovering renewable sources of energy that can substitute for fossil fuels. Lignocellulosic biomass, which is the most abundant and inexpensive renewable feedstock on the planet, has a great potential for sustainable production of fuels, chemicals, and carbon-based materials. Fast pyrolysis integrated with hydrotreating is one of the simplest, most cost-effective and most efficient processes to convert lignocellulosic biomass to liquid hydrocarbon fuels for transportation, which has attracted significant attention in recent decades. However, effective hydrotreating of pyrolysis bio-oil presents a daunting challenge to the commercialization of biomass conversion via pyrolysis-hydrotreating. Specifically, development of active, selective, and stable hydrotreating catalysts is the bottleneck due to the poor quality of pyrolysis bio-oil feedstock (high oxygen content, molecular complexity, coking propensity, and corrosiveness). Significant research has been conducted to address the practical issues and provide the fundamental understanding of the hydrotreating/hydrodeoxygenation (HDO) of bio-oils and their oxygen-containing model compounds, including phenolics, furans, and carboxylic acids. A wide range of catalysts have been studied, including conventional Mo-based sulfide catalysts and noble metal catalysts, with the latter being the primary focus of the recent research because of their excellent catalytic performances and no requirement of environmentally unfriendly sulfur. The reaction mechanisms of HDO of model compounds on noble metal catalysts as well as their efficacy for hydrotreating or stabilization of bio-oil have been recently reported. This review provides a survey of the relevant literatures of recent 10 years about the advances in the understanding of the HDO chemistry of bio-oils and their model compounds mainly on noble metal catalysts.

  10. Pathways in coal thermolysis: a theoretical and experimental study with model compounds

    SciTech Connect

    Ekpenyong, I.A.; Virk, P.S.

    1982-01-01

    Fundamental aspects of coal thermolysis were investigated, including how the chemical structures of aromatics, hydroaromatics, and alcohols affect their reactivities as hydrogen donors and acceptors in coal processing. The susceptibilities of substructural entities in coals to fragmentation via a number of thermal pericyclic and free radical mechanisms were probed, as were the factors governing relative reactivities within series of such coal model compounds. The theoretical part of the work applied perturbation molecular orbital (PMO) and frontier orbital theories, in conjunction with ..pi..- and pseudo-..pi.. MO's, to the study of model compound reactivity. This enabled prediction of reactivity patterns of H-donors, H-acceptors and coal-like structures as functions of their ..pi..- and sigma-bond configurations, including heteroatomic effects. Experimentally, the liquid phase reactions of the coal model compound PhOCH/sub 2/Ph (Benzyl phenyl ether, BPE) were detailed for the first time in each of four hydronaphthalene H-donor solvents in the temperature range 220/sup 0/ to 300/sup 0/C. The thermolysis of BPE exhibited a pronounced dependence on solvent structure, both with respect to product selectivities and reaction kinetics. BPE thermolysis pathways were delineated as involving (a) rearrangement, leading to isomerization, (b) hydrogenations, leading ultimately to PhOH and PhCH/sub 3/ products, and (c) addition reactions, engendering heavy products. Pathways (b) and (c) are competitive and, in each, self-reactions of BPE-derivatives vie against reactions between these and the donor solvent. Of the detailed free radical and pericyclic reaction mechanisms postulated, the latter rationalized many more facets of the BPE results than the former. The theoretical and experimental results were appraised against previous coal thermolysis literature.

  11. A nonlinear dynamic model of DNA with a sequence-dependent stacking term

    PubMed Central

    Alexandrov, Boian S.; Gelev, Vladimir; Monisova, Yevgeniya; Alexandrov, Ludmil B.; Bishop, Alan R.; Rasmussen, Kim Ø.; Usheva, Anny

    2009-01-01

    No simple model exists that accurately describes the melting behavior and breathing dynamics of double-stranded DNA as a function of nucleotide sequence. This is especially true for homogenous and periodic DNA sequences, which exhibit large deviations in melting temperature from predictions made by additive thermodynamic contributions. Currently, no method exists for analysis of the DNA breathing dynamics of repeats and of highly G/C- or A/T-rich regions, even though such sequences are widespread in vertebrate genomes. Here, we extend the nonlinear Peyrard–Bishop–Dauxois (PBD) model of DNA to include a sequence-dependent stacking term, resulting in a model that can accurately describe the melting behavior of homogenous and periodic sequences. We collect melting data for several DNA oligos, and apply Monte Carlo simulations to establish force constants for the 10 dinucleotide steps (CG, CA, GC, AT, AG, AA, AC, TA, GG, TC). The experiments and numerical simulations confirm that the GG/CC dinucleotide stacking is remarkably unstable, compared with the stacking in GC/CG and CG/GC dinucleotide steps. The extended PBD model will facilitate thermodynamic and dynamic simulations of important genomic regions such as CpG islands and disease-related repeats. PMID:19264801

  12. Quantitative mechanistically based dose-response modeling with endocrine-active compounds.

    PubMed Central

    Andersen, M E; Conolly, R B; Faustman, E M; Kavlock, R J; Portier, C J; Sheehan, D M; Wier, P J; Ziese, L

    1999-01-01

    A wide range of toxicity test methods is used or is being developed for assessing the impact of endocrine-active compounds (EACs) on human health. Interpretation of these data and their quantitative use in human and ecologic risk assessment will be enhanced by the availability of mechanistically based dose-response (MBDR) models to assist low-dose, interspecies, and (italic)in vitro(/italic) to (italic)in vivo(/italic) extrapolations. A quantitative dose-response modeling work group examined the state of the art for developing MBDR models for EACs and the near-term needs to develop, validate, and apply these models for risk assessments. Major aspects of this report relate to current status of these models, the objectives/goals in MBDR model development for EACs, low-dose extrapolation issues, regulatory inertia impeding acceptance of these approaches, and resource/data needs to accelerate model development and model acceptance by the research and the regulatory community. PMID:10421774

  13. An Integrated Modeling Approach for Describing Fate and Transport of Perfluorinated Compounds (PFCs) in Estuarine Reservoir

    NASA Astrophysics Data System (ADS)

    Zhang, J.; Nguyen Viet, T.; Wang, X.; Chen, H.; Gin, K. Y. H.

    2014-12-01

    The fate and transport processes of emerging contaminants in aquatic ecosystems are complex, which are not only determined by their own properties but also influenced by the environmental setting, physical, chemical and biological processes. A 3D-emerging contaminant model has been developed based on Delft3D water quality model and coupled with a hydrodynamic model and a catchment-scale 1D- hydrological and hydraulic model to study the possible fate and transport mechanisms of perfluorinated compounds (PFCs) in Marina Reservoir in Singapore. The main processes in the contaminant model include partitioning (among detritus, dissolved organic matter and phytoplankton), settling, resuspension and degradation. We used the integrated model to quantify the distribution of the total PFCs and two major components, namely perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) in the water, sediments and organisms in the reservoir. The model yielded good agreement with the field measurements when evaluated based on the datasets in 2009 and 2010 as well as recent observations in 2013 and 2014. Our results elucidate that the model can be a useful tool to characterize the occurrence, sources, sinks and trends of PFCs both in the water column and in the sediments in the reservoir. Thisapproach provides a better understanding of mechanisms that influence the fate and transport of emerging contaminants and lays down a framework for future experiments to further explore how the dominant environmental factors change towards mitigation of emerging contaminants in the reservoirs.

  14. Substitution of carcinogenic solvent dichloromethane for the extraction of volatile compounds in a fat-free model food system.

    PubMed

    Cayot, Nathalie; Lafarge, Céline; Bou-Maroun, Elias; Cayot, Philippe

    2016-07-22

    Dichloromethane is known as a very efficient solvent, but, as other halogenated solvents, is recognized as a hazardous product (CMR substance). The objective of the present work is to propose substitution solvent for the extraction of volatile compounds. The most important physico-chemical parameters in the choice of an appropriate extraction solvent of volatile compounds are reviewed. Various solvents are selected on this basis and on their hazard characteristics. The selected solvents, safer than dichloromethane, are compared using the extraction efficiency of volatile compounds from a model food product able to interact with volatile compounds. Volatile compounds with different hydrophobicity are used. High extraction yields were positively correlated with high boiling points and high Log Kow values of volatile compounds. Mixtures of solvents such as azeotrope propan-2-one/cyclopentane, azeotrope ethyl acetate/ethanol, and mixture ethyl acetate/ethanol (3:1, v/v) gave higher extraction yields than those obtained with dichloromethane.

  15. Substitution of carcinogenic solvent dichloromethane for the extraction of volatile compounds in a fat-free model food system.

    PubMed

    Cayot, Nathalie; Lafarge, Céline; Bou-Maroun, Elias; Cayot, Philippe

    2016-07-22

    Dichloromethane is known as a very efficient solvent, but, as other halogenated solvents, is recognized as a hazardous product (CMR substance). The objective of the present work is to propose substitution solvent for the extraction of volatile compounds. The most important physico-chemical parameters in the choice of an appropriate extraction solvent of volatile compounds are reviewed. Various solvents are selected on this basis and on their hazard characteristics. The selected solvents, safer than dichloromethane, are compared using the extraction efficiency of volatile compounds from a model food product able to interact with volatile compounds. Volatile compounds with different hydrophobicity are used. High extraction yields were positively correlated with high boiling points and high Log Kow values of volatile compounds. Mixtures of solvents such as azeotrope propan-2-one/cyclopentane, azeotrope ethyl acetate/ethanol, and mixture ethyl acetate/ethanol (3:1, v/v) gave higher extraction yields than those obtained with dichloromethane. PMID:27320380

  16. The catalytic ozonization of model lignin compounds in the presence of Fe(III) ions

    NASA Astrophysics Data System (ADS)

    Ben'ko, E. M.; Mukovnya, A. V.; Lunin, V. V.

    2007-05-01

    The ozonization of several model lignin compounds (guaiacol, 2,6-dimethoxyphenol, phenol, and vanillin) was studied in acid media in the presence of iron(III) ions. It was found that Fe3+ did not influence the initial rate of the reactions between model phenols and ozone but accelerated the oxidation of intermediate ozonolysis products. The metal concentration dependences of the total ozone consumption and effective rate constants of catalytic reaction stages were determined. Data on reactions in the presence of oxalic acid as a competing chelate ligand showed that complex formation with Fe3+ was the principal factor that accelerated the ozonolysis of model phenols at the stage of the oxidation of carboxylic dibasic acids and C2 aldehydes formed as intermediate products.

  17. An anisotropic model of diffuse solar radiation with application to an optimization of compound parabolic collectors

    NASA Astrophysics Data System (ADS)

    Perez, R. R.

    Based on a simple geometrical description of the sky hemisphere and the magnitude of the horizontal diffuse radiation, a model for estimating diffuse radiation impinging on sloping surfaces was developed. Tests against data show that substantial improvement is achieved over the classical isotropic model for any collector slope or orientation. Improvement is found for instantaneous as well as accumulated data. The application of the model to compound parabolic collectors (CPC) accounts partly for the role played by forward scattered radiation in the total energy they receive. An optimization of CPC's geometrical characteristics is performed for photovoltaic generation in the area of Albany, NY. This calculation is used to assess the relative effects of meteorological conditions and economic assumptions or optimum concentration values, and provides the reader with information pertaining to the variation of the cost of electrical energy produced as a function of the cost of silicon solar cells.

  18. Perspectives on zebrafish models of hallucinogenic drugs and related psychotropic compounds.

    PubMed

    Neelkantan, Nikhil; Mikhaylova, Alina; Stewart, Adam Michael; Arnold, Raymond; Gjeloshi, Visar; Kondaveeti, Divya; Poudel, Manoj K; Kalueff, Allan V

    2013-08-21

    Among different classes of psychotropic drugs, hallucinogenic agents exert one of the most prominent effects on human and animal behaviors, markedly altering sensory, motor, affective, and cognitive responses. The growing clinical and preclinical interest in psychedelic, dissociative, and deliriant hallucinogens necessitates novel translational, sensitive, and high-throughput in vivo models and screens. Primate and rodent models have been traditionally used to study cellular mechanisms and neural circuits of hallucinogenic drugs' action. The utility of zebrafish ( Danio rerio ) in neuroscience research is rapidly growing due to their high physiological and genetic homology to humans, ease of genetic manipulation, robust behaviors, and cost effectiveness. Possessing a fully characterized genome, both adult and larval zebrafish are currently widely used for in vivo screening of various psychotropic compounds, including hallucinogens and related drugs. Recognizing the growing importance of hallucinogens in biological psychiatry, here we discuss hallucinogenic-induced phenotypes in zebrafish and evaluate their potential as efficient preclinical models of drug-induced states in humans.

  19. Modeling and simulation of DNA flow in a microfluidic-based pathogen detection system

    SciTech Connect

    Trebotich, D; Miller, G H

    2005-01-31

    We present simulation results from a new computational model of DNA flow in microfluidic devices. This work is important because computational models are needed to design miniaturized biomedical devices that are becoming the state-of-the-art in many significant applications including pathogen detection as well as continuous monitoring and drug delivery. Currently advanced algorithms in design tools are non-existent but necessary to understand the complex fluid and polymer dynamics involved in biological flow at small scales. Our model is based on a fully coupled fluid-particle numerical algorithm with both stochastic and deterministic components in a bead-rod polymer representation. We have applied this work to DNA extraction configurations in a microfluidic PCR chamber used in a pathogen detection system. We demonstrate our method on the test problem of flow of a single DNA molecule in a 2D packed array microchannel. We are also investigating mechanisms for molecular ''sticking'' using short range forces.

  20. Approaching mathematical model of the immune network based DNA Strand Displacement system.

    PubMed

    Mardian, Rizki; Sekiyama, Kosuke; Fukuda, Toshio

    2013-12-01

    One biggest obstacle in molecular programming is that there is still no direct method to compile any existed mathematical model into biochemical reaction in order to solve a computational problem. In this paper, the implementation of DNA Strand Displacement system based on nature-inspired computation is observed. By using the Immune Network Theory and Chemical Reaction Network, the compilation of DNA-based operation is defined and the formulation of its mathematical model is derived. Furthermore, the implementation on this system is compared with the conventional implementation by using silicon-based programming. From the obtained results, we can see a positive correlation between both. One possible application from this DNA-based model is for a decision making scheme of intelligent computer or molecular robot.

  1. Green improved processes to extract bioactive phenolic compounds from brown macroalgae using Sargassum muticum as model.

    PubMed

    Anaëlle, Tanniou; Serrano Leon, Esteban; Laurent, Vandanjon; Elena, Ibanez; Mendiola, Jose A; Stéphane, Cerantola; Nelly, Kervarec; Stéphane, La Barre; Luc, Marchal; Valérie, Stiger-Pouvreau

    2013-01-30

    A comparative study between "alternative" extraction processes such as centrifugal partition extraction (CPE), supercritical fluid extraction (SFE) and pressurized liquid extraction (PLE) and classical solid/liquid used in the laboratory are currently focusing on the efficiency (selectivity and productivity) to obtain bioactive phenolic compounds from the phaeophyte Sargassum muticum model. The choice of the best process was based on several measurements: (i) the total phenolic content measured by the colorimetric Folin-Ciocalteu assay, (ii) radical scavenger and antioxidant activities assessed by the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay, and the β-carotene bleaching method and finally (iii) the method productivity. Irrespective of the solvent used in the processes, alternative methods are always sharply more effective than classical ones. With the exception of SFE which does not allow extracting the totality of the active phenolic compounds, two of the other extraction methods were particularly promising. First, CPE afforded the most important yields in concentrated phenolic compounds (PC) (22.90±0.65% DW) also displaying the best activities (0.52±0.02 and 0.58±0.19 mg/mL for IC50 and AAC700, respectively). Secondly, PLE using an EtOH:water mixture 75:25 (v/v) allowed a good PC extraction (10.18±0.25% DW) with huge efficiency. Despite a lesser activity of the extracts (0.77±0.01 and 1.59±0.15 mg/mL for IC50 and AAC700, respectively) PLE is a green process and potentially complies European norms requirements for the prospective valorization of phenolic compounds from S. muticum in Brittany. PMID:23597887

  2. A Developmental Model for Branching Morphogenesis of Lake Cress Compound Leaf

    PubMed Central

    Nakamasu, Akiko; Nakayama, Hokuto; Nakayama, Naomi; Suematsu, Nobuhiko J.; Kimura, Seisuke

    2014-01-01

    Lake cress, Rorippa aquatica (Brassicaceae), is a semi-aquatic plant that exhibits a variety of leaf shapes, from simple leaves to highly branched compound leaves, depending on the environment. Leaf shape can vary within a single plant, suggesting that the variation can be explained by a simple model. In order to simulate the branched structure in the compound leaves of R. aquatica, we implemented reaction-diffusion (RD) patterning onto a theoretical framework that had been developed for serration distribution in the leaves of Arabidopsis thaliana, with the modification of the one-dimensional reaction-diffusion domain being deformed with the spatial periodicity of the RD pattern while expanding. This simple method using an iterative pattern could create regular and nested branching patterns. Subsequently, we verified the plausibility of our theoretical model by comparing it with the experimentally observed branching patterns. The results suggested that our model successfully predicted both the qualitative and quantitative aspects of the timing and positioning of branching in growing R. aquatica leaves. PMID:25375102

  3. Code System for the Analysis of Component Failure Data with a Compound Statistical Model.

    2000-08-22

    Version 00 Two separate but similar Fortran computer codes have been developed for the analysis of component failure data with a compound statistical model: SAFE-D and SAFE-R. The SAFE-D code (Statistical Analysis for Failure Estimation-failure-on-Demand) analyzes data which give the observed number of failures (failure to respond properly) in a specified number of demands for several similar components that should change their condition upon demand. The second program, SAFE-R (Statistical Analysis for Failure Estimation-failure Rate)more » is to be used to analyze normally operating components for which the observed number of failures in a specified operating time is given. In both these codes the failure parameter (failure probability per demand for SAFE-D or failure rate for SAFE-R) may be assumed equal for all similar components (the homogeneous failure model) or may be assumed to be a random variable distributed among similar components according to a prior distribution (the heterogeneous or compound failure model). Related information can be found at the developer's web site: http://www.mne.ksu.edu/~jks/.« less

  4. Drosophila melanogaster as a model to characterize fungal volatile organic compounds.

    PubMed

    Inamdar, Arati A; Zaman, Taslim; Morath, Shannon U; Pu, David C; Bennett, Joan W

    2014-05-01

    Fungi are implicated in poor indoor air quality and may pose a potential risk factor for building/mold related illnesses. Fungi emit numerous volatile organic compounds (VOCs) as alcohols, esters, ethers, ketones, aldehydes, terpenoids, thiols, and their derivatives. The toxicity profile of these VOCs has never been explored in a model organism, which could enable the performance of high throughput toxicological assays and lead to a better understanding of the mechanism of toxicity. We have established a reductionist Drosophila melanogaster model to evaluate the toxicity of fungal VOCs. In this report, we assessed the toxicity of fungal VOCs emitted from living cultures of species in the genera, Trichoderma, Aspergillus, and Penicillium and observed a detrimental effect on larval survival. We then used chemical standards of selected fungal VOCs to assess their toxicity on larval and adult Drosophila. We compared the survival of adult flies exposed to these fungal VOCs with known industrial toxic chemicals (formaldehyde [37%], xylene, benzene, and toluene). Among the tested fungal VOC standards, the compounds with eight carbons (C8) caused greater truncation of fly lifespan than tested non-C8 fungal VOCs and industrial toxins. Our data validate the use of Drosophila melanogaster as a model with the potential to elucidate the mechanistic attributes of different toxic VOCs emitted by fungi and also to explore the potential link between reported human illnesses/symptoms and exposure to water damaged and mold contaminated buildings.

  5. A developmental model for branching morphogenesis of lake cress compound leaf.

    PubMed

    Nakamasu, Akiko; Nakayama, Hokuto; Nakayama, Naomi; Suematsu, Nobuhiko J; Kimura, Seisuke

    2014-01-01

    Lake cress, Rorippa aquatica (Brassicaceae), is a semi-aquatic plant that exhibits a variety of leaf shapes, from simple leaves to highly branched compound leaves, depending on the environment. Leaf shape can vary within a single plant, suggesting that the variation can be explained by a simple model. In order to simulate the branched structure in the compound leaves of R. aquatica, we implemented reaction-diffusion (RD) patterning onto a theoretical framework that had been developed for serration distribution in the leaves of Arabidopsis thaliana, with the modification of the one-dimensional reaction-diffusion domain being deformed with the spatial periodicity of the RD pattern while expanding. This simple method using an iterative pattern could create regular and nested branching patterns. Subsequently, we verified the plausibility of our theoretical model by comparing it with the experimentally observed branching patterns. The results suggested that our model successfully predicted both the qualitative and quantitative aspects of the timing and positioning of branching in growing R. aquatica leaves.

  6. Drosophila melanogaster as a model to characterize fungal volatile organic compounds.

    PubMed

    Inamdar, Arati A; Zaman, Taslim; Morath, Shannon U; Pu, David C; Bennett, Joan W

    2014-05-01

    Fungi are implicated in poor indoor air quality and may pose a potential risk factor for building/mold related illnesses. Fungi emit numerous volatile organic compounds (VOCs) as alcohols, esters, ethers, ketones, aldehydes, terpenoids, thiols, and their derivatives. The toxicity profile of these VOCs has never been explored in a model organism, which could enable the performance of high throughput toxicological assays and lead to a better understanding of the mechanism of toxicity. We have established a reductionist Drosophila melanogaster model to evaluate the toxicity of fungal VOCs. In this report, we assessed the toxicity of fungal VOCs emitted from living cultures of species in the genera, Trichoderma, Aspergillus, and Penicillium and observed a detrimental effect on larval survival. We then used chemical standards of selected fungal VOCs to assess their toxicity on larval and adult Drosophila. We compared the survival of adult flies exposed to these fungal VOCs with known industrial toxic chemicals (formaldehyde [37%], xylene, benzene, and toluene). Among the tested fungal VOC standards, the compounds with eight carbons (C8) caused greater truncation of fly lifespan than tested non-C8 fungal VOCs and industrial toxins. Our data validate the use of Drosophila melanogaster as a model with the potential to elucidate the mechanistic attributes of different toxic VOCs emitted by fungi and also to explore the potential link between reported human illnesses/symptoms and exposure to water damaged and mold contaminated buildings. PMID:23139201

  7. Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

    PubMed Central

    Pereira, Edna F. R.; Aracava, Yasco; DeTolla, Louis J.; Beecham, E. Jeffrey; Basinger, G. William; Wakayama, Edgar J.

    2014-01-01

    The translational capacity of data generated in preclinical toxicological studies is contingent upon several factors, including the appropriateness of the animal model. The primary objectives of this article are: 1) to analyze the natural history of acute and delayed signs and symptoms that develop following an acute exposure of humans to organophosphorus (OP) compounds, with an emphasis on nerve agents; 2) to identify animal models of the clinical manifestations of human exposure to OPs; and 3) to review the mechanisms that contribute to the immediate and delayed OP neurotoxicity. As discussed in this study, clinical manifestations of an acute exposure of humans to OP compounds can be faithfully reproduced in rodents and nonhuman primates. These manifestations include an acute cholinergic crisis in addition to signs of neurotoxicity that develop long after the OP exposure, particularly chronic neurologic deficits consisting of anxiety-related behavior and cognitive deficits, structural brain damage, and increased slow electroencephalographic frequencies. Because guinea pigs and nonhuman primates, like humans, have low levels of circulating carboxylesterases—the enzymes that metabolize and inactivate OP compounds—they stand out as appropriate animal models for studies of OP intoxication. These are critical points for the development of safe and effective therapeutic interventions against OP poisoning because approval of such therapies by the Food and Drug Administration is likely to rely on the Animal Efficacy Rule, which allows exclusive use of animal data as evidence of the effectiveness of a drug against pathologic conditions that cannot be ethically or feasibly tested in humans. PMID:24907067

  8. Modeling DNA sequence-based cis-regulatory gene networks.

    PubMed

    Bolouri, Hamid; Davidson, Eric H

    2002-06-01

    Gene network analysis requires computationally based models which represent the functional architecture of regulatory interactions, and which provide directly testable predictions. The type of model that is useful is constrained by the particular features of developmentally active cis-regulatory systems. These systems function by processing diverse regulatory inputs, generating novel regulatory outputs. A computational model which explicitly accommodates this basic concept was developed earlier for the cis-regulatory system of the endo16 gene of the sea urchin. This model represents the genetically mandated logic functions that the system executes, but also shows how time-varying kinetic inputs are processed in different circumstances into particular kinetic outputs. The same basic design features can be utilized to construct models that connect the large number of cis-regulatory elements constituting developmental gene networks. The ultimate aim of the network models discussed here is to represent the regulatory relationships among the genomic control systems of the genes in the network, and to state their functional meaning. The target site sequences of the cis-regulatory elements of these genes constitute the physical basis of the network architecture. Useful models for developmental regulatory networks must represent the genetic logic by which the system operates, but must also be capable of explaining the real time dynamics of cis-regulatory response as kinetic input and output data become available. Most importantly, however, such models must display in a direct and transparent manner fundamental network design features such as intra- and intercellular feedback circuitry; the sources of parallel inputs into each cis-regulatory element; gene battery organization; and use of repressive spatial inputs in specification and boundary formation. Successful network models lead to direct tests of key architectural features by targeted cis-regulatory analysis. PMID

  9. Electronic structure, stacking energy, partial charge, and hydrogen bonding in four periodic B-DNA models.

    PubMed

    Poudel, Lokendra; Rulis, Paul; Liang, Lei; Ching, W Y

    2014-08-01

    We present a theoretical study of the electronic structure of four periodic B-DNA models labeled (AT)(10), (GC)(10), (AT)(5)(GC)(5), and (AT-GC)(5) where A denotes adenine, T denotes thymine, G denotes guanine, and C denotes cytosine. Each model has ten base pairs with Na counterions to neutralize the negative phosphate group in the backbone. The (AT)(5)(GC)(5) and (AT-GC)(5) models contain two and five AT-GC bilayers, respectively. When compared against the average of the two pure models, we estimate the AT-GC bilayer interaction energy to be 19.015 Kcal/mol, which is comparable to the hydrogen bonding energy between base pairs obtained from the literature. Our investigation shows that the stacking of base pairs plays a vital role in the electronic structure, relative stability, bonding, and distribution of partial charges in the DNA models. All four models show a highest occupied molecular orbital (HOMO) to lowest unoccupied molecular orbital (LUMO) gap ranging from 2.14 to 3.12 eV with HOMO states residing on the PO(4) + Na functional group and LUMO states originating from the bases. Our calculation implies that the electrical conductance of a DNA molecule should increase with increased base-pair mixing. Interatomic bonding effects in these models are investigated in detail by analyzing the distributions of the calculated bond order values for every pair of atoms in the four models including hydrogen bonding. The counterions significantly affect the gap width, the conductivity, and the distribution of partial charge on the DNA backbone. We also evaluate quantitatively the surface partial charge density on each functional group of the DNA models.

  10. Study on kinetic model of microwave thermocatalytic treatment of biomass tar model compound.

    PubMed

    Anis, Samsudin; Zainal, Z A

    2014-01-01

    Kinetic model parameters for toluene conversion under microwave thermocatalytic treatment were evaluated. The kinetic rate constants were determined using integral method based on experimental data and coupled with Arrhenius equation for obtaining the activation energies and pre-exponential factors. The model provides a good agreement with the experimental data. The kinetic model was also validated with standard error of 3% on average. The extrapolation of the model showed a reasonable trend to predict toluene conversion and product yield both in thermal and catalytic treatments. Under microwave irradiation, activation energy of toluene conversion was lower in the range of 3-27 kJ mol(-1) compared to those of conventional heating reported in the literatures. The overall reaction rate was six times higher compared to conventional heating. As a whole, the kinetic model works better for tar model removal in the absence of gas reforming within a level of reliability demonstrated in this study. PMID:24231266

  11. Mesoscopic modeling of DNA denaturation rates: Sequence dependence and experimental comparison

    SciTech Connect

    Dahlen, Oda Erp, Titus S. van

    2015-06-21

    Using rare event simulation techniques, we calculated DNA denaturation rate constants for a range of sequences and temperatures for the Peyrard-Bishop-Dauxois (PBD) model with two different parameter sets. We studied a larger variety of sequences compared to previous studies that only consider DNA homopolymers and DNA sequences containing an equal amount of weak AT- and strong GC-base pairs. Our results show that, contrary to previous findings, an even distribution of the strong GC-base pairs does not always result in the fastest possible denaturation. In addition, we applied an adaptation of the PBD model to study hairpin denaturation for which experimental data are available. This is the first quantitative study in which dynamical results from the mesoscopic PBD model have been compared with experiments. Our results show that present parameterized models, although giving good results regarding thermodynamic properties, overestimate denaturation rates by orders of magnitude. We believe that our dynamical approach is, therefore, an important tool for verifying DNA models and for developing next generation models that have higher predictive power than present ones.

  12. A DNA-based semantic fusion model for remote sensing data.

    PubMed

    Sun, Heng; Weng, Jian; Yu, Guangchuang; Massawe, Richard H

    2013-01-01

    Semantic technology plays a key role in various domains, from conversation understanding to algorithm analysis. As the most efficient semantic tool, ontology can represent, process and manage the widespread knowledge. Nowadays, many researchers use ontology to collect and organize data's semantic information in order to maximize research productivity. In this paper, we firstly describe our work on the development of a remote sensing data ontology, with a primary focus on semantic fusion-driven research for big data. Our ontology is made up of 1,264 concepts and 2,030 semantic relationships. However, the growth of big data is straining the capacities of current semantic fusion and reasoning practices. Considering the massive parallelism of DNA strands, we propose a novel DNA-based semantic fusion model. In this model, a parallel strategy is developed to encode the semantic information in DNA for a large volume of remote sensing data. The semantic information is read in a parallel and bit-wise manner and an individual bit is converted to a base. By doing so, a considerable amount of conversion time can be saved, i.e., the cluster-based multi-processes program can reduce the conversion time from 81,536 seconds to 4,937 seconds for 4.34 GB source data files. Moreover, the size of result file recording DNA sequences is 54.51 GB for parallel C program compared with 57.89 GB for sequential Perl. This shows that our parallel method can also reduce the DNA synthesis cost. In addition, data types are encoded in our model, which is a basis for building type system in our future DNA computer. Finally, we describe theoretically an algorithm for DNA-based semantic fusion. This algorithm enables the process of integration of the knowledge from disparate remote sensing data sources into a consistent, accurate, and complete representation. This process depends solely on ligation reaction and screening operations instead of the ontology.

  13. Synthesis of model compounds for coal liquefaction research. Final report, April 15, 1990--April 14, 1991

    SciTech Connect

    Not Available

    1991-11-01

    Coal liquefaction investigations required the availability of model compounds for mechanistic investigations. Towards this end, IITRI was funded to develop an approach for the synthesis of one of the target compound. This study was carried out in several phases as outlined here. Initial synthetic investigations on obtaining 2-tetrolol was carried out using high pressure and temperature reduction with Raney nickel catalyst. The next step consisted in incorporation of a hydroxymethyelene group at the C-3 position. This was successfully carried out utilizing 2-tetrolol, formaldehyde, and calcium oxide. An alternate improved method was developed using 3-carboxyl-2-naphthol. This required less time, gave a cheer product in higher yield. Efforts at the introduction of a chloromethylene group only yielded polymeric material or starting material in spite of protection the phenolic group by various groups. They synthesis of 3, 5-dimethyl-6- bromobenzyl chloride was successfully carried out by performing the Blank reaction of 2, 4-dimethyl bromobenzene. The product was characterized by GC/MS. Purification was not possible, as it was a complex mixture. Efforts at converting it to the acetate followed by separation to was not feasible. Unlike in the case of 2- hydroxyteralol, hydroxymetylation by established procedure yielded only the starting materials. Commercially available 4-methoxy-1- maphthaldehyde was protected as the ethylene acetal. The Wittig reagent 3-chlorobenzyl phosphonium bromide was prepared and condensed with 4-methoxy-1-napthaldehyde successfully and proved that the overall synthetic approach was proceeding in the desired direction. All the necessary intermediates have been synthesized,and we have demonstrated using model compounds, that the synthetic objective can be attained.

  14. Ionic distribution around simple B-DNA models II. Deviations from cylindrical symmetry

    NASA Astrophysics Data System (ADS)

    Montoro, Juan Carlos Gil; Abascal, José L. F.

    1998-10-01

    The structure of the ions around two B-DNA models with added monovalent salt at the continuum solvent level is investigated by computer simulation. The salt concentrations cover a wide range, from 0.05 to 4.5 M. The simplicity of the so-called grooved primitive model (unit electron charges at the phosphate positions of canonical DNA and the grooves shape approximated by means of simple geometric elements) enables a detailed study of the counterion and coion distributions with a very small statistical noise. The inhomogeneity of the ionic distributions is noticeable along the axial direction up to distances of about 20 Å from the DNA axis. The counterions deeply penetrate into the DNA grooves even at very low added salt concentrations. In the minor groove, the counterions are preferentially located in its center whereas they lie at the sides of the major groove, close to the phosphate positions. The coions also enter within the major groove, especially in the systems at high added salt concentrations for which regions of absolute negative charge can be found within the groove. This can be explained in terms of an arrangement of ions with alternating charges. The grooved primitive model has also been solved in the context of the finite difference Poisson-Boltzmann theory. The theory accurately describes the ionic structure around DNA at low salt concentrations but the results deteriorate with increasing salt missing important qualitative features at or above molar concentrations. The other model investigated differs from the more detailed one in that the shape of DNA is not taken into account; a soft cylinder is used instead. The counterions accumulate in this model in front of the phosphates and the axial inhomogeneity of the distribution quickly vanishes. These results together with those of previous investigations lead to the conclusion that the coupling of the discrete description of the DNA charge with the steric effects due to the presence of the grooves is

  15. Correction of the lack of commutability between plasmid DNA and genomic DNA for quantification of genetically modified organisms using pBSTopas as a model.

    PubMed

    Zhang, Li; Wu, Yuhua; Wu, Gang; Cao, Yinglong; Lu, Changming

    2014-10-01

    Plasmid calibrators are increasingly applied for polymerase chain reaction (PCR) analysis of genetically modified organisms (GMOs). To evaluate the commutability between plasmid DNA (pDNA) and genomic DNA (gDNA) as calibrators, a plasmid molecule, pBSTopas, was constructed, harboring a Topas 19/2 event-specific sequence and a partial sequence of the rapeseed reference gene CruA. Assays of the pDNA showed similar limits of detection (five copies for Topas 19/2 and CruA) and quantification (40 copies for Topas 19/2 and 20 for CruA) as those for the gDNA. Comparisons of plasmid and genomic standard curves indicated that the slopes, intercepts, and PCR efficiency for pBSTopas were significantly different from CRM Topas 19/2 gDNA for quantitative analysis of GMOs. Three correction methods were used to calibrate the quantitative analysis of control samples using pDNA as calibrators: model a, or coefficient value a (Cva); model b, or coefficient value b (Cvb); and the novel model c or coefficient formula (Cf). Cva and Cvb gave similar estimated values for the control samples, and the quantitative bias of the low concentration sample exceeded the acceptable range within ±25% in two of the four repeats. Using Cfs to normalize the Ct values of test samples, the estimated values were very close to the reference values (bias -13.27 to 13.05%). In the validation of control samples, model c was more appropriate than Cva or Cvb. The application of Cf allowed pBSTopas to substitute for Topas 19/2 gDNA as a calibrator to accurately quantify the GMO. PMID:25182967

  16. Correction of the lack of commutability between plasmid DNA and genomic DNA for quantification of genetically modified organisms using pBSTopas as a model.

    PubMed

    Zhang, Li; Wu, Yuhua; Wu, Gang; Cao, Yinglong; Lu, Changming

    2014-10-01

    Plasmid calibrators are increasingly applied for polymerase chain reaction (PCR) analysis of genetically modified organisms (GMOs). To evaluate the commutability between plasmid DNA (pDNA) and genomic DNA (gDNA) as calibrators, a plasmid molecule, pBSTopas, was constructed, harboring a Topas 19/2 event-specific sequence and a partial sequence of the rapeseed reference gene CruA. Assays of the pDNA showed similar limits of detection (five copies for Topas 19/2 and CruA) and quantification (40 copies for Topas 19/2 and 20 for CruA) as those for the gDNA. Comparisons of plasmid and genomic standard curves indicated that the slopes, intercepts, and PCR efficiency for pBSTopas were significantly different from CRM Topas 19/2 gDNA for quantitative analysis of GMOs. Three correction methods were used to calibrate the quantitative analysis of control samples using pDNA as calibrators: model a, or coefficient value a (Cva); model b, or coefficient value b (Cvb); and the novel model c or coefficient formula (Cf). Cva and Cvb gave similar estimated values for the control samples, and the quantitative bias of the low concentration sample exceeded the acceptable range within ±25% in two of the four repeats. Using Cfs to normalize the Ct values of test samples, the estimated values were very close to the reference values (bias -13.27 to 13.05%). In the validation of control samples, model c was more appropriate than Cva or Cvb. The application of Cf allowed pBSTopas to substitute for Topas 19/2 gDNA as a calibrator to accurately quantify the GMO.

  17. DNA Cleaving “Tandem-Array” Metallopeptides Activated With KHSO5: Towards the Development of Multi-Metallated Bioactive Conjugates and Compounds

    PubMed Central

    Lewis, Mark A.; Williams, Katie M.; Fang, Ya-Yin; Schultz, Franklin A.; Long, Eric C.

    2014-01-01

    Amino terminal peptides of the general form Gly-Gly-His have been used to introduce single sites of metal binding and redox activity into a wide range of biomolecules to create bioactive compounds and conjugates capable of substrate oxidation. We report here that Gly-Gly-His-like peptides linked in a tandem fashion can also be generated leading to multi-metal binding arrays. While metal binding by the native Gly-Gly-His motif (typically to Cu2+, Ni2+, or Co2+) requires a terminal peptide amine ligand, previous work has demonstrated that an ornithine (Orn) residue can be substituted for the terminal Gly residue to allow solid-phase peptide synthesis to continue via the side chain N-δ. This strategy thus frees the Orn residue N-α for metal binding and permits placement of a Gly-Gly-His-like metal binding domain at any location within a linear, synthetic peptide chain. As we show here, this strategy also permits the assembly of tandem arrays of metal binding units in linear peptides of the form: NH2-Gly-Gly-His-[(δ)-Orn-Gly-His]n-(δ)-Orn-Gly-His-CONH2 (where n = 0, 1, and 2). Metal binding titrations of these tandem arrays monitored by UV-vis and ESI-MS indicated that they bind Cu2+, Ni2+, or Co2+ at each available metal binding site. Further, it was found that these systems retained their ability to modify DNA oxidatively and to an extent greater than their parent M(II)•Gly-Gly-His. These findings suggest that the tandem array metallopeptides described here may function with increased efficiency as “next generation” appendages in the design of bioactive compounds and conjugates. PMID:25408625

  18. Sequence-dependent dynamics of duplex DNA: the applicability of a dinucleotide model.

    PubMed Central

    Okonogi, T M; Alley, S C; Reese, A W; Hopkins, P B; Robinson, B H

    2002-01-01

    The short-time (submicrosecond) bending dynamics of duplex DNA were measured to determine the effect of sequence on dynamics. All measurements were obtained from a single site on duplex DNA, using a single, site-specific modified base containing a rigidly tethered, electron paramagnetic resonance active spin probe. The observed dynamics are interpreted in terms of single-step sequence-dependent bending force constants, determined from the mean squared amplitude of bending relative to the end-to-end vector using the modified weakly bending rod model. The bending dynamics at a single site are a function of the sequence of the nucleotides constituting the duplex DNA. We developed and examined several dinucleotide-based models for flexibility. The models indicate that the dominant feature of the dynamics is best explained in terms of purine- and pyrimidine-type steps, although distinction is made among all 10 unique steps: It was found that purine-purine steps (which are the same as pyrimidine-pyrimidine steps) were near average in flexibility, but the pyrimidine-purine steps (5' to 3') were nearly twice as flexible, whereas purine-pyrimidine steps were more than half as flexible as average DNA. Therefore, the range of stepwise flexibility is approximately fourfold and is characterized by both the type of base pair step (pyrimidine/purine combination) and the identity of the bases within the pair (G, A, T, or C). All of the four models considered here underscore the complexity of the dependence of dynamics on DNA sequence with certain sequences not satisfactorily explainable in terms of any dinucleotide model. These findings provide a quantitative basis for interpreting the dynamics and kinetics of DNA-sequence-dependent biological processes, including protein recognition and chromatin packaging. PMID:12496111

  19. Preliminary Investigation of Microdosimetric Track Structure Physics Models in Geant4-DNA and RITRACKS

    PubMed Central

    Bezak, Eva

    2015-01-01

    The major differences between the physics models in Geant4-DNA and RITRACKS Monte Carlo packages are investigated. Proton and electron ionisation interactions and electron excitation interactions in water are investigated in the current work. While these packages use similar semiempirical physics models for inelastic cross-sections, the implementation of these models is demonstrated to be significantly different. This is demonstrated in a simple Monte Carlo simulation designed to identify differences in interaction cross-sections. PMID:26124856

  20. The activity of an anti-allergic compound, proxicromil, on models of immunity and inflammation.

    PubMed

    Keogh, R W; Bundick, R V; Cunnington, P G; Jenkins, S N; Blackham, A; Orr, T S

    1981-07-01

    A tricyclic chromone, proxicromil (sodium 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-naphtho (2,3-b) pyran-2-carboxylate), has been tested for activity against certain immunological and inflammatory reactions. When given parenterally it suppressed the development of delayed hypersensitivity reactions in sensitized mice and guinea-pigs but did not affect the rejection of skin allografts in mice. The compound had no activity against certain in vitro correlates of delayed hypersensitivity reactions (lymphocyte transformation and lymphokine activity), but did have an inhibitory effect on lymphokine (MIF) productions at 10(-4) M but not at 10(-5) M. Proxicromil was also found to be active in non-immunologically mediated models of inflammation and in models having an immunological component which are known to be sensitive to non-steroidal anti-inflammatory drugs (adjuvant arthritis, reversed passive Arthus reaction). The activity of this compound was enhanced when administered in arachis oil when compared to its activity in saline. Proxicromil has not direct activity on the development of immune responsiveness but appear to suppress the expression of delayed hypersensitivity and immune complex mediated hypersensitivity reactions by virtue and its anti-inflammatory properties. This activity is not associated with inhibition of cyclo-oxygenase.

  1. Molecular dynamics in polymers, polymer networks, and model compounds by dielectric relaxation spectroscopy

    NASA Astrophysics Data System (ADS)

    Fitz, Benjamin David

    Segmental dynamics are investigated in model compounds, polymers, and network-forming polymers. Two aspects of these materials are investigated: (1) the role of molecular structure and connectivity on determining the characteristics of the segmental relaxation, and (2) monitoring the variations in the segmental dynamics during network-forming chemical reactions. We quantify the most important aspects of the dynamics: the relaxation shape, the relaxation strength, the relaxation time, and the temperature dependencies of these properties. Additionally, two general segmental dynamics issues of interest are the length-scale and the homogeneous/heterogeneous aspects. A judicious choice of network-forming polymer provides for the determination of an upper bound on the length-scale. A comparison of relaxation characteristics between dynamic light scattering (measuring density fluctuations) and dielectric relaxation spectroscopy (measuring segmental dipolar reorientation) provides one evaluation of the heterogeneity issue. Dipole dynamics in small molecule model compounds show the influence of molecular connectivity on the cooperative molecular response associated with the glass transition. A rigid, nonpolar, cyanate ester network is shown to develop an anomalous relaxation process during crosslinking. A specific local mode of motion is assigned. Additionally, the main relaxation becomes extraordinarily broad during the course of the network formation, due to markedly increased segmental rigidity and loss of configurational entropy.

  2. Reaction pathways for the deoxygenation of vegetable oils and related model compounds.

    PubMed

    Gosselink, Robert W; Hollak, Stefan A W; Chang, Shu-Wei; van Haveren, Jacco; de Jong, Krijn P; Bitter, Johannes H; van Es, Daan S

    2013-09-01

    Vegetable oil-based feeds are regarded as an alternative source for the production of fuels and chemicals. Paraffins and olefins can be produced from these feeds through catalytic deoxygenation. The fundamentals of this process are mostly studied by using model compounds such as fatty acids, fatty acid esters, and specific triglycerides because of their structural similarity to vegetable oils. In this Review we discuss the impact of feedstock, reaction conditions, and nature of the catalyst on the reaction pathways of the deoxygenation of vegetable oils and its derivatives. As such, we conclude on the suitability of model compounds for this reaction. It is shown that the type of catalyst has a significant effect on the deoxygenation pathway, that is, group 10 metal catalysts are active in decarbonylation/decarboxylation whereas metal sulfide catalysts are more selective to hydrodeoxygenation. Deoxygenation studies performed under H2 showed similar pathways for fatty acids, fatty acid esters, triglycerides, and vegetable oils, as mostly deoxygenation occurs indirectly via the formation of fatty acids. Deoxygenation in the absence of H2 results in significant differences in reaction pathways and selectivities depending on the feedstock. Additionally, using unsaturated feedstocks under inert gas results in a high selectivity to undesired reactions such as cracking and the formation of heavies. Therefore, addition of H2 is proposed to be essential for the catalytic deoxygenation of vegetable oil feeds.

  3. Investigation of the influence of vanadium compounds treatment in NZO mice model--preliminary study.

    PubMed

    Krośniak, Mirosław; Francik, Renata; Kołodziejczyk, Katarzyna; Wojtanowska-Krośniak, Agnieszka; Tedeschi, Cinzia; Petrone, Veronica; Gryboś, Ryszard

    2014-01-01

    Abstract: New Zealand obese mice (NZO) are characterized by symptoms similar to human metabolic syndrome. Vanadium in different investigations showed anti-diabetic activity but until now an NZO mice model has not been tested with this element. The aim of this study was to investigate anti-diabetic activity of three vanadium compounds (VOSO4, VO(mal)2 and Na(VO(O2)2bpy) x 8H2O) in the NZO model. Metabolic syndrome was induced by special diet (1.5% of cholesterol and 15% of saturated fatty acids) during 8 weeks. In the next 5 weeks, the tested vanadium compounds were administered once daily, in a dose of 0.063 mmol/kg of body mass. At the end of the experiment, glucose, cholesterol, triglycerides and alanine transaminase were measured in the serum. The obtained results showed that the glucose level was decreased nearly to the healthy NZO mice in comparison to the NZO mice with metabolic syndrome. In all groups on the diet with cholesterol, the level of this parameter was statistically higher in comparison to the group without cholesterol addition. Vanadium treatment in a dose 0.063 mmol/kg of body mass does not influence cholesterol, triglycerides and alanine transaminase activity.

  4. Saturation magnetization of Ni(II) in metalloproteins and model compounds

    SciTech Connect

    Sendova, M.; Day, E.P.; Kiick, K.; Johnson, M.; Ma, L.; Scott, B.; Hausinger, R.; Todd, M.; Peterson, J. Univ. of Georgia, Athens Michigan State Univ., East Lansing Univ. of Alabama, Tuscaloosa )

    1992-01-01

    The Ni(II) sites of urease (from Klebsiella aerogenes and jack bean), coenzyme F[sub 430] (from Methanobacterium thermoautotrophicum), and several model compounds having octahedral symmetry have been studied using the saturation megnetization technique. Data were collected at four fixed fields over the temperature range from 2 - 200K. Theoretical curves calculated from the spin Hamiltonian were used to fit the experimentally obtained magnetization curves. The following parameters were determined: the spine state (S), the amount of the sample in this spin state ([S]), the gyromagnetic ratio (g), and the zero field splitting parameters (D, E/D). The amount of S=1 paramagnetism of the Ni(II) sites was found to depend on the pH of the buffer and on the concentration of the protein in D[sub 2]O (for coenzyme F[sub 430]). The relationship of the strength of the ligand field to the zero field splitting parameter was studied for the model compounds. There was no evidence for exchange coupling between the two Ni(II) ions at the active sites of either plant or bacterial urease.

  5. Biodesulfurization of model compounds and de-asphalted bunker oil by mixed culture.

    PubMed

    Jiang, Xia; Yang, Senlin; Li, Wangling

    2014-01-01

    In this study, complicated model sulfur compounds in bunker oil and de-asphalted bunker oil were biodesulfurized in a batch process by microbial consortium enriched from oil sludge. Dibenzothiophene (DBT) and benzo[b]naphtho[1,2-d]thiophene (BNT1) were selected as model sulfur compounds. The results show that the mixed culture was able to grow by utilizing DBT and BNT1 as the sole sulfur source, while the cell density was higher using DBT than BNT1 as the sulfur source. GC-MS analysis of their desulfurized metabolites indicates that both DBT and BNT1 could be desulfurized through the sulfur-specific degradation pathway with the selective cleavage of carbon-sulfur bonds. When DBT and BNT1 coexisted, the biodesulfurization efficiency of BNT1 decreased significantly as the DBT concentrations increased (>0.1 mmol/L). BNT1 desulfurization efficiency also decreased along with the increase of 2-hydroxybiphenyl as the end product of DBT desulfurization. For real bunker oil, only 2.8 % of sulfur was removed without de-asphalting after 7 days of biotreatment. After de-asphalting, the biodesulfurization efficiency was significantly improved (26.2-36.5 %), which is mainly attributed to fully mixing of the oil and water due to the decreased viscosity of bunker oil. PMID:24046256

  6. Compounds from Silicones Alter Enzyme Activity in Curing Barnacle Glue and Model Enzymes

    PubMed Central

    Rittschof, Daniel; Orihuela, Beatriz; Harder, Tilmann; Stafslien, Shane; Chisholm, Bret; Dickinson, Gary H.

    2011-01-01

    Background Attachment strength of fouling organisms on silicone coatings is low. We hypothesized that low attachment strength on silicones is, in part, due to the interaction of surface available components with natural glues. Components could alter curing of glues through bulk changes or specifically through altered enzyme activity. Methodology/Principal Findings GC-MS analysis of silicone coatings showed surface-available siloxanes when the coatings were gently rubbed with a cotton swab for 15 seconds or given a 30 second rinse with methanol. Mixtures of compounds were found on 2 commercial and 8 model silicone coatings. The hypothesis that silicone components alter glue curing enzymes was tested with curing barnacle glue and with commercial enzymes. In our model, barnacle glue curing involves trypsin-like serine protease(s), which activate enzymes and structural proteins, and a transglutaminase which cross-links glue proteins. Transglutaminase activity was significantly altered upon exposure of curing glue from individual barnacles to silicone eluates. Activity of purified trypsin and, to a greater extent, transglutaminase was significantly altered by relevant concentrations of silicone polymer constituents. Conclusions/Significance Surface-associated silicone compounds can disrupt glue curing and alter enzyme properties. Altered curing of natural glues has potential in fouling management. PMID:21379573

  7. LakeVOC; A Deterministic Model to Estimate Volatile Organic Compound Concentrations in Reservoirs and Lakes

    USGS Publications Warehouse

    Bender, David A.; Asher, William E.; Zogorski, John S.

    2003-01-01

    This report documents LakeVOC, a model to estimate volatile organic compound (VOC) concentrations in lakes and reservoirs. LakeVOC represents the lake or reservoir as a two-layer system and estimates VOC concentrations in both the epilimnion and hypolimnion. The air-water flux of a VOC is characterized in LakeVOC in terms of the two-film model of air-water exchange. LakeVOC solves the system of coupled differential equations for the VOC concentration in the epilimnion, the VOC concentration in the hypolimnion, the total mass of the VOC in the lake, the volume of the epilimnion, and the volume of the hypolimnion. A series of nine simulations were conducted to verify LakeVOC representation of mixing, dilution, and gas exchange characteristics in a hypothetical lake, and two additional estimates of lake volume and MTBE concentrations were done in an actual reservoir under environmental conditions. These 11 simulations showed that LakeVOC correctly handled mixing, dilution, and gas exchange. The model also adequately estimated VOC concentrations within the epilimnion in an actual reservoir with daily input parameters. As the parameter-input time scale increased (from daily to weekly to monthly, for example), the differences between the measured-averaged concentrations and the model-estimated concentrations generally increased, especially for the hypolimnion. This may be because as the time scale is increased from daily to weekly to monthly, the averaging of model inputs may cause a loss of detail in the model estimates.

  8. Stoichiometric modeling of oxidation of reduced inorganic sulfur compounds (Riscs) in Acidithiobacillus thiooxidans.

    PubMed

    Bobadilla Fazzini, Roberto A; Cortés, Maria Paz; Padilla, Leandro; Maturana, Daniel; Budinich, Marko; Maass, Alejandro; Parada, Pilar

    2013-08-01

    The prokaryotic oxidation of reduced inorganic sulfur compounds (RISCs) is a topic of utmost importance from a biogeochemical and industrial perspective. Despite sulfur oxidizing bacterial activity is largely known, no quantitative approaches to biological RISCs oxidation have been made, gathering all the complex abiotic and enzymatic stoichiometry involved. Even though in the case of neutrophilic bacteria such as Paracoccus and Beggiatoa species the RISCs oxidation systems are well described, there is a lack of knowledge for acidophilic microorganisms. Here, we present the first experimentally validated stoichiometric model able to assess RISCs oxidation quantitatively in Acidithiobacillus thiooxidans (strain DSM 17318), the archetype of the sulfur oxidizing acidophilic chemolithoautotrophs. This model was built based on literature and genomic analysis, considering a widespread mix of formerly proposed RISCs oxidation models combined and evaluated experimentally. Thiosulfate partial oxidation by the Sox system (SoxABXYZ) was placed as central step of sulfur oxidation model, along with abiotic reactions. This model was coupled with a detailed stoichiometry of biomass production, providing accurate bacterial growth predictions. In silico deletion/inactivation highlights the role of sulfur dioxygenase as the main catalyzer and a moderate function of tetrathionate hydrolase in elemental sulfur catabolism, demonstrating that this model constitutes an advanced instrument for the optimization of At. thiooxidans biomass production with potential use in biohydrometallurgical and environmental applications.

  9. Prediction model of the buildup of volatile organic compounds on urban roads.

    PubMed

    Mahbub, Parvez; Goonetilleke, Ashantha; Ayoko, Godwin A

    2011-05-15

    A model to predict the buildup of mainly traffic-generated volatile organic compounds or VOCs (toluene, ethylbenzene, ortho-xylene, meta-xylene, and para-xylene) on urban road surfaces is presented. The model required three traffic parameters, namely average daily traffic (ADT), volume to capacity ratio (V/C), and surface texture depth (STD), and two chemical parameters, namely total suspended solid (TSS) and total organic carbon (TOC), as predictor variables. Principal component analysis and two phase factor analysis were performed to characterize the model calibration parameters. Traffic congestion was found to be the underlying cause of traffic-related VOC buildup on urban roads. The model calibration was optimized using orthogonal experimental design. Partial least squares regression was used for model prediction. It was found that a better optimized orthogonal design could be achieved by including the latent factors of the data matrix into the design. The model performed fairly accurately for three different land uses as well as five different particle size fractions. The relative prediction errors were 10-40% for the different size fractions and 28-40% for the different land uses while the coefficients of variation of the predicted intersite VOC concentrations were in the range of 25-45% for the different size fractions. Considering the sizes of the data matrices, these coefficients of variation were within the acceptable interlaboratory range for analytes at ppb concentration levels.

  10. Modeling of DNA-Directed Colloidal Self-Assembly and Crystallization

    NASA Astrophysics Data System (ADS)

    Li, Ting; Sknepnek, Rastko; Macfarlane, Robert J.; Mirkin, Chad A.; Olvera de La Cruz, Monica

    2012-02-01

    A series of design rules have recently been developed for using gold nanoparticles conjugated with a dense layer of double stranded DNA chains to assemble a wide variety of nanoparticle superlattice structures [1]. Key design parameters for obtaining different structures in a binary system were shown to be the ratio of the hydrodynamic radii of the DNA-conjugated particles, the ratio of the number of DNA strands per particle, and the self- or non-self-complementary nature of the DNA sequences guiding the assembly process. Guided by those experiments, we have built a coarse grained model that faithfully mimics relative design parameters in the experimental system. Working with nanoparticles in the size range from 8nm to 15nm, overall DNA-nanoparticle hydrodynamic radii of 10nm to 30nm, and the number of DNA strands per particle between 30 and 100, we have developed a simulation method that confirms that these design rules can be used to assemble a variety of different crystal structures. In particular, we have identified FCC, BCC, CsCl, AlB2 and Cr3Si structures. With these data, we have constructed a detailed phase diagram that closely corresponds to the experimentally obtained phase diagram developed in ref. [1]. [1] R. J. Macfarlane, B. Lee, M. R. Jones, N. Harris, G.

  11. A one-dimensional statistical mechanics model for nucleosome positioning on genomic DNA.

    PubMed

    Tesoro, S; Ali, I; Morozov, A N; Sulaiman, N; Marenduzzo, D

    2016-02-01

    The first level of folding of DNA in eukaryotes is provided by the so-called '10 nm chromatin fibre', where DNA wraps around histone proteins (∼10 nm in size) to form nucleosomes, which go on to create a zig-zagging bead-on-a-string structure. In this work we present a one-dimensional statistical mechanics model to study nucleosome positioning within one such 10 nm fibre. We focus on the case of genomic sheep DNA, and we start from effective potentials valid at infinite dilution and determined from high-resolution in vitro salt dialysis experiments. We study positioning within a polynucleosome chain, and compare the results for genomic DNA to that obtained in the simplest case of homogeneous DNA, where the problem can be mapped to a Tonks gas. First, we consider the simple, analytically solvable, case where nucleosomes are assumed to be point-like. Then, we perform numerical simulations to gauge the effect of their finite size on the nucleosomal distribution probabilities. Finally we compare nucleosome distributions and simulated nuclease digestion patterns for the two cases (homogeneous and sheep DNA), thereby providing testable predictions of the effect of sequence on experimentally observable quantities in experiments on polynucleosome chromatin fibres reconstituted in vitro. PMID:26871546

  12. Probing the interaction of anthraquinone with DNA by spectroscopy, molecular modeling and cancer cell imaging technique.

    PubMed

    Yang, Lei; Fu, Zheng; Niu, Xiaoqing; Zhang, Guisheng; Cui, Fengling; Zhou, Chunwu

    2015-05-25

    A new anthraquinone derivative, (E)-2-(1-(4,5-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-2-yloxyimino)ethyl)-1,4-dihydroxyanthracene-9,10-dione (AODGlc), was synthesized and its binding properties towards DNA were explored under physiological conditions by fluorescence spectroscopy, DNA melting as well as docking techniques. The experimental results revealed that AODGlc could bind to calf thymus DNA (ctDNA) through intercalation between DNA base pairs. The values of thermodynamic parameters at different temperatures including ΔG, ΔH, and ΔS and the molecular modeling study implied that hydrophobic interactions and hydrogen bonds were the main interactions in the AODGlc-ctDNA system. Cervical cancer cells (HepG2 cells) were used in cell viability assay and cell imaging experiment. AODGlc could interact with HepG2 cells and kill HepG2 cells under high concentration with nice curative effect, indicating its potential bioapplication in the future.

  13. A one-dimensional statistical mechanics model for nucleosome positioning on genomic DNA

    NASA Astrophysics Data System (ADS)

    Tesoro, S.; Ali, I.; Morozov, A. N.; Sulaiman, N.; Marenduzzo, D.

    2016-02-01

    The first level of folding of DNA in eukaryotes is provided by the so-called ‘10 nm chromatin fibre’, where DNA wraps around histone proteins (∼10 nm in size) to form nucleosomes, which go on to create a zig-zagging bead-on-a-string structure. In this work we present a one-dimensional statistical mechanics model to study nucleosome positioning within one such 10 nm fibre. We focus on the case of genomic sheep DNA, and we start from effective potentials valid at infinite dilution and determined from high-resolution in vitro salt dialysis experiments. We study positioning within a polynucleosome chain, and compare the results for genomic DNA to that obtained in the simplest case of homogeneous DNA, where the problem can be mapped to a Tonks gas [1]. First, we consider the simple, analytically solvable, case where nucleosomes are assumed to be point-like. Then, we perform numerical simulations to gauge the effect of their finite size on the nucleosomal distribution probabilities. Finally we compare nucleosome distributions and simulated nuclease digestion patterns for the two cases (homogeneous and sheep DNA), thereby providing testable predictions of the effect of sequence on experimentally observable quantities in experiments on polynucleosome chromatin fibres reconstituted in vitro.

  14. A one-dimensional statistical mechanics model for nucleosome positioning on genomic DNA.

    PubMed

    Tesoro, S; Ali, I; Morozov, A N; Sulaiman, N; Marenduzzo, D

    2016-02-01

    The first level of folding of DNA in eukaryotes is provided by the so-called '10 nm chromatin fibre', where DNA wraps around histone proteins (∼10 nm in size) to form nucleosomes, which go on to create a zig-zagging bead-on-a-string structure. In this work we present a one-dimensional statistical mechanics model to study nucleosome positioning within one such 10 nm fibre. We focus on the case of genomic sheep DNA, and we start from effective potentials valid at infinite dilution and determined from high-resolution in vitro salt dialysis experiments. We study positioning within a polynucleosome chain, and compare the results for genomic DNA to that obtained in the simplest case of homogeneous DNA, where the problem can be mapped to a Tonks gas. First, we consider the simple, analytically solvable, case where nucleosomes are assumed to be point-like. Then, we perform numerical simulations to gauge the effect of their finite size on the nucleosomal distribution probabilities. Finally we compare nucleosome distributions and simulated nuclease digestion patterns for the two cases (homogeneous and sheep DNA), thereby providing testable predictions of the effect of sequence on experimentally observable quantities in experiments on polynucleosome chromatin fibres reconstituted in vitro.

  15. Hysteresis in DNA compaction by Dps is described by an Ising model.

    PubMed

    Vtyurina, Natalia N; Dulin, David; Docter, Margreet W; Meyer, Anne S; Dekker, Nynke H; Abbondanzieri, Elio A

    2016-05-01

    In all organisms, DNA molecules are tightly compacted into a dynamic 3D nucleoprotein complex. In bacteria, this compaction is governed by the family of nucleoid-associated proteins (NAPs). Under conditions of stress and starvation, an NAP called Dps (DNA-binding protein from starved cells) becomes highly up-regulated and can massively reorganize the bacterial chromosome. Although static structures of Dps-DNA complexes have been documented, little is known about the dynamics of their assembly. Here, we use fluorescence microscopy and magnetic-tweezers measurements to resolve the process of DNA compaction by Dps. Real-time in vitro studies demonstrated a highly cooperative process of Dps binding characterized by an abrupt collapse of the DNA extension, even under applied tension. Surprisingly, we also discovered a reproducible hysteresis in the process of compaction and decompaction of the Dps-DNA complex. This hysteresis is extremely stable over hour-long timescales despite the rapid binding and dissociation rates of Dps. A modified Ising model is successfully applied to fit these kinetic features. We find that long-lived hysteresis arises naturally as a consequence of protein cooperativity in large complexes and provides a useful mechanism for cells to adopt unique epigenetic states.

  16. Femtosecond to microsecond photochemistry of a [FeFe]hydrogenase enzyme model compound.

    PubMed

    Kaziannis, Spyridon; Santabarbara, Stefano; Wright, Joseph A; Greetham, Gregory M; Towrie, Michael; Parker, Anthony W; Pickett, Christopher J; Hunt, Neil T

    2010-11-25

    The photochemistry and dynamics of a model compound of the active site of the [FeFe]hydrogenase enzyme system have been studied on a wide range of time scales using a unique combination of femtosecond time-resolved infrared spectroscopy, nanosecond time-resolved infrared spectroscopy, and steady-state UV-FTIR methods. Using three different solvents, heptane, acetonitrile, and cyanoheptane, we have observed the rapid formation of solvent adduct species from the first solvation shell of the solute following photolysis of a carbonyl ligand and global fitting techniques have been employed to provide new insights into the ultrafast dynamics of this process. In addition, the use of solvent mixtures has enabled the observation of competitive ligand substitution processes at the newly created coordination site on time scales of a few nanoseconds, shedding new light on the chemical behavior of these enzyme models.

  17. NMR structural study of the prototropic equilibrium in solution of Schiff bases as model compounds.

    PubMed

    Ortegón-Reyna, David; Garcías-Morales, Cesar; Padilla-Martínez, Itzia; García-Báez, Efren; Aríza-Castolo, Armando; Peraza-Campos, Ana; Martínez-Martínez, Francisco

    2013-12-31

    An NMR titration method has been used to simultaneously measure the acid dissociation constant (pKa) and the intramolecular NHO prototropic constant ΔKNHO on a set of Schiff bases. The model compounds were synthesized from benzylamine and substituted ortho-hydroxyaldehydes, appropriately substituted with electron-donating and electron-withdrawing groups to modulate the acidity of the intramolecular NHO hydrogen bond. The structure in solution was established by 1H-, 13C- and 15N-NMR spectroscopy. The physicochemical parameters of the intramolecular NHO hydrogen bond (pKa, ΔKNHO and ΔΔG°) were obtained from 1H-NMR titration data and pH measurements. The Henderson-Hasselbalch data analysis indicated that the systems are weakly acidic, and the predominant NHO equilibrium was established using Polster-Lachmann δ-diagram analysis and Perrin model data linearization.

  18. Genomic Survey, Gene Expression Analysis and Structural Modeling Suggest Diverse Roles of DNA Methyltransferases in Legumes

    PubMed Central

    Garg, Rohini; Kumari, Romika; Tiwari, Sneha; Goyal, Shweta

    2014-01-01

    DNA methylation plays a crucial role in development through inheritable gene silencing. Plants possess three types of DNA methyltransferases (MTases), namely Methyltransferase (MET), Chromomethylase (CMT) and Domains Rearranged Methyltransferase (DRM), which maintain methylation at CG, CHG and CHH sites. DNA MTases have not been studied in legumes so far. Here, we report the identification and analysis of putative DNA MTases in five legumes, including chickpea, soybean, pigeonpea, Medicago and Lotus. MTases in legumes could be classified in known MET, CMT, DRM and DNA nucleotide methyltransferases (DNMT2) subfamilies based on their domain organization. First three MTases represent DNA MTases, whereas DNMT2 represents a transfer RNA (tRNA) MTase. Structural comparison of all the MTases in plants with known MTases in mammalian and plant systems have been reported to assign structural features in context of biological functions of these proteins. The structure analysis clearly specified regions crucial for protein-protein interactions and regions important for nucleosome binding in various domains of CMT and MET proteins. In addition, structural model of DRM suggested that circular permutation of motifs does not have any effect on overall structure of DNA methyltransferase domain. These results provide valuable insights into role of various domains in molecular recognition and should facilitate mechanistic understanding of their function in mediating specific methylation patterns. Further, the comprehensive gene expression analyses of MTases in legumes provided evidence of their role in various developmental processes throughout the plant life cycle and response to various abiotic stresses. Overall, our study will be very helpful in establishing the specific functions of DNA MTases in legumes. PMID:24586452

  19. Application of a source apportionment model in consideration of volatile organic compounds in an urban stream

    USGS Publications Warehouse

    Asher, W.E.; Luo, W.; Campo, K.W.; Bender, D.A.; Robinson, K.W.; Zogorski, J.S.; Pankow, J.F.

    2007-01-01

    Position-dependent concentrations of trichloroethylene and methyl-tert-butyl ether are considered for a 2.81-km section of the Aberjona River in Massachusetts, USA. This river flows through Woburn and Winchester (Massachusetts, USA), an area that is highly urbanized, has a long history of industrial activities dating to the early 1800s, and has gained national attention because of contamination from chlorinated solvent compounds in Woburn wells G and H. The river study section is in Winchester and begins approximately five stream kilometers downstream from the Woburn wells superfund site. Approximately 300 toxic release sites are documented in the watershed upstream from the terminus of the study section. The inflow to the river study section is considered one source of contamination. Other sources are the atmosphere, a tributary flow, and groundwater flows entering the river; the latter are categorized according to stream zone (1, 2, 3, etc.). Loss processes considered include outflows to groundwater and water-to-atmosphere transfer of volatile compounds. For both trichloroethylene and methyl-rerf-butyl ether, degradation is neglected over the timescale of interest. Source apportionment fractions with assigned values ??inflow, ??1, ??2, ??3, etc. are tracked by a source apportionment model. The strengths of the groundwater and tributary sources serve as fitting parameters when minimizing a reduced least squares statistic between water concentrations measured during a synoptic study in July 2001 versus predictions from the model. The model fits provide strong evidence of substantial unknown groundwater sources of trichloroethylene and methyl-tert-butyl ether amounting to tens of grams per day of trichloroethylene and methyl-tert-butyl ether in the river along the study section. Modeling in a source apportionment manner can be useful to water quality managers allocating limited resources for remediation and source control. ?? 2007 SETAC.

  20. Application of a source apportionment model in consideration of volatile organic compounds in an urban stream.

    PubMed

    Asher, William E; Luo, Wentai; Campo, Kimberly W; Bender, David A; Robinson, Keith W; Zogorski, John S; Pankow, James F

    2007-08-01

    Position-dependent concentrations of trichloroethylene and methyl-tert-butyl ether are considered for a 2.81-km section of the Aberjona River in Massachusetts, USA. This river flows through Woburn and Winchester (Massachusetts, USA), an area that is highly urbanized, has a long history of industrial activities dating to the early 1800s, and has gained national attention because of contamination from chlorinated solvent compounds in Woburn wells G and H. The river study section is in Winchester and begins approximately five stream kilometers downstream from the Woburn wells superfund site. Approximately 300 toxic release sites are documented in the watershed upstream from the terminus of the study section. The inflow to the river study section is considered one source of contamination. Other sources are the atmosphere, a tributary flow, and groundwater flows entering the river; the latter are categorized according to stream zone (1, 2, 3, etc.). Loss processes considered include outflows to groundwater and water-to-atmosphere transfer of volatile compounds. For both trichloroethylene and methyl-tert-butyl ether, degradation is neglected over the timescale of interest. Source apportionment fractions with assigned values alphainflow, alpha2, alpha3, etc. are tracked by a source apportionment model. The strengths of the groundwater and tributary sources serve as fitting parameters when minimizing a reduced least squares statistic between water concentrations measured during a synoptic study in July 2001 versus predictions from the model. The model fits provide strong evidence of substantial unknown groundwater sources of trichloroethylene and methyl-tert-butyl ether amounting to tens of grams per day of trichloroethylene and methyl-tert-butyl ether in the river along the study section. Modeling in a source apportionment manner can be useful to water quality managers allocating limited resources for remediation and source control.

  1. Chronic hepatitis B infection and HBV DNA-containing capsids: Modeling and analysis

    NASA Astrophysics Data System (ADS)

    Manna, Kalyan; Chakrabarty, Siddhartha P.

    2015-05-01

    We analyze the dynamics of chronic HBV infection taking into account both uninfected and infected hepatocytes along with the intracellular HBV DNA-containing capsids and the virions. While previous HBV models have included either the uninfected hepatocytes or the intracellular HBV DNA-containing capsids, our model accounts for both these two populations. We prove the conditions for local and global stability of both the uninfected and infected steady states in terms of the basic reproduction number. Further, we incorporate a time lag in the model to encompass the intracellular delay in the production of the infected hepatocytes and find that this delay does not affect the overall dynamics of the system. The results for the model and the delay model are finally numerically illustrated.

  2. A parsimonious model for the release of volatile organic compounds (VOCs) encapsulated in products

    NASA Astrophysics Data System (ADS)

    Huang, Lei; Jolliet, Olivier

    2016-02-01

    Studies have demonstrated that near-field chemical intakes may exceed environmentally mediated exposures and are therefore essential to be considered when assessing chemical emissions across a product's life cycle. VOCs encapsulated in materials/products can be a major emission source in the use phase. Previous models describing such emissions require complex analytical or numerical solutions, which poses a great computational burden and lack transparency for use in high-throughput screening of chemicals. In the present study, we adapted a model which describes VOC emissions from building materials and subsequent removal by ventilation, and decoupled the material and air governing equations by assuming a pseudo-steady-state between emission and loss. Results of this decoupled model show good agreement with the original more complex model and the experimental data. The solution of this decoupled model for mass fraction emitted, which still consists of an infinite sum of exponential terms, is further reduced to a sum of only two exponentials with parameters which can be predicted from physiochemical properties using explicit equations. Results of this simple two-exponential model agree well with the original full model over a 15-year time period with R-square greater than 0.99 for a wide range of compounds and material thicknesses. Moreover, the chemical concentration at the material surface can be simply calculated from the derivative of this two-exponential model, which also agrees well with the surface concentration calculated using the original full model. The present parsimonious approach greatly reduces the computational burden, and can be easily implemented for high-throughput screening.

  3. Aqueous and Tissue Residue-Based Interspecies Correlation Estimation Models Provide Conservative Hazard Estimates for Aromatic Compounds

    EPA Science Inventory

    Interspecies correlation estimation (ICE) models were developed for 30 nonpolar aromatic compounds to allow comparison of prediction accuracy between 2 data compilation approaches. Type 1 models used data combined across studies, and type 2 models used data combined only within s...

  4. VOLATILE ORGANIC COMPOUND EMISSIONS FROM LATEX PAINT-PART 2. TEST HOUSE STUDIES AND INDOOR AIR QUALITY (IAQ) MODELING

    EPA Science Inventory

    Emission models developed using small chamber data were combined with an Indoor Air Quality (IAQ) model to analyze the impact of volatile organic compound (VOC) emissions from latex paint on indoor environments. Test house experiments were conducted to verify the IAQ model's pred...

  5. Sub-Terrahertz Spectroscopy of E.COLI Dna: Experiment, Statistical Model, and MD Simulations

    NASA Astrophysics Data System (ADS)

    Sizov, I.; Dorofeeva, T.; Khromova, T.; Gelmont, B.; Globus, T.

    2012-06-01

    We will present result of combined experimental and computational study of sub-THz absorption spectra from Escherichia coli (E.coli) DNA. Measurements were conducted using a Bruker FTIR spectrometer with a liquid helium cooled bolometer and a recently developed frequency domain sensor operating at room temperature, with spectral resolution of 0.25 cm-1 and 0.03 cm-1, correspondingly. We have earlier demonstrated that molecular dynamics (MD) simulation can be effectively applied for characterizing relatively small biological molecules, such as transfer RNA or small protein thioredoxin from E. coli , and help to understand and predict their absorption spectra. Large size of DNA macromolecules ( 5 million base pairs for E. coli DNA) prevents, however, direct application of MD simulation at the current level of computational capabilities. Therefore, by applying a second order Markov chain approach and Monte-Carlo technique, we have developed a new statistical model to construct DNA sequences from biological cells. These short representative sequences (20-60 base pairs) are built upon the most frequently repeated fragments (2-10 base pairs) in the original DNA. Using this new approach, we constructed DNA sequences for several non-pathogenic strains of E.coli, including a well-known strain BL21, uro-pathogenic strain, CFT073, and deadly EDL933 strain (O157:H7), and used MD simulations to calculate vibrational absorption spectra of these strains. Significant differences are clearly present in spectra of strains in averaged spectra and in all components for particular orientations. The mechanism of interaction of THz radiation with a biological molecule is studied by analyzing dynamics of atoms and correlation of local vibrations in the modeled molecule. Simulated THz vibrational spectra of DNA are compared with experimental results. With the spectral resolution of 0.1 cm-1 or better, which is now available in experiments, the very easy discrimination between different

  6. Exploring the common molecular basis for the universal DNA mutation bias: Revival of Loewdin mutation model

    SciTech Connect

    Fu, Liang-Yu; Wang, Guang-Zhong; Ma, Bin-Guang; Zhang, Hong-Yu

    2011-06-10

    Highlights: {yields} There exists a universal G:C {yields} A:T mutation bias in three domains of life. {yields} This universal mutation bias has not been sufficiently explained. {yields} A DNA mutation model proposed by Loewdin 40 years ago offers a common explanation. -- Abstract: Recently, numerous genome analyses revealed the existence of a universal G:C {yields} A:T mutation bias in bacteria, fungi, plants and animals. To explore the molecular basis for this mutation bias, we examined the three well-known DNA mutation models, i.e., oxidative damage model, UV-radiation damage model and CpG hypermutation model. It was revealed that these models cannot provide a sufficient explanation to the universal mutation bias. Therefore, we resorted to a DNA mutation model proposed by Loewdin 40 years ago, which was based on inter-base double proton transfers (DPT). Since DPT is a fundamental and spontaneous chemical process and occurs much more frequently within GC pairs than AT pairs, Loewdin model offers a common explanation for the observed universal mutation bias and thus has broad biological implications.

  7. The melting phenomenon in random-walk model of DNA

    SciTech Connect

    Hayrapetyan, G. N.; Mamasakhlisov, E. Sh.; Papoyan, Vl. V.; Poghosyan, S. S.

    2012-10-15

    The melting phenomenon in a double-stranded homopolypeptide is considered. The relative distance between the corresponding monomers of two polymer chains is modeled by the two-dimensional random walk on the square lattice. Returns of the random walk to the origin describe the formation of hydrogen bonds between complementary units. To take into account the two competing interactions of monomers inside the chains, we obtain a completely denatured state at finite temperature T{sub c}.

  8. A matter of life or death: modeling DNA damage and repair in bacteria.

    PubMed

    Karschau, Jens; de Almeida, Camila; Richard, Morgiane C; Miller, Samantha; Booth, Ian R; Grebogi, Celso; de Moura, Alessandro P S

    2011-02-16

    DNA damage is a hazard all cells must face, and evolution has created a number of mechanisms to repair damaged bases in the chromosome. Paradoxically, many of these repair mechanisms can create double-strand breaks in the DNA molecule which are fatal to the cell. This indicates that the connection between DNA repair and death is far from straightforward, and suggests that the repair mechanisms can be a double-edged sword. In this report, we formulate a mathematical model of the dynamics of DNA damage and repair, and we obtain analytical expressions for the death rate. We predict a counterintuitive relationship between survival and repair. We can discriminate between two phases: below a critical threshold in the number of repair enzymes, the half-life decreases with the number of repair enzymes, but becomes independent of the number of repair enzymes above the threshold. We are able to predict quantitatively the dependence of the death rate on the damage rate and other relevant parameters. We verify our analytical results by simulating the stochastic dynamics of DNA damage and repair. Finally, we also perform an experiment with Escherichia coli cells to test one of the predictions of our model. PMID:21320424

  9. Chlamydomonas reinhardtii: a convenient model system for the study of DNA repair in photoautotrophic eukaryotes.

    PubMed

    Vlcek, Daniel; Sevcovicová, Andrea; Sviezená, Barbara; Gálová, Eliska; Miadoková, Eva

    2008-01-01

    The green alga Chlamydomonas reinhardtii is a convenient model organism for the study of basic biological processes, including DNA repair investigations. This review is focused on the studies of DNA repair pathways in C. reinhardtii. Emphasis is given to the connection of DNA repair with other cellular functions, namely the regulation of the cell cycle. Comparison with the results of repair investigations that are already available revealed the presence of all basic repair pathways in C. reinhardtii as well as special features characteristic of this alga. Among others, the involvement of UVSE1 gene in recombinational repair and uniparental inheritance of chloroplast genome, the specific role of TRXH1 gene in strand break repair, the requirement of PHR1 gene for full activity of PHR2 gene, or encoding of two excision repair proteins by the single REX1 gene. Contrary to yeast, mammals and higher plants, C. reinhardtii does not appear to contain the ortholog of RAD6 gene, which plays an important role in DNA translesion synthesis and mutagenesis. Completed genome sequences will be a basis for molecular analyses allowing to explain the differences that have been observed in DNA repair of this alga in comparison with other model organisms.

  10. Modeling Human Exposure Levels to Airborne Volatile Organic Compounds by the Hebei Spirit Oil Spill

    PubMed Central

    Kim, Jong Ho; Kwak, Byoung Kyu; Ha, Mina; Cheong, Hae-Kwan

    2012-01-01

    Objectives The goal was to model and quantify the atmospheric concentrations of volatile organic compounds (VOCs) as the result of the Hebei Spirit oil spill, and to predict whether the exposure levels were abnormally high or not. Methods We developed a model for calculating the airborne concentration of VOCs that are produced in an oil spill accident. The model was applied to a practical situation, namely the Hebei Spirit oil spill. The accuracy of the model was verified by comparing the results with previous observation data. The concentrations were compared with the currently used air quality standards. Results Evaporation was found to be 10- to 1,000-fold higher than the emissions produced from a surrounding industrial complex. The modeled concentrations for benzene failed to meet current labor environmental standards, and the concentration of benzene, toluene, ortho- meta- para-xylene were higher than the values specified by air quality standards and guideline values on the ocean. The concentrations of total VOCs were much higher than indoor environmental criteria for the entire Taean area for a few days. Conclusions The extent of airborne exposure was clearly not the same as that for normal conditions. PMID:22468262

  11. A multi-scale model for the analysis of the inhomogeneity of elastic properties of DNA biofilm on microcantilevers.

    PubMed

    Zhang, Neng-Hui; Meng, Wei-Lie; Tan, Zou-Qing

    2013-02-01

    In nanoscale diagnostic systems, inhomogeneity in near-surface systems and flexibility in biostructures greatly influence the mechanical/electrical/thermal properties of biosensors and resultant detection signals. This study focuses on inhomogeneity and flexibility of DNA biofilm and characterizes its local interactions and mechanical properties. First, a flexible cylinder model of DNA chain is employed to capture the local geometric deformation characteristics of DNA molecules on microcantilever. In order to describe the inhomogeneous properties of DNA biofilm at thickness direction, the Strey's empirical formula for mesoscopic DNA liquid crystal theory is improved with the assumption of a net charge distribution in film. The model parameters are obtained by curve fitting with experimental data. Second, the biaxial iso-strain compression of thought experiment and the energy conservation law are used to predict macroscopic effective tangent modulus of DNA biofilm in terms of nanoscopic properties of dsDNA, buffer salt concentration. PMID:23228426

  12. Phenolic mediators enhance the manganese peroxidase catalyzed oxidation of recalcitrant lignin model compounds and synthetic lignin.

    PubMed

    Nousiainen, Paula; Kontro, Jussi; Manner, Helmiina; Hatakka, Annele; Sipilä, Jussi

    2014-11-01

    Fungal oxidative enzymes, such as peroxidases and laccases, are the key catalysts in lignin biodegradation in vivo, and consequently provide an important source for industrial ligninolytic biocatalysts. Recently, it has been shown that some syringyl-type phenolics have potential as industrial co-oxidants or mediators, in laccase-catalyzed modification of lignocellulosic material. We have now studied the effect of such mediators with ligninolytic peroxidases on oxidation of the most recalcitrant lignin model compounds. We found that they are able to enhance the manganese peroxidase (MnP) catalyzed oxidation reactions of small non-phenolic compounds, veratryl alcohol and veratrylglycerol β-guaiacyl ether (adlerol), which are not usually oxidized by manganese peroxidases alone. In these experiments we compared two peroxidases from white-rot fungi, MnP from Phlebia sp. Nf b19 and versatile peroxidase (VP) from Bjerkandera adusta under two oxidation conditions: (i) the Mn(III) initiated mediated oxidation by syringyl compounds and (ii) the system involving MnP-dependent lipid peroxidation, both with production of (hydrogen) peroxides in situ to maintain the peroxidase catalytic cycle. It was found that both peroxidases produced α-carbonyl oxidation product of veratryl alcohol in clearly higher yields in reactions mediated by phenoxy radicals than in lipid-peroxyl radical system. The oxidation of adlerol, on the other hand, was more efficient in lipid-peroxidation-system. VP was more efficient than MnP in the oxidation of veratryl alcohol and showed its lignin peroxidase type activity in the reaction conditions indicated by some cleavage of Cα-Cβ-bond of adlerol. Finally, the mediator assisted oxidation conditions were applied in the oxidation of synthetic lignin (DHP) and the structural analysis of the oxidized polymers showed clear modifications in the polymer outcome, e.g. the oxidation resulted in reduced amount of aliphatic hydroxyls indicated by (31)P NMR.

  13. Phenolic mediators enhance the manganese peroxidase catalyzed oxidation of recalcitrant lignin model compounds and synthetic lignin.

    PubMed

    Nousiainen, Paula; Kontro, Jussi; Manner, Helmiina; Hatakka, Annele; Sipilä, Jussi

    2014-11-01

    Fungal oxidative enzymes, such as peroxidases and laccases, are the key catalysts in lignin biodegradation in vivo, and consequently provide an important source for industrial ligninolytic biocatalysts. Recently, it has been shown that some syringyl-type phenolics have potential as industrial co-oxidants or mediators, in laccase-catalyzed modification of lignocellulosic material. We have now studied the effect of such mediators with ligninolytic peroxidases on oxidation of the most recalcitrant lignin model compounds. We found that they are able to enhance the manganese peroxidase (MnP) catalyzed oxidation reactions of small non-phenolic compounds, veratryl alcohol and veratrylglycerol β-guaiacyl ether (adlerol), which are not usually oxidized by manganese peroxidases alone. In these experiments we compared two peroxidases from white-rot fungi, MnP from Phlebia sp. Nf b19 and versatile peroxidase (VP) from Bjerkandera adusta under two oxidation conditions: (i) the Mn(III) initiated mediated oxidation by syringyl compounds and (ii) the system involving MnP-dependent lipid peroxidation, both with production of (hydrogen) peroxides in situ to maintain the peroxidase catalytic cycle. It was found that both peroxidases produced α-carbonyl oxidation product of veratryl alcohol in clearly higher yields in reactions mediated by phenoxy radicals than in lipid-peroxyl radical system. The oxidation of adlerol, on the other hand, was more efficient in lipid-peroxidation-system. VP was more efficient than MnP in the oxidation of veratryl alcohol and showed its lignin peroxidase type activity in the reaction conditions indicated by some cleavage of Cα-Cβ-bond of adlerol. Finally, the mediator assisted oxidation conditions were applied in the oxidation of synthetic lignin (DHP) and the structural analysis of the oxidized polymers showed clear modifications in the polymer outcome, e.g. the oxidation resulted in reduced amount of aliphatic hydroxyls indicated by (31)P NMR. PMID

  14. Overlapping gene expression profiles of model compounds provide opportunities for immunotoxicity screening

    SciTech Connect

    Baken, Kirsten A. Pennings, Jeroen L.A.; Jonker, Martijs J.; Schaap, Mirjam M.; Vries, Annemieke de; Steeg, Harry van; Breit, Timo M.; Loveren, Henk van

    2008-01-01

    In order to investigate immunotoxic effects of a set of model compounds in mice, a toxicogenomics approach was combined with information on macroscopical and histopathological effects on spleens and on modulation of immune function. Bis(tri-n-butyltin)oxide (TBTO), cyclosporin A (CsA), and benzo[a]pyrene (B[a]P) were administered to C57BL/6 mice at immunosuppressive dose levels. Acetaminophen (APAP) was included in the study since indications of immunomodulating properties of this compound have appeared in the literature. TBTO exposure caused the most pronounced effect on gene expression and also resulted in the most severe reduction of body weight gain and induction of splenic irregularities. All compounds caused inhibition of cell division in the spleen as shown by microarray analysis as well as by suppression of lymphocyte proliferation after application of a contact sensitizer as demonstrated in an immune function assay that was adapted from the local lymph node assay. The immunotoxicogenomics approach applied in this study thus pointed to immunosuppression through cell cycle arrest as a common mechanism of action of immunotoxicants, including APAP. Genes related to cell division such as Ccna2, Brca1, Birc5, Incenp, and Cdkn1a (p21) were identified as candidate genes to indicate anti-proliferative effects of xenobiotics in immune cells for future screening assays. The results of our experiments also show the value of group wise pathway analysis for detection of more subtle transcriptional effects and the potency of evaluation of effects in the spleen to demonstrate immunotoxicity.

  15. Inhibition of growth of Zymomonas mobilis by model compounds found in lignocellulosic hydrolysates

    PubMed Central

    2013-01-01

    Background During the pretreatment of biomass feedstocks and subsequent conditioning prior to saccharification, many toxic compounds are produced or introduced which inhibit microbial growth and in many cases, production of ethanol. An understanding of the toxic effects of compounds found in hydrolysate is critical to improving sugar utilization and ethanol yields in the fermentation process. In this study, we established a useful tool for surveying hydrolysate toxicity by measuring growth rates in the presence of toxic compounds, and examined the effects of selected model inhibitors of aldehydes, organic and inorganic acids (along with various cations), and alcohols on growth of Zymomonas mobilis 8b (a ZM4 derivative) using glucose or xylose as the carbon source. Results Toxicity strongly correlated to hydrophobicity in Z. mobilis, which has been observed in Escherichia coli and Saccharomyces cerevisiae for aldehydes and with some exceptions, organic acids. We observed Z. mobilis 8b to be more tolerant to organic acids than previously reported, although the carbon source and growth conditions play a role in tolerance. Growth in xylose was profoundly inhibited by monocarboxylic organic acids compared to growth in glucose, whereas dicarboxylic acids demonstrated little or no effects on growth rate in either substrate. Furthermore, cations can be ranked in order of their toxicity, Ca++ > > Na+ > NH4+ > K+. HMF (5-hydroxymethylfurfural), furfural and acetate, which were observed to contribute to inhibition of Z. mobilis growth in dilute acid pretreated corn stover hydrolysate, do not interact in a synergistic manner in combination. We provide further evidence that Z. mobilis 8b is capable of converting the aldehydes furfural, vanillin, 4-hydroxybenzaldehyde and to some extent syringaldehyde to their alcohol forms (furfuryl, vanillyl, 4-hydroxybenzyl and syringyl alcohol) during fermentation. Conclusions Several key findings in this report provide a

  16. DNA damage and repair in plants – from models to crops

    PubMed Central

    Manova, Vasilissa; Gruszka, Damian

    2015-01-01

    The genomic integrity of every organism is constantly challenged by endogenous and exogenous DNA-damaging factors. Mutagenic agents cause reduced stability of plant genome and have a deleterious effect on development, and in the case of crop species lead to yield reduction. It is crucial for all organisms, including plants, to develop efficient mechanisms for maintenance of the genome integrity. DNA repair processes have been characterized in bacterial, fungal, and mammalian model systems. The description of these processes in plants, in contrast, was initiated relatively recently and has been focused largely on the model plant Arabidopsis thaliana. Consequently, our knowledge about DNA repair in plant genomes - particularly in the genomes of crop plants - is by far more limited. However, the relatively small size of the Arabidopsis genome, its rapid life cycle and availability of various transformation methods make this species an attractive model for the study of eukaryotic DNA repair mechanisms and mutagenesis. Moreover, abnormalities in DNA repair which proved to be lethal for animal models are tolerated in plant genomes, although sensitivity to DNA damaging agents is retained. Due to the high conservation of DNA repair processes and factors mediating them among eukaryotes, genes and proteins that have been identified in model species may serve to identify homologous sequences in other species, including crop plants, in which these mechanisms are poorly understood. Crop breeding programs have provided remarkable advances in food quality and yield over the last century. Although the human population is predicted to “peak” by 2050, further advances in yield will be required to feed this population. Breeding requires genetic diversity. The biological impact of any mutagenic agent used for the creation of genetic diversity depends on the chemical nature of the induced lesions and on the efficiency and accuracy of their repair. More recent targeted mutagenesis

  17. Developing ICP-MS/MS for the detection and determination of synthetic DNA-protein crosslink models via phosphorus and sulfur detection.

    PubMed

    Gong, Jiawei; Solivio, Morwena J; Merino, Edward J; Caruso, Joseph A; Landero-Figueroa, Julio A

    2015-03-01

    Various endogenous and exogenous agents drive the un-directed formation of covalent bonds between proteins and DNA. These complex molecules are of great biological relevance, as can derive in mutations, but are difficult to study because of their heterogeneous chemical properties. New analytical approaches with sufficient detection capabilities to detect and quantify these compounds can help to standardize study models based on synthesized standards. The use of atomic spectrometry can provide quantitative information on the DNA-protein cross-link reaction yield along with basic stoichiometry of the products, based on internal elemental tags, sulfur from Cys and Met amino acids, and phosphorus from the DNA. A new instrumental approach to remove isobaric and polyatomic interferences from (31)P(+) and (32)S(+) was developed recently, with state-of-the-art for interference removal that captures (31)P(+) in Q1; it reacts with O2 in an octopole collision-reaction cell generating (47)PO(+), therefore allowing detection in Q3 without (31)NOH(+)/(48)Ca/(47)Ti interferences. Similarly, (32)S(+) is reacted to (48)SO(+), eliminating the polyatomic interferences at m/z = 32. In conjunction with the high resolving power of high-performance liquid chromatography (HPLC), this newer technology was applied by to the product purification of a DNA-protein cross link model and some preliminary structural studies. PMID:25651903

  18. Developing ICP-MS/MS for the detection and determination of synthetic DNA-protein crosslink models via phosphorus and sulfur detection

    PubMed Central

    Gong, Jiawei; Solivio, Morwena J.; Merino, Edward J.; Caruso, Joseph A.

    2015-01-01

    Various endogenous and exogenous agents drive the un-directed formation of covalent bonds between proteins and DNA. These complex molecules are of great biological relevance, as can derive in mutations, but are difficult to study because of their heterogeneous chemical properties. New analytical approaches with sufficient detection capabilities to detect and quantify these compounds can help to standardize study models based on synthesized standards. The use of atomic spectrometry can provide quantitative information on the DNA-protein cross-link reaction yield along with basic stoichiometry of the products, based on internal elemental tags, sulfur from Cys and Met amino acids, and phosphorus from the DNA. A new instrumental approach to remove isobaric and poly-atomic interferences from 31P+ and 32S+ was developed recently, with state-of-the-art for interference removal that captures 31P+ in Q1; it reacts with O2 in an octopole collision-reaction cell generating 47PO+, therefore allowing detection in Q3 without 31NOH+/48Ca/47Ti interferences. Similarly, 32S+ is reacted to 48SO+, eliminating the polyatomic interferences at m/z=32. In conjunction with the high resolving power of high-performance liquid chromatography (HPLC), this newer technology was applied by to the product purification of a DNA-protein cross link model and some preliminary structural studies. PMID:25651903

  19. Synthesis of a naphthalene-hydroxynaphthalene polymer model compound. Quarterly report No. 4, March 13, 1991--June 12, 1991

    SciTech Connect

    Kwong, C.D.

    1991-07-22

    The objective of this project is the synthesis of a new naphthalene-hydroxynaphthalene polymer model compound for use in coal combustion studies. Since this compound is an unreported compound, this effort also requires the development of a synthetic route to this compound, including the synthesis of unreported intermediates leading to its synthesis. Complex product mixtures have been consistently obtained with all of our approaches. As a result, we have been constantly making small modifications to our technical approach. These changes are discussed in this report. Our synthesis efforts resulted in a number of potential precursors and intermediates. When appropriate, these compounds were submitted to the Organic Chemistry Research Area`s Analytical Section for characterization and identification.

  20. Synthesis of a naphthalene-hydroxynaphthalene polymer model compound. Quarterly report, December 13, 1990--March 12, 1991

    SciTech Connect

    Kwong, C.D.

    1991-04-15

    The objective of this contract is the synthesis of a new naphthalene-hydroxynaphthalene polymer model compound for coal combustion studies. This effort also requires the development of a synthetic procedure for this compound since it has not been reported before. We can only report that we are still unable to provide the target polymer or even any of the key intermediates leading to this target Dr. Rao has been informed of our progress (or lack of progress), and he has suggested that we begin to design other alternative compounds which contain the functionalities required by the target compound. In response to this suggestion, we have quickly designed the potential targets shown in Scheme VIL We are currently evaluating the schemes further and we will continue designing routes to the other analogous compounds.

  1. DNA looping increases the range of bistability in a stochastic model of the lac genetic switch.

    PubMed

    Earnest, Tyler M; Roberts, Elijah; Assaf, Michael; Dahmen, Karin; Luthey-Schulten, Zaida

    2013-04-01

    Conditions and parameters affecting the range of bistability of the lac genetic switch in Escherichia coli are examined for a model which includes DNA looping interactions with the lac repressor and a lactose analogue. This stochastic gene-mRNA-protein model of the lac switch describes DNA looping using a third transcriptional state. We exploit the fast bursting dynamics of mRNA by combining a novel geometric burst extension with the finite state projection method. This limits the number of protein/mRNA states, allowing for an accelerated search of the model's parameter space. We evaluate how the addition of the third state changes the bistability properties of the model and find a critical region of parameter space where the phenotypic switching occurs in a range seen in single molecule fluorescence studies. Stochastic simulations show induction in the looping model is preceded by a rare complete dissociation of the loop followed by an immediate burst of mRNA rather than a slower build up of mRNA as in the two-state model. The overall effect of the looped state is to allow for faster switching times while at the same time further differentiating the uninduced and induced phenotypes. Furthermore, the kinetic parameters are consistent with free energies derived from thermodynamic studies suggesting that this minimal model of DNA looping could have a broader range of application. PMID:23406725

  2. DNA looping increases the range of bistability in a stochastic model of the lac genetic switch

    NASA Astrophysics Data System (ADS)

    Earnest, Tyler M.; Roberts, Elijah; Assaf, Michael; Dahmen, Karin; Luthey-Schulten, Zaida

    2013-04-01

    Conditions and parameters affecting the range of bistability of the lac genetic switch in Escherichia coli are examined for a model which includes DNA looping interactions with the lac repressor and a lactose analogue. This stochastic gene-mRNA-protein model of the lac switch describes DNA looping using a third transcriptional state. We exploit the fast bursting dynamics of mRNA by combining a novel geometric burst extension with the finite state projection method. This limits the number of protein/mRNA states, allowing for an accelerated search of the model's parameter space. We evaluate how the addition of the third state changes the bistability properties of the model and find a critical region of parameter space where the phenotypic switching occurs in a range seen in single molecule fluorescence studies. Stochastic simulations show induction in the looping model is preceded by a rare complete dissociation of the loop followed by an immediate burst of mRNA rather than a slower build up of mRNA as in the two-state model. The overall effect of the looped state is to allow for faster switching times while at the same time further differentiating the uninduced and induced phenotypes. Furthermore, the kinetic parameters are consistent with free energies derived from thermodynamic studies suggesting that this minimal model of DNA looping could have a broader range of application.

  3. Evaluation of MolYsis™ Complete5 DNA Extraction Method for Detecting Staphylococcus aureus DNA from Whole Blood in a Sepsis Model Using PCR/Pyrosequencing

    PubMed Central

    McCann, Chase D.; Jordan, Jeanne A.

    2014-01-01

    Bacterial bloodstream infections (BSI) and ensuing sepsis are important causes of morbidity and mortality. Early diagnosis and rapid treatment with appropriate antibiotics are vital for improving outcome. Nucleic acid amplification of bacteria directly from whole blood has the potential of providing a faster means of diagnosing BSI than automated blood culture. However, effective DNA extraction of commonly low levels of bacterial target from whole blood is critical for this approach to be successful. This study compared the Molzyme MolYsis™ Complete5 DNA extraction method to a previously described organic bead-based method for use with whole blood. A well-characterized S. aureus-induced pneumonia model of sepsis in canines was used to provide clinically relevant whole blood samples. DNA extracts were assessed for purity and concentration and analyzed for bacterial rRNA gene targets using PCR and sequence-based identification. Both extraction methods yielded relatively pure DNA with median A260/280 absorbance ratios of 1.71 (MolYsis™) and 1.97 (bead-based). The organic bead-based extraction method yielded significantly higher average DNA concentrations (P <0.05) at each time point throughout the experiment, closely correlating with changes observed in white blood cell (WBC) concentrations during this same time period, while DNA concentrations of the MolYsis™ extracts closely mirrored quantitative blood culture results. Overall, S. aureus DNA was detected from whole blood samples in 70.7% (58/82) of MolYsis™ DNA extracts, and in 59.8% (49/82) of organic bead-based extracts, with peak detection rates seen at 48 h for both MolYsis™ (87.0%) and organic bead-based (82.6%) methods. In summary, the MolYsis™ Complete5 DNA extraction kit proved to be the more effective method for isolating bacterial DNA directly from extracts made from whole blood. PMID:24503182

  4. Spatial Arrangement of Organic Compounds on a Model Mineral Surface: Implications for Soil Organic Matter Stabilization

    NASA Astrophysics Data System (ADS)

    Ambaye, Haile; Petridis, Loukas; Jagadamma, Sindhu; Kilbey, Michael; Lauter, Valeria; Lokitz, Bradley; Mayes, Melanie

    2015-03-01

    Stability of organic carbon compounds in soil is important for global climate futures which could be affected by the complexity of the mineral-organic carbon interfaces. We examined the nanoscale structure of model interfaces by depositing films of organic carbon compounds of contrasting chemical character, hydrophilic glucose, deuterated-amphiphilic stearic acid (SA) and Natural Organic Matters (NOM) onto a soil mineral analogue (Al2O3) . The NOM was separated into its constituent components such as NOM-Philic and NOM-Phobic when it is deposited onto the soil mineral. We used Neutron Reflectivity technique to understand the depth organization of the thin films. The result indicates that glucose molecules reside in a layer between Al2O3 and stearic acid and SA self-assembles. No self-assembly of SA was observed when SA and NOM-Phobic was deposited on the mineral soil. Molecular dynamics simulations reveal the thermodynamic driving force behind glucose partitioning on the mineral interface. Funded by ORNL Director's Research and Development Program. Research at ORNL was sponsored by the BES, DOE.

  5. Compound nucleus formation probability PCN defined within the dynamical cluster-decay model

    NASA Astrophysics Data System (ADS)

    Chopra, Sahila; Kaur, Arshdeep; Gupta, Raj K.

    2015-01-01

    With in the dynamical cluster-decay model (DCM), the compound nucleus fusion/ formation probability PCN is defined for the first time, and its variation with CN excitation energy E* and fissility parameter χ is studied. In DCM, the (total) fusion cross section σfusion is sum of the compound nucleus (CN) and noncompound nucleus (nCN) decay processes, each calculated as the dynamical fragmentation process. The CN cross section σCN is constituted of the evaporation residues (ER) and fusion-fission (ff), including the intermediate mass fragments (IMFs), each calculated for all contributing decay fragments (A1, A2) in terms of their formation and barrier penetration probabilities P0 and P. The nCN cross section σnCN is determined as the quasi-fission (qf) process where P0=1 and P is calculated for the entrance channel nuclei. The calculations are presented for six different target-projectile combinations of CN mass A~100 to superheavy, at various different center-of-mass energies with effects of deformations and orientations of nuclei included in it. Interesting results are that the PCN=1 for complete fusion, but PCN <1 or ≪1 due to the nCN conribution, depending strongly on both E* and χ.

  6. High-temperature pyrolysis mechanisms of coal model compounds. 1990 annual report

    SciTech Connect

    Penn, J.H.; Owens, W.H.

    1991-01-01

    The degradation of the carboxylic acid group has been examined with respect to potential pretreatment strategies for fossil fuel conversion processes. In one potential pretreatment strategy involving cation exchange of the carboxylic acid group, a series of benzoic acid and stearic acid salts have been chosen to model the ``tight`` carboxylic acids of immature fossil fuel feedstocks and have been pyrolyzed with an entrained flow reactor. Our preliminary results indicate that Group I and II salts yield primarily the parent acid. Benzoate salts also yield small amounts of benzene while the stearic acid salts give no other detectable products. In two alternative treatment strategies, esterification and anhydride preparation have also been accomplished with these compounds being subjected to the entrained flow reactor conditions. The benzoate esters give a number of products, such as benzaldehyde, benzene, and low MW gases. The formation of these compounds is extremely dependent on pyrolysis conditions and alkoxy chain length. A xenon flashlamp and an entrained flow reactor have been used to heat organic substrates to varying temperatures using different heating rates. Ultrarapid flashlamp pyrolysis (heating rate>10{sup 50}C/s) has been performed. Since the ultrarapid pyrolysis products differ from those observed with traditional heating techniques and differ from the products formed photochemically, the flashlamp pyrolysis products are attributed to high temperature thermal activation.

  7. Effect of confinement on DNA, solvent and counterion dynamics in a model biological nanopore

    NASA Astrophysics Data System (ADS)

    Markosyan, Suren; de Biase, Pablo M.; Czapla, Luke; Samoylova, Olga; Singh, Gurpreet; Cuervo, Javier; Tieleman, D. Peter; Noskov, Sergei Yu.

    2014-07-01

    The application of recent advances in nanopore technology to high-throughput DNA sequencing requires a more detailed understanding of solvent, ion and DNA interactions occurring within these pores. Here we present a combination of atomistic and coarse-grained modeling studies of the dynamics of short single-stranded DNA (ssDNA) homopolymers within the alpha-hemolysin pore, for the two single-stranded homopolymers poly(dA)40 and poly(dC)40. Analysis of atomistic simulations along with the per-residue decomposition of protein-DNA interactions in these simulations gives new insight into the very complex issues that have yet to be fully addressed with detailed MD simulations. We discuss a modification of the solvent properties and ion distribution around DNA within nanopore confinement and put it into the general framework of counterion condensation theory. There is a reasonable agreement in computed properties from our all-atom simulations and the resulting predictions from analytical theories with experimental data, and our equilibrium results here support the conclusions from our previous non-equilibrium Brownian dynamics studies with a recently developed BROMOC protocol that cations are the primary charge carriers through alpha-hemolysin nanopores under an applied voltage in the presence of ssDNA. Clustering analysis led to an identification of distinct conformational states of captured polymer and depth of the current blockade. Therefore, our data suggest that confined polymer may act as a flickering gate, thus contributing to excess noise phenomena. We also discuss the extent of water structuring due to nanopore confinement and the relationship between the conformational dynamics of a captured polymer and the distribution of blocked current.The application of recent advances in nanopore technology to high-throughput DNA sequencing requires a more detailed understanding of solvent, ion and DNA interactions occurring within these pores. Here we present a

  8. Experimental validation of a model for diffusion-controlled absorption of organic compounds in the trachea

    SciTech Connect

    Gerde, P.; Muggenburg, B.A.; Thornton-Manning, J.R.

    1995-12-01

    Most chemically induced lung cancer originates in the epithelial cells in the airways. Common conceptions are that chemicals deposited on the airway surface are rapidly absorbed through mucous membranes, limited primarily by the rate of blood perfusion in the mucosa. It is also commonly thought that for chemicals to induce toxicity at the site of entry, they must be either rapidly reactive, readily metabolizable, or especially toxic to the tissues at the site of entry. For highly lipophilic toxicants, there is a third option. Our mathematical model predicts that as lipophilicity increases, chemicals partition more readily into the cellular lipid membranes and diffuse more slowly through the tissues. Therefore, absorption of very lipophilic compounds will be almost entirely limited by the rate of diffusion through the epithelium rather than by perfusion of the capillary bed in the subepithelium. We have reported on a preliminary model for absorption through mucous membranes of any substance with a lipid/aqueous partition coefficient larger than one. The purpose of this work was to experimentally validate the model in Beagle dogs. This validated model on toxicant absorption in the airway mucosa will improve risk assessment of inhaled

  9. QSAR classification models for the screening of the endocrine-disrupting activity of perfluorinated compounds.

    PubMed

    Kovarich, S; Papa, E; Li, J; Gramatica, P

    2012-01-01

    Perfluorinated compounds (PFCs) are a class of emerging pollutants still widely used in different materials as non-adhesives, waterproof fabrics, fire-fighting foams, etc. Their toxic effects include potential for endocrine-disrupting activity, but the amount of experimental data available for these pollutants is limited. The use of predictive strategies such as quantitative structure-activity relationships (QSARs) is recommended under the REACH regulation, to fill data gaps and to screen and prioritize chemicals for further experimentation, with a consequent reduction of costs and number of tested animals. In this study, local classification models for PFCs were developed to predict their T4-TTR (thyroxin-transthyretin) competing potency. The best models were selected by maximizing the sensitivity and external predictive ability. These models, characterized by robustness, good predictive power and a defined applicability domain, were applied to predict the activity of 33 other PFCs of environmental concern. Finally, classification models recently published by our research group for T4-TTR binding of brominated flame retardants and for estrogenic and anti-androgenic activity were applied to the studied perfluorinated chemicals to compare results and to further evaluate the potential for these PFCs to cause endocrine disruption.

  10. Developing a QSAR model for hepatotoxicity screening of the active compounds in traditional Chinese medicines.

    PubMed

    Huang, Shan-Han; Tung, Chun-Wei; Fülöp, Ferenc; Li, Jih-Heng

    2015-04-01

    The perception that natural substances are deemed safe has made traditional Chinese medicine (TCM) popular in the treatment and prevention of disease globally. However, such an assumption is often misleading owing to a lack of scientific validation. To assess the safety of TCM, in silico screening provides major advantages over the classical laboratory approaches in terms of resource- and time-saving and full reproducibility. To screen the hepatotoxicity of the active compounds of TCMs, a quantitative structure-activity relationship (QSAR) model was firstly established by utilizing drugs from the Liver Toxicity Knowledge Base. These drugs were annotated with drug-induced liver injury information obtained from clinical trials and post-marketing surveillance. The performance of the model after nested 10-fold cross-validation was 79.1%, 91.2%, 53.8% for accuracy, sensitivity, and specificity, respectively. The external validation of 91 well-known ingredients of common herbal medicines yielded a high accuracy (87%). After screening the TCM Database@Taiwan, the world's largest TCM database, a total of 6853 (74.8%) ingredients were predicted to have hepatotoxic potential. The one-hundred chemical ingredients predicted to have the highest hepatotoxic potential by our model were further verified by published literatures. Our study indicated that this model can serve as a complementary tool to evaluate the safety of TCM.

  11. Developing a QSAR model for hepatotoxicity screening of the active compounds in traditional Chinese medicines.

    PubMed

    Huang, Shan-Han; Tung, Chun-Wei; Fülöp, Ferenc; Li, Jih-Heng

    2015-04-01

    The perception that natural substances are deemed safe has made traditional Chinese medicine (TCM) popular in the treatment and prevention of disease globally. However, such an assumption is often misleading owing to a lack of scientific validation. To assess the safety of TCM, in silico screening provides major advantages over the classical laboratory approaches in terms of resource- and time-saving and full reproducibility. To screen the hepatotoxicity of the active compounds of TCMs, a quantitative structure-activity relationship (QSAR) model was firstly established by utilizing drugs from the Liver Toxicity Knowledge Base. These drugs were annotated with drug-induced liver injury information obtained from clinical trials and post-marketing surveillance. The performance of the model after nested 10-fold cross-validation was 79.1%, 91.2%, 53.8% for accuracy, sensitivity, and specificity, respectively. The external validation of 91 well-known ingredients of common herbal medicines yielded a high accuracy (87%). After screening the TCM Database@Taiwan, the world's largest TCM database, a total of 6853 (74.8%) ingredients were predicted to have hepatotoxic potential. The one-hundred chemical ingredients predicted to have the highest hepatotoxic potential by our model were further verified by published literatures. Our study indicated that this model can serve as a complementary tool to evaluate the safety of TCM. PMID:25660478

  12. A model to predict rate of dissolution of toxic compounds into seawater from an oil spill.

    PubMed

    Riazi, M R; Roomi, Y A

    2008-01-01

    In this paper a semianalytical model has been proposed to predict the rate at which oil components dissolve in water when an oil spill occurs in a marine environment. The model breaks the oil into a number of pseudocomponents proportional to the number of compounds originally present in the oil and calculates the rate of dissolution for each component. In addition, the components are divided into paraffinic, naphthenic, and aromatic hydrocarbon types and the amount of dissolution of each pseudocomponent is calculated versus time. In this method the concentration of most toxic components of oil (mainly monoaromatics) is determined. The model considers variable surface area and slick thickness and requires oil specifications (i.e., American Petroleum Institute [API] gravity and boiling point) in addition to air and water temperatures and speeds. The model has been applied to a Kuwaiti crude oil and its products naphtha and kerosene samples at 20 degrees C and 40 degrees C. The results could be useful in selection of an appropriate method for oil spill clean up as well as simulation of environmental impact of oil spill from toxicity points of view. PMID:19037808

  13. Diagnosis of air quality through observation and modeling of volatile organic compounds (VOCs) as pollution tracers

    NASA Astrophysics Data System (ADS)

    Liu, Wen-Tzu; Hsieh, Hsin-Cheng; Chen, Sheng-Po; Chang, Julius S.; Lin, Neng-Huei; Chang, Chih-Chung; Wang, Jia-Lin

    2012-08-01

    This study used selected ambient volatile organic compounds (VOCs) as pollution tracers to study the effects of meteorology on air quality. A remote coastal site was chosen as a receptor to monitor pollutants transported upwind from urban traffic and industrial sources. Large concentration variability in VOC concentrations was observed at the coastal site due to rapid changes in meteorology, which caused periodic land-sea exchange of air masses. To assure the quality of the on-line measurements, uniform concentrations of chlorofluorocarbon-113 (CFC-113) were exploited as an internal check of the instrument's stability and the resulting data quality. A VOC speciated air quality model was employed to simulate both temporal and spatial distributions of VOC plumes. The model successfully captured the general features of the variations of toluene as a pollution tracer, which suggests that emissions and meteorology were reasonably well simulated in the model. Through validation by observation, the model can display both the temporal and spatial distribution of air pollutants in a dynamic manner. Thus, a more insightful understanding of how local air quality is affected by meteorology can be obtained.

  14. Modeling specific heat and entropy change in La(Fe-Mn-Si)13-H compounds

    NASA Astrophysics Data System (ADS)

    Piazzi, Marco; Bennati, Cecilia; Curcio, Carmen; Kuepferling, Michaela; Basso, Vittorio

    2016-02-01

    In this paper we model the magnetocaloric effect of LaFexMnySiz-H1.65 compound (x + y + z = 13), a system showing a transition temperature finely tunable around room temperature by Mn substitution. The thermodynamic model takes into account the coupling between magnetism and specific volume as introduced by Bean and Rodbell. We find a good qualitative agreement between experimental and modeled entropy change - Δs(H , T). The main result is that the magnetoelastic coupling drives the phase transition of the system, changing it from second to first order by varying a model parameter η. It is also responsible for a decrease of - Δs at the transition, due to a small lattice contribution to the entropy counteracting the effect of the magnetic one. The role of Mn is reflected exclusively in a decrease of the strength of the exchange interaction, while the value of the coefficient β, responsible for the coupling between volume and exchange energy, is independent on the Mn content and it appears to be an intrinsic property of the La(Fe-Si)13 structure.

  15. Use of computational modeling approaches in studying the binding interactions of compounds with human estrogen receptors.

    PubMed

    Wang, Pan; Dang, Li; Zhu, Bao-Ting

    2016-01-01

    Estrogens have a whole host of physiological functions in many human organs and systems, including the reproductive, cardiovascular, and central nervous systems. Many naturally-occurring compounds with estrogenic or antiestrogenic activity are present in our environment and food sources. Synthetic estrogens and antiestrogens are also important therapeutic agents. At the molecular level, estrogen receptors (ERs) mediate most of the well-known actions of estrogens. Given recent advances in computational modeling tools, it is now highly practical to use these tools to study the interaction of human ERs with various types of ligands. There are two common categories of modeling techniques: one is the quantitative structure activity relationship (QSAR) analysis, which uses the structural information of the interacting ligands to predict the binding site properties of a macromolecule, and the other one is molecular docking-based computational analysis, which uses the 3-dimensional structural information of both the ligands and the receptor to predict the binding interaction. In this review, we discuss recent results that employed these and other related computational modeling approaches to characterize the binding interaction of various estrogens and antiestrogens with the human ERs. These examples clearly demonstrate that the computational modeling approaches, when used in combination with other experimental methods, are powerful tools that can precisely predict the binding interaction of various estrogenic ligands and their derivatives with the human ERs.

  16. Model Development and Validation of Personal Exposure to Volatile Organic Compound Concentrations

    PubMed Central

    Delgado-Saborit, Juana Mari; Aquilina, Noel J.; Meddings, Claire; Baker, Stephen; Harrison, Roy M.

    2009-01-01

    Background Direct measurement of exposure to volatile organic compounds (VOCs) via personal monitoring is the most accurate exposure assessment method available. However, its wide-scale application to evaluating exposures at the population level is prohibitive in terms of both cost and time. Consequently, indirect measurements via a combination of microenvironment concentrations and personal activity diaries represent a potentially useful alternative. Objective The aim of this study was to optimize a model of personal exposures (PEs) based on microenvironment concentrations and time/activity diaries and to compare modeled with measured exposures in an independent data set. Materials VOC PEs and a range of microenvironment concentrations were collected with active samplers and sorbent tubes. Data were supplemented with information collected through questionnaires. Seven models were tested to predict PE to VOCs in 75% (n = 370) of the measured PE data set, whereas the other 25% (n = 120) was used for validation purposes. Results The best model able to predict PE with independence of measurements was based upon stratified microenvironment concentrations, lifestyle factors, and individual-level activities. The proposed model accounts for 40–85% of the variance for individual VOCs and was validated for almost all VOCs, showing normalized mean bias and mean fractional bias below 25% and predicting 60% of the values within a factor of 2. Conclusions The models proposed identify the most important non-weather-related variables for VOC exposures; highlight the effect of personal activities, use of solvents, and exposure to environmental tobacco smoke on PE levels; and may assist in the development of specific models for other locations. PMID:20019908

  17. Weighted Feature Significance: A Simple, Interpretable Model of Compound Toxicity Based on the Statistical Enrichment of Structural Features

    PubMed Central

    Huang, Ruili; Southall, Noel; Xia, Menghang; Cho, Ming-Hsuang; Jadhav, Ajit; Nguyen, Dac-Trung; Inglese, James; Tice, Raymond R.; Austin, Christopher P.

    2009-01-01

    In support of the U.S. Tox21 program, we have developed a simple and chemically intuitive model we call weighted feature significance (WFS) to predict the toxicological activity of compounds, based on the statistical enrichment of structural features in toxic compounds. We trained and tested the model on the following: (1) data from quantitative high–throughput screening cytotoxicity and caspase activation assays conducted at the National Institutes of Health Chemical Genomics Center, (2) data from Salmonella typhimurium reverse mutagenicity assays conducted by the U.S. National Toxicology Program, and (3) hepatotoxicity data published in the Registry of Toxic Effects of Chemical Substances. Enrichments of structural features in toxic compounds are evaluated for their statistical significance and compiled into a simple additive model of toxicity and then used to score new compounds for potential toxicity. The predictive power of the model for cytotoxicity was validated using an independent set of compounds from the U.S. Environmental Protection Agency tested also at the National Institutes of Health Chemical Genomics Center. We compared the performance of our WFS approach with classical classification methods such as Naive Bayesian clustering and support vector machines. In most test cases, WFS showed similar or slightly better predictive power, especially in the prediction of hepatotoxic compounds, where WFS appeared to have the best performance among the three methods. The new algorithm has the important advantages of simplicity, power, interpretability, and ease of implementation. PMID:19805409

  18. Fluctuating bottleneck model studies on kinetics of DNA escape from α-hemolysin nanopores.

    PubMed

    Bian, Yukun; Wang, Zilin; Chen, Anpu; Zhao, Nanrong

    2015-11-14

    We have proposed a fluctuation bottleneck (FB) model to investigate the non-exponential kinetics of DNA escape from nanometer-scale pores. The basic idea is that the escape rate is proportional to the fluctuating cross-sectional area of DNA escape channel, the radius r of which undergoes a subdiffusion dynamics subjected to fractional Gaussian noise with power-law memory kernel. Such a FB model facilitates us to obtain the analytical result of the averaged survival probability as a function of time, which can be directly compared to experimental results. Particularly, we have applied our theory to address the escape kinetics of DNA through α-hemolysin nanopores. We find that our theoretical framework can reproduce the experimental results very well in the whole time range with quite reasonable estimation for the intrinsic parameters of the kinetics processes. We believe that FB model has caught some key features regarding the long time kinetics of DNA escape through a nanopore and it might provide a sound starting point to study much wider problems involving anomalous dynamics in confined fluctuating channels. PMID:26567685

  19. Fluctuating bottleneck model studies on kinetics of DNA escape from α-hemolysin nanopores

    NASA Astrophysics Data System (ADS)

    Bian, Yukun; Wang, Zilin; Chen, Anpu; Zhao, Nanrong

    2015-11-01

    We have proposed a fluctuation bottleneck (FB) model to investigate the non-exponential kinetics of DNA escape from nanometer-scale pores. The basic idea is that the escape rate is proportional to the fluctuating cross-sectional area of DNA escape channel, the radius r of which undergoes a subdiffusion dynamics subjected to fractional Gaussian noise with power-law memory kernel. Such a FB model facilitates us to obtain the analytical result of the averaged survival probability as a function of time, which can be directly compared to experimental results. Particularly, we have applied our theory to address the escape kinetics of DNA through α-hemolysin nanopores. We find that our theoretical framework can reproduce the experimental results very well in the whole time range with quite reasonable estimation for the intrinsic parameters of the kinetics processes. We believe that FB model has caught some key features regarding the long time kinetics of DNA escape through a nanopore and it might provide a sound starting point to study much wider problems involving anomalous dynamics in confined fluctuating channels.

  20. Track structure based modelling of light ion radiation effects on nuclear and mitochondrial DNA

    NASA Astrophysics Data System (ADS)

    Schmitt, Elke; Ottolenghi, Andrea; Dingfelder, Michael; Friedland, Werner; Kundrat, Pavel; Baiocco, Giorgio

    2016-07-01

    Space radiation risk assessment is of great importance for manned spaceflights in order to estimate risks and to develop counter-measures to reduce them. Biophysical simulations with PARTRAC can help greatly to improve the understanding of initial biological response to ionizing radiation. Results from modelling radiation quality dependent DNA damage and repair mechanisms up to chromosomal aberrations (e.g. dicentrics) can be used to predict radiation effects depending on the kind of mixed radiation field exposure. Especially dicentric yields can serve as a biomarker for an increased risk due to radiati