Science.gov

Sample records for dna model compounds

  1. 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/

  2. 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)

  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. 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.

  6. 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.

  7. Making Models of Chemical Compounds.

    ERIC Educational Resources Information Center

    Hoehn, Robert G.

    1992-01-01

    Describes the benefits and techniques of having students create models of chemical compounds. This hands-on approach uses colored paper and other inexpensive materials to construct the models. A step-by-step approach provides objectives, materials, an explanation on how to calculate chemical ratios, procedures, follow-up activities, and a resource…

  8. Specific Inhibition of the Eubacterial DNA Ligase by Arylamino Compounds

    PubMed Central

    Ciarrocchi, Giovanni; MacPhee, Donald G.; Deady, Les W.; Tilley, Leann

    1999-01-01

    All known DNA ligases catalyze the formation of a phosphodiester linkage between adjacent termini in double-stranded DNA via very similar mechanisms. The ligase family can, however, be divided into two classes: eubacterial ligases, which require NAD+ as a cofactor, and other ligases, from viruses, archaea, and eukaryotes, which use ATP. Drugs that discriminate between DNA ligases from different sources may have antieubacterial activity. We now report that a group of arylamino compounds, including some commonly used antimalarial and anti-inflammatory drugs and a novel series of bisquinoline compounds, are specific inhibitors of eubacterial DNA ligases. Members of this group of inhibitors have different heterocyclic ring systems with a common amino side chain in which the two nitrogens are separated by four carbon atoms. The potency, but not the specificity of action, is influenced by the DNA-binding characteristics of the inhibitor, and the inhibition is noncompetitive with respect to NAD+. The arylamino compounds appear to target eubacterial DNA ligase in vivo, since a Salmonella Lig− strain that has been rescued with the ATP-dependent T4 DNA ligase is less sensitive than the parental Salmonella strain. PMID:10543760

  9. Characterization of DNA-conjugated compounds using a regenerable chip.

    PubMed

    Lin, Weilin; Reddavide, Francesco V; Uzunova, Veselina; Gür, Fatih Nadi; Zhang, Yixin

    2015-01-20

    DNA-encoded chemical library (DECL) technology has emerged as a new avenue in the field of drug discovery. Combined with high-throughput sequencing, DECL selection experiments can provide not only many lead compounds but also insights into the structure-affinity relationship. However, the counts of individual DNA codes reflect, but cannot be used to precisely rank, the binding affinities of the corresponding compounds to protein targets. Herein, we describe a chip-based approach to realize an automated high-throughput assay for the kinetic characterization of the interaction between DNA-conjugated small organic compounds and protein targets. Importantly, this method can be applied to both single-pharmacophore DECLs and self-assembled dual-pharmacophore DECLs.

  10. Structure elucidation, DNA binding specificity and antiproliferative proficiency of isolated compounds from Garcinia nervosa.

    PubMed

    Parveen, Mehtab; Azaz, Shaista; Zafar, Atif; Ahmad, Faheem; Silva, Manuela Ramos; Silva, Pedro Sidonio Pereira

    2017-02-01

    Garcinia nervosa is an abundant source of bioactive phytochemicals. The present paper deals with the isolation of a novel isoflavone 5,7-dihydroxy-3-(3'-hydroxy-4',5'-dimethoxyphenyl)-6-methoxy-4H-chromen-4-one (1) along with a known compound DL-Allantoin (2) from the ethanolic extract of the leaves of Garcinia nervosa (Family: Guttiferae). 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. Single-crystal X-ray analysis was further used for the authentication of structure of both compounds (1 and 2). Interaction studies of compound (1) and (2) with ctDNA were studied by UV-Visible spectroscopy, fluorescence, KI quenching studies, competitive displacement assay and circular dichroism studies, which showed groove binding interaction (non-intercalation) of both the compounds 1 and 2 with ctDNA. However, compound 1 (K=3.9×10(4)M(-1)) shows higher binding affinity to the ctDNA than compound 2 (K=1.44×10(4)M(-1)). The molecular modeling results also illustrated that compound 1 strongly binds to groove of DNA by relative binding energy of docked structure -6.82kcal/mol. In addition the antiproliferative activity also showed high potential of compound 1 against MCF-7 and MDA-MB 231 cell line with IC50 value 8.44±3.5μM and 6.94±2.6μM, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

  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. A new compound, withangulatin A, promotes type II DNA topoisomerase-mediated DNA damage.

    PubMed

    Juang, J K; Huang, H W; Chen, C M; Liu, H J

    1989-03-31

    Withangulatin A, a new compound with a known chemical structure and from the antitumor Chinese herb Physalis angulata L, was found to act on topoisomerase II to induce topoisomerase II-mediated DNA damage in vitro. It has two effective dosage ranges of approximate 0.5 and 20 microM, with about one-third the activity of 20 microM VM-26.

  13. 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.

  14. 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.

  15. Investigation of DNA binding, DNA photocleavage, topoisomerase I inhibition and antioxidant activities of water soluble titanium(IV) phthalocyanine compounds.

    PubMed

    Özel, Arzu; Barut, Burak; Demirbaş, Ümit; Biyiklioglu, Zekeriya

    2016-04-01

    The binding mode of water soluble peripherally tetra-substituted titanium(IV) phthalocyanine (Pc) compounds Pc1, Pc2 and Pc3 with calf thymus (CT) DNA was investigated by using UV-Vis spectroscopy and thermal denaturation studies in this work. The results of DNA binding constants (Kb) and the changes in the thermal denaturation profile of DNA with the addition of Pc compounds indicated that Pc1, Pc2 and Pc3 are able to bind to CT-DNA with different binding affinities. DNA photocleavage studies of Pc compounds were performed in the absence and presence of oxidizing agents such as hydrogen peroxide (H2O2), ascorbic acid (AA) and 2-mercaptoethanol (ME) using the agarose gel electrophoresis method at irradiation 650 nm. According to the results of electrophoresis studies, Pc1, Pc2 and Pc3 cleaved of supercoiled pBR322 DNA via photocleavage pathway. The Pc1, Pc2 and Pc3 compounds were examined for topoisomerase I inhibition by measuring the relaxation of supercoiled pBR322 DNA. The all of Pc compounds inhibited topoisomerase I at 20 μM concentration. A series of antioxidant assays, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, superoxide radical scavenging (SOD) assay and metal chelating effect assay were performed for Pc1, Pc2 and Pc3 compounds. The results of antioxidant assays indicated that Pc1, Pc2 and Pc3 compounds have remarkable superoxide radical scavenging activities, moderate 2,2-diphenyl-1-picrylhydrazyl activities and metal chelating effect activities. All the experimental studies showed that Pc1, Pc2 and Pc3 compounds bind to CT-DNA via minor groove binding, cleave of supercoiled pBR322 DNA via photocleavage pathway, inhibit topoisomerase I and have remarkable superoxide radical scavenging activities. Thanks to these properties the Pc1, Pc2 and Pc3 compounds are suitable agents for photo dynamic therapy.

  16. Modeling inhomogeneous DNA replication kinetics.

    PubMed

    Gauthier, Michel G; Norio, Paolo; Bechhoefer, John

    2012-01-01

    In eukaryotic organisms, DNA replication is initiated at a series of chromosomal locations called origins, where replication forks are assembled proceeding bidirectionally to replicate the genome. The distribution and firing rate of these origins, in conjunction with the velocity at which forks progress, dictate the program of the replication process. Previous attempts at modeling DNA replication in eukaryotes have focused on cases where the firing rate and the velocity of replication forks are homogeneous, or uniform, across the genome. However, it is now known that there are large variations in origin activity along the genome and variations in fork velocities can also take place. Here, we generalize previous approaches to modeling replication, to allow for arbitrary spatial variation of initiation rates and fork velocities. We derive rate equations for left- and right-moving forks and for replication probability over time that can be solved numerically to obtain the mean-field replication program. This method accurately reproduces the results of DNA replication simulation. We also successfully adapted our approach to the inverse problem of fitting measurements of DNA replication performed on single DNA molecules. Since such measurements are performed on specified portion of the genome, the examined DNA molecules may be replicated by forks that originate either within the studied molecule or outside of it. This problem was solved by using an effective flux of incoming replication forks at the model boundaries to represent the origin activity outside the studied region. Using this approach, we show that reliable inferences can be made about the replication of specific portions of the genome even if the amount of data that can be obtained from single-molecule experiments is generally limited.

  17. Model Compound Interactions Characterizing Aquatic Humic Substances

    DTIC Science & Technology

    1990-01-01

    Isolation...............48 3.3.2 Titration Apparatus..............49 3.3.3 Potentiometric Titrations ..........52 3.3.4 Complexometric Titrations ...Potentiometric Titrations ..........57 4.2.2 Complexometric Titrations ..........61 4.3 Natural Sources and Model Compound Mixtures . .. 69 4.3.1...groundwater ........ .................... 50 3.4 Milli-Q complexometric titrations ... ......... .54 4.1a Potentiometric titration of model compounds

  18. Antineoplastic DNA-binding compounds: intercalating and minor groove binding drugs.

    PubMed

    Mišković, Katarina; Bujak, Maro; Baus Lončar, Mirela; Glavaš-Obrovac, Ljubica

    2013-12-01

    DNA intercalating and minor groove binding compounds are new weapons in the battle against malignant diseases. These antineoplastic agents target the DNA molecule and interfere with the cell cycle leading to rapidly proliferating cell death. They are mainly derivates of a naturally occurring organic compound derived from a microorganism or plant. Intercalators usually act as topoisomerase I and/or II poisons, while the mechanisms of DNA minor groove binders are a combination of several steps including topoisomerase poisoning. This paper gives an overview of some of the developed DNA intercalating and minor groove binding compounds, as well as an explanation of their chemical structures, origins, and application in chemotherapy.

  19. 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...

  20. DNA-binding and cytotoxic efficacy studies of organorhenium pentylcarbonate compounds.

    PubMed

    Medley, Jewel; Payne, Gloria; Banerjee, Hirendra N; Giri, Dipak; Winstead, Angela; Wachira, James M; Krause, Jeanette A; Shaw, Roosevelt; Pramanik, Saroj K; Mandal, Santosh K

    2015-01-01

    Seven organorhenium pentylcarbonate compounds (PC1-PC7) have been synthesized. DNA-binding studies of the PC-series compounds using electronic spectroscopy and gel electrophoresis suggest that the compounds presumably bind to DNA in an intercalative mode. The intrinsic binding constants for PC4, PC6, and PC7 were found to be 1.6 × 10(4), 3.9 × 10(4), and 4.2 × 10(4) M(-1), respectively. The X-ray structure determinations and density functional theory calculations indicate that the polypyridyl ligands in the compounds are nearly planar facilitating DNA binding through an intercalation mechanism. Cytotoxicity studies of 10 µM pentylcarbonate compounds against HTB-12 human astrocytoma brain cancer cells were studied for 48 h. It was observed that each of the pentylcarbonate compounds is active against the cancer cells. However, under analogous conditions, CRL-2005 rat astrocyte normal brain cells are not affected significantly.

  1. 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.

  2. Global Exposure Modelling of Semivolatile Organic Compounds

    NASA Astrophysics Data System (ADS)

    Guglielmo, F.; Lammel, G.; Maier-Reimer, E.

    2008-12-01

    Organic compounds which are persistent and toxic as the agrochemicals γ-hexachlorocyclohexane (γ-HCH, lindane) and dichlorodiphenyltrichloroethane (DDT) pose a hazard for the ecosystems. These compounds are semivolatile, hence multicompartmental substances and subject to long-range transport (LRT) in atmosphere and ocean. Being lipophilic, they accumulate in exposed organism tissues and biomagnify along food chains. The multicompartmental global fate and LRT of DDT and lindane in the atmosphere and ocean have been studied using application data for 1980, on a decadal scale using a model based on the coupling of atmosphere and (for the first time for these compounds) ocean General Circulation Models (ECHAM5 and MPI-OM). The model system encompasses furthermore 2D terrestrial compartments (soil and vegetation) and sea ice, a fully dynamic atmospheric aerosol (HAM) module and an ocean biogeochemistry module (HAMOCC5). Large mass fractions of the compounds are found in soil. Lindane is also found in comparable amount in ocean. DDT has the longest residence time in almost all compartments. The sea ice compartment locally almost inhibits volatilization from the sea. The air/sea exchange is also affected , up to a reduction of 35 % for DDT by partitioning to the organic phases (suspended and dissolved particulate matter) in the global oceans. Partitioning enhances vertical transport in the sea. Ocean dynamics are found to be more significant for vertical transport than sinking associated with particulate matter. LRT in the global environment is determined by the fast atmospheric circulation. Net meridional transport taking place in the ocean is locally effective mostly via western boundary currents, upon applications at mid- latitudes. The pathways of the long-lived semivolatile organic compounds studied include a sequence of several cycles of volatilisation, transport in the atmosphere, deposition and transport in the ocean (multihopping substances). Multihopping is

  3. Methods of DNA adduct determination and their application to testing compounds for genotoxicity.

    PubMed

    Phillips, D H; Farmer, P B; Beland, F A; Nath, R G; Poirier, M C; Reddy, M V; Turteltaub, K W

    2000-01-01

    At the International Workshop on Genotoxicity Test Procedures (IWGTP) held in Washington, DC (March 25-26, 1999), a working group considered the uses of DNA adduct determination methods for testing compounds for genotoxicity. When a drug or chemical displays an unusual or inconsistent combination of positive and negative results in in vitro and in vivo genotoxicity assays and/or in carcinogenicity experiments, investigations into whether or not DNA adducts are formed may be helpful in assessing whether or not the test compound is a genotoxin. DNA adduct determinations can be carried out using radiolabeled compounds and measuring radioactive decay (scintillation counting) or isotope ratios (accelerator mass spectrometry) in the isolated DNA. With unlabeled compounds adducts may be measured by (32)P-postlabeling analysis of the DNA, or by physicochemical methods including mass spectrometry, fluorescence spectroscopy, or electrochemical detection, or by immunochemical methods. Each of these approaches has different strengths and limitations, influenced by sensitivity, cost, time, and interpretation of results. The design of DNA binding studies needs to be on a case-by-case basis, depending on the compound's profile of activity. DNA purity becomes increasingly important the more sensitive, and less chemically specific, the assay. While there may be adduct levels at which there is no observable biological effect, there are at present insufficient data on which to set a threshold level for biological significance. Copyright 2000 Wiley-Liss, Inc.

  4. Enhanced anti-fibrotic activity of plasmid DNA expressing small interference RNA for TGF-beta type II receptor for a mouse model of obstructive nephropathy by cationized gelatin prepared from different amine compounds.

    PubMed

    Kushibiki, Toshihiro; Nagata-Nakajima, Natsuki; Sugai, Manabu; Shimizu, Akira; Tabata, Yasuhiko

    2006-02-21

    The objective of this study is to increase the transfection efficiency of a plasmid DNA expressing small interference RNA (siRNA) for transforming growth factor-beta receptor (TGF-betaR) by various cationized gelatins of non-viral carrier and evaluate the anti-fibrotic effect with a mouse model of unilateral ureteral obstruction (UUO). Ethylenediamine, putrescine, spermidine or spermine was chemically introduced to the carboxyl groups of gelatin for the cationization. The plasmid DNA of TGF-betaR siRNA expression vector with or without complexation of each cationized gelatin was injected to the left kidney of mice via the ureter to prevent the progression of renal fibrosis of UUO mice. Irrespective of the type of cationized gelatin, the injection of plasmid DNA-cationized gelatin complex significantly decreased the renal level of TGF-betaR over-expression and the collagen content of mice kidney, in marked contrast to free plasmid DNA injection. It is concluded that retrograde injection of TGF-betaR siRNA expression vector plasmid DNA complexed with the cationized gelatin is available to suppress the progression of renal interstitial fibrosis.

  5. 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.

  6. Natural Compounds as Anticancer Agents Targeting DNA Topoisomerases

    PubMed Central

    Jain, Chetan Kumar; Majumder, Hemanta Kumar; Roychoudhury, Susanta

    2017-01-01

    DNA topoisomerases are important cellular enzymes found in almost all types of living cells (eukaryotic and prokaryotic). These enzymes are essential for various DNA metabolic processes e.g. replication, transcription, recombination, chromosomal decatenation etc. These enzymes are important molecular drug targets and inhibitors of these enzymes are widely used as effective anticancer and antibacterial drugs. However, topoisomerase inhibitors have some therapeutic limitations and they exert serious side effects during cancer chemotherapy. Thus, development of novel anticancer topoisomerase inhibitors is necessary for improving cancer chemotherapy. Nature serves as a repertoire of structurally and chemically diverse molecules and in the recent years many DNA topoisomerase inhibitors have been identified from natural sources. The present review discusses anticancer properties and therapeutic importance of eighteen recently identified natural topoisomerase inhibitors (from the year 2009 to 2015). Structural characteristics of these novel inhibitors provide backbones for designing and developing new anticancer drugs. PMID:28503091

  7. Compound K suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair in human keratinocytes.

    PubMed

    Cai, Bao-Xiang; Luo, Dan; Lin, Xiang-Fei; Gao, Jie

    2008-11-01

    Ultraviolet (UV)-induced DNA damage is a crucial molecular trigger for sunburn cell formation and skin cancer. Nucleotide excision repair (NER) is the main mechanism in repairing UVB-induced DNA damage of mammalian cells. The purpose of this study is to investigate the functional role of ginsenoside compound K on HaCaT cells (a keratinocyte-derived permanent cell line) irradiated by UV. Hoechst 33258 staining were performed in analyzing UV-induced apoptosis on keratinocytes which were treated with compound K. ImmunoDotBlot assay was used in detecting cyclobutane pyrimidine dimers, the main DNA damage. Western blot analysis was applied for analyzing XPC and ERCC1, two of the NER proteins. Compound K inhibited UV-induced apoptosis of keratinocytes and caused a notable reduction in UV-specific DNA lesions which was due to induction of DNA repair. In agreement with this, compound K induced the expression of particular components of the NER complex, such as XPC and ERCC1. Our results demonstrate that compound K can protect cells from apoptosis induced by UV radiation by inducing DNA repair.

  8. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. A nonlinear model for DNA dynamics

    SciTech Connect

    Muto, V.; Scott, A.C.; Christiansen, P.L.

    1989-07-01

    In this paper the thermal equilibrium number of solitons in DNA as a function of absolute temperature and the number of base pairs is calculated. These calculations are effected by modeling DNA as a Toda lattice with parameters chosen to match experimentally measured properties of DNA. It is found that a significant number of solitons is generated at physiological temperature. 23 refs., 2 figs.

  10. Modelling the emplacement of compound lava flows

    NASA Astrophysics Data System (ADS)

    Blake, S.; Bruno, B. C.

    2000-12-01

    The physical variables controlling crust-dominated lava flow have been investigated using laboratory experiments in which molten polyglycol wax was extruded from a point source on to a horizontal plane under cold water. The wax initially spread axisymmetrically and a crust of solid wax grew. Eventually wax broke out from the flow's periphery, sending out a flow lobe which in turn cooled and produced another breakout. The process repeated itself many times, building a 'compound lava'. The time for the first breakout to form correlates well with the theoretically predicted time ( tc) required for cooling to form a crust thick enough for its strength to limit the flow's spreading rate. This time is proportional to the product of effusion rate ( Q) and initial magma viscosity ( μ) and inversely proportional to the square of the crust strength at the flow front. The number of flow units and the apparent fractal dimension of the flow perimeter increase with time normalised by tc. Our model illuminates the physical basis for the observation by Walker [G.P.L. Walker, Bull. Volcanol. 35 (1972) 579-590] that compound lava flows form by slow effusion of low viscosity magma, whereas faster effusion and higher viscosity favour lavas with fewer flow units. Because compound flows require t≫ tc, and given that tc∝ Qμ and the relationship between volume and effusion rate is V= Qt, simple and compound lava flows are predicted to fall in separate fields on a graph of μ against V/ Q2, all else being equal. Compound flows plot at small values of μ and large values of V/ Q2, with the position of the simple/compound boundary defined by field data implying a crust strength of order 10 4 Pa for basaltic to intermediate lavas. Whether a flow remains as a simple flow or matures into a compound flow field depends on the combined effect of viscosity, eruption rate and eruption duration (and hence volume) and these parameters need to be taken in to account when using morphology to infer

  11. Preparation of ds-DNA functionalized magnetic nanobaits for screening of bioactive compounds from medicinal plant.

    PubMed

    Yuan, Li; Xu, Pei-Li; Zeng, Qiong; Liu, Yi-Ming; Ding, Li-Sheng; Liao, Xun

    2015-11-01

    A novel magnetic nanocomposite (MNPs@DNA) was synthesized by bonding double strand DNA (ds-DNA) onto Fe3O4 magnetic nanoparticles (MNPs) directly. MNPs@DNA was characterized by cyclic voltammetry (CV), differential pulse voltammetry (DPV), Fourier transform infrared spectroscopy (FT-IR) and thermo-gravimetric analysis (TGA), which indicated that ds-DNA was immobilized onto MNPs. Vibrating sample magnetometer (VSM) analysis indicated that the MNPs@DNA had a high saturation magnetization of 42.97emu/g. A novel method for screening of active compounds from natural sources was developed by employing MNPs@DNA as a nanobait and high-performance liquid chromatography-mass spectrometry as detecting system. Columbamine, palmatine, jateorhizine, epiberberine and berberine were identified as DNA binders from the extract of Rhizoma coptidis. In addition, a comparison of the binding abilities among MNPs with different DNA strand lengths (25, 200 and 1200bp) showed that the shortest one exhibited the highest binding ability. This is the first report on fast chemical characterization of active ingredients in medicinal plant using ds-DNA immobilized on magnetic nano-baits. This method can be used not only for screening of DNA binders from complex herbal matrices, but also for assessing the affinities between a specific ds-DNA and its potential binders. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Site-specific hydroxylation at polyguanosine in double-stranded DNA by nickel(II) in the presence of SH compounds: comparison with singlet oxygen-induced DNA damage.

    PubMed

    Oikawa, Shinji; Hiraku, Yusuke; Fujiwara, Tatsuhiko; Saito, Isao; Kawanishi, Shosuke

    2002-08-01

    We examined the mechanism of DNA damage induced by carcinogenic Ni(II) in the presence of SH compounds. In the presence of model endogenous SH compounds, dithiothreitol (DTT), 1,4-dithio-L-threitol, and dithioerythritol, Ni(II) induced damage to (32)P-5'-end-labeled DNA fragments obtained from the human c-Ha-ras-1 protooncogene and the p53 tumor suppressor gene. The intensity of Ni(II)-mediated DNA damage induced by DTT was stronger than that by other model endogenous SH compounds, 1,4-dithio-L-threitol and dithioerythritol. DNA damage induced by Ni(II) plus DTT was observed only when the DNA was treated with piperidine, suggesting that Ni(II) plus DTT caused only base damage. Formamidopyrimidine-DNA glycosylase, which is known to recognize 8-oxodG as well as Fapy residues, treatment induced cleavage sites, mainly guanine residues, particularly at the 5'-GG-3', 5'-GGG-3', and 5'-GGGG-3' sequences, in DNA incubated with Ni(II) in the presence of DTT. SOD and catalase inhibited the DNA damage, suggesting that DNA damage involved superoxide anion and hydrogen peroxide. Sodium azide, a potent and relatively specific scavenger of (1)O(2), inhibited DNA damage by Ni(II) in the presence of DTT, whereas the sequence specificity of DNA damage was different from that obtained by (1)O(2) generating agent. The formation of 8-oxodG in calf thymus DNA by Ni(II) was observed with the physiological thiols, dihydrolipoic acid and mercaptopyruvate, as well as with DTT. These results suggest that Ni(II) and DTT form a reactive species, which may be responsible for causing guanine-specific DNA damage. Endogenous SH compounds, which have similar chemical structures to DTT, would participate in nickel carcinogenesis through causing oxidative DNA damage.

  13. Toxicokinetics of DNA adducts and biliary fluorescent aromatic compounds in fish exposed to PAC-contaminated sediments

    SciTech Connect

    French, B.; Reichert, W.L.; Hom, T.; Sanborn, H.R.; Stein, J.E.

    1995-12-31

    Exposure of fish to polycyclic aromatic compounds (PACs) can be assessed by measuring fluorescent aromatic compounds (FACs) in bile or xenobiotic-DNA adducts in liver. Acute exposures in fish to model PACs or PAC contaminated sediment extracts have shown dose-responsive increases in levels of DNA adducts and biliary FACS. FAC levels have been shown to decline rapidly after exposure, whereas a substantial proportion of DNA adducts persist. However, the time and dose responses of these biomarkers with chronic exposure to sediment-associated PACs have not been examined in fish. In this study, the authors examined the effects of varying the PAC concentrations and length of exposure on levels of DNA adducts and biliary FACs in English sole (Pleuronectes vetulus) exposed for up to 5 weeks to reference sediment amended with PAC-contaminated sediment from Eagle Harbor, WA. DNA adduct levels increased linearly with both PAC concentration and length of exposure, while biliary FAC concentrations were responsive to PAC levels but had attained steady-state concentrations after 2 weeks of exposure. Further, levels of DNA adducts and biliary FACs in feral fish captured from Eagle Harbor were within the ranges of levels found in the laboratory-exposed fish. Comparison of the data from field and laboratory-exposed fish strengthened the finding that hepatic DNA adducts accumulated with chronic exposure. The results showing accumulation of hepatic DNA adducts in English sole during continuous exposure to PACs is consistent with previous studies showing a relatively low rate of DNA repair in fish.

  14. 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.

  15. A coarse grain model for DNA.

    PubMed

    Knotts, Thomas A; Rathore, Nitin; Schwartz, David C; de Pablo, Juan J

    2007-02-28

    Understanding the behavior of DNA at the molecular level is of considerable fundamental and engineering importance. While adequate representations of DNA exist at the atomic and continuum level, there is a relative lack of models capable of describing the behavior of DNA at mesoscopic length scales. We present a mesoscale model of DNA that reduces the complexity of a nucleotide to three interactions sites, one each for the phosphate, sugar, and base, thereby rendering the investigation of DNA up to a few microns in length computationally tractable. The charges on these sites are considered explicitly. The model is parametrized using thermal denaturation experimental data at a fixed salt concentration. The validity of the model is established by its ability to predict several aspects of DNA behavior, including salt-dependent melting, bubble formation and rehybridization, and the mechanical properties of the molecule as a function of salt concentration.

  16. A coarse grain model for DNA

    NASA Astrophysics Data System (ADS)

    Knotts, Thomas A.; Rathore, Nitin; Schwartz, David C.; de Pablo, Juan J.

    2007-02-01

    Understanding the behavior of DNA at the molecular level is of considerable fundamental and engineering importance. While adequate representations of DNA exist at the atomic and continuum level, there is a relative lack of models capable of describing the behavior of DNA at mesoscopic length scales. We present a mesoscale model of DNA that reduces the complexity of a nucleotide to three interactions sites, one each for the phosphate, sugar, and base, thereby rendering the investigation of DNA up to a few microns in length computationally tractable. The charges on these sites are considered explicitly. The model is parametrized using thermal denaturation experimental data at a fixed salt concentration. The validity of the model is established by its ability to predict several aspects of DNA behavior, including salt-dependent melting, bubble formation and rehybridization, and the mechanical properties of the molecule as a function of salt concentration.

  17. In vitro transfection of plasmid DNA by cationized gelatin prepared from different amine compounds.

    PubMed

    Kushibiki, Toshihiro; Tomoshige, Ryuji; Iwanaga, Kazunori; Kakemi, Masawo; Tabata, Yasuhiko

    2006-01-01

    The objective of this paper is to compare the in vitro transfection efficiency of a luciferase plasmid DNA using cationized gelatin prepared from different amine compounds. The compounds used here were ethylenediamine, putrescine, spermidine and spermine, chemically introduced to the carboxyl group of gelatin for the cationization. Complexation of the cationized gelatin with the plasmid DNA was performed by simply mixing the two materials at various N+/P- mixing ratios (the molar number ratio of amino groups of gelatin to the phosphate groups of DNA) in aqueous solution. Gel retardation studies revealed that the formation of cationized-gelatin-plasmid DNA complexes depended on the N+/P- mixing ratio. The stronger interaction of plasmid DNA with the cationized gelatin of spermine compared to the other cationized gelatins was observed by an ethidium bromide intercalation assay and Scatchard binding analysis. When the transfection efficiency of plasmid DNA complexed with the various cationized gelatins at different N+/P- mixing ratios was evaluated for mouse L929 fibroblasts, the highest transfection efficiency was observed for the complex prepared from the cationized gelatin of spermine at a N+/P- mixing ratio of 2. The present study indicates that there is an optimal N+/P- mixing ratio and a type of amine compound or cationization extent of cationized gelatin to enhance the transfection efficiency of plasmid DNA.

  18. Study on the interaction of amino phosphine ester derivatives with DNA by spectroscopy, modeling and calorimetry.

    PubMed

    Lu, Yan; Wang, Gongke; Tang, Wen; Hao, Xiaoxiao; Xu, Meihua; Li, Xiang

    2011-11-01

    The binding properties of amino phosphate ester derivatives, compound 1 and 2 with calf thymus DNA (CT-DNA) were investigated by UV spectra, fluorescence spectra, molecular modeling and isothermal titration calorimetry (ITC). The intrinsic binding constants K(b) of compound 1 and 2 with CT-DNA were determined by fluorescence spectroscopy and ITC, respectively. The results indicated that the two compounds bind to CT-DNA with different binding affinity, which is in the order of compound 1>compound 2. At the same time, fluorescence spectra suggested that the mechanism of the binding of the two compounds to CT-DNA is a static enhancing type. According to the ethidium bromide displacement experiments, UV spectra, molecular modeling and ITC studies, it can be concluded that compound 1 and 2 are intercalators that can slide into the G-C rich region of CT-DNA. Furthermore, ITC data showed that compound/DNA binding is enthalpy controlled. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Controlled release of plasmid DNA from hydrogels prepared from gelatin cationized by different amine compounds.

    PubMed

    Kushibiki, Toshihiro; Tomoshige, Ryuji; Iwanaga, Kazunori; Kakemi, Masawo; Tabata, Yasuhiko

    2006-05-15

    This paper is an investigation to compare the in vivo controlled release of a plasmid DNA from biodegradable hydrogels prepared from gelatin cationized by different amine compounds, ethylenediamine, putrescine, spermidine, and spermine and the consequent profile of gene expression. Cationized gelatin prepared through the chemical introduction of each amine compound was crosslinked by various concentrations of glutaraldehyde to obtain cationized gelatin hydrogels for the carrier of plasmid DNA release. When the cationized gelatin hydrogels incorporating 125I-labeled plasmid DNA were implanted into the femoral muscle of mice, the radioactivity remaining decreased with time and the retention period of radioactivity prolonged with a decrease in the water content of hydrogels. When 125I-labeled cationized gelatin hydrogels with the higher water content was implanted, the radioactivity remaining was decreased faster with time. The remaining time profile of plasmid DNA radioactivity was in good accordance with that of hydrogel radioactivity, irrespective of the type of cationized gelatin. Following intramuscular implantation, any cationized gelatin hydrogel incorporating plasmid DNA enhanced the expression level of plasmid DNA to a significantly higher extent than the free plasmid DNA injection. In addition, prolonged time period of gene expression was observed although there was no significant difference in the expressed period between the cationized gelatin hydrogels. It was concluded that plasmid DNA of biological activity was released from every cationized gelatin hydrogel accompanied with the in vivo degradation, resulting in enhanced and prolonged gene expression.

  20. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. 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

  2. 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. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. Modeling the Forced Extension of Nicked DNA

    NASA Astrophysics Data System (ADS)

    Balaeff, Alexander; Craig, Stephen; Beratan, David

    2007-03-01

    The design and study of DNA-based nanodevices has been a topic of considerable interest in the last decade. While the applications of classical continuous DNA structures have been thoroughly studied, nicked DNA structures, i.e., ones that contains breaks (``nicks'') in one or both DNA backbone chains, have received much less attention. Recently, Kersey et al. (JACS, 2004) reported the force spectroscopy of long DNA chains with periodic nicks, self-assembled from short DNA oligomers. We attempt to model the experimental force-extension profiles in a series of steered molecular dynamics simulations. The simulated all-atom model of a basic unit of the long self-assembled chain, a 16bp-long DNA segment with a nick in the middle of one strand, is extended by applying either a constant force or a moving harmonic potential to the DNA ends. The computed force-extension profiles are compared to those for a non-nicked DNA; the dynamics of structural changes in the nicked DNA during the forced extension is discussed. A theoretical framework is established to link the extension and rupture in the simulated basic unit to the corresponding events in the long self-assembled chain.

  4. Model studies of DNA photoreactivation

    NASA Astrophysics Data System (ADS)

    Scannell, Michael P.

    1997-12-01

    This research was undertaken with the goal of understanding DNA damage and repair, specifically damage caused by the ultraviolet (UV) component of sunlight. The main type of DNA damage by UV irradiation is dimerization of adjacent thymines. This occurs through a (2+2) cycloaddition resulting in a cyclobutyl linkage between the thymines. These mutagenic lesions are repaired by an enzyme called photolyase, which repairs the dimers through a complex photochemical reaction. The work presented here is divided into three main topics. The first topic (Chapter 3) describes the measurement of the enthalpy of cleavage of dimethylthymine dimer. The enthalpy for the cleavage reaction of cis-syn 1,3-dimethylthymine dimer (DMTD) was measured by photothermal beam deflection calorimetry (PBD), and fluorescence quenching. These results show that the enthalpy of cleavage of the cyclobutyl ring is -19 kcal/mol. For the second topic (Chapters 4 and 5), the interactions of various pyrimidines and their corresponding cis-syn cyclobutane dimers with a series of excited-state electron donors were examined with the goal of understanding the energetics and mechanism of the repair step. For each substrate there is a good correlation between the excited state oxidation potential (E ox/sp/*) and the quenching rate constant (k q). The value for k q increases as E ox/sp/* becomes more negative, asymptotically approaching a value that is at or below the solvent diffusion limit. The data from this study were fit to the Rehm-Weller model of electron transfer. Reduction potentials for each of the substrates could be extracted from this analysis: -2.20 V (vs. SCE) for DMTD; -2.14 V for DMT; -2.17 V for DMCD; and -2.16 for DMC. The reduction potential of trans-syn dimethylthymine was also measured. This dimer shows a remarkably low reduction potential when compared to the cis-syn dimer. This is attributed to unfavorable charge-charge dipole interactions in the cis-syn dimer not presence in the trans

  5. 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).

  6. Superstatistical model of bacterial DNA architecture

    PubMed Central

    Bogachev, Mikhail I.; Markelov, Oleg A.; Kayumov, Airat R.; Bunde, Armin

    2017-01-01

    Understanding the physical principles that govern the complex DNA structural organization as well as its mechanical and thermodynamical properties is essential for the advancement in both life sciences and genetic engineering. Recently we have discovered that the complex DNA organization is explicitly reflected in the arrangement of nucleotides depicted by the universal power law tailed internucleotide interval distribution that is valid for complete genomes of various prokaryotic and eukaryotic organisms. Here we suggest a superstatistical model that represents a long DNA molecule by a series of consecutive ~150 bp DNA segments with the alternation of the local nucleotide composition between segments exhibiting long-range correlations. We show that the superstatistical model and the corresponding DNA generation algorithm explicitly reproduce the laws governing the empirical nucleotide arrangement properties of the DNA sequences for various global GC contents and optimal living temperatures. Finally, we discuss the relevance of our model in terms of the DNA mechanical properties. As an outlook, we focus on finding the DNA sequences that encode a given protein while simultaneously reproducing the nucleotide arrangement laws observed from empirical genomes, that may be of interest in the optimization of genetic engineering of long DNA molecules. PMID:28225058

  7. Superstatistical model of bacterial DNA architecture

    NASA Astrophysics Data System (ADS)

    Bogachev, Mikhail I.; Markelov, Oleg A.; Kayumov, Airat R.; Bunde, Armin

    2017-02-01

    Understanding the physical principles that govern the complex DNA structural organization as well as its mechanical and thermodynamical properties is essential for the advancement in both life sciences and genetic engineering. Recently we have discovered that the complex DNA organization is explicitly reflected in the arrangement of nucleotides depicted by the universal power law tailed internucleotide interval distribution that is valid for complete genomes of various prokaryotic and eukaryotic organisms. Here we suggest a superstatistical model that represents a long DNA molecule by a series of consecutive ~150 bp DNA segments with the alternation of the local nucleotide composition between segments exhibiting long-range correlations. We show that the superstatistical model and the corresponding DNA generation algorithm explicitly reproduce the laws governing the empirical nucleotide arrangement properties of the DNA sequences for various global GC contents and optimal living temperatures. Finally, we discuss the relevance of our model in terms of the DNA mechanical properties. As an outlook, we focus on finding the DNA sequences that encode a given protein while simultaneously reproducing the nucleotide arrangement laws observed from empirical genomes, that may be of interest in the optimization of genetic engineering of long DNA molecules.

  8. 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.

  9. Composite model for DNA torsion dynamics.

    PubMed

    Cadoni, Mariano; De Leo, Roberto; Gaeta, Giuseppe

    2007-02-01

    DNA torsion dynamics is essential in the transcription process; a simple model for it, in reasonable agreement with experimental observations, has been proposed by Yakushevich (Y) and developed by several authors; in this, the nucleotides (the DNA subunits made of a sugar-phosphate group and the attached nitrogen base) are described by a single degree of freedom. In this paper we propose and investigate, both analytically and numerically, a "composite" version of the Y model, in which the sugar-phosphate group and the base are described by separate degrees of freedom. The model proposed here contains as a particular case the Y model and shares with it many features and results, but represents an improvement from both the conceptual and the phenomenological point of view. It provides a more realistic description of DNA and possibly a justification for the use of models which consider the DNA chain as uniform. It shows that the existence of solitons is a generic feature of the underlying nonlinear dynamics and is to a large extent independent of the detailed modeling of DNA. The model we consider supports solitonic solutions, qualitatively and quantitatively very similar to the Y solitons, in a fully realistic range of all the physical parameters characterizing the DNA.

  10. Polymer chain models of DNA and chromatin

    NASA Astrophysics Data System (ADS)

    Langowski, J.

    2006-03-01

    Many properties of the genome in the cell nucleus can be understood by modeling DNA and chromatin as a flexible polymer chain. This article introduces into current models for such a coarse-grained description and reviews some recent results from our own group. Examples given are the unrolling of DNA from the histone core and the response of the 30nm chromatin fiber to mechanical stretching.

  11. Palladium(II) and platinum(II) organometallic complexes with the model nucleobase anions of thymine, uracil, and cytosine: antitumor activity and interactions with DNA of the platinum compounds.

    PubMed

    Ruiz, José; Lorenzo, Julia; Sanglas, Laura; Cutillas, Natalia; Vicente, Consuelo; Villa, María Dolores; Avilés, Francesc X; López, Gregorio; Moreno, Virtudes; Pérez, José; Bautista, Delia

    2006-08-07

    Pd(II) and Pt(II) complexes with the anions of the model nucleobases 1-methylthymine (1-MethyH), 1-methyluracil (1-MeuraH), and 1-methylcytosine (1-MecytH) of the types [Pd(dmba)(mu-L)]2 [dmba = N,C-chelating 2-((dimethylamino)methyl)phenyl; L = 1-Methy, 1-Meura or 1-Mecyt] and [M(dmba)(L)(L')] [L = 1-Methy or 1-Meura; L' = PPh(3) (M = Pd or Pt), DMSO (M = Pt)] have been obtained. Palladium complexes of the types [Pd(C6F5)(N-N)(L)] [L = 1-Methy or 1-Meura; N-N = N,N,N',N'-tetramethylethylenediamine (tmeda), 2,2'-bipyridine (bpy), or 4,4'-dimethyl-2,2'-bipyridine (Me2bpy)] and [NBu4][Pd(C6F5)(1-Methy)2(H2O)] have also been prepared. The crystal structures of [Pd(dmba)(mu-1-Methy)]2, [Pd(dmba)(mu-1-Mecyt)]2.2CHCl3, [Pd(dmba)(1-Methy)(PPh3)].3CHCl3, [Pt(dmba)(1-Methy)(PPh3)], [Pd(tmeda)(C6F5)(1-Methy)], and [NBu4][Pd(C6F5)(1-Methy)2(H2O)].H2O have been established by X-ray diffraction. The DNA adduct formation of the new platinum complexes synthesized was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by the platinum complexes on plasmid DNA pBR322 were also obtained. Values of IC50 were also calculated for the new platinum complexes against the tumor cell line HL-60. All the new platinum complexes were more active than cisplatin (up to 20-fold in some cases).

  12. 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.

  13. 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.

  14. Model for melting of confined DNA

    NASA Astrophysics Data System (ADS)

    Werner, E.; Reiter-Schad, M.; Ambjörnsson, T.; Mehlig, B.

    2015-06-01

    When DNA molecules are heated they denature. This occurs locally so that loops of molten single DNA strands form, connected by intact double-stranded DNA pieces. The properties of this "melting" transition have been intensively investigated. Recently there has been a surge of interest in this question, in part caused by experiments determining the properties of partially bound DNA confined to nanochannels. But how does such confinement affect the melting transition? To answer this question we introduce and solve a model predicting how confinement affects the melting transition for a simple model system by first disregarding the effect of self-avoidance. We find that the transition is smoother for narrower channels. By means of Monte Carlo simulations we then show that a model incorporating self-avoidance shows qualitatively the same behavior and that the effect of confinement is stronger than in the ideal case.

  15. Study on the Keggin zinctungstates based hybrid compound with like DNA spiral chain

    NASA Astrophysics Data System (ADS)

    Li, Liang; Sha, Jing-Quan; Zong, Xi-Ming; Liu, Cui-Juan; Zhang, Qian-Nan; Wang, Dong-Wen; Yang, Xiao-Ning; Wang, Yu

    2014-05-01

    A new compound based on polyoxometalates (POMs) and the quinolone antibacterial pipemidic acid (HPPA), {[Zn(HPPA)2H2O]2[H2ZnW12O40]}ṡ9H2O (1), was hydrothermally synthesized and characterized by elemental analyses, IR and XPRD. Single-crystal X-ray diffraction analysis reveals that the [ZnW12O40 ] 6 - clusters and Zn-HPPA complexes constructed both right- and left-double-stranded like DNA helical chains in the title compound, and these helical chains are further connected together forming the fascinating quadruple-stranded helices via sharing the ZnW12 clusters. Note that the compound 1 represents the first example of zinctungstate POMs modified by antibacterial drugs. In addition, the antibacterial properties of the compound 1 were investigated.

  16. 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.

  17. Modeling and Global Optimization of DNA separation

    PubMed Central

    Fahrenkopf, Max A.; Ydstie, B. Erik; Mukherjee, Tamal; Schneider, James W.

    2014-01-01

    We develop a non-convex non-linear programming problem that determines the minimum run time to resolve different lengths of DNA using a gel-free micelle end-labeled free solution electrophoresis separation method. Our optimization framework allows for efficient determination of the utility of different DNA separation platforms and enables the identification of the optimal operating conditions for these DNA separation devices. The non-linear programming problem requires a model for signal spacing and signal width, which is known for many DNA separation methods. As a case study, we show how our approach is used to determine the optimal run conditions for micelle end-labeled free-solution electrophoresis and examine the trade-offs between a single capillary system and a parallel capillary system. Parallel capillaries are shown to only be beneficial for DNA lengths above 230 bases using a polydisperse micelle end-label otherwise single capillaries produce faster separations. PMID:24764606

  18. 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. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. 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. © 2014 Blackwell Verlag GmbH.

  20. 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.

  1. A statistical model of DNA denaturation

    NASA Astrophysics Data System (ADS)

    Resendis-Antonio, O.; Garcia-Colin, L. S.; Larralde, H.

    2003-02-01

    In this work we present a statistical model describing the denaturation process of DNA as a Markov process along the length of the chain. By identifying the stationary state of the Markov process with the equilibrium state of the system, we are able to obtain a relationship between the melting temperature and the fraction of base pairs of Cytosine-Guanine, [ C+ G] in the sequence. This relation is in close agreement with the experimental values reported by Marmur and Doty for long DNA chains of higher organisms in a biological range of temperatures. This model has two biological implications; on the one hand, it contributes to an understanding of the fundamental process of melting transition in DNA, and as a consequence, to have better conditions in the control of techniques such as polymerases chain reaction. On the other hand, this theoretical study could be an adequate framework to study the denaturation effects for long DNA and RNA chains at different physiological conditions.

  2. 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

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

    PubMed

    Guerrero-Preston, Rafael; Goldman, Lynn R; Brebi-Mieville, Priscilla; Ili-Gangas, Carmen; Lebron, Cynthia; Witter, Frank R; Apelberg, Ben J; Hernández-Roystacher, Marina; Jaffe, Andrew; Halden, Rolf U; Sidransky, David

    2010-08-16

    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= -0.72, p < 0.01) 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.

  4. Radiosensitization of DNA in presence of Pt(II)-based compounds

    NASA Astrophysics Data System (ADS)

    Śmiałek, Małgorzata A.; Ptasińska, Sylwia; Gow, Jason; Pieve, Chiara Da; Mason, Nigel J.

    2014-04-01

    X-ray irradiation of plasmid DNA in presence of platinum (II)-based compounds was carried out in order to assess the radiosensitization capabilities of these drugs. In present investigations pBR322 plasmid DNA was used to monitor the effectiveness of chosen compounds in inducing strand breaks. Samples were incubated in the presence of potential radiosensitisers: platinum (II) bromide and cis-diamminedibromoplatinum (II). The results were examined against a common cancer chemotherapy drug cis-diamminedichloroplatinum (II). It was found that platinum (II) bromide can greatly increase the levels of single- and double-strand break formation observed in the irradiated samples with respect to the samples containing platinum as a radiosensitizer only, possessing very little chemotherapeutic activity. The suggested drugs exhibit much higher level of radiosensitivity than widely used cisplatin and thus may be good candidates for cancer treatment.

  5. Application of the DNA adductome approach to assess the DNA-damaging capability of in vitro micronucleus test-positive compounds.

    PubMed

    Kato, Kyoko; Yamamura, Eiji; Kawanishi, Masanobu; Yagi, Takashi; Matsuda, Tomonari; Sugiyama, Akio; Uno, Yoshifumi

    2011-03-18

    The in vitro micronucleus (MN) test is widely used for screening genotoxic compounds, but it often produces false-positive results. To consider the significance of positive results, it is important to know whether DNA adducts are formed in the cells treated with the test compound. Recently, Matsuda et al. developed the DNA adductome approach to detect DNA adducts comprehensively ([4] Kanaly, et al., Antioxid. Redox Signal., 2006, 8, 993-1001). We applied this method to assess the DNA-damaging capability of in vitro MN test-positive compounds. CHL/IU cells were treated with compounds from three categories: (1) carcinogens causing DNA alkylation, ethyl methanesulfonate and N-methyl-N'-nitro-N-nitrosoguanidine; (2) carcinogens producing DNA bulky adducts, 2-amino-6-phenyl-1-methylimidazo[4,5-b]pyrene, benzo[a]pyrene, 7,12-dimethylbenz[a]anthracene, and 4-nitroquinoline-1-oxide, and (3) non-carcinogens, caffeine, maltol, and sodium chloride, with or without metabolic activation. With the conditions in which all test compounds gave positive results in the MN tests, DNA was extracted from the cells and hydrolyzed to deoxyribonucleosides, which were subsequently subjected to LC/ESI-MS/MS analysis. All carcinogens (categories 1 and 2) produced various DNA adduct peaks, and some of the m/z peak values corresponded to known adducts. No non-carcinogens produced DNA adducts, indicating that these compounds produced MN through different mechanisms from the adduct formation. These results indicate that the adductome approach is useful to demonstrate DNA damage formation of MN test-positive compounds and to understand their mechanisms of action.

  6. 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

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

    PubMed

    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

    2014-03-18

    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 [(η(6)-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η(6)-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.

  8. Structure-based design, synthesis and biological testing of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds designed to covalently bind to topoisomerase II and DNA

    PubMed Central

    Yadav, Arun A.; Wu, Xing; Patel, Daywin; Yalowich, Jack C.; Hasinoff, Brian B.

    2014-01-01

    Drugs that target DNA topoisomerase II isoforms and alkylate DNA represent two mechanistically distinct and clinically important classes of anticancer drugs. Guided by molecular modeling and docking a series of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds were designed, synthesized and biologically characterized. These hybrids were designed to alkylate nucleophilic protein residues on topoisomerase II and thus produce inactive covalent adducts and to also alkylate DNA. The most potent hybrid had a mean GI50 in the NCI-60 cell screen 17-fold lower than etoposide. Using a variety of in vitro and cell-based assays all of the hybrids tested were shown to target topoisomerase II. A COMPARE analysis indicated that the hybrids had NCI 60-cell growth inhibition profiles matching both etoposide and the N-mustard compounds from which they were derived. These results supported the conclusion that the hybrids displayed characteristics that were consistent with having targeted both topoisomerase II and DNA. PMID:25282653

  9. Modeling biominerals formed by apatites and DNA.

    PubMed

    Revilla-López, Guillermo; Casanovas, Jordi; Bertran, Oscar; Turon, Pau; Puiggalí, Jordi; Alemán, Carlos

    2013-12-01

    Different aspects of biominerals formed by apatite and DNA have been investigated using computer modeling tools. Firstly, the structure and stability of biominerals in which DNA molecules are embedded into hydroxyapatite and fluoroapatite nanopores have been examined by combining different molecular mechanics methods. After this, the early processes in the nucleation of hydroxyapatite at a DNA template have been investigated using molecular dynamics simulations. Results indicate that duplexes of DNA adopting a B double helix can be encapsulated inside nanopores of hydroxyapatite without undergoing significant distortions in the inter-strand hydrogen bonds and the intra-strand stacking. This ability of hydroxyapatite is practically independent of the DNA sequence, which has been attributed to the stabilizing role of the interactions between the calcium atoms of the mineral and the phosphate groups of the biomolecule. In contrast, the fluorine atoms of fluoroapatite induce pronounced structural distortions in the double helix when embedded in a pore of the same dimensions, resulting in the loss of its most relevant characteristics. On the other hand, molecular dynamics simulations have allowed us to observe the formation of calcium phosphate clusters at the surface of the B-DNA template. Electrostatic interactions between the phosphate groups of DNA and Ca(2+) have been found to essential for the formation of stable ion complexes, which were the starting point of calcium phosphate clusters by incorporating PO3(4) from the solution.

  10. Molecular Models for DNA Damaged by Photoreaction

    NASA Astrophysics Data System (ADS)

    Pearlman, David A.; Holbrook, Stephen R.; Pirkle, David H.; Kim, Sung-Hou

    1985-03-01

    Structural models of a DNA molecule containing a radiation-induced psoralen cross-link and of a DNA containing a thymine photodimer were constructed by applying energy-minimization techniques and model-building procedures to data from x-ray crystallographic studies. The helical axes of the models show substantial kinking and unwinding at the sites of the damage, which may have long-range as well as local effects arising from the concomitant changes in the supercoiling and overall structure of the DNA. The damaged areas may also serve as recognition sites for repair enzymes. These results should help in understanding the biologic effects of radiation-induced damage on cells.

  11. Molecular models for DNA damaged by photoreaction

    SciTech Connect

    Pearlman, D.A.; Holbrook, S.R.; Pirkle, D.H.; Kim, S.H.

    1985-03-15

    Structural models of a DNA molecule containing a radiation-induced psoralen cross-link and of a DNA containing a thymine photodimer were constructed by applying energy-minimization techniques and model-building procedures to data from x-ray crystallographic studies. The helical axes of the models show substantial kinking and unwinding at the sites of the damage, which may have long-range as well as local effects arising from the concomitant changes in the supercoiling and overall structure of the DNA. The damaged areas may also serve as recognition sites for repair enzymes. These results should help in understanding the biologic effects of radiation-induced damage on cells.

  12. Discrete model for DNA-promoter dynamics

    NASA Astrophysics Data System (ADS)

    Salerno, Mario

    1991-10-01

    We introduce a discrete model for DNA that takes into account the information about specific base sequences along the double helix. We use this model to study nonlinear wave dynamics of the T7A1 DNA promoter. As results we show the existence in the promoter of a dynamically active region in which static solitons acquire finite velocities, which contrasts with regions where solitons simply remain static. Furthermore, when they pass through this region moving solitons are accelerated, decelerated, or reflected, depending on their initial velocities. The possibility that these dynamical effects play a role in the mechanism of genetic activation is suggested.

  13. Identification of genotoxic compounds using isogenic DNA repair deficient DT40 cell lines on a quantitative high throughput screening platform

    PubMed Central

    Nishihara, Kana; Huang, Ruili; Zhao, Jinghua; Shahane, Sampada A.; Witt, Kristine L.; Smith-Roe, Stephanie L.; Tice, Raymond R.; Takeda, Shunichi; Xia, Menghang

    2016-01-01

    DNA repair pathways play a critical role in maintaining cellular homeostasis by repairing DNA damage induced by endogenous processes and xenobiotics, including environmental chemicals. Induction of DNA damage may lead to genomic instability, disruption of cellular homeostasis and potentially tumours. Isogenic chicken DT40 B-lymphocyte cell lines deficient in DNA repair pathways can be used to identify genotoxic compounds and aid in characterising the nature of the induced DNA damage. As part of the US Tox21 program, we previously optimised several different DT40 isogenic clones on a high-throughput screening platform and confirmed the utility of this approach for detecting genotoxicants by measuring differential cytotoxicity in wild-type and DNA repair-deficient clones following chemical exposure. In the study reported here, we screened the Tox21 10K compound library against two isogenic DNA repair-deficient DT40 cell lines (KU70 −/−/RAD54 −/− and REV3 −/−) and the wild-type cell line using a cell viability assay that measures intracellular adenosine triphosphate levels. KU70 and RAD54 are genes associated with DNA double-strand break repair processes, and REV3 is associated with translesion DNA synthesis pathways. Active compounds identified in the primary screening included many well-known genotoxicants (e.g. adriamycin, melphalan) and several compounds previously untested for genotoxicity. A subset of compounds was further evaluated by assessing their ability to induce micronuclei and phosphorylated H2AX. Using this comprehensive approach, three compounds with previously undefined genotoxicity—2-oxiranemethanamine, AD-67 and tetraphenylolethane glycidyl ether—were identified as genotoxic. These results demonstrate the utility of this approach for identifying and prioritising compounds that may damage DNA. PMID:26243743

  14. 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.

  15. 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 ...

  16. 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 ...

  17. The structure-based design, synthesis and biological evaluation of DNA-binding bisintercalating bisanthrapyrazole anticancer compounds

    PubMed Central

    Hasinoff, Brian B.; Liang, Hong; Wu, Xing; Guziec, Lynn J.; Guziec, Frank S.; Marshall, Kyle; Yalowich, Jack C.

    2008-01-01

    Anticancer drugs that bind to DNA and inhibit DNA-processing enzymes represent an important class of anticancer drugs. In order to find stronger DNA binding and more potent cytotoxic compounds, a series of ester-coupled bisanthrapyrazole derivatives of 7-chloro-2-[2-[(2-hydroxyethyl)methylamino]ethyl]anthra[1,9-cd]pyrazol-6(2H)-one (AP9) were designed and evaluated by molecular docking techniques. Because the anthrapyrazoles are unable to be reductively activated like doxorubicin and other anthracyclines, they should not be cardiotoxic like the anthracyclines. Based on the docking scores of a series of bisanthrapyrazoles with different numbers of methylene linkers (n) that were docked into an X-ray structure of double-stranded DNA, five bisanthrapyrazoles (n = 1 to 5) were selected for synthesis and physical and biological evaluation. The synthesized compounds were evaluated for DNA binding and bisintercalation by measuring the DNA melting temperature increase, for growth inhibitory effects on the human erythroleukemic K562 cell line, and for DNA topoisomerase IIα-mediated cleavage of DNA and inhibition of DNA topoisomerase IIα decatenation activities. The results suggest that the bisanthrapyrazoles with n = 2 to 5 formed bisintercalation complexes with DNA. In conclusion, a novel group of bisintercalating anthrapyrazole compounds have been designed, synthesized and biologically evaluated as possible anticancer agents. PMID:18258442

  18. Prediction model of biocrude yield and nitrogen heterocyclic compounds analysis by hydrothermal liquefaction of microalgae with model compounds.

    PubMed

    Sheng, Lili; Wang, Xin; Yang, Xiaoyi

    2017-08-05

    The model of biocrude yield and the nitrogen heterocyclic compounds in biocrude of microalgae hydrothermal liquefaction are two of the most concerned issues in this field at present. This study explored a hydrothermal liquefaction biocrude yield model involved in the interaction among biochemical compounds in microalgae and analysed nitrogen heterocyclic compounds in biocrude. The model compound (castor oil, soya protein and glucose) and Nanochloropsis were liquefied at 280°C for 1h. The products were analyzed by GC-MS, element analysis and FTIR. The results suggested that interactions among different components in microalgae enhanced biocrude yield. The biocrude yield prediction model involved cross-interactions performed more accurate than previous models.When the ratio of protein and carbohydrate around 3, the cross-interaction and nitrogen heterocyclic compounds in biocrude would both reach the highest extent. Copyright © 2017. Published by Elsevier Ltd.

  19. Compound

    NASA Astrophysics Data System (ADS)

    Suzumura, Akitoshi; Watanabe, Masaki; Nagasako, Naoyuki; Asahi, Ryoji

    2014-06-01

    Recently, Cu-based chalcogenides such as Cu3SbSe4, Cu2Se, and Cu2SnSe3 have attracted much attention because of their high thermoelectric performance and their common feature of very low thermal conductivity. However, for practical use, materials without toxic elements such as selenium are preferable. In this paper, we report Se-free Cu3SbS4 thermoelectric material and improvement of its figure of merit ( ZT) by chemical substitutions. Substitutions of 3 at.% Ag for Cu and 2 at.% Ge for Sb lead to significant reductions in the thermal conductivity by 37% and 22%, respectively. These substitutions do not sacrifice the power factor, thus resulting in enhancement of the ZT value. The sensitivity of the thermal conductivity to chemical substitutions in these compounds is discussed in terms of the calculated phonon dispersion and previously proposed models for Cu-based chalcogenides. To improve the power factor, we optimize the hole carrier concentration by substitution of Ge for Sb, achieving a power factor of 16 μW/cm K2 at 573 K, which is better than the best reported for Se-based Cu3SbSe4 compounds.

  20. 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.

  1. Curcumin, resveratrol and flavonoids as anti-inflammatory, cyto- and DNA-protective dietary compounds.

    PubMed

    Bisht, Kavita; Wagner, Karl-Heinz; Bulmer, Andrew C

    2010-11-28

    Numerous dietary compounds, ubiquitous in fruits, vegetables and spices have been isolated and evaluated during recent years for their therapeutic potential. These compounds include flavonoid and non-flavonoid polyphenols, which describe beneficial effects against a variety of ailments. The notion that these plant products have health promoting effects emerged because their intake was related to a reduced incidence of cancer, cardiovascular, neurological, respiratory, and age-related diseases. Exposure of the body to a stressful environment challenges cell survival and increases the risk of chronic disease developing. The polyphenols afford protection against various stress-induced toxicities through modulating intercellular cascades which inhibit inflammatory molecule synthesis, the formation of free radicals, nuclear damage and induce antioxidant enzyme expression. These responses have the potential to increase life expectancy. The present review article focuses on curcumin, resveratrol, and flavonoids and seeks to summarize their anti-inflammatory, cytoprotective and DNA-protective properties.

  2. Braiding DNA: experiments, simulations, and models.

    PubMed

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

    2005-06-01

    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): C(b) approximately 48 nm (as compared with C approximately 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.

  3. Improved machine learning models for predicting selective compounds.

    PubMed

    Ning, Xia; Walters, Michael; Karypis, George; Karypisxy, George

    2012-01-23

    The identification of small potent compounds that selectively bind to the target under consideration with high affinities is a critical step toward successful drug discovery. However, there is still a lack of efficient and accurate computational methods to predict compound selectivity properties. In this paper, we propose a set of machine learning methods to do compound selectivity prediction. In particular, we propose a novel cascaded learning method and a multitask learning method. The cascaded method decomposes the selectivity prediction into two steps, one model for each step, so as to effectively filter out nonselective compounds. The multitask method incorporates both activity and selectivity models into one multitask model so as to better differentiate compound selectivity properties. We conducted a comprehensive set of experiments and compared the results with those of other conventional selectivity prediction methods, and our results demonstrated that the cascaded and multitask methods significantly improve the selectivity prediction performance.

  4. A low-density DNA microchip for the detection of (anti-)estrogenic compounds and their relative potencies.

    PubMed

    Wang, Si; Rijk, Jeroen C W; Pen, Marieke J; Aarts, Jac M M J G; Peijnenburg, Ad A C M; Rietjens, Ivonne M C M; Bovee, Toine F H

    2013-04-01

    In the current study, a set of 12 reference compounds was tested in a low-density DNA microchip that contains probes for 11 different estrogen-responsive marker genes. Our results show that the seven most informative marker genes on the chip resulted in fingerprints that correctly predicted the (anti-)estrogenic activity of the model compounds except that of the negative control testosterone. Two marker genes, myeloid leukemia factor-1 interacting protein and ubiquitin-conjugating enzyme E2C, were even capable of correctly predicting the estrogenic potency of all five estrogen receptor (ER) agonists tested and correlated well with the potencies as determined in the MCF-7/BOS proliferation assay and the in vivo uterotrophic assay. In addition, it was demonstrated that the estrogenic responses of testosterone, both in the array tube assay and in the proliferation assay, were partially due to the conversion of testosterone into 17β-estradiol by aromatase but also due to formation of other estrogenic metabolites, the presence and estrogenic potency of which were confirmed by gas chromatography-tandem mass spectrometry analysis and a yeast-based reporter gene assay, respectively. It is concluded that low-density DNA microchip-based fingerprinting in MCF-7/BOS cells for estrogenicity marker genes provides a faster in vitro alternative to the current MCF-7/BOS cell proliferation assay (E-screen).

  5. Is DNA a Good Model Polymer?

    PubMed Central

    Tree, Douglas R.; Muralidhar, Abhiram; Doyle, Patrick S.; Dorfman, Kevin D.

    2013-01-01

    The details surrounding the cross-over from wormlike-specific to universal polymeric behavior has been the subject of debate and confusion even for the simple case of a dilute, unconfined wormlike chain. We have directly computed the polymer size, form factor, free energy and Kirkwood diffusivity for unconfined wormlike chains as a function of molecular weight, focusing on persistence lengths and effective widths that represent single-stranded and double-stranded DNA in a high ionic strength buffer. To do so, we use a chain-growth Monte Carlo algorithm, the Pruned-Enriched Rosenbluth Method (PERM), which allows us to estimate equilibrium and near-equilibrium dynamic properties of wormlike chains over an extremely large range of contour lengths. From our calculations, we find that very large DNA chains (≈ 1,000,000 base pairs depending on the choice of size metric) are required to reach flexible, swollen non-draining coils. Furthermore, our results indicate that the commonly used model polymer λ-DNA (48,500 base pairs) does not exhibit “ideal” scaling, but exists in the middle of the transition to long-chain behavior. We subsequently conclude that typical DNA used in experiments are too short to serve as an accurate model of long-chain, universal polymer behavior. PMID:24347685

  6. Solid-State, Dye-Labeled DNA Detects Volatile Compounds in the Vapor Phase

    PubMed Central

    White, Joel; Truesdell, Kathleen; Williams, Lloyd B; AtKisson, Mary S; Kauer, John S

    2008-01-01

    This paper demonstrates a previously unreported property of deoxyribonucleic acid—the ability of dye-labeled, solid-state DNA dried onto a surface to detect odors delivered in the vapor phase by changes in fluorescence. This property is useful for engineering systems to detect volatiles and provides a way for artificial sensors to emulate the way cross-reactive olfactory receptors respond to and encode single odorous compounds and mixtures. Recent studies show that the vertebrate olfactory receptor repertoire arises from an unusually large gene family and that the receptor types that have been tested so far show variable breadths of response. In designing biomimetic artificial noses, the challenge has been to generate a similarly large sensor repertoire that can be manufactured with exact chemical precision and reproducibility and that has the requisite combinatorial complexity to detect odors in the real world. Here we describe an approach for generating and screening large, diverse libraries of defined sensors using single-stranded, fluorescent dye–labeled DNA that has been dried onto a substrate and pulsed with brief exposures to different odors. These new solid-state DNA-based sensors are sensitive and show differential, sequence-dependent responses. Furthermore, we show that large DNA-based sensor libraries can be rapidly screened for odor response diversity using standard high-throughput microarray methods. These observations describe new properties of DNA and provide a generalized approach for producing explicitly tailored sensor arrays that can be rationally chosen for the detection of target volatiles with different chemical structures that include biologically derived odors, toxic chemicals, and explosives. PMID:18215112

  7. New spiro tria(thia)zolidine-acridines as topoisomerase inhibitors, DNA binders and cytostatic compounds.

    PubMed

    Salem, Othman M; Vilková, Mária; Janočková, Jana; Jendželovský, Rastislav; Fedoročko, Peter; Žilecká, Eva; Kašpárková, Jana; Brabec, Viktor; Imrich, Ján; Kožurková, Mária

    2016-05-01

    Three new diphenylsubstituted spirotriazolidine- and thiazolidinone-acridines were prepared and their interaction with calf thymus DNA investigated with UV-vis, fluorescence, circular dichroism spectroscopy and viscometry. The binding constants K were estimated to range from 0.34 to 0.93 × 10(4) M(-1). UV-vis, fluorescence and circular dichroism measurements indicated that the compounds act as effective DNA-interacting agents. Electrophoretic separation proved that ligands inhibited topoisomerase I and II. The biological activity of compounds 3, 5 &6 at several different concentrations (10, 20 and 50 μM) was evaluated both 48 h and 72 h following their addition to HL-60 cancer cells. The results were analysed using various different techniques (MMP detection, changes in metabolic activity/viability and analysis of cell cycle distribution). Acridine was also used as the positive control in these assays. The results from MMP analysis demonstrate the strong effect of 3-diphenylamino-2-(acridin-9-yl)imino-1,3-thiazolidin-4-one (5) on mitochondrial physiology. Cell viability analysis showed that acridine derivatives 3 and 6 were less effective than derivative 5 and the acridine control.

  8. Kinetic model for phenolic compound oxidation by Fenton's reagent.

    PubMed

    De Heredia, J B; Torregrosa, J; Dominguez, J R; Peres, J A

    2001-10-01

    A kinetic model is developed for the oxidation of phenolic compounds by Fenton's reagent. In the first stage a rigorous kinetic model is applied to calculate the different kinetic rate constants for the oxidation process of p-hydroxybenzoic acid. In a second phase a competitive method is applied to calculate these kinetic constants for another 10 phenolic compounds present in agroindustrial and pulp paper wastewaters. These 10 phenolic compounds were: beta-resorcylic acid, 3-(4-hydroxyphenyl)-propionic acid, ferulic acid, protocatechuic acid, caffeic acid, p-coumaric acid, vanillic acid, syringic acid, veratric acid and 3,4,5-trimethoxybenzoic acid.

  9. Rational design, synthesis, pharmacophore modeling, and docking studies for identification of novel potent DNA-PK inhibitors.

    PubMed

    Ihmaid, Saleh; Ahmed, Hany E A; Al-Sheikh Ali, Adeeb; Sherif, Yousery E; Tarazi, Hamadeh M; Riyadh, Sayed M; Zayed, Mohamed F; Abulkhair, Hamada S; Rateb, Heba S

    2017-06-01

    Drugs of cancer based upon ionizing radiation or chemotherapeutic treatment may affect breaking of DNA double strand in cell. DNA-PK enzyme has emerged as an attractive target for drug discovery efforts toward DNA repair pathways. Hence, the search for potent and selective DNA-PK inhibitors has particularly considered state-of-the art and several series of inhibitors have been designed. In this article, a novel benchmark DNA-PK database of 43 compounds was built and described. Ligand-based approaches including pharmacophore and QSAR modeling were applied and novel models were introduced and analyzed for predicting activity test for DNA-PK drug candidates. Based upon the modeling results, we gave a report of synthesis of fifteen novel 2-((8-methyl-2-morpholino-4-oxo-4H-benzo[e][1,3]oxazin-7-yl)oxy)acetamide derivatives and in vitro evaluation for DNA-PK inhibitory and antiproliferative activities. These fifteen compounds overall are satisfied with Lipinski's rule of five. The biological testing of target compounds showed five promising active compounds 7c, 7d, 7f, 9e and 9f with micromolar DNA-PK activity range from 0.25 to 5µM. In addition, SAR of the compounds activity was investigated and confirmed that the terminal aryl moiety was found to be quite crucial for DNA-PK activity. Moreover flexible docking simulation was done for the potent compounds into the putative binding site of the 3D homology model of DNA-PK enzyme and the probable interaction model between DNA-PK and the ligands was investigated and interpreted. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. 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.

  11. How aromatic compounds block DNA binding of HcaR catabolite regulator

    SciTech Connect

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

    2016-04-25

    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. Furthermore, the current study contributes to a better understanding of the hca catabolic operon regulation mechanism by the transcription factor HcaR.

  12. How aromatic compounds block DNA binding of HcaR catabolite regulator

    DOE PAGES

    Kim, Youngchang; Joachimiak, Grazyna; Bigelow, Lance; ...

    2016-04-25

    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 Åmore » 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. Furthermore, the current study contributes to a better understanding of the hca catabolic operon regulation mechanism by the transcription factor HcaR.« less

  13. How aromatic compounds block DNA binding of HcaR catabolite regulator

    SciTech Connect

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

    2016-04-25

    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. Furthermore, the current study contributes to a better understanding of the hca catabolic operon regulation mechanism by the transcription factor HcaR.

  14. 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.

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

    PubMed

    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, (1)H 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 (K(b)) 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.

  16. 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.

  17. 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.

  18. The discovery of macrocyclic XIAP antagonists from a DNA-programmed chemistry library, and their optimization to give lead compounds with in vivo antitumor activity.

    PubMed

    Seigal, Benjamin A; Connors, William H; Fraley, Andrew; Borzilleri, Robert M; Carter, Percy H; Emanuel, Stuart L; Fargnoli, Joseph; Kim, Kyoung; Lei, Ming; Naglich, Joseph G; Pokross, Matthew E; Posy, Shana L; Shen, Henry; Surti, Neha; Talbott, Randy; Zhang, Yong; Terrett, Nicholas K

    2015-03-26

    Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.

  19. Combining a Ru(II) "Building Block" and Rapid Screening Approach to Identify DNA Structure-Selective "Light Switch" Compounds.

    PubMed

    Wachter, Erin; Moyá, Diego; Glazer, Edith C

    2017-02-13

    A chemically reactive Ru(II) "building block", able to undergo condensation reactions with substituted diamines, was utilized to create a small library of luminescent "light switch" dipyrido-[3,2-a:2',3'-c] phenazine (dppz) complexes. The impact of substituent identity, position, and the number of substituents on the light switch effect was investigated. An unbiased, parallel screening approach was used to evaluate the selectivity of the compounds for a variety of different biomolecules, including protein, nucleosides, single stranded DNA, duplex DNA, triplex DNA, and G-quadruplex DNA. Combining these two approaches allowed for the identification of hit molecules that showed different selectivities for biologically relevant DNA structures, particularly triplex and quadruplex DNA.

  20. Quantum dynamics of a hole migration through DNA: A single strand DNA model.

    PubMed

    Shirmovsky, S Eh

    2016-10-01

    A model predicting the behavior of a hole acting on the DNA strand was investigated. The hole-DNA interaction on the basis of a quantum-classical, non-linear DNA single strand model was described. The fact that a DNA molecule is formed by a furanose ring as its sugar, phosphate group and bases was taken into consideration. Based on the model, results were obtained for the probability of a hole location on the DNA base sequences, such as GTTGGG, GATGTGGG, GTTGTTGGG as well as on the sugar-phosphate groups mated with them.

  1. Behavior of asphaltene model compounds at w/o interfaces.

    PubMed

    Nordgård, Erland L; Sørland, Geir; Sjöblom, Johan

    2010-02-16

    Asphaltenes, present in significant amounts in heavy crude oil, contains subfractions capable of stabilizing water-in-oil emulsions. Still, the composition of these subfractions is not known in detail, and the actual mechanism behind emulsion stability is dependent on perceived interfacial concentrations and compositions. This study aims at utilizing polyaromatic surfactants which contains an acidic moiety as model compounds for the surface-active subfraction of asphaltenes. A modified pulse-field gradient (PFG) NMR method has been used to study droplet sizes and stability of emulsions prepared with asphaltene model compounds. The method has been compared to the standard microscopy droplet counting method. Arithmetic and volumetric mean droplet sizes as a function of surfactant concentration and water content clearly showed that the interfacial area was dependent on the available surfactant at the emulsion interface. Adsorption of the model compounds onto hydrophilic silica has been investigated by UV depletion, and minor differences in the chemical structure of the model compounds caused significant differences in the affinity toward this highly polar surface. The cross-sectional areas obtained have been compared to areas from the surface-to-volume ratio found by NMR and gave similar results for one of the two model compounds. The mean molecular area for this compound suggested a tilted geometry of the aromatic core with respect to the interface, which has also been proposed for real asphaltenic samples. The film behavior was further investigated using a liquid-liquid Langmuir trough supporting the ability to form stable interfacial films. This study supports that acidic, or strong hydrogen-bonding fractions, can promote stable water-in-oil emulsion. The use of model compounds opens up for studying emulsion behavior and demulsifier efficiency based on true interfacial concentrations rather than perceived interfaces.

  2. Aroma compound sorption by oak wood in a model wine.

    PubMed

    Ramirez Ramirez, G; Lubbers, S; Charpentier, C; Feuillat, M; Voilley, A; Chassagne, D

    2001-08-01

    Oak wood used for wine barrels was immersed into a model wine containing eight aroma compounds (e.g., aromatic and terpene alcohols, ethyl esters, and aldehyde), for which activity coefficients in water and model wine were determined using the mutual solubility measurement. A mass balance of these volatiles considering their reactivity in model wine was established. For most of the studied aroma compounds, and mainly for linalool and ethyl octanoate, a sorption behavior into wood was reported for the first time. This phenomenon was selective and could not be related to the solubilities in model wine and hydrophobicities of the studied aroma compounds, suggesting that acid-base and polar characteristics of wood were more involved in this sorption mechanism. This study has also shown that the level of sorption is a function of the ratio of wood surface area/solution volume.

  3. 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). Copyright © 2015 Elsevier B.V. All rights reserved.

  4. A mechanical model of bacteriophage DNA ejection

    NASA Astrophysics Data System (ADS)

    Arun, Rahul; Ghosal, Sandip

    2017-08-01

    Single molecule experiments on bacteriophages show an exponential scaling for the dependence of mobility on the length of DNA within the capsid. It has been suggested that this could be due to the ;capstan mechanism; - the exponential amplification of friction forces that result when a rope is wound around a cylinder as in a ship's capstan. Here we describe a desktop experiment that illustrates the effect. Though our model phage is a million times larger, it exhibits the same scaling observed in single molecule experiments.

  5. Chemotherapeutic compounds targeting the DNA double-strand break repair pathways: the good, the bad, and the promising.

    PubMed

    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.

  6. Impact of estrogenic compounds on DNA integrity in human spermatozoa: evidence for cross-linking and redox cycling activities.

    PubMed

    Bennetts, L E; De Iuliis, G N; Nixon, B; Kime, M; Zelski, K; McVicar, C M; Lewis, S E; Aitken, R J

    2008-05-10

    A great deal of circumstantial evidence has linked DNA damage in human spermatozoa with adverse reproductive outcomes including reduced fertility and high rates of miscarriage. Although oxidative stress is thought to make a significant contribution to DNA damage in the male germ line, the factors responsible for creating this stress have not been elucidated. One group of compounds that are thought to be active in this context are the estrogens, either generated as a result of the endogenous metabolism of androgens within the male reproductive tract or gaining access to the latter as a consequence of environmental exposure. In this study, a wide variety of estrogenic compounds were assessed for their direct effects on human spermatozoa in vitro. DNA integrity was assessed using the Comet and TUNEL assays, lesion frequencies were quantified by QPCR using targets within the mitochondrial and nuclear (beta-globin) genomes, DNA adducts were characterized by mass spectrometry and redox activity was monitored using dihydroethidium (DHE) as the probe. Of the estrogenic and estrogen analogue compounds evaluated, catechol estrogens, quercetin, diethylstilbestrol and pyrocatechol stimulated intense redox activity while genistein was only active at the highest doses tested. Other estrogens and estrogen analogues, such as 17beta-estradiol, nonylphenol, bisphenol A and 2,3-dihydroxynaphthalene were inactive. Estrogen-induced redox activity was associated with a dramatic loss of motility and, in the case of 2-hydroxyestradiol, the induction of significant DNA fragmentation. Mass spectrometry also indicated that catechol estrogens were capable of forming dimers that can cross-link the densely packed DNA strands in sperm chromatin, impairing nuclear decondensation. These results highlight the potential importance of estrogenic compounds in creating oxidative stress and DNA damage in the male germ line and suggest that further exploration of these compounds in the aetiology of male

  7. Modeling background intensity in DNA microarrays

    NASA Astrophysics Data System (ADS)

    Kroll, K. M.; Barkema, G. T.; Carlon, E.

    2008-06-01

    DNA microarrays are devices that are able, in principle, to detect and quantify the presence of specific nucleic acid sequences in complex biological mixtures. The measurement consists in detecting fluorescence signals from several spots on the microarray surface onto which different probe sequences are grafted. One of the problems of the data analysis is that the signal contains a noisy background component due to nonspecific binding. We present a physical model for background estimation in Affymetrix Genechips. It combines two different approaches. The first is based on the sequence composition, specifically its sequence-dependent hybridization affinity. The second is based on the strong correlation of intensities from locations which are the physical neighbors of a specific spot on the chip. Both effects are incorporated in a background estimator which contains 24 free parameters, fixed by minimization on a training data set. In all data analyzed the sequence-specific parameters, obtained by minimization, are found to strongly correlate with empirically determined stacking free energies for RNA-DNA hybridization in solution. Moreover, there is an overall agreement with experimental background data and we show that the physics-based model that we propose performs on average better than purely statistical approaches for background calculations. The model thus provides an interesting alternative method for background subtraction schemes in Affymetrix Genechips.

  8. Two Half-Sandwiched Ruthenium (II) Compounds Containing 5-Fluorouracil Derivatives: Synthesis and Study of DNA Intercalation

    PubMed Central

    Li, Zhao-Jun; Hou, Yong; Qin, Da-An; Jin, Zhi-Min; Hu, Mao-Lin

    2015-01-01

    Two novel coordination compounds of half-sandwiched ruthenium(II) containing 2-(5-fluorouracil)-yl-N-(pyridyl)-acetamide were synthesized, and their intercalation binding modes with calf thymus DNA were revealed by hyperchromism of ultraviolet-visible spectroscopy; the binding constants were determined according to a Langmuir adsorption equation that was deduced on the base of careful cyclic voltammetry measurements. The two compounds exhibited DNA intercalation binding activities with the binding constants of 1.13×106 M-1 and 5.35 ×105 M-1, respectively. PMID:25789618

  9. 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. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

  10. Langmuir films of asphaltene model compounds and their fluorescent properties.

    PubMed

    Nordgård, Erland L; Landsem, Eva; Sjöblom, Johan

    2008-08-19

    The relationship between the physicochemical properties of asphaltenes and asphaltene structure is an issue of increasing focus. Surface pressure-area isotherms of asphaltene model compounds have been investigated to gain more knowledge of their arrangement at an aqueous surface. Variations in interfacial activity have been correlated to proposed arrangements. The presence of a carboxylic acid has shown to be crucial for their interfacial activity and film properties. The acid group directs the molecules normal to the surface, forming a stable monolayer film. The high stability was absent when no acidic groups were present. Fluorescence spectra of deposited Langmuir-Blodgett films showed only the presence of the excimer emission for thin films of acidic model compounds, indicating a close face-to-face arrangement of the molecules. Time-correlated single photon counting (TCSPC) of the model compounds in toluene indicated the presence of aggregates for two of four compounds at low concentrations. However, a sudden drop of interfacial tension observed could not be correlated to the aggregation. Instead, aggregation induced by addition of a "poor" solvent showed decreased interfacial activity when aggregated due to decrease of monomers in bulk. The findings regarding these asphaltene model compounds and their structural differences show the great effect an acidic group has on their physicochemical properties.

  11. Theoretical modelling of epigenetically modified DNA sequences

    PubMed Central

    Carvalho, Alexandra Teresa Pires; Gouveia, Maria Leonor; Raju Kanna, Charan; Wärmländer, Sebastian K. T. S.; Platts, Jamie; Kamerlin, Shina Caroline Lynn

    2015-01-01

    We report herein a set of calculations designed to examine the effects of epigenetic modifications on the structure of DNA. The incorporation of methyl, hydroxymethyl, formyl and carboxy substituents at the 5-position of cytosine is shown to hardly affect the geometry of CG base pairs, but to result in rather larger changes to hydrogen-bond and stacking binding energies, as predicted by dispersion-corrected density functional theory (DFT) methods. The same modifications within double-stranded GCG and ACA trimers exhibit rather larger structural effects, when including the sugar-phosphate backbone as well as sodium counterions and implicit aqueous solvation. In particular, changes are observed in the buckle and propeller angles within base pairs and the slide and roll values of base pair steps, but these leave the overall helical shape of DNA essentially intact. The structures so obtained are useful as a benchmark of faster methods, including molecular mechanics (MM) and hybrid quantum mechanics/molecular mechanics (QM/MM) methods. We show that previously developed MM parameters satisfactorily reproduce the trimer structures, as do QM/MM calculations which treat bases with dispersion-corrected DFT and the sugar-phosphate backbone with AMBER. The latter are improved by inclusion of all six bases in the QM region, since a truncated model including only the central CG base pair in the QM region is considerably further from the DFT structure. This QM/MM method is then applied to a set of double-stranded DNA heptamers derived from a recent X-ray crystallographic study, whose size puts a DFT study beyond our current computational resources. These data show that still larger structural changes are observed than in base pairs or trimers, leading us to conclude that it is important to model epigenetic modifications within realistic molecular contexts. PMID:26448859

  12. 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.

  13. 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.

  14. Comparison of DNA strand-break simulated with different DNA models

    NASA Astrophysics Data System (ADS)

    Xie, Wenzhang; Li, Junli; Li, Chunyan; Qiu, Rui; Yan, Congchong; Zeng, Zhi

    2014-06-01

    In Monte Carlo simulation of DNA damage, the geometric model of DNA is of great importance. To study the influence of DNA model on the simulation of DNA damage, three DNA models were created in this paper. They were a volume model and two atomic models with different parameters. Direct DNA strand-break induced by low-energy electrons were simulated respectively with the three models. The results show that most of the energy depositions in the DNA segments do not lead to strand-breaks. The simple single strand-break (SSB) tends to be the predominant damage type, and the contribution of complex double strand-break (DSB) to the total DSB cannot be neglected. Among the yields of all the three DNA target models applied here, the yields of the volume model are the highest, the yields of the atomic model with double van der Waals radii (r) take the second place, whereas the yields of the atomic model with single r come last. On average, the ratios of SSB yields are approximately equivalent to the corresponding ratios of the models' volume. However, there seems to be no clear relationship between the DSB yields and the models' volume.

  15. Improved forensic DNA analysis through the use of alternative DNA polymerases and statistical modeling of DNA profiles.

    PubMed

    Hedman, Johannes; Nordgaard, Anders; Rasmusson, Birgitta; Ansell, Ricky; Rådström, Peter

    2009-11-01

    DNA evidence, linking perpetrators to crime scenes, is central to many legal proceedings. However, DNA samples from crime scenes often contain PCR-inhibitory substances, which may generate blank or incomplete DNA profiles. Extensive DNA purification can be required to rid the sample of these inhibitors, although these procedures increase the risk of DNA loss. Most forensic laboratories use commercial DNA amplification kits (e.g., AmpFlSTR SGM Plus) with the DNA polymerase AmpliTaq Gold as the gold standard. Here, we show that alternative DNA polymerase-buffer systems can improve the quality of forensic DNA analysis and efficiently circumvent PCR inhibition in crime scene samples, without additional sample preparation. DNA profiles from 20 of 32 totally or partially inhibited crime scene saliva samples were significantly improved using Bio-X-Act Short, ExTaq Hot Start, or PicoMaxx High Fidelity instead of AmpliTaq Gold. A statistical model for unbiased quality control of forensic DNA profiles was developed to quantify the results. Our study demonstrates the importance of adjusting the chemistry of the PCR to enhance forensic DNA analysis and diagnostic PCR, providing an alternative to laborious sample preparation protocols.

  16. Sensitivity Analysis of QSAR Models for Assessing Novel Military Compounds

    DTIC Science & Technology

    2009-01-01

    erties, such as log P, would aid in estimating a chemical’s environmental fate and toxicology when applied to QSAR modeling. Granted, QSAR mod- els, such...ER D C TR -0 9 -3 Strategic Environmental Research and Development Program Sensitivity Analysis of QSAR Models for Assessing Novel...Environmental Research and Development Program ERDC TR-09-3 January 2009 Sensitivity Analysis of QSAR Models for Assessing Novel Military Compound

  17. DNA gel electrophoresis: the reptation model(s).

    PubMed

    Slater, Gary W

    2009-06-01

    DNA gel electrophoresis has been the most important experimental tool to separate DNA fragments for several decades. The introduction of PFGE in the 1980s and capillary gel electrophoresis in the 1990s made it possible to study, map and sequence entire genomes. Explaining how very large DNA molecules move in a gel and why PFGE is needed to separate them has been an active field of research ever since the launch of the journal Electrophoresis. This article presents a personal and historical overview of the development of the theory of gel electrophoresis, focusing on the reptation model, the band broadening mechanisms, and finally the factors that limit the read length and the resolution of electrophoresis-based sequencing systems. I conclude with a short discussion of some of the questions that remain unanswered.

  18. The role of model compound studies in coal research

    SciTech Connect

    Buchanan, A.C. III; Britt, P.F.

    1994-03-01

    The extraordinarily complex chemical and physical structure of coals continues to present coal scientists with major challenges in advancing the base of scientific knowledge required for the development of substantially improved coal utilization technologies. As a consequence, model compound studies play a foundational role in advancing coal science. Model compounds are employed in studies for: (a) determination of kinetic and mechanistic information relevant to coal pyrolysis and liquefaction chemistry, and to computational modeling of these processes; (b) development of new catalysts for coal conversion or upgrading of coal-derived liquids; (c) development and benchmarking of various spectroscopic methods for analysis of coal structure and constitution by NMR, FTIR, mass spectrometry, X-ray techniques (XPS, XANES), etc.; and, (d) exploration and development of new chemical reactions for coal such as deploymerization under mild conditions, selective heteroatom removal etc. The choice of a model compound should not be prescribed, and the rational for the selection can vary with the goal of the research. The breadth of use of model compounds in coal research precludes a thorough examination in this report.

  19. Insights on protein-DNA recognition by coarse grain modelling.

    PubMed

    Poulain, P; Saladin, A; Hartmann, B; Prévost, C

    2008-11-30

    Coarse grain modelling of macromolecules is a new approach, potentially well adapted to answer numerous issues, ranging from physics to biology. We propose here an original DNA coarse grain model specifically dedicated to protein-DNA docking, a crucial, but still largely unresolved, question in molecular biology. Using a representative set of protein-DNA complexes, we first show that our model is able to predict the interaction surface between the macromolecular partners taken in their bound form. In a second part, the impact of the DNA sequence and electrostatics, together with the DNA and protein conformations on docking is investigated. Our results strongly suggest that the overall DNA structure mainly contributes in discriminating the interaction site on cognate proteins. Direct electrostatic interactions between phosphate groups and amino acid side chains strengthen the binding. Overall, this work demonstrates that coarse grain modeling can reveal itself a precious auxiliary for a general and complete description and understanding of protein-DNA association mechanisms.

  20. Molecular mechanisms of DNA damage initiated by. alpha. ,. beta. -unsaturated carbonyl compounds as criteria for genotoxicity and mutagenicity

    SciTech Connect

    Eder, E.; Hoffman, C.; Bastian, H.; Deininger, C.; Scheckenbach, S. )

    1990-08-01

    {alpha},{beta}-Unsaturated carbonyl compounds are important not only from a theoretical but also a practical standpoint. These ubiquitous compounds can interact with DNA through various mechanisms. The predominant interaction is the formation of cyclic 1,N{sup 2}-deoxyguanosine adducts; 7,8-cyclic guanine adducts are also found. The authors have synthesized and characterized the stereoisomers of adducts formed by about 20 {alpha},{beta}-unsaturated carbonyl compounds. The different types of adducts and the mutagenic and genotoxic response can be explained by the molecular structures of the agents. Metabolic epoxidation of the double bond and other metabolic activation, e.g., activation of the nitrogroups via nitroreductases, were also found to contribute to genotoxic and mutagenic activities. The results have further elucidated the genotoxic mechanisms of these compounds; however, additional investigations are required for a complete understanding of the genotoxic activity of this class of compounds.

  1. Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells

    PubMed Central

    Borland, Kayla M.; AbdulSalam, Safnas F.; Solivio, Morwena J.; Burke, Matthew P.; Wolfkiel, Patrick R.; Lawson, Sean M.; Stockman, Courtney A.; Andersen, Joel M.; Smith, Skyler; Tolstolutskaya, Julia N.; Gurjar, Purujit N.; Bercz, Aron P.; Merino, Edward J.; Litosh, Vladislav A.

    2015-01-01

    Current FDA-approved chemotherapeutic antimetabolites elicit severe side effects that warrant their improvement; therefore, we designed compounds with mechanisms of action focusing on inhibiting DNA replication rather than targeting multiple pathways. We previously discovered that 5-(α-substituted-2-nitrobenzyloxy)methyluridine-5′-triphosphates were exquisite DNA synthesis terminators; therefore, we synthesized a library of 35 thymidine analogs and evaluated their activity using an MTT cell viability assay of MCF7 breast cancer cells chosen for their vulnerability to these nucleoside derivatives. Compound 3a, having an α-tert-butyl-2-nitro-4-(phenyl)alkynylbenzyloxy group, showed an IC50 of 9 ± 1 μM. The compound is more selective for cancer cells than for fibroblast cells compared with 5-fluorouracil. Treatment of MCF7 cells with 3a elicits the DNA damage response as indicated by phosphorylation of γ-H2A. A primer extension assay of the 5′-triphosphate of 3a revealed that 3aTP is more likely to inhibit DNA polymerase than to lead to termination events upon incorporation into the DNA replication fork. PMID:25778768

  2. A wavelet-based feature vector model for DNA clustering.

    PubMed

    Bao, J P; Yuan, R Y

    2015-12-29

    DNA data are important in the bioinformatic domain. To extract useful information from the enormous collection of DNA sequences, DNA clustering is often adopted to efficiently deal with DNA data. The alignment-free method is a very popular way of creating feature vectors from DNA sequences, which are then used to compare DNA similarities. This paper proposes a wavelet-based feature vector (WFV) model, which is also an alignment-free method. From the perspective of signal processing, a DNA sequence is a sequence of digital signals. However, most traditional alignment-free models only extract features in the time domain. The WFV model uses discrete wavelet transform to adaptively yield feature vectors with a fixed dimension based on the features in both the time and frequency domains. The level of wavelet transform is adjusted according to the length of the DNA sequence rather than a fixed manually set value. The WFV model prefers a 32-dimension feature vector, which greatly promotes system performance. We compared the WFV model with the other five alignment-free models, i.e., k-tuple, DMK, TSM, AMI, and CV, on several large-scale DNA datasets on the DNA clustering application by means of the K-means algorithm. The experimental results showed that the WFV model outperformed the other models in terms of both the clustering results and the running time.

  3. Laccase-mediator catalyzed conversion of model lignin compounds

    USDA-ARS?s Scientific Manuscript database

    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...

  4. Modeling emissions of volatile organic compounds from silage

    USDA-ARS?s Scientific Manuscript database

    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...

  5. QSAR modeling and chemical space analysis of antimalarial compounds

    NASA Astrophysics Data System (ADS)

    Sidorov, Pavel; Viira, Birgit; Davioud-Charvet, Elisabeth; Maran, Uko; Marcou, Gilles; Horvath, Dragos; Varnek, Alexandre

    2017-05-01

    Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including 3000 molecules tested in one or several of 17 anti- Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models. Zones preferentially populated by active and inactive molecules, respectively, clearly emerge in the class landscapes supported by the GTM model. Their analysis resulted in identification of privileged structural motifs of potential antimalarial compounds. Projection of marketed antimalarial drugs on this map allowed us to delineate several areas in the chemical space corresponding to different mechanisms of antimalarial activity. This helped us to make a suggestion about the mode of action of the molecules populating these zones.

  6. QSAR modeling and chemical space analysis of antimalarial compounds.

    PubMed

    Sidorov, Pavel; Viira, Birgit; Davioud-Charvet, Elisabeth; Maran, Uko; Marcou, Gilles; Horvath, Dragos; Varnek, Alexandre

    2017-04-03

    Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including ~3000 molecules tested in one or several of 17 anti-Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models. Zones preferentially populated by active and inactive molecules, respectively, clearly emerge in the class landscapes supported by the GTM model. Their analysis resulted in identification of privileged structural motifs of potential antimalarial compounds. Projection of marketed antimalarial drugs on this map allowed us to delineate several areas in the chemical space corresponding to different mechanisms of antimalarial activity. This helped us to make a suggestion about the mode of action of the molecules populating these zones.

  7. 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.

  8. An autonomous DNA model for finite state automata.

    PubMed

    Martinez-Perez, Israel M; Zimmermann, Karl-Heinz; Ignatova, Zoya

    2009-01-01

    In this paper we introduce an autonomous DNA model for finite state automata. This model called sticker automaton model is based on the hybridisation of single stranded DNA molecules (stickers) encoding transition rules and input data. The computation is carried out in an autonomous manner by one enzyme which allows us to determine whether a resulting double-stranded DNA molecule belongs to the automaton's language or not.

  9. Modeling amplified p53 responses under DNA-PK inhibition in DNA damage response

    PubMed Central

    Sun, Tingzhe; Li, Xinda; Shen, Pingping

    2017-01-01

    During DNA double strand breaks (DSBs) repair, coordinated activation of phosphatidylinositol 3-kinase (PI3K)-like kinases can activate p53 signaling pathway. Recent findings have identified novel interplays among these kinases demonstrating amplified first p53 pulses under DNA-PK inhibition. However, no theoretical model has been developed to characterize such dynamics. In current work, we modeled the prolonged p53 pulses with DNA-PK inhibitor. We could identify a dose-dependent increase in the first pulse amplitude and width. Meanwhile, weakened DNA-PK mediated ATM inhibition was insufficient to reproduce such dynamic behavior. Moreover, the information flow was shifted predominantly to the first pulse under DNA-PK inhibition. Furthermore, the amplified p53 responses were relatively robust. Taken together, our model can faithfully replicate amplified p53 responses under DNA-PK inhibition and provide insights into cell fate decision by manipulating p53 dynamics. PMID:28177883

  10. 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

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

    PubMed

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

    2016-05-11

    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.

  12. Structure-based design, synthesis and biological testing of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds designed to covalently bind to topoisomerase II and DNA.

    PubMed

    Yadav, Arun A; Wu, Xing; Patel, Daywin; Yalowich, Jack C; Hasinoff, Brian B

    2014-11-01

    Drugs that target DNA topoisomerase II isoforms and alkylate DNA represent two mechanistically distinct and clinically important classes of anticancer drugs. Guided by molecular modeling and docking a series of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds were designed, synthesized and biologically characterized. These hybrids were designed to alkylate nucleophilic protein residues on topoisomerase II and thus produce inactive covalent adducts and to also alkylate DNA. The most potent hybrid had a mean GI(50) in the NCI-60 cell screen 17-fold lower than etoposide. Using a variety of in vitro and cell-based assays all of the hybrids tested were shown to target topoisomerase II. A COMPARE analysis indicated that the hybrids had NCI 60-cell growth inhibition profiles matching both etoposide and the N-mustard compounds from which they were derived. These results supported the conclusion that the hybrids displayed characteristics that were consistent with having targeted both topoisomerase II and DNA. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. 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.

  14. 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.

  15. Odorous Compounds from Poultry Manure Induce DNA Damage, Nuclear Changes, and Decrease Cell Membrane Integrity in Chicken Liver Hepatocellular Carcinoma Cells

    PubMed Central

    Matusiak, Katarzyna; Gałęcki, Remigiusz; Borowski, Sebastian; Gutarowska, Beata

    2017-01-01

    Animal breeding and management of organic wastes pose a serious problem to the health of livestock and workers, as well as the nearby residents. The aim of the present study was to determine the mechanisms of toxicity of selected common odorous compounds from poultry manure, including ammonia, dimethylamine (DMA), trimethylamine (TMA), butyric acid, phenol, and indole. We measured their genotoxic and cytotoxic activity in the model chicken cell line (LMH), in vitro, by comet assay and lactate dehydrogenase assay, respectively. We also made microscopic observations of any morphological changes in these cells by DAPI staining. Four compounds, namely ammonia, DMA, TMA, and butyric acid increased DNA damage in a dose-dependent manner (p < 0.05), reaching genotoxicity as high as 73.2 ± 1.9%. Phenol and indole induced extensive DNA damage independent of the concentration used. Ammonia, DMA, and TMA caused a dose-dependent release of lactate dehydrogenase (p < 0.05). The IC50 values were 0.02%, 0.05%, and 0.1% for DMA, ammonia and TMA, respectively. These compounds also induced nuclear morphological changes, such as chromatin condensation, shrinkage, nuclear fragmentation (apoptotic bodies), and chromatin lysis. Our study exhibited the damaging effects of odorous compounds in chick LMH cell line. PMID:28820500

  16. Odorous Compounds from Poultry Manure Induce DNA Damage, Nuclear Changes, and Decrease Cell Membrane Integrity in Chicken Liver Hepatocellular Carcinoma Cells.

    PubMed

    Nowak, Adriana; Bakuła, Tadeusz; Matusiak, Katarzyna; Gałęcki, Remigiusz; Borowski, Sebastian; Gutarowska, Beata

    2017-08-18

    Animal breeding and management of organic wastes pose a serious problem to the health of livestock and workers, as well as the nearby residents. The aim of the present study was to determine the mechanisms of toxicity of selected common odorous compounds from poultry manure, including ammonia, dimethylamine (DMA), trimethylamine (TMA), butyric acid, phenol, and indole. We measured their genotoxic and cytotoxic activity in the model chicken cell line (LMH), in vitro, by comet assay and lactate dehydrogenase assay, respectively. We also made microscopic observations of any morphological changes in these cells by DAPI staining. Four compounds, namely ammonia, DMA, TMA, and butyric acid increased DNA damage in a dose-dependent manner (p < 0.05), reaching genotoxicity as high as 73.2 ± 1.9%. Phenol and indole induced extensive DNA damage independent of the concentration used. Ammonia, DMA, and TMA caused a dose-dependent release of lactate dehydrogenase (p < 0.05). The IC50 values were 0.02%, 0.05%, and 0.1% for DMA, ammonia and TMA, respectively. These compounds also induced nuclear morphological changes, such as chromatin condensation, shrinkage, nuclear fragmentation (apoptotic bodies), and chromatin lysis. Our study exhibited the damaging effects of odorous compounds in chick LMH cell line.

  17. Nuclear aggregates of polyamines in a radiation-induced DNA damage model.

    PubMed

    Iacomino, Giuseppe; Picariello, Gianluca; Stillitano, Ilaria; D'Agostino, Luciano

    2014-02-01

    Polyamines (PA) are believed to protect DNA minimizing the effect of radiation damage either by inducing DNA compaction and aggregation or acting as scavengers of free radicals. Using an in vitro pDNA double strand breakage assay based on gel electrophoretic mobility, we compared the protective capability of PA against γ-radiation with that of compounds generated by the supramolecular self-assembly of nuclear polyamines and phosphates, named Nuclear Aggregates of Polyamines (NAPs). Both unassembled PA and in vitro produced NAPs (ivNAPs) were ineffective in conferring pDNA protection at the sub-mM concentration. Single PA showed an appreciable protective effect only at high (mM) concentrations. However, concentrations of spermine (4+) within a critical range (0.481 mM) induced pDNA precipitation, an event that was not observed with NAPs-pDNA interaction. We conclude that the interaction of individual PA is ineffective to assure DNA protection, simultaneously preserving the flexibility and charge density of the double strand. Furthermore, data obtained by testing polyamine and ivNAPS with the current radiation-induced DNA damage model support the concept that PA-phosphate aggregates are the only forms through which PA interact with DNA.

  18. 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.

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

    PubMed

    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.

  20. 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

  1. Inhibition of DNA topoisomerases I and II and growth inhibition of HL-60 cells by novel acridine-based compounds.

    PubMed

    Janočková, Jana; Plšíková, Jana; Kašpárková, Jana; Brabec, Viktor; Jendželovský, Rastislav; Mikeš, Jaromír; Kovaľ, Ján; Hamuľaková, Slávka; Fedoročko, Peter; Kuča, Kamil; Kožurková, Mária

    2015-08-30

    HL-60 cancer cells were treated with a series of novel acridine derivatives (derivatives 1-4) in order to test the compounds' ability to inhibit both cancer cell growth and topoisomerase I and II activity. Binding studies of derivatives 1-4 with calf thymus DNA were also performed using a number of techniques (UV-Vis and fluorescence spectroscopy, thermal denaturation, linear dichroism and viscometry) to determine the nature of the interaction between the compounds and ctDNA. The binding constants for the complexes of the studied acridine derivatives with DNA were calculated from UV-Vis spectroscopic titrations (K=3.1×10(4)-2.0×10(3)M(-1)). Some of the compounds showed a strong inhibitory effect against Topo II at the relatively low concentration of 5μM. Topo I/II inhibition mode assays were also performed and verified that the novel compounds are topoisomerase suppressors rather than poisons. The biological activities of derivatives were studied using MTT assay and flow cytometric methods (detection of mitochondrial membrane potential, measurement of cell viability) after 24 and 48h incubation. The ability of derivatives to impair cell proliferation was tested by an analysis of cell cycle distribution.

  2. 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.

  3. Modeling emissions of volatile organic compounds from new carpets

    NASA Astrophysics Data System (ADS)

    Little, John C.; Hodgson, Alfred T.; Gadgil, Ashok J.

    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 partition coefficients generally increase as the vapor pressure of the compounds decreases. 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 prediction of VOC 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.

  4. The Peyrard-Bishop-Dauxois Model of DNA Dynamics

    NASA Astrophysics Data System (ADS)

    Alexandrov, Boian; Bishop, Alan; Usheva, Anny; Rasmussen, Kim

    2008-03-01

    This presentation details aspects of the rapid development of the connection between the dynamics of double strand DNA, and experimental findings that has occurred in the recent years. We will approach this topic by demonstrating the Peyrard-Bishop-Dauxois model's ability to provide useful insight on several experimental observations. Specifically, we will discuss the melting behavior of various DNA sequences, and mechanical unzipping through dynamic force spectroscopy. Focusing on viral transcription initiation we will further show how the connection between DNA dynamics and DNA's biological functionality is becoming increasingly strong. Finally, we will describe a probable connection between DNA dynamics and the ability of repair proteins to recognize UV-radiation damages.

  5. Monitoring the Activation of the DNA Damage Response Pathway in a 3D Spheroid Model.

    PubMed

    Mondesert, Odile; Frongia, Céline; Clayton, Olivia; Boizeau, Marie-Laure; Lobjois, Valérie; Ducommun, Bernard

    2015-01-01

    Monitoring the DNA-Damage Response (DDR) activated pathway in multicellular tumor spheroid models is an important challenge as these 3D models have demonstrated their major relevance in pharmacological evaluation. Herein we present DDR-Act-FP, a fluorescent biosensor that allows detection of DDR activation through monitoring of the p21 promoter p53-dependent activation. We show that cells expressing the DDR-Act-FP biosensor efficiently report activation of the DDR pathway after DNA damage and its pharmacological manipulation using ATM kinase inhibitors. We also report the successful use of this assay to screen a small compound library in order to identify activators of the DDR response. Finally, using multicellular spheroids expressing the DDR-Act-FP we demonstrate that DDR activation and its pharmacological manipulation with inhibitory and activatory compounds can be efficiently monitored in live 3D spheroid model. This study paves the way for the development of innovative screening and preclinical evaluation assays.

  6. 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. Copyright 2010 Elsevier B.V. All rights reserved.

  7. 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

  8. Mycobacterial DNA gyrB inhibitors: Ligand based pharmacophore modelling and in vitro enzyme inhibition studies.

    PubMed

    Saxena, Shalini; Renuka, Janupally; Jeankumar, Variam Ullas; Yogeeswari, Perumal; Sriram, Dharmarajan

    2014-01-01

    Among the topoisomerases, DNA gyrase belongs to the type II classes that catalysing DNA supercoiling or relaxation, catenation or decatenation, knotting or unknotting. It is one of the validated targets for anti-tubercular drug discovery and inhibitors from this group are also active against non-replicating, persistent mycobacteria, which might be important for shortening the duration of TB therapy. From past few years, extensive research was carried out towards potent DNA gyrase inhibitor design. The current review focuses on the most of potent series of DNA gyrase inhibitors and its structure activity relationships (SAR). The current manuscript also reports the current research on identification of potent DNA gyrase inhibitors using ligand based virtual screening approaches. The pharmacophore model was developed and validated against 65 known Mycobacterium smegmatics (MS) DNA Gyrase inhibitors. Validated pharmacophore model consists of HBA, HY, and RA features were essential for DNA Gyrase inhibition and this model was used to screen virtual screening to retrieve potential inhibitors from our in house database. Finally, 15 hits were ranked as potential leads based on pharmacophoric fit value and estimated activity. Furthermore, in-vitro enzymatic inhibition studies were performed for these 15 most promising candidates and these compounds were found to exhibit inhibition at 30 µM.

  9. Screening for compounds that affect the interaction between bacterial two-component signal transduction response regulator protein and cognate promoter DNA.

    PubMed

    Erickson, Matthew G; Ulijasz, Andrew T; Weisblum, Bernard

    2008-01-01

    Bacterial signal transduction systems can be used as drug targets. The signal transduction targets fall into two groups--sensor kinases and response regulators. Previously reported studies describe hits that were thought to inactivate sensor kinases but on closer examination were found to act elsewhere instead; a possible reason for this is that full-length sensor kinases are integral membrane proteins whose activity might reflect interaction with the cell membrane or with membrane components. We describe a model system that instead is based on the interaction between a test compound and a response regulator in a homogeneous phase reaction. In this system, response regulator-DNA complex formation and its inhibition by a test compound are measured by fluorescence polarization. The model system should be readily adaptable to drug discovery based on other bacterial two-component s transduction systems.

  10. A Signal Detection Model of Compound Decision Tasks

    DTIC Science & Technology

    2006-12-01

    A signal detection model of compound decision tasks Matthew Duncan Defence R& D Canada Technical Report DRDC Toronto TR 2006-256 December 2006...tasks Matthew Duncan Defence R& D Canada – Toronto Technical Report DRDC Toronto TR 2006-256 December 2006 Author Original approved by...la prise de décision, il faut une méthode formelle pour distinguer (clarifier) les effets des divers facteurs, et pour simplifier l’évaluation des

  11. A Paper Model of DNA Structure and Replication.

    ERIC Educational Resources Information Center

    Sigismondi, Linda A.

    1989-01-01

    A paper model which is designed to give students a hands-on experience during lecture and blackboard instruction on DNA structure is provided. A list of materials, paper patterns, and procedures for using the models to teach DNA structure and replication are given. (CW)

  12. A model of the cell nucleus for DNA damage calculations.

    PubMed

    Nikjoo, Hooshang; Girard, Peter

    2012-01-01

    Development of a computer model of genomic deoxyribonucleic acid (DNA) in the human cell nucleus for DNA damage and repair calculations. The model comprises the human genomic DNA, chromosomal domains, and loops attached to factories. A model of canonical B-DNA was used to build the nucleosomes and the 30-nanometer solenoidal chromatin. In turn the chromatin was used to form the loops of factories in chromosome domains. The entire human genome was placed in a spherical nucleus of 10 micrometers diameter. To test the new target model, tracks of protons and alpha-particles were generated using Monte Carlo track structure codes PITS99 (Positive Ion Track Structure) and KURBUC. Damage sites induced in the genome were located and classified according to type and complexity. The three-dimensional structure of the genome starting with a canonical B-DNA model, nucleosomes, and chromatin loops in chromosomal domains are presented. The model was used to obtain frequencies of DNA damage induced by protons and alpha-particles by direct energy deposition, including single- and double-strand breaks, base damage, and clustered lesions. This three-dimensional model of the genome is the first such model using the full human genome for the next generation of more comprehensive modelling of DNA damage and repair. The model combines simple geometrical structures at the level of domains and factories with potentially full detail at the level of atoms in particular genes, allowing damage patterns in the latter to be simulated.

  13. Nanoparticles inhibit DNA replication by binding to DNA: modeling and experimental validation.

    PubMed

    Li, Kungang; Zhao, Xiaonan; K Hammer, Brian; Du, Songyan; Chen, Yongsheng

    2013-11-26

    Predictive models are beneficial tools for researchers to use in prioritizing nanoparticles (NPs) for toxicological tests, but experimental evaluation can be time-consuming and expensive, and thus, priority should be given to tests that identify the NPs most likely to be harmful. For characterization of NPs, the physical binding of NPs to DNA molecules is important to measure, as interference with DNA function may be one cause of toxicity. Here, we determined the interaction energy between 12 types of NPs and DNA based on the Derjaguin-Landau-Verwey-Overbeek (DLVO) model and then predicted the affinity of the NPs for DNA. Using the single-molecule imaging technique known as atomic force microscopy (AFM), we experimentally determined the binding affinity of those NPs for DNA. Theoretical predictions and experimental observations of the binding affinity agreed well. Furthermore, the effect of NPs on DNA replication in vitro was investigated with the polymerase chain reaction (PCR) technique. The results showed that NPs with a high affinity for DNA strongly inhibited DNA replication, whereas NPs with low affinity had no or minimal effects on DNA replication. The methodology here is expected to benefit the genotoxicological testing of NPs as well as the design of safe NPs.

  14. Linear and nonlinear optical properties of new materials based on DNA-CTMA and aromatic compounds (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Lazar, Cosmina Andreea; Kajzar, François; Rau, Ileana; Puntus, Lada N.; Manea, Ana-Maria

    2016-10-01

    In order to find eco-friendly materials for different applications an important research effort was devoted to the materials science in the last decade. A particular attention attracted the deoxyribonucleic acid (DNA). The interest is due to its versatility, biodegradability, abundance and their origin from renewable sources. DNA based new materials, functionalized with hexadecyltrimethylammonium chloride (CTMA) and aromatic compounds were prepared. Solutions with two different concentrations of aromatic compounds were obtained in butanol. The obtained, new complexes were processed into good optical quality thin films by spin coating method. Films were deposited on glass substrates and characterized for their spectroscopic, linear and nonlinear optical properties. The third-order nonlinear optical (NLO) properties of thin films were determined by the optical third-harmonic generation technique at 1 064.2 nm fundamental wavelength. The obtained materials, with improved fluorescence efficiency, present a potential interest for application in photonics.

  15. 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.

  16. Prototype Systems Containing Human Cytochrome P450 for High-Throughput Real-Time Detection of DNA Damage by Compounds That Form DNA-Reactive Metabolites.

    PubMed

    Brito Palma, Bernardo; Fisher, Charles W; Rueff, José; Kranendonk, Michel

    2016-05-16

    The formation of reactive metabolites through biotransformation is the suspected cause of many adverse drug reactions. Testing for the propensity of a drug to form reactive metabolites has increasingly become an integral part of lead-optimization strategy in drug discovery. DNA reactivity is one undesirable facet of a drug or its metabolites and can lead to increased risk of cancer and reproductive toxicity. Many drugs are metabolized by cytochromes P450 in the liver and other tissues, and these reactions can generate hard electrophiles. These hard electrophilic reactive metabolites may react with DNA and may be detected in standard in vitro genotoxicity assays; however, the majority of these assays fall short due to the use of animal-derived organ extracts that inadequately represent human metabolism. The current study describes the development of bacterial systems that efficiently detect DNA-damaging electrophilic reactive metabolites generated by human P450 biotransformation. These assays use a GFP reporter system that detects DNA damage through induction of the SOS response and a GFP reporter to control for cytotoxicity. Two human CYP1A2-competent prototypes presented here have appropriate characteristics for the detection of DNA-damaging reactive metabolites in a high-throughput manner. The advantages of this approach include a short assay time (120-180 min) with real-time measurement, sensitivity to small amounts of compound, and adaptability to a microplate format. These systems are suitable for high-throughput assays and can serve as prototypes for the development of future enhanced versions.

  17. 3D-DART: a DNA structure modelling server

    PubMed Central

    van Dijk, Marc; Bonvin, Alexandre M. J. J.

    2009-01-01

    There is a growing interest in structural studies of DNA by both experimental and computational approaches. Often, 3D-structural models of DNA are required, for instance, to serve as templates for homology modeling, as starting structures for macro-molecular docking or as scaffold for NMR structure calculations. The conformational adaptability of DNA when binding to a protein is often an important factor and at the same time a limitation in such studies. As a response to the demand for 3D-structural models reflecting the intrinsic plasticity of DNA we present the 3D-DART server (3DNA-Driven DNA Analysis and Rebuilding Tool). The server provides an easy interface to a powerful collection of tools for the generation of DNA-structural models in custom conformations. The computational engine beyond the server makes use of the 3DNA software suite together with a collection of home-written python scripts. The server is freely available at http://haddock.chem.uu.nl/dna without any login requirement. PMID:19417072

  18. A computational atomistic model of radiation damage to DNA

    NASA Astrophysics Data System (ADS)

    Aydogan, Bulent

    A review of past and current biophysical models of DNA damage reveals that current DNA damage models have become increasingly complex in their attempts to model the full 3D structure of the nucleosome and chromatin fiber. As such, many of the finer details of direct, quasi-direct, and indirect action on DNA become difficult to study in isolation. Also, experimental comparisons that seek to validate these models become increasingly difficult to make. A better approach may be to perform the atomistic modeling of direct, indirect, and quasi-direct effects in total isolation from considerations of the macroscopic conformation of the DNA target. This would permit the highly detailed atomistic modeling to be performed only once in order to produce a database of outcome probabilities that can then be used in radiation chemistry modeling of different and more complex conformations of double-stranded DNA. This work is performed to establish the groundwork to accomplish this goal. A system of Monte Carlo computer codes that model radiation damage to DNA at the atomistic level is developed and used to predict the radiation damage to a 167-bp DNA molecule. A database of the OOH attack outcomes is generated for a 167-bp DNA molecule and used in the prediction of radiation-induced damage to DNA. Do (the dose required to create, on average, one single strand break per 167-bp DNA molecule) is calculated to be 69.9 Gy. There are no experimental study found in the literature that studied small DNA molecules like the one used in this study. Nevertheless, the results from this computational study can be compared to experimental studies preformed with larger DNA molecules such as plasmids when DNA concentrations are scaled. The `concentration scaled D0 (ssb)' values from Klimczak et al. [1993] and Tomita et al. [1998] were approximately 65 and 80 Gy, respectively. These experimental results compare favorably with the computational value of 69.9 Gy calculated in this study. With the

  19. Modeling Spatial Correlation of DNA Deformation: DNA Allostery in Protein Binding

    PubMed Central

    Xu, Xinliang; Ge, Hao; Gu, Chan; Gao, Yi Qin; Wang, Siyuan S.; Thio, Beng Joo Reginald; Hynes, James T.; Xie, X. Sunney; Cao, Jianshu

    2013-01-01

    We report a study of DNA deformations using a coarse-grained mechanical model and quantitatively interpret the allosteric effects in protein-DNA binding affinity. A recent single molecule study (Kim et al. (2013) Science, 339, 816) showed that when a DNA molecule is deformed by specific binding of a protein, the binding affinity of a second protein separated from the first protein is altered. Experimental observations together with molecular dynamics simulations suggested that the origin of the DNA allostery is related to the observed deformation of DNA’s structure, in particular the major groove width. In order to unveil and quantify the underlying mechanism for the observed major groove deformation behavior related to the DNA allostery, here we provide a simple but effective analytical model where DNA deformations upon protein binding are analyzed and spatial correlations of local deformations along the DNA are examined. The deformation of the DNA base orientations, which directly affect the major groove width, is found in both an analytical derivation and coarse-grained Monte Carlo simulations. This deformation oscillates with a period of 10 base pairs with an amplitude decaying exponentially from the binding site with a decay length lD~10 base pairs, as a result of the balance between two competing terms in DNA base stacking energy. This length scale is in agreement with that reported from the single molecule experiment. Our model can be reduced to the worm-like chain form at length scales larger than lP but is able to explain DNA’s mechanical properties on shorter length scales, in particular the DNA allostery of protein-DNA interactions. PMID:23795567

  20. 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.

  1. Oxidative DNA damage is prevented by extracts of olive oil, hydroxytyrosol, and other olive phenolic compounds in human blood mononuclear cells and HL60 cells.

    PubMed

    Fabiani, Roberto; Rosignoli, Patrizia; De Bartolomeo, Angelo; Fuccelli, Raffaela; Servili, Maurizio; Montedoro, Gian Francesco; Morozzi, Guido

    2008-08-01

    Our aim in this study was to provide further support to the hypothesis that phenolic compounds may play an important role in the anticarcinogenic properties of olive oil. We measured the effect of olive oil phenols on hydrogen peroxide (H(2)O(2))-induced DNA damage in human peripheral blood mononuclear cells (PBMC) and promyelocytic leukemia cells (HL60) using single-cell gel electrophoresis (comet assay). Hydroxytyrosol [3,4-dyhydroxyphenyl-ethanol (3,4-DHPEA)] and a complex mixture of phenols extracted from both virgin olive oil (OO-PE) and olive mill wastewater (WW-PE) reduced the DNA damage at concentrations as low as 1 micromol/L when coincubated in the medium with H(2)O(2) (40 micromol/L). At 10 micromol/L 3,4-DHPEA, the protection was 93% in HL60 and 89% in PBMC. A similar protective activity was also shown by the dialdehydic form of elenoic acid linked to hydroxytyrosol (3,4-DHPEA-EDA) on both kinds of cells. Other purified compounds such as isomer of oleuropein aglycon (3,4-DHPEA-EA), oleuropein, tyrosol, [p-hydroxyphenyl-ethanol (p-HPEA)] the dialdehydic form of elenoic acid linked to tyrosol, caffeic acid, and verbascoside also protected the cells against H(2)O(2)-induced DNA damage although with a lower efficacy (range of protection, 25-75%). On the other hand, when tested in a model system in which the oxidative stress was induced by phorbole 12-myristate 13-acetate-activated monocytes, p-HPEA was more effective than 3,4-DHPEA in preventing the oxidative DNA damage. Overall, these results suggest that OO-PE and WW-PE may efficiently prevent the initiation step of carcinogenesis in vivo, because the concentrations effective against the oxidative DNA damage could be easily reached with normal intake of olive oil.

  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. A numerical model for edge waves on a compound slope

    NASA Astrophysics Data System (ADS)

    Lu, Yang; Feng, Wei-bing; Zhang, Yu; Feng, Xi

    2017-04-01

    An edge wave is a kind of surface gravity wave basically travelling along a shoaling beach. Based on the periodic assumption in the longshore direction, a second order ordinary differential equation is obtained for numerical simulation of the cross-shore surface elevation. Given parameters at the shoreline, a cross-shore elevation profile is obtained through integration with fourth-order Runge-Kutta technique. For a compound slope, a longshore wavenumber is obtained by following a geometrical approach and solving a transcendental equation with an asymptotic method. Numerical results on uniform and compound sloping beaches with different wave periods, slope angles, modes and turning point positions are presented. Some special scenarios, which cannot be predicted by analytical models are also discussed.

  4. Causal Network Models for Predicting Compound Targets and Driving Pathways in Cancer.

    PubMed

    Jaeger, Savina; Min, Junxia; Nigsch, Florian; Camargo, Miguel; Hutz, Janna; Cornett, Allen; Cleaver, Stephen; Buckler, Alan; Jenkins, Jeremy L

    2014-06-01

    Gene-expression data are often used to infer pathways regulating transcriptional responses. For example, differentially expressed genes (DEGs) induced by compound treatment can help characterize hits from phenotypic screens, either by correlation with known drug signatures or by pathway enrichment. Pathway enrichment is, however, typically computed with DEGs rather than "upstream" nodes that are potentially causal of "downstream" changes. Here, we present graph-based models to predict causal targets from compound-microarray data. We test several approaches to traversing network topology, and show that a consensus minimum-rank score (SigNet) beat individual methods and could highly rank compound targets among all network nodes. In addition, larger, less canonical networks outperformed linear canonical interactions. Importantly, pathway enrichment using causal nodes rather than DEGs recovers relevant pathways more often. To further validate our approach, we used integrated data sets from the Cancer Genome Atlas to identify driving pathways in triple-negative breast cancer. Critical pathways were uncovered, including the epidermal growth factor receptor 2-phosphatidylinositide 3-kinase-AKT-MAPK growth pathway andATR-p53-BRCA DNA damage pathway, in addition to unexpected pathways, such as TGF-WNT cytoskeleton remodeling, IL12-induced interferon gamma production, and TNFR-IAP (inhibitor of apoptosis) apoptosis; the latter was validated by pooled small hairpin RNA profiling in cancer cells. Overall, our approach can bridge transcriptional profiles to compound targets and driving pathways in cancer.

  5. A coarse-grained DNA model for the prediction of current signals in DNA translocation experiments

    NASA Astrophysics Data System (ADS)

    Weik, Florian; Kesselheim, Stefan; Holm, Christian

    2016-11-01

    We present an implicit solvent coarse-grained double-stranded DNA (dsDNA) model confined to an infinite cylindrical pore that reproduces the experimentally observed current modulations of a KaCl solution at various concentrations. Our model extends previous coarse-grained and mean-field approaches by incorporating a position dependent friction term on the ions, which Kesselheim et al. [Phys. Rev. Lett. 112, 018101 (2014)] identified as an essential ingredient to correctly reproduce the experimental data of Smeets et al. [Nano Lett. 6, 89 (2006)]. Our approach reduces the computational effort by orders of magnitude compared with all-atom simulations and serves as a promising starting point for modeling the entire translocation process of dsDNA. We achieve a consistent description of the system's electrokinetics by using explicitly parameterized ions, a friction term between the DNA beads and the ions, and a lattice-Boltzmann model for the solvent.

  6. 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

  7. High Temperature High Pressure Thermodynamic Measurements for Coal Model Compounds

    SciTech Connect

    John C. Chen; Vinayak N. Kabadi

    1998-11-12

    The overall objective of this project is to develop a better thermodynamic model for predicting properties of high-boiling coal derived liquids, especially the phase equilibria of different fractions at elevated temperatures and pressures. The development of such a model requires data on vapor-liquid equilibria (VLE), enthalpy, and heat capacity which would be experimentally determined for binary systems of coal model compounds and compiled into a database. The data will be used to refine existing models such as UNIQUAC and UNIFAC. The flow VLE apparatus designed and built for a previous project was upgraded and recalibrated for data measurements for thk project. The modifications include better and more accurate sampling technique and addition of a digital recorder to monitor temperature, pressure and liquid level inside the VLE cell. VLE data measurements for system benzene-ethylbenzene have been completed. The vapor and liquid samples were analysed using the Perkin-Elmer Autosystem gas chromatography.

  8. 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

  9. Discovery of the first dual G-triplex/G-quadruplex stabilizing compound: a new opportunity in the targeting of G-rich DNA structures?

    PubMed

    Amato, Jussara; Pagano, Alessia; Cosconati, Sandro; Amendola, Giorgio; Fotticchia, Iolanda; Iaccarino, Nunzia; Marinello, Jessica; De Magis, Alessio; Capranico, Giovanni; Novellino, Ettore; Pagano, Bruno; Randazzo, Antonio

    2017-05-01

    Guanine-rich DNA motifs can form non-canonical structures known as G-quadruplexes, whose role in tumorigenic processes makes them attractive drug-target candidates for cancer therapy. Recent studies revealed that the folding and unfolding pathways of G-quadruplexes proceed through a quite stable intermediate named G-triplex. Virtual screening was employed to identify a small set of putative G-triplex ligands. The G-triplex stabilizing properties of these compounds were analyzed by CD melting assay. DSC, non-denaturing gel electrophoresis, NMR and molecular modeling studies were performed to investigate the interaction between the selected compound 1 and G-rich DNA structures. Cytotoxic activity of 1 was evaluated by MTT cell proliferation assay. The experiments led to the identification of a promising hit that was shown to bind preferentially to G-triplex and parallel-stranded G-quadruplexes over duplex and antiparallel G-quadruplexes. Molecular modeling results suggested a partial end-stacking of 1 to the external G-triad/G-tetrads as a binding mode. Biological assays showed that 1 is endowed with cytotoxic effect on human osteosarcoma cells. A tandem application of virtual screening along with the experimental investigation was employed to discover a G-triplex-targeting ligand. Experiments revealed that the selected compound actually acts as a dual G-triplex/G-quadruplex stabilizer, thus stimulating further studies aimed at its optimization. The discovery of molecules able to bind and stabilize G-triplex structures is highly appealing, but their transient state makes challenging their recognition. These findings suggest that the identification of ligands with dual G-triplex/G-quadruplex stabilizing properties may represent a new route for the design of anticancer agents targeting the G-rich DNA structures. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. Copyright © 2016 Elsevier B

  10. A two-scale mathematical model for DNA transcription.

    PubMed

    Chiu, Chichia; Fakhouri, Walid; Liu, Nianzheng; Dayringer, Evan; Dresch, Jacqueline; Arnosti, David

    2012-04-01

    Unlike the earlier description of regulation of DNA transcription as a biological switch which simply turns on and off, scientists now understand that DNA transcription is a much more complex process. It can depend on several transcription factors (proteins) and DNA regulatory elements (transcription factor binding sites). The combination of these two groups of different scaled factors determines the transcription outcome. In this paper, we propose a two-scale mathematical model for the DNA transcription processes, which integrates the characteristics of both transcription factors and DNA cis-regulatory elements. The model was tested on a well designed synthetic system during early development stage of Drosophila embryo. The system involves three transcription factors (two activators and one repressor) and a reporter gene. The predicted results using the model were compared with the real experimental data using both graphical methods and statistical methods. Parameter estimation will also be discussed in the paper. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Model of Biological Quantum Logic in DNA

    PubMed Central

    Mihelic, F. Matthew

    2013-01-01

    The DNA molecule has properties that allow it to act as a quantum logic processor. It has been demonstrated that there is coherent conduction of electrons longitudinally along the DNA molecule through pi stacking interactions of the aromatic nucleotide bases, and it has also been demonstrated that electrons moving longitudinally along the DNA molecule are subject to a very efficient electron spin filtering effect as the helicity of the DNA molecule interacts with the spin of the electron. This means that, in DNA, electrons are coherently conducted along a very efficient spin filter. Coherent electron spin is held in a logically and thermodynamically reversible chiral symmetry between the C2-endo and C3-endo enantiomers of the deoxyribose moiety in each nucleotide, which enables each nucleotide to function as a quantum gate. The symmetry break that provides for quantum decision in the system is determined by the spin direction of an electron that has an orbital angular momentum that is sufficient to overcome the energy barrier of the double well potential separating the C2-endo and C3-endo enantiomers, and that enantiomeric energy barrier is appropriate to the Landauer limit of the energy necessary to randomize one bit of information. PMID:25369816

  12. Model of biological quantum logic in DNA.

    PubMed

    Mihelic, F Matthew

    2013-08-02

    The DNA molecule has properties that allow it to act as a quantum logic processor. It has been demonstrated that there is coherent conduction of electrons longitudinally along the DNA molecule through pi stacking interactions of the aromatic nucleotide bases, and it has also been demonstrated that electrons moving longitudinally along the DNA molecule are subject to a very efficient electron spin filtering effect as the helicity of the DNA molecule interacts with the spin of the electron. This means that, in DNA, electrons are coherently conducted along a very efficient spin filter. Coherent electron spin is held in a logically and thermodynamically reversible chiral symmetry between the C2-endo and C3-endo enantiomers of the deoxyribose moiety in each nucleotide, which enables each nucleotide to function as a quantum gate. The symmetry break that provides for quantum decision in the system is determined by the spin direction of an electron that has an orbital angular momentum that is sufficient to overcome the energy barrier of the double well potential separating the C2-endo and C3-endo enantiomers, and that enantiomeric energy barrier is appropriate to the Landauer limit of the energy necessary to randomize one bit of information.

  13. Easy DNA Modeling and More with GraphiteLifeExplorer

    PubMed Central

    Hornus, Samuel; Lévy, Bruno; Larivière, Damien; Fourmentin, Eric

    2013-01-01

    The GraphiteLifeExplorer tool enables biologists to reconstruct 3D cellular complexes built from proteins and DNA molecules. Models of DNA molecules can be drawn in an intuitive way and assembled to proteins or others globular structures. Real time navigation and immersion offer a unique view to the reconstructed biological machinery. PMID:23308263

  14. 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.

  15. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

    PubMed Central

    Voorhees, Jaymie R.; Rohlman, Diane S.; Lein, Pamela J.; Pieper, Andrew A.

    2017-01-01

    Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally. PMID:28149268

  16. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.

    PubMed

    Voorhees, Jaymie R; Rohlman, Diane S; Lein, Pamela J; Pieper, Andrew A

    2016-01-01

    Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.

  17. Modeling chain folding in protein-constrained circular DNA.

    PubMed Central

    Martino, J A; Olson, W K

    1998-01-01

    An efficient method for sampling equilibrium configurations of DNA chains binding one or more DNA-bending proteins is presented. The technique is applied to obtain the tertiary structures of minimal bending energy for a selection of dinucleosomal minichromosomes that differ in degree of protein-DNA interaction, protein spacing along the DNA chain contour, and ring size. The protein-bound portions of the DNA chains are represented by tight, left-handed supercoils of fixed geometry. The protein-free regions are modeled individually as elastic rods. For each random spatial arrangement of the two nucleosomes assumed during a stochastic search for the global minimum, the paths of the flexible connecting DNA segments are determined through a numerical solution of the equations of equilibrium for torsionally relaxed elastic rods. The minimal energy forms reveal how protein binding and spacing and plasmid size differentially affect folding and offer new insights into experimental minichromosome systems. PMID:9591675

  18. DNA base excision repair nanosystem engineering: model development.

    PubMed

    Sokhansanj, B A

    2005-01-01

    DNA base damage results from a combination of endogenous sources, (normal metabolism, increased metabolism due to obesity, stress from diseases such as arthritis and diabetes, and ischemia) and the environment (ingested toxins, ionizing radiation, etc.). If unrepaired DNA base damage can lead to diminished cell function, and potentially diseases and eventually mutations that lead to cancer. Sophisticated DNA repair mechanisms have evolved in all living cells to preserve the integrity of inherited genetic information and transcriptional control. Understanding a system like DNA repair is greatly enhanced by using engineering methods, in particular modeling interactions and using predictive simulation to analyze the impact of perturbations. We describe the use of such a "nanosystem engineering" approach to analyze the DNA base excision repair pathway in human cells, and use simulation to predict the impact of varying enzyme concentration on DNA repair capacity.

  19. 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.

  20. Melatonin and a spin-trap compound block radiofrequency electromagnetic radiation-induced DNA strand breaks in rat brain cells.

    PubMed

    Lai, H; Singh, N P

    1997-01-01

    Effects of in vivo microwave exposure on DNA strand breaks, a form of DNA damage, were investigated in rat brain cells. In previous research, we have found that acute (2 hours) exposure to pulsed (2 microseconds pulses, 500 pps) 2450-MHz radiofrequency electromagnetic radiation (RFR) (power density 2 mW/cm2, average whole body specific absorption rate 1.2 W/kg) caused an increase in DNA single- and double-strand breaks in brain cells of the rat when assayed 4 hours post exposure using a microgel electrophoresis assay. In the present study, we found that treatment of rats immediately before and after RFR exposure with either melatonin (1 mg/kg/injection, SC) or the spin-trap compound N-tert-butyl-alpha-phenylnitrone (PBN) (100 mg/kg/injection, i.p.) blocks this effects of RFR. Since both melatonin and PBN are efficient free radical scavengers it is hypothesized that free radicals are involved in RFR-induced DNA damage in the brain cells of rats. Since cumulated DNA strand breaks in brain cells can lead to neurodegenerative diseases and cancer and an excess of free radicals in cells has been suggested to be the cause of various human diseases, data from this study could have important implications for the health effects of RFR exposure.

  1. Homology modeling, docking and structure-based pharmacophore of inhibitors of DNA methyltransferase

    NASA Astrophysics Data System (ADS)

    Yoo, Jakyung; Medina-Franco, José L.

    2011-06-01

    DNA methyltransferase 1 (DNMT1) is an emerging epigenetic target for the treatment of cancer and other diseases. To date, several inhibitors from different structural classes have been published. In this work, we report a comprehensive molecular modeling study of 14 established DNTM1 inhibitors with a herein developed homology model of the catalytic domain of human DNTM1. The geometry of the homology model was in agreement with the proposed mechanism of DNA methylation. Docking results revealed that all inhibitors studied in this work have hydrogen bond interactions with a glutamic acid and arginine residues that play a central role in the mechanism of cytosine DNA methylation. The binding models of compounds such as curcumin and parthenolide suggest that these natural products are covalent blockers of the catalytic site. A pharmacophore model was also developed for all DNMT1 inhibitors considered in this work using the most favorable binding conformations and energetic terms of the docked poses. To the best of our knowledge, this is the first pharmacophore model proposed for compounds with inhibitory activity of DNMT1. The results presented in this work represent a conceptual advance for understanding the protein-ligand interactions and mechanism of action of DNMT1 inhibitors. The insights obtained in this work can be used for the structure-based design and virtual screening for novel inhibitors targeting DNMT1.

  2. 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.

  3. Sorption and Interfacial Rheology Study of Model Asphaltene Compounds.

    PubMed

    Pradilla, Diego; Simon, Sébastien; Sjöblom, Johan; Samaniuk, Joseph; Skrzypiec, Marta; Vermant, Jan

    2016-03-29

    The sorption and rheological properties of an acidic polyaromatic compound (C5PeC11), which can be used to further our understanding of the behavior of asphaltenes, are determined experimentally. The results show that C5PeC11 exhibits the type of pH-dependent surface activity and interfacial shear rheology observed in C6-asphaltenes with a decrease in the interfacial tension concomitant with the elastic modulus when the pH increases. Surface pressure-area (Π-A) isotherms show evidence of aggregation behavior and π-π stacking at both the air/water and oil/water interfaces. Similarly, interactions between adsorbed C5PeC11 compounds are evidenced through desorption experiments at the oil/water interface. Contrary to indigenous asphaltenes, adsorption is reversible, but desorption is slower than for noninteracting species. The reversibility enables us to create layers reproducibly, whereas the presence of interactions between the compounds enables us to mimic the key aspects of interfacial activity in asphaltenes. Shear and dilatational rheology show that C5PeC11 forms a predominantly elastic film both at the liquid/air and the liquid/liquid interfaces. Furthermore, a soft glassy rheology model (SGR) fits the data obtained at the liquid/liquid interface. However, it is shown that the effective noise temperature determined from the SGR model for C5PeC11 is higher than for indigenous asphaltenes measured under similar conditions. Finally, from a colloidal and rheological standpoint, the results highlight the importance of adequately addressing the distinction between the material functions and true elasticity extracted from a shear measurement and the apparent elasticity measured in dilatational-pendant drop setups.

  4. 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.

  5. 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

  6. Modeling spatial correlation of DNA deformations: Allosteric effects of DNA protein binding

    NASA Astrophysics Data System (ADS)

    Xu, Xinliang; Cao, Jianshu; Hao Ge Collaboration; X. Sunney Xie Collaboration

    2013-03-01

    We report a study of DNA deformations by a coarse grained mechanical model. Recent single molecule experimental studies show that when DNA molecule is deformed by its binding to a protein, the binding affinity of a second protein at distance L away from the first binding site is altered. To explain this observation, the relaxation of deformation along the DNA chain is examined. Our method predicts a general exponentially decaying behavior for differenct deformation modes. As an example, inter-helical distance deformation is studied in details, and is found to decay at a previously unknown lengthscale of 10 base pairs as a result of the balance between inter and intra DNA strand energy. This lengthscale is in good agreement with the said single molecule experimental observation. This model of local deformation relaxation helps us better understand many important issues in DNA such as the enhanced flexibility of DNA at short lengthscales and DNA repair mechanism inside cells. Biodynamic Optical Imaging Center, Peking University

  7. 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.

  8. Yeast as a model system to study metabolic impact of selenium compounds

    PubMed Central

    Herrero, Enrique; Wellinger, Ralf E.

    2015-01-01

    Inorganic Se forms such as selenate or selenite (the two more abundant forms in nature) can be toxic in Saccharomyces cerevisiae cells, which constitute an adequate model to study such toxicity at the molecular level and the functions participating in protection against Se compounds. Those Se forms enter the yeast cell through other oxyanion transporters. Once inside the cell, inorganic Se forms may be converted into selenide through a reductive pathway that in physiological conditions involves reduced glutathione with its consequent oxidation into diglutathione and alteration of the cellular redox buffering capacity. Selenide can subsequently be converted by molecular oxygen into elemental Se, with production of superoxide anions and other reactive oxygen species. Overall, these events result in DNA damage and dose-dependent reversible or irreversible protein oxidation, although additional oxidation of other cellular macromolecules cannot be discarded. Stress-adaptation pathways are essential for efficient Se detoxification, while activation of DNA damage checkpoint and repair pathways protects against Se-mediated genotoxicity. We propose that yeast may be used to improve our knowledge on the impact of Se on metal homeostasis, the identification of Se-targets at the DNA and protein levels, and to gain more insights into the mechanism of Se-mediated apoptosis. PMID:28357286

  9. Moving Beyond Watson-Crick Models of Coarse Grained DNA

    NASA Astrophysics Data System (ADS)

    Dorfman, Kevin; Linak, Margaret; Tourdot, Richard

    2012-02-01

    DNA structure possesses several levels of complexity, ranging from the sequence of bases (primary structure) to base pairing (secondary structure) to its three-dimensional shape (tertiary structure) and can produce a wide variety of conformations in addition to canonical double stranded DNA. By including non-Watson-Crick interactions in a coarse-grained model, we developed a system that not only can capture the traditional B-form double helix, but also can adopt a wide variety of other DNA conformations. In our experimentally parameterized, coarse-grained DNA model we are able to reproduce the microscopic features of double-stranded DNA without the need for explicit constraints and capture experimental melting curves for a number of short DNA hairpins. We demonstrate the utility of the model by simulating more complex tertiary structures such as the folding of the thrombin aptamer, which includes G-quartets, and strand invasion during triplex formation. Our results highlight the importance of non-canonical interactions in DNA coarse- grained models.

  10. Insights on protein-DNA recognition by coarse grain modelling

    PubMed Central

    Poulain, Pierre; Saladin, Adrien; Hartmann, Brigitte; Prévost, Chantal

    2008-01-01

    Coarse grain modelling of macromolecules is a new approach potentially well adapted to answer numerous issues, ranging from physics to biology. We propose here an original DNA coarse grain model specifically dedicated to protein–DNA docking, a crucial, but still largely unresolved, question in molecular biology. Using a representative set of protein–DNA complexes, we first show that our model is able to predict the interaction surface between the macromolecular partners taken in their bound form. In a second part, the impact of the DNA sequence and electrostatics, together with the DNA and protein conformations on docking is investigated. Our results strongly suggest that the overall DNA structure mainly contributes in discriminating the interaction site on cognate proteins. Direct electrostatic interactions between phosphate groups and amino acids side chains strengthen the binding. Overall, this work demonstrates that coarse grain modelling can reveal itself a precious auxiliary for a general and complete description and understanding of protein–DNA association mechanisms. PMID:18478582

  11. 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.

  12. 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

  13. Semi-automated high-throughput fluorescent intercalator displacement-based discovery of cytotoxic DNA binding agents from a large compound library.

    PubMed

    Glass, Lateca S; Bapat, Aditi; Kelley, Mark R; Georgiadis, Millie M; Long, Eric C

    2010-03-01

    High-throughput fluorescent intercalator displacement (HT-FID) was adapted to the semi-automated screening of a commercial compound library containing 60,000 molecules resulting in the discovery of cytotoxic DNA-targeted agents. Although commercial libraries are routinely screened in drug discovery efforts, the DNA binding potential of the compounds they contain has largely been overlooked. HT-FID led to the rapid identification of a number of compounds for which DNA binding properties were validated through demonstration of concentration-dependent DNA binding and increased thermal melting of A/T- or G/C-rich DNA sequences. Selected compounds were assayed further for cell proliferation inhibition in glioblastoma cells. Seven distinct compounds emerged from this screening procedure that represent structures unknown previously to be capable of targeting DNA leading to cell death. These agents may represent structures worthy of further modification to optimally explore their potential as cytotoxic anti-cancer agents. In addition, the general screening strategy described may find broader impact toward the rapid discovery of DNA targeted agents with biological activity. Copyright 2010 Elsevier Ltd. All rights reserved.

  14. Semi-automated high-throughput fluorescent intercalator displacement-based discovery of cytotoxic DNA binding agents from a large compound library

    PubMed Central

    Glass, LaTeca S.; Bapat, Aditi; Kelley, Mark R.; Georgiadis, Millie M.; Long, Eric C.

    2010-01-01

    High-throughput fluorescent intercalator displacement (HT-FID) was adapted to the semi-automated screening of a commercial compound library containing 60,000 molecules resulting in the discovery of cytotoxic DNA-targeted agents. Although commercial libraries are routinely screened in drug discovery efforts, the DNA binding potential of the compounds they contain has largely been overlooked. HT-FID led to the rapid identification of a number of compounds for which DNA binding properties were validated through demonstration of concentration-dependent DNA binding and increased thermal melting of A/T- or G/C-rich DNA sequences. Selected compounds were assayed further for cell proliferation inhibition in glioblastoma cells. Seven distinct compounds emerged from this screening procedure that represent structures unknown previously to be capable of targeting DNA leading to cell death. These agents may represent structures worthy of further modification to optimally explore their potential as cytotoxic anti-cancer agents. In addition, the general screening strategy described may find broader impact toward the rapid discovery of DNA targeted agents with biological activity. PMID:20144868

  15. 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.

  16. Markovian language model of the DNA and its information content

    PubMed Central

    Srivastava, S.; Baptista, M. S.

    2016-01-01

    This work proposes a Markovian memoryless model for the DNA that simplifies enormously the complexity of it. We encode nucleotide sequences into symbolic sequences, called words, from which we establish meaningful length of words and groups of words that share symbolic similarities. Interpreting a node to represent a group of similar words and edges to represent their functional connectivity allows us to construct a network of the grammatical rules governing the appearance of groups of words in the DNA. Our model allows us to predict the transition between groups of words in the DNA with unprecedented accuracy, and to easily calculate many informational quantities to better characterize the DNA. In addition, we reduce the DNA of known bacteria to a network of only tens of nodes, show how our model can be used to detect similar (or dissimilar) genes in different organisms, and which sequences of symbols are responsible for most of the information content of the DNA. Therefore, the DNA can indeed be treated as a language, a Markovian language, where a ‘word’ is an element of a group, and its grammar represents the rules behind the probability of transitions between any two groups. PMID:26909179

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. Testing of compounds in models of pulmonary emphysema.

    PubMed

    Gardi, Concetta; Arezzini, Beatrice; Martorana, Piero A

    2008-01-01

    There is a pressing need for the development of new therapies for emphysema, particularly as no existing treatment has been shown to reduce disease progression. Compounds with a potential activity against the pathological mechanisms postulated to play a role in the development and progression of emphysema should be tested in vivo in animal models of this disease. The choice of the model is of capital importance. While models of elastase-induced emphysema are relatively easy to execute, require low personnel capacity and provide fast results, they also have a limited clinical relevance. On the other hand, models of chronic smoke exposure are time-consuming, expensive and require high personnel capacity but have a high clinical relevance. Presently, mainly two pharmacological approaches are being considered and investigated in experimental studies. The first approach consists of pharmacological interventions designed to slow down the rate at which alveolar wall is lost in emphysema. In this approach we find anti-inflammatory agents, protease inhibitors and antioxidants. The attempt to reduce lung inflammatory cell infiltration is most appealing since such an effect would also reduce the lung burden of both proteases and oxidants. The second approach is an attempt to reverse the process of alveolar loss by inducing alveolar growth. To our knowledge here only the effects of retinoids and/or retinoid receptor agonists have been investigated. This report presents a selected review of the literature of animal studies using these pharmacological approaches.

  2. 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.

  3. Phosphorus-nitrogen compounds. Part 23: Syntheses, structural investigations, biological activities, and DNA interactions of new N/O spirocyclotriphosphazenes

    NASA Astrophysics Data System (ADS)

    Asmafiliz, Nuran; Kılıç, Zeynel; Hayvalı, Zeliha; Açık, Leyla; Hökelek, Tuncer; Dal, Hakan; Öner, Yağmur

    2012-02-01

    The Schiff base compounds ( 1 and 2) are synthesized by the condensation reactions of 2-furan-2-yl-methylamine with 2-hydroxy-3-methoxy- and 2-hydroxy-5-methoxy-benzaldehydes and reduced with NaBH 4 to give the new N/O-donor-type ligands ( 3 and 4). The monospirocyclotriphosphazenes containing 1,3,2-oxazaphosphorine rings ( 5 and 6) are prepared from the reactions of N 3P 3Cl 6 with 3 and 4, respectively. The reactions of 5 and 6 with excess pyrrolidine, morpholine, and 1,4-dioxa-8-azaspiro [4,5] decane (DASD) produce tetrapyrrolidino ( 5a and 6a), morpholino ( 5b and 6b), and 1,4-dioxa-8-azaspiro [4,5] deca ( 5c and 6c) spirocyclotriphosphazenes. The structural investigations of the compounds are examined by 1H, 13C, 31P NMR, DEPT, HSQC, and HMBC techniques. The solid-state structures of 5, 5a, and 6 are determined using X-ray crystallography. The compounds 5a, 5b, 5c, 6a, 6b, and 6c are subjected to antimicrobial activity against six patojen bacteria and two yeast strains. In addition, interactions between these compounds and pBR322 plasmid DNA are presented by agarose gel electrophoresis.

  4. Kinetic assessment of persistent halogenated xenobiotics in cell culture models: comparison of mono- and poly-halogenated compounds.

    PubMed

    Mühlebach, S F; Karlaganis, G; Honegger, U E

    2006-03-01

    We evaluated the suitability of single and multiple cell type cultures as model systems to characterise cellular kinetics of highly lipophilic compounds with potential ecotoxicological impact. Confluent mono-layers of human skin fibroblasts, rat astrocytoma C6 cells, non-differentiated and differentiated mouse 3T3 cells were kept in culture medium supplemented with 10% foetal calf serum. For competitive uptake experiments up to four different cell types, grown on glass sectors, were exposed for 3h to (14)C-labelled model compounds, dissolved either in organic solvents or incorporated into unilamellar lecithin liposomes. Bromo-, or chloro-benzenes, decabromodiphenylether (DBP), and dichlorodiphenyl ethylene (DDE) were tested in rather high concentration of 20 microM. Cellular toxicity was low. Compound levels were related to protein, DNA, and triglyceride contents. Cellular uptake was fast and dependent on physico-chemical properties of the compounds (lipophilicity, molecular size), formulation, and cell type. Mono-halogenated benzenes showed low and similar uptake levels (=low accumulation compounds). DBP and DDE showed much higher cellular accumulations (=high accumulation compounds) except for DBP in 3T3 cells. Uptake from liposomal formulations was mostly higher than if compounds were dissolved in organic solvents. The extent of uptake correlated with the cellular content of triglycerides, except for DBP. Uptake competition between different cell types was studied in a sectorial multi-cell culture model. For low accumulation compounds negligible differences were found among C6 cells and fibroblasts. Uptake of DDE was slightly and that of DBP highly increased in fibroblasts. Well-defined cell culture systems, especially the sectorial model, are appropriate to screen for bioaccumulation and cytotoxicity of (unknown) chemical entities in vitro.

  5. Reverse osmosis processing of organic model compounds and fermentation broths.

    PubMed

    Diltz, Robert A; Marolla, Theodore V; Henley, Michael V; Li, Lixiong

    2007-02-01

    Post-treatment of an anaerobic fermentation broth was evaluated using a 150 gal/day, single cartridge prototype reverse osmosis (RO) system. Baseline tests were conducted at 25 degrees C using six organic model compounds representing key species found in the fermentation broth: ethanol, butanol, acetic acid, oxalic acid, lactic acid, and butyric acid. Correlations of the rejection and recovery efficiencies for these organic species, individually and in simulated mixtures, were obtained as a function of feed pressure with and without recirculation of the retentate. The actual fermentation broth obtained from a continuous-flow biohydrogen process was treated by the RO system under the operating conditions similar to those used in the baseline tests, resulting in greater than 95% removal of total organic carbon. These results are encouraging and useful for further studies on the feasibility of incorporating the RO technology into an integrated and field deployable wastewater management and water recovery system.

  6. Stereodefined phosphorothioate analogues of DNA: relative thermodynamic stability of the model PS-DNA/DNA and PS-DNA/RNA complexes.

    PubMed

    Boczkowska, Małgorzata; Guga, Piotr; Stec, Wojciech J

    2002-10-15

    Thermodynamic data regarding the influence of P-chirality on stability of duplexes formed between phosphorothioate DNA oligonucleotides (of either stereo-defined all-R(P) or all-S(P) or random configuration at the P atoms) and complementary DNA or RNA strands are presented. Measured melting temperatures and calculated DeltaG(37)(o) values showed that duplexes formed by PS-DNA oligomers with DNA strands are less stable than their unmodified counterparts. However, relative stability of the duplexes ([all-R(P)]-PS-DNA/DNA vs [all-S(P)]-PS-DNA/DNA) depends on their sequential composition rather than on the absolute configuration of PS-oligos, contrary to the results of theoretical considerations and molecular modeling reported in the literature. On the other hand, for all six analyzed pairs of diastereomers, the [all-R(P)]-PS isomers form more stable duplexes with RNA templates, but the origin of stereodifferentiation depends on the sequence with more favorable entropy and enthalpy factors which correlated with dT-rich and dA/dG-rich PS-oligomers, respectively.

  7. Cooperativity-based modeling of heterotypic DNA nanostructure assembly

    PubMed Central

    Shapiro, Anastasia; Hozeh, Avital; Girshevitz, Olga; Abu-Horowitz, Almogit; Bachelet, Ido

    2015-01-01

    DNA origami is a robust method for the fabrication of nanoscale 2D and 3D objects with complex features and geometries. The process of DNA origami folding has been recently studied, however quantitative understanding of it is still elusive. Here, we describe a systematic quantification of the assembly process of DNA nanostructures, focusing on the heterotypic DNA junction—in which arms are unequal—as their basic building block. Using bulk fluorescence studies we tracked this process and identified multiple levels of cooperativity from the arms in a single junction to neighboring junctions in a large DNA origami object, demonstrating that cooperativity is a central underlying mechanism in the process of DNA nanostructure assembly. We show that the assembly of junctions in which the arms are consecutively ordered is more efficient than junctions with randomly-ordered components, with the latter showing assembly through several alternative trajectories as a potential mechanism explaining the lower efficiency. This highlights consecutiveness as a new design consideration that could be implemented in DNA nanotechnology CAD tools to produce more efficient and high-yield designs. Altogether, our experimental findings allowed us to devise a quantitative, cooperativity-based heuristic model for the assembly of DNA nanostructures, which is highly consistent with experimental observations. PMID:26071955

  8. DNA modifications in models of alcohol use disorders.

    PubMed

    Tulisiak, Christopher T; Harris, R Adron; Ponomarev, Igor

    2017-05-01

    Chronic alcohol use and abuse result in widespread changes to gene expression, some of which contribute to the development of alcohol-use disorders (AUD). Gene expression is controlled, in part, by a group of regulatory systems often referred to as epigenetic factors, which includes, among other mechanisms, chemical marks made on the histone proteins around which genomic DNA is wound to form chromatin, and on nucleotides of the DNA itself. In particular, alcohol has been shown to perturb the epigenetic machinery, leading to changes in gene expression and cellular functions characteristic of AUD and, ultimately, to altered behavior. DNA modifications in particular are seeing increasing research in the context of alcohol use and abuse. To date, studies of DNA modifications in AUD have primarily looked at global methylation profiles in human brain and blood, gene-specific methylation profiles in animal models, methylation changes associated with prenatal ethanol exposure, and the potential therapeutic abilities of DNA methyltransferase inhibitors. Future studies may be aimed at identifying changes to more recently discovered DNA modifications, utilizing new methods to discriminate methylation profiles between cell types, thus clarifying how alcohol influences the methylomes of cell-type populations and how this may affect downstream processes. These studies and more in-depth probing of DNA methylation will be key to determining whether DNA-level epigenetic regulation plays a causative role in AUD and can thus be targeted for treatment of the disorder. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Cooperativity-based modeling of heterotypic DNA nanostructure assembly.

    PubMed

    Shapiro, Anastasia; Hozeh, Avital; Girshevitz, Olga; Abu-Horowitz, Almogit; Bachelet, Ido

    2015-07-27

    DNA origami is a robust method for the fabrication of nanoscale 2D and 3D objects with complex features and geometries. The process of DNA origami folding has been recently studied, however quantitative understanding of it is still elusive. Here, we describe a systematic quantification of the assembly process of DNA nanostructures, focusing on the heterotypic DNA junction-in which arms are unequal-as their basic building block. Using bulk fluorescence studies we tracked this process and identified multiple levels of cooperativity from the arms in a single junction to neighboring junctions in a large DNA origami object, demonstrating that cooperativity is a central underlying mechanism in the process of DNA nanostructure assembly. We show that the assembly of junctions in which the arms are consecutively ordered is more efficient than junctions with randomly-ordered components, with the latter showing assembly through several alternative trajectories as a potential mechanism explaining the lower efficiency. This highlights consecutiveness as a new design consideration that could be implemented in DNA nanotechnology CAD tools to produce more efficient and high-yield designs. Altogether, our experimental findings allowed us to devise a quantitative, cooperativity-based heuristic model for the assembly of DNA nanostructures, which is highly consistent with experimental observations.

  10. Compound dislocation models (CDMs) for volcano deformation analyses

    NASA Astrophysics Data System (ADS)

    Nikkhoo, Mehdi; Walter, Thomas R.; Lundgren, Paul R.; Prats-Iraola, Pau

    2017-02-01

    Volcanic crises are often preceded and accompanied by volcano deformation caused by magmatic and hydrothermal processes. Fast and efficient model identification and parameter estimation techniques for various sources of deformation are crucial for process understanding, volcano hazard assessment and early warning purposes. As a simple model that can be a basis for rapid inversion techniques, we present a compound dislocation model (CDM) that is composed of three mutually orthogonal rectangular dislocations (RDs). We present new RD solutions, which are free of artefact singularities and that also possess full rotational degrees of freedom. The CDM can represent both planar intrusions in the near field and volumetric sources of inflation and deflation in the far field. Therefore, this source model can be applied to shallow dikes and sills, as well as to deep planar and equidimensional sources of any geometry, including oblate, prolate and other triaxial ellipsoidal shapes. In either case the sources may possess any arbitrary orientation in space. After systematically evaluating the CDM, we apply it to the co-eruptive displacements of the 2015 Calbuco eruption observed by the Sentinel-1A satellite in both ascending and descending orbits. The results show that the deformation source is a deflating vertical lens-shaped source at an approximate depth of 8 km centred beneath Calbuco volcano. The parameters of the optimal source model clearly show that it is significantly different from an isotropic point source or a single dislocation model. The Calbuco example reflects the convenience of using the CDM for a rapid interpretation of deformation data.

  11. DNA-Encoded Compound Libraries as Open Source: A Powerful Pathway to New Drugs.

    PubMed

    Lerner, Richard A; Brenner, Sydney

    2017-01-24

    "… We envisioned an iterative system where a unique DNA tag identifier that encoded the event was appended to each newly formed molecule. These vast collections of molecules are known today as DNA- encoded chemical libraries (DECLs), and allow scientists to do selections on the benchtop that previously required access to large and complex high-throughput screening centers …" Read more in the Guest Editorial by Richard A. Lerner and Sydney Brenner. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Model carcinogen adsorption dynamics of DNA gel.

    PubMed

    Tomita, Naoko; Naito, Daisuke; Rokugawa, Isamu; Yamamoto, Takao; Dobashi, Toshiaki

    2014-09-01

    We have derived theoretical equations describing the adsorption of carcinogen to gels in an immersion medium containing carcinogens. The theory was developed for a cylindrical boundary condition under the assumption of a carcinogen diffusion-limited process combined with the "moving boundary picture (Furusawa et al., 2007)". The time course of the adsorbed carcinogen layer thickness and that of the carcinogen concentration in an immersion medium were expressed by a set of scaled variables, and the asymptotic behavior in the initial stage was derived. Experiments based on the theory were performed using a DNA gel sandwiched between a set of coverglasses in a medium containing acridine orange (AO). The boundary between the AO-adsorbed gel layer and AO-nonadsorbed gel layer was traced during the immersion. The time courses of the AO-adsorbed gel layer thickness and the AO concentration in the immersion medium were well explained by the theory, and the number ratio of the total AO molecules to the adsorption sites in the DNA gel was determined. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Preventive Role of Specific Dietary Factors and Natural Compounds Against DNA Damage and Oxidative Stress.

    DTIC Science & Technology

    1998-08-01

    environmental contaminants in the air, food , and cigarette smoke may result in significant levels of DNA damage, it was more recently recognized that...as fruits and vegetables (vitamins C and E), the popular medicine honeybee propolis (CAPE), or green tea (EGCG). Studies carried out to date suggest

  14. Hidden Markov models from molecular dynamics simulations on DNA.

    PubMed

    Thayer, Kelly M; Beveridge, D L

    2002-06-25

    An enhanced bioinformatics tool incorporating the participation of molecular structure as well as sequence in protein DNA recognition is proposed and tested. Boltzmann probability models of sequence-dependent DNA structure from all-atom molecular dynamics simulations were obtained and incorporated into hidden Markov models (HMMs) that can recognize molecular structural signals as well as sequence in protein-DNA binding sites on a genome. The binding of catabolite activator protein (CAP) to cognate DNA sequences was used as a prototype case for implementation and testing of the method. The results indicate that even HMMs based on probabilistic roll/tilt dinucleotide models of sequence-dependent DNA structure have some capability to discriminate between known CAP binding and nonbinding sites and to predict putative CAP binding sites in unknowns. Restricting HMMs to sequence only in regions of strong consensus in which the protein makes base specific contacts with the cognate DNA further improved the discriminatory capabilities of the HMMs. Comparison of results with controls based on sequence only indicates that extending the definition of consensus from sequence to structure improves the transferability of the HMMs, and provides further supportive evidence of a role for dynamical molecular structure as well as sequence in genomic regulatory mechanisms.

  15. 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.

  16. 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.

  17. Thermocatalytic treatment of biomass tar model compounds via radio frequency.

    PubMed

    Anis, Samsudin; Zainal, Z A; Bakar, M Z A

    2013-05-01

    A new effective RF tar thermocatalytic treatment process with low energy intensive has been proposed to remove tar from biomass gasification. Toluene and naphthalene as biomass tar model compounds were removed via both thermal and catalytic treatment over a wide temperature range from 850 °C to 1200 °C and 450 °C to 900 °C, respectively at residence time of 0-0.7 s. Thermal characteristics of the new technique are also described in this paper. This study clearly clarified that toluene was much easier to be removed than naphthalene. Soot was found as the final product of thermal treatment of the tar model and completely removed during catalytic treatment. Radical reactions generated by RF non-thermal effect improve the tar removal. The study showed that Y-zeolite has better catalytic activity compared to dolomite on toluene and naphthalene removal due to its acidic nature and large surface area, even at lower reaction temperature of about 550 °C.

  18. Statistical mechanics of a nonlinear model for DNA denaturation

    SciTech Connect

    Peyrard, M.; Bishop, A. R.

    1989-06-05

    We investigate the statistical mechanics of a simple lattice model for thedenaturation of the DNA double helix. The model consists of two chainsconnected by Morse potentials representing the H bonds. We determine thetemperature dependence of the interstrand separation and we show that amechanism involving an energy localization analogous to self-focusing mayinitiate the denaturation.

  19. 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

  20. Analysis of the DNA interaction of copper compounds belonging to the Casiopeínas® antitumoral series.

    PubMed

    Becco, Lorena; García-Ramos, Juan Carlos; Azuara, Lena Ruiz; Gambino, Dinorah; Garat, Beatriz

    2014-11-01

    Casiopeínas® are mixed-chelate copper complexes with antitumor tested potential. Their activity, both in vitro and in vivo, as antiproliferative, cytotoxic, and genotoxic drugs has been assessed. Biological results of these copper compounds have deserved some of them entering clinical trials. Significant efforts have been devoted to the in-depth identification of their mechanism of action. Using gel electrophoresis analysis, we have previously shown that the interaction of the Casiopeínas® Cas II-gly, [Cu(4,7-dimethyl-1,10-phenanthroline)(glycinate)]NO3 with DNA, triggers the cleavage of the biomolecule by a free radical mechanism. In this work, we further study the behavior of different complexes of the same Casiopeínas® series also including glycinate as co-ligand {Cas VI-gly (5,6 dimethyl-1,10-phenanthroline glycinato copper(II) nitrate), Cas VII-gly (1,10-phenanthroline glycinato copper(II) nitrate), and Cas IX-gly (2,2'-bipyridine glycinato copper(II) nitrate)} and of a Casiopeínas® with a different co-ligand (Cas III-Cs; 4,7-dimethyl-1,10-phenanthroline salicylaldehydato-copper(II) nitrate). While all of them produce DNA degradation, the performance in the presence of a radical scavenger suggests the existence of differences in their mechanism of interaction with DNA.

  1. Inhibition of DNA gyrase by levofloxacin and related fluorine-containing heterocyclic compounds.

    PubMed

    Tunitskaya, V L; Khomutov, A R; Kochetkov, S N; Kotovskaya, S K; Charushin, V N

    2011-10-01

    Fluoroquinolones are an important class of modern and efficient antibacterial drugs with a broad spectrum of activity. Levofloxacin (the optically active form of ofloxacin) is one of the most promising fluoroquinolone drugs, and its antibacterial activity is substantially higher than the activity of other drugs of the fluoroquinolone family. Earlier, in the Postovsky Institute of Organic Synthesis, UB RAS, an original method of levofloxacin synthesis was developed, and now the pilot batch of the drug is being prepared. Bacterial DNA gyrase is a specific target of fluoroquinolones; hence, the study of the enzyme-drug interaction is of theoretical and practical importance. Moreover, the parameters of DNA gyrase inhibition may serve as a criterion for drug quality. Here, we present the results of studying the interaction of DNA gyrase with a number of fluoroquinolones and their analogs: intermediates and semi-products of the levofloxacin synthesis, and also samples from the pilot batches of this drug. The importance of two structural elements of the levofloxacin molecule for the efficiency of the inhibition is revealed. The data obtained may be useful for the design of new drugs derived from levofloxacin.

  2. Complexity reduction in context-dependent DNA substitution models.

    PubMed

    Majoros, William H; Ohler, Uwe

    2009-01-15

    The modeling of conservation patterns in genomic DNA has become increasingly popular for a number of bioinformatic applications. While several systems developed to date incorporate context-dependence in their substitution models, the impact on computational complexity and generalization ability of the resulting higher order models invites the question of whether simpler approaches to context modeling might permit appreciable reductions in model complexity and computational cost, without sacrificing prediction accuracy. We formulate several alternative methods for context modeling based on windowed Bayesian networks, and compare their effects on both accuracy and computational complexity for the task of discriminating functionally distinct segments in vertebrate DNA. Our results show that substantial reductions in the complexity of both the model and the associated inference algorithm can be achieved without reducing predictive accuracy.

  3. An effective mesoscopic model of double-stranded DNA.

    PubMed

    Jeon, Jae-Hyung; Sung, Wokyung

    2014-01-01

    Watson and Crick's epochal presentation of the double helix structure in 1953 has paved the way to intense exploration of DNA's vital functions in cells. Also, recent advances of single molecule techniques have made it possible to probe structures and mechanics of constrained DNA at length scales ranging from nanometers to microns. There have been a number of atomistic scale quantum chemical calculations or molecular level simulations, but they are too computationally demanding or analytically unfeasible to describe the DNA conformation and mechanics at mesoscopic levels. At micron scales, on the other hand, the wormlike chain model has been very instrumental in describing analytically the DNA mechanics but lacks certain molecular details that are essential in describing the hybridization, nano-scale confinement, and local denaturation. To fill this fundamental gap, we present a workable and predictive mesoscopic model of double-stranded DNA where the nucleotides beads constitute the basic degrees of freedom. With the inter-strand stacking given by an interaction between diagonally opposed monomers, the model explains with analytical simplicity the helix formation and produces a generalized wormlike chain model with the concomitant large bending modulus given in terms of the helical structure and stiffness. It also explains how the helical conformation undergoes overstretch transition to the ladder-like conformation at a force plateau, in agreement with the experiment.

  4. 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.

  5. Analysis of a DNA simulation model through hairpin melting experiments

    PubMed Central

    Linak, Margaret C.; Dorfman, Kevin D.

    2010-01-01

    We compare the predictions of a two-bead Brownian dynamics simulation model to melting experiments of DNA hairpins with complementary AT or GC stems and noninteracting loops in buffer A. This system emphasizes the role of stacking and hydrogen bonding energies, which are characteristics of DNA, rather than backbone bending, stiffness, and excluded volume interactions, which are generic characteristics of semiflexible polymers. By comparing high throughput data on the open-close transition of various DNA hairpins to the corresponding simulation data, we (1) establish a suitable metric to compare the simulations to experiments, (2) find a conversion between the simulation and experimental temperatures, and (3) point out several limitations of the model, including the lack of G-quartets and cross stacking effects. Our approach and experimental data can be used to validate similar coarse-grained simulation models. PMID:20886965

  6. Formation of DNA-damaging N-nitroso compounds from the interaction of calcium-channel blockers with nitrite.

    PubMed

    Martelli, Antonietta; Robbiano, Luigi; Grossi, Sarah; Mattioli, Francesca; Brambilla, Giovanni

    2007-09-05

    A large number of drugs have been shown to react with nitrite to give genotoxic-carcinogenic N-nitroso compounds (NOC). However, the majority of drugs remain to be examined in this respect, among which calcium-channel blockers, all theoretically nitrosatable and widely used in the therapy of hypertension and other cardiovascular diseases. In this preliminary investigation, seven calcium-channel blockers have been examined either for their in vitro nitrosation according to the procedure recommended by the WHO, or for occurrence of liver DNA fragmentation, as detected by the Comet assay, in rats given by gavage 1/2 LD50 of the drug and 80 mg/kg of sodium nitrite. After 6h incubation the yields of NOC formed in vitro from nicardipine, nifedipine, nimodipine and nitrendipine ranged from 37 to 45% of the theoretical one, whereas the yields of NOC formed from diltiazem, gallopamil and verapamil ranged from 2 to 5%. In vivo, as compared with the effect of the same dose of the drug alone, a significant increase of both tail length and tail moment, indicative of an increased frequency of DNA single-strand breaks and alkali-labile sites, was produced in rat liver DNA by the administration with nitrite of gallopamil, nifedipine, nimodipine and nitrendipine, the ratio [tail length of drug+NaNO(2)/tail length of drug alone] being 3.2 for nimodipine, 3.1 for gallopamil 2.2 for nifedipine, and 2.1 for nitrendipine. Even if present, the increase in the degree of DNA fragmentation did not reach the statistical significance in rats given with nitrite nicardipine, diltiazem and verapamil. Further studies should be performed to investigate the formation of NOC in conditions simulating those occurring in the stomach of humans treated with a therapeutic dose, and to quantitate their genotoxic potency.

  7. DNA computation model to solve 0-1 programming problem.

    PubMed

    Zhang, Fengyue; Yin, Zhixiang; Liu, Bo; Xu, Jin

    2004-01-01

    0-1 programming problem is an important problem in opsearch with very widespread applications. In this paper, a new DNA computation model utilizing solution-based and surface-based methods is presented to solve the 0-1 programming problem. This model contains the major benefits of both solution-based and surface-based methods; including vast parallelism, extraordinary information density and ease of operation. The result, verified by biological experimentation, revealed the potential of DNA computation in solving complex programming problem.

  8. 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.

  9. Feruloylacetone as the model compound of half-curcumin: synthesis and antioxidant properties.

    PubMed

    Feng, Jian-Ying; Liu, Zai-Qun

    2011-04-01

    In order to clarify the contribution of phenolic and enolic hydroxyl group to the antioxidant capacity of feruloylacetone, a model compound of half-curcumin, 6-(p-hydroxy-m-methoxyphenyl)-5-hexene-2,4-dione (FT), 6-(p-benzyloxy-m-methoxyphenyl)-5-hexene-2,4-dione (BMFT), 6-(m,p-dihydroxyphenyl)-5-hexene-2,4-dione (DDFT), 6-(p-hydroxy-m-methoxyphenyl)hexane-2,4-dione (DHFT), 6-(p-hydroxy-m-methoxyphenyl)-5-hexene-2,4-diol (THFT), and ethyl 2-(p-hydroxy-m-methoxybenzylidene)-3-oxobutanoate (EOFT) were synthesized. The radical-scavenging abilities of these compounds were tested by trapping 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+·)), 2,2'-diphenyl-1-picrylhydrazyl (DPPH), and galvinoxyl radicals. The reductive capacities were screened by quenching singlet oxygen and by inhibiting the oxidation of linoleic acid. They were also employed to inhibit the oxidation of DNA mediated by hydroxyl radical and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH). In addition, they were applied to protect erythrocytes against AAPH- and hemin-induced hemolysis. The obtained results revealed that the antioxidant capacity of half-curcumin was derived from the phenolic-OH and the conjugated linkage between phenolic and enolic-OH. The enolic-OH itself cannot trap radicals. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  10. 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

  11. Effect of phenazine compounds XR11576 and XR5944 on DNA topoisomerases.

    PubMed

    Jobson, Andrew G; Willmore, Elaine; Tilby, Michael J; Mistry, Prakash; Charlton, Peter; Austin, Caroline A

    2009-04-01

    Previous in vitro cleavage data showed that XR11576 and XR5944 stabilised topoisomerase I and topoisomerase II complexes on DNA in a dose-dependent fashion. However, some studies indicated a possible topoisomerase-independent mechanism of action for these drugs. Three methods, the TARDIS assay, immunoband depletion and the K(+)/SDS assay have been used to assess topoisomerase complex formation induced by XR11576 or XR5944 in human leukaemic K562 cells. TARDIS and immunoband depletion assays demonstrated that XR11576 and XR5944 induced complex formation for both topoisomerase I and topoisomerase II (alpha and beta) in a dose- and time-dependent manner, following exposure times of 24 and 48 h at concentrations of 1 or 10 microM. The K(+)/SDS assay showed the formation of protein/DNA complexes after a 1 h exposure to 1 or 10 muM XR11576. Our data confirm that XR11576 or XR5944 can form topoisomerase complexes, after long periods of exposure.

  12. Drosophila Mcm10 Is Required for DNA Replication and Differentiation in the Compound Eye

    PubMed Central

    Vo, Nicole; Taga, Ayano; Inaba, Yasuhiro; Yoshida, Hideki; Cotterill, Sue; Yamaguchi, Masamitsu

    2014-01-01

    Mini chromosome maintenance 10 (Mcm10) is an essential protein, which is conserved from S. cerevisiae to Drosophila and human, and is required for the initiation of DNA replication. Knockdown of Drosophila Mcm10 (dMcm10) by RNA interference in eye imaginal discs induces abnormal eye morphology (rough eye phenotype), and the number of ommatidia is decreased in adult eyes. We also observed a delay in the S phase and M phase in eye discs of dMcm10 knockdown fly lines. These results show important roles for dMcm10 in the progression of S and M phases. Furthermore, genome damage and apoptosis were induced by dMcm10 knockdown in eye imaginal discs. Surprisingly, when we used deadpan-lacZ and klingon-lacZ enhancer trap lines to monitor the photoreceptor cells in eye discs, knockdown of dMcm10 by the GMR-GAL4 driver reduced the signals of R7 photoreceptor cells. These data suggest an involvement of dMcm10 in R7 cell differentiation. This involvement appears to be independent of the apoptosis induced by dMcm10 knockdown. Together, these results suggest that dMcm10 knockdown has an effect on DNA replication and R7 cell differentiation. PMID:24686397

  13. Drosophila Mcm10 is required for DNA replication and differentiation in the compound eye.

    PubMed

    Vo, Nicole; Taga, Ayano; Inaba, Yasuhiro; Yoshida, Hideki; Cotterill, Sue; Yamaguchi, Masamitsu

    2014-01-01

    Mini chromosome maintenance 10 (Mcm10) is an essential protein, which is conserved from S. cerevisiae to Drosophila and human, and is required for the initiation of DNA replication. Knockdown of Drosophila Mcm10 (dMcm10) by RNA interference in eye imaginal discs induces abnormal eye morphology (rough eye phenotype), and the number of ommatidia is decreased in adult eyes. We also observed a delay in the S phase and M phase in eye discs of dMcm10 knockdown fly lines. These results show important roles for dMcm10 in the progression of S and M phases. Furthermore, genome damage and apoptosis were induced by dMcm10 knockdown in eye imaginal discs. Surprisingly, when we used deadpan-lacZ and klingon-lacZ enhancer trap lines to monitor the photoreceptor cells in eye discs, knockdown of dMcm10 by the GMR-GAL4 driver reduced the signals of R7 photoreceptor cells. These data suggest an involvement of dMcm10 in R7 cell differentiation. This involvement appears to be independent of the apoptosis induced by dMcm10 knockdown. Together, these results suggest that dMcm10 knockdown has an effect on DNA replication and R7 cell differentiation.

  14. 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.

  15. DNA for crime investigation: European co-operation model.

    PubMed

    Fiodorova, Anna

    2014-01-01

    The article presents DNA related data exchange mechanism established within the framework of the European Union for the transnational crime investigation. First of all, it provides with the comprehensive overview of legal and practical state of play, pointing out that approved legal basis seeks to ensure legality and reliability in this area by establishing information exchange purposes and competent authorities involved, setting up technical requirements for the DNA analysis and DNA data bases, laying down provisions on accreditation of forensic service providers, foreseeing at least minimum common data protection requirements. Secondly, it reveals that despite being the most exhaustive international regulation on DNA related data exchange among law enforcement and judicial authorities it misses effective data protection mechanism, does not harmonize neither backgrounds for DNA collection in criminal process in general nor storage requirements and that results the variation in categories of subjects related to the crime investigation and included in data bases of different Member States. These gaps make the use of data collected and stored in another Member State vulnerable from the perspective of different rules on evidences' legality within the criminal process. The article also reveals the model's weakness in terms of assessment of its efficiency as statistics gathered for the time being show only number of coincidences (hits) of searched DNA profiles, but not the impact on crime investigation and its results.

  16. Sliding of Proteins Non-specifically Bound to DNA: Brownian Dynamics Studies with Coarse-Grained Protein and DNA Models

    PubMed Central

    Ando, Tadashi; Skolnick, Jeffrey

    2014-01-01

    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. PMID:25504215

  17. 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.

  18. 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

  19. Model steatogenic compounds (amiodarone, valproic acid, and tetracycline) alter lipid metabolism by different mechanisms in mouse liver slices.

    PubMed

    Szalowska, Ewa; van der Burg, Bart; Man, Hai-Yen; Hendriksen, Peter J M; Peijnenburg, Ad A C M

    2014-01-01

    Although drug induced steatosis represents a mild type of hepatotoxicity it can progress into more severe non-alcoholic steatohepatitis. Current models used for safety assessment in drug development and chemical risk assessment do not accurately predict steatosis in humans. Therefore, new models need to be developed to screen compounds for steatogenic properties. We have studied the usefulness of mouse precision-cut liver slices (PCLS) as an alternative to animal testing to gain more insight into the mechanisms involved in the steatogenesis. To this end, PCLS were incubated 24 h with the model steatogenic compounds: amiodarone (AMI), valproic acid (VA), and tetracycline (TET). Transcriptome analysis using DNA microarrays was used to identify genes and processes affected by these compounds. AMI and VA upregulated lipid metabolism, whereas processes associated with extracellular matrix remodelling and inflammation were downregulated. TET downregulated mitochondrial functions, lipid metabolism, and fibrosis. Furthermore, on the basis of the transcriptomics data it was hypothesized that all three compounds affect peroxisome proliferator activated-receptor (PPAR) signaling. Application of PPAR reporter assays classified AMI and VA as PPARγ and triple PPARα/(β/δ)/γ agonist, respectively, whereas TET had no effect on any of the PPARs. Some of the differentially expressed genes were considered as potential candidate biomarkers to identify PPAR agonists (i.e. AMI and VA) or compounds impairing mitochondrial functions (i.e. TET). Finally, comparison of our findings with publicly available transcriptomics data showed that a number of processes altered in the mouse PCLS was also affected in mouse livers and human primary hepatocytes exposed to known PPAR agonists. Thus mouse PCLS are a valuable model to identify early mechanisms of action of compounds altering lipid metabolism.

  20. Model Steatogenic Compounds (Amiodarone, Valproic Acid, and Tetracycline) Alter Lipid Metabolism by Different Mechanisms in Mouse Liver Slices

    PubMed Central

    Szalowska, Ewa; van der Burg, Bart; Man, Hai-Yen; Hendriksen, Peter J. M.; Peijnenburg, Ad A. C. M.

    2014-01-01

    Although drug induced steatosis represents a mild type of hepatotoxicity it can progress into more severe non-alcoholic steatohepatitis. Current models used for safety assessment in drug development and chemical risk assessment do not accurately predict steatosis in humans. Therefore, new models need to be developed to screen compounds for steatogenic properties. We have studied the usefulness of mouse precision-cut liver slices (PCLS) as an alternative to animal testing to gain more insight into the mechanisms involved in the steatogenesis. To this end, PCLS were incubated 24 h with the model steatogenic compounds: amiodarone (AMI), valproic acid (VA), and tetracycline (TET). Transcriptome analysis using DNA microarrays was used to identify genes and processes affected by these compounds. AMI and VA upregulated lipid metabolism, whereas processes associated with extracellular matrix remodelling and inflammation were downregulated. TET downregulated mitochondrial functions, lipid metabolism, and fibrosis. Furthermore, on the basis of the transcriptomics data it was hypothesized that all three compounds affect peroxisome proliferator activated-receptor (PPAR) signaling. Application of PPAR reporter assays classified AMI and VA as PPARγ and triple PPARα/(β/δ)/γ agonist, respectively, whereas TET had no effect on any of the PPARs. Some of the differentially expressed genes were considered as potential candidate biomarkers to identify PPAR agonists (i.e. AMI and VA) or compounds impairing mitochondrial functions (i.e. TET). Finally, comparison of our findings with publicly available transcriptomics data showed that a number of processes altered in the mouse PCLS was also affected in mouse livers and human primary hepatocytes exposed to known PPAR agonists. Thus mouse PCLS are a valuable model to identify early mechanisms of action of compounds altering lipid metabolism. PMID:24489787

  1. Base composition at mtDNA boundaries suggests a DNA triple helix model for human mitochondrial DNA large-scale rearrangements.

    PubMed

    Rocher, Christophe; Letellier, Thierry; Copeland, William C; Lestienne, Patrick

    2002-06-01

    Different mechanisms have been proposed to account for mitochondrial DNA (mtDNA) instability based on the presence of short homologous sequences (direct repeats, DR) at the potential boundaries of mtDNA rearrangements. Among them, slippage-mispairing of the replication complex during the asymmetric replication cycle of the mammalian mitochondrial DNA has been proposed to account for the preferential localization of deletions. This mechanism involves a transfer of the replication complex from the first neo-synthesized heavy (H) strand of the DR1, to the DR2, thus bypassing the intervening sequence and producing a deleted molecule. Nevertheless, the nature of the bonds between the DNA strands remains unknown as the forward sequence of DR2, beyond the replication complex, stays double-stranded. Here, we have analyzed the base composition of the DR at the boundaries of mtDNA deletions and duplications and found a skewed pyrimidine content of about 75% in the light-strand DNA template. This suggests the possible building of a DNA triple helix between the G-rich neo-synthesized DR1 and the base-paired homologous G.C-rich DR2. In vitro experiments with the purified human DNA polymerase gamma subunits enabled us to show that the third DNA strand may be used as a primer for DNA replication, using a template with the direct repeat forming a hairpin, with which the primer could initiate DNA replication. These data suggest a novel molecular basis for mitochondrial DNA rearrangements through the distributive nature of the DNA polymerase gamma, at the level of the direct repeats. A general model accounting for large-scale mitochondrial DNA deletion and duplication is proposed. These experiments extend to a DNA polymerase from an eucaryote source the use of a DNA triple helix strand as a primer, like other DNA polymerases from phage and bacterial origins.

  2. 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

  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. Spectroscopic and molecular modeling methods to study the interaction between naphthalimide-polyamine conjugates and DNA.

    PubMed

    Tian, Zhiyong; Huang, Yingying; Zhang, Yan; Song, Lina; Qiao, Yan; Xu, Xuejun; Wang, Chaojie

    2016-05-01

    The effect of polyamine side chains on the interaction between naphthalimide-polyamine conjugates (1-7) and herring sperm DNA was studied by UV/vis absorption and fluorescent spectra under physiological conditions (pH=7.4). The diverse spectral data and further molecular docking simulation in silico indicated that the aromatic moiety of these compounds could intercalate into the DNA base pairs while the polyamine motif might simultaneously locate in the minor groove. The triamine compound 7 can interact more potently with DNA than the corresponding diamine compounds (1-6). The presence of the bulky terminal group in the diamine side chain reduced the binding strength of compound 1 with DNA, compared to other diamine compounds (2-6). In addition, the increasing methylene number in the diamine backbone generally results in the elevated binding constant of compounds-DNA complex. The fluorescent tests at different temperature revealed that the quenching mechanism was a static type. The binding constant and thermodynamic parameter showed that the binding strength and the type of interaction force, associated with the side chains, were mainly hydrogen bonding and hydrophobic force. And the calculated free binding energies of molecular docking are generally consistent with the stability of polyamine-DNA complexes. The circular dichroism assay about the impact of compounds 1-7 on DNA conformation testified the B to A-like conformational change. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. 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

  6. 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.

  7. 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. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. In-silico screening for DNA-dependent protein kinase (DNA-PK) inhibitors: Combined homology modeling, docking, molecular dynamic study followed by biological investigation.

    PubMed

    Tarazi, Hamadeh; Saleh, Ekram; El-Awady, Raafat

    2016-10-01

    DNA-dependent protein kinase (DNA-PK) is a key enzyme in non-homologous DNA end joining (NHEJ) repair pathway. The targeted inhibition of such enzyme would furnish a valuable option for cancer treatment. In this study we report the development of validation of enzyme homology model, and the subsequent use of this model to perform docking-based virtual screening against a database of FDA-approved drugs. The nominated highest ranking hits (Praziquantel and Dutasteride) were subjected to biological investigation. Additionally, molecular dynamic study was carried-out for binding mode exploration. Results of the biological evaluation revealed that both compounds inhibit the DNA-PK enzymatic activity at relatively high concentration levels with an IC50 of 17.3μM for praziquantel and >20μM for dutasteride. Furthermore, both agents enhanced the anti-proliferative effects of doxorubicin and cisplatin on breast cancer (MCF7) and lung cancer (A549) cell lines. This result indicates that these two hits are good candidate as DNA-PK inhibitors and worth further structural modifications to enhance their enzyme inhibitory effects. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency.

    PubMed

    Tamura, Shinobu; Higuchi, Kohei; Tamaki, Masaharu; Inoue, Chizuko; Awazawa, Ryoko; Mitsuki, Noriko; Nakazawa, Yuka; Mishima, Hiroyuki; Takahashi, Kenzo; Kondo, Osamu; Imai, Kohsuke; Morio, Tomohiro; Ohara, Osamu; Ogi, Tomoo; Furukawa, Fukumi; Inoue, Masami; Yoshiura, Koh-ichiro; Kanazawa, Nobuo

    2015-10-01

    We herein describe a case of a 17-year-old boy with intractable common warts, short stature, microcephaly and slowly-progressing pancytopenia. Simultaneous quantification of T-cell receptor recombination excision circles (TREC) and immunoglobulin κ-deleting recombination excision circles (KREC) suggested very poor generation of both T-cells and B-cells. By whole exome sequencing, novel compound heterozygous mutations were identified in the patient's DNA ligase IV (LIG4) gene. The diagnosis of LIG4 syndrome was confirmed by delayed DNA double-strand break repair kinetics in γ-irradiated fibroblasts from the patient and their restoration by an introduction of wild-type LIG4. Although the patient received allogeneic hematopoietic stem cell transplantation from his haploidentical mother, he unfortunately expired due to an insufficiently reconstructed immune system. An earlier definitive diagnosis using TREC/KREC quantification and whole exome sequencing would thereby allow earlier intervention, which would be essential for improving long-term survival in similar cases with slowly-progressing LIG4 syndrome masked in adolescents.

  10. Predicting Variation of DNA Shape Preferences in Protein-DNA Interaction in Cancer Cells with a New Biophysical Model.

    PubMed

    Batmanov, Kirill; Wang, Junbai

    2017-09-18

    DNA shape readout is an important mechanism of transcription factor target site recognition, in addition to the sequence readout. Several machine learning-based models of transcription factor-DNA interactions, considering DNA shape features, have been developed in recent years. Here, we present a new biophysical model of protein-DNA interactions by integrating the DNA shape properties. It is based on the neighbor dinucleotide dependency model BayesPI2, where new parameters are restricted to a subspace spanned by the dinucleotide form of DNA shape features. This allows a biophysical interpretation of the new parameters as a position-dependent preference towards specific DNA shape features. Using the new model, we explore the variation of DNA shape preferences in several transcription factors across various cancer cell lines and cellular conditions. The results reveal that there are DNA shape variations at FOXA1 (Forkhead Box Protein A1) binding sites in steroid-treated MCF7 cells. The new biophysical model is useful for elucidating the finer details of transcription factor-DNA interaction, as well as for predicting cancer mutation effects in the future.

  11. New bimetallic dicyanidoargentate(I)-based coordination compounds: Synthesis, characterization, biological activities and DNA-BSA binding affinities

    NASA Astrophysics Data System (ADS)

    Korkmaz, Nesrin; Aydın, Ali; Karadağ, Ahmet; Yanar, Yusuf; Maaşoğlu, Yelis; Şahin, Ertan; Tekin, Şaban

    2017-02-01

    Four compounds -two (2 and 3) completely new- of composition [Ni(edbea)Ag3(CN)5] (1), [Cu(edbea)Ag2(CN)4]·H2O (2), [Cd(edbea)Ag3(CN)5]·H2O (3) and [Cd(edbea)2] [Ag(CN)2]2·H2O (4) {edbea; 2,2‧-(ethylenedioxy)bis (ethylamine)}, were synthesized and characterized using elemental, FT-IR, X-Ray (4), thermal, variable temperature magnetic measurement (1 and 2) and biological techniques. The DNA/BSA binding affinities of 2 and 3 were evaluated by UV-Vis spectrophotometric titrations, ethidium bromide exchange experiments and electrophoretic mobility measurements. Compounds 1 and 4 have previously been characterized and shown to reduce the proliferation and migration of tumor cells. For the sake of clarity, 1 precise mechanism of action on microbial organisms and temperature magnetic measurement were determined. The crystallographic analyses showed that 4 was built up of [Cd(edbea)2]II cations and [Ag2(CN)4]II anions. Complexes demonstrated a remarkable antibacterial (1-4), antifungal (1-4) and antiproliferative activities (2 and 3) to ten human bacterial pathogens, four plant pathogenic fungi or three tumor cells (HeLa, HT29, and C6), respectively. Therefore, our results strongly confirm that cell proliferation, cell morphology, Bcl-2, P53 changes and apoptosis can be related to the pharmacological effects of the complexes as suitable candidate for clinical trials.

  12. 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.

  13. 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

  14. Coarse-grained modeling of protein unspecifically bound to DNA

    NASA Astrophysics Data System (ADS)

    Guardiani, Carlo; Cencini, Massimo; Cecconi, Fabio

    2014-04-01

    There is now a certain consensus that transcription factors (TFs) reach their target sites, where they regulate gene transcription, via a mechanism dubbed facilitated diffusion (FD). In FD, the TF cycles between events of 3D diffusion in solution (jumps), 1D diffusion along DNA (sliding), and small jumps (hopping), achieving association rates higher than for 3D diffusion alone. We investigate the FD phenomenology through molecular dynamics simulations in the framework of coarse-grained modeling. We show that, despite the crude approximations, the model generates, upon varying the equilibrium distance of the DNA-TF interaction, a phenomenology matching a number of experimental and numerical results obtained with more refined models. In particular, focusing on the kinematics of the process, we characterize the geometrical properties of TF trajectories during sliding. We find that sliding occurs via helical paths around the DNA helix, leading to a coupling of translation along the DNA axis with rotation around it. The 1D diffusion constant measured in simulations is found to be interwoven with the geometrical properties of sliding and we develop a simple argument that can be used to quantitatively reproduce the measured values.

  15. An unenumerative DNA computing model for vertex coloring problem.

    PubMed

    Xu, Jin; Qiang, Xiaoli; Yang, Yan; Wang, Baoju; Yang, Dongliang; Luo, Liang; Pan, Linqiang; Wang, Shudong

    2011-06-01

    The solution space exponential explosion caused by the enumeration of the candidate solutions maybe is the biggest obstacle in DNA computing. In the paper, a new unenumerative DNA computing model for graph vertex coloring problem is presented based on two techniques: 1) ordering the vertex sequence for a given graph in such a way that any two consecutive labeled vertices i and i+1 should be adjacent in the graph as much as possible; 2) reducing the number of encodings representing colors according to the construture of the given graph. A graph with 12 vertices without triangles is solved and its initial solution space includes only 283 DNA strands, which is 0.0532 of 3(12) (the worst complexity).

  16. 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.

  17. 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

  18. Characterization of initial cure reactions in propargyl and nadic end capped model compounds

    NASA Technical Reports Server (NTRS)

    Young, P. R.

    1981-01-01

    Imide model compounds containing propargyl and nadic groups were studied to obtain a fundamental understanding of the reaction of these groups attached to imide oligomers. The initial cure reactions were examined by a variety of characterization techniques including high pressure liquid chromatography, infrared spectroscopy, thermal analyses, and mass spectroscopy. The initial step in the cure of propargyl end capped model compounds probably involved the formation of a new terminal acetylenic group. Configurational changes involving endo/exo isomerism was found in the nadimide model compounds. Nadimide compounds heated in air and in nitrogen appeared to cure by different mechanisms.

  19. Nitrite curing of chicken, pork, and beef inhibits oxidation but does not affect N-nitroso compound (NOC)-specific DNA adduct formation during in vitro digestion.

    PubMed

    Van Hecke, Thomas; Vanden Bussche, Julie; Vanhaecke, Lynn; Vossen, Els; Van Camp, John; De Smet, Stefaan

    2014-02-26

    Uncured and nitrite-cured chicken, pork, and beef were used as low, medium, and high sources of heme-Fe, respectively, and exposed to an in vitro digestion model simulating the mouth, stomach, duodenum, and colon. With increasing content of iron compounds, up to 25-fold higher concentrations of the toxic lipid oxidation products malondialdehyde, 4-hydroxy-2-nonenal, and other volatile aldehydes were formed during digestion, together with increased protein carbonyl compounds as measurement of protein oxidation. Nitrite curing of all meats lowered lipid and protein oxidation to the level of oxidation in uncured chicken. Strongly depending on the individual fecal inoculum, colonic digestion of beef resulted in significantly higher concentrations of the NOC-specific DNA adduct O(6)-carboxymethyl-guanine compared to chicken and pork, whereas nitrite curing had no significant effect. This study confirms previously reported evidence that heme-Fe is involved in the epidemiological association between red meat consumption and colorectal cancer, but questions the role of nitrite curing in this association.

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

    NASA Astrophysics Data System (ADS)

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

    2016-09-01

    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.

  1. Model identification for DNA sequence-structure relationships.

    PubMed

    Hawley, Stephen Dwyer; Chiu, Anita; Chizeck, Howard Jay

    2006-11-01

    We investigate the use of algebraic state-space models for the sequence dependent properties of DNA. By considering the DNA sequence as an input signal, rather than using an all atom physical model, computational efficiency is achieved. A challenge in deriving this type of model is obtaining its structure and estimating its parameters. Here we present two candidate model structures for the sequence dependent structural property Slide and a method of encoding the models so that a recursive least squares algorithm can be applied for parameter estimation. These models are based on the assumption that the value of Slide at a base-step is determined by the surrounding tetranucleotide sequence. The first model takes the four bases individually as inputs and has a median root mean square deviation of 0.90 A. The second model takes the four bases pairwise and has a median root mean square deviation of 0.88 A. These values indicate that the accuracy of these models is within the useful range for structure prediction. Performance is comparable to published predictions of a more physically derived model, at significantly less computational cost.

  2. Probabilistic models for semisupervised discriminative motif discovery in DNA sequences.

    PubMed

    Kim, Jong Kyoung; Choi, Seungjin

    2011-01-01

    Methods for discriminative motif discovery in DNA sequences identify transcription factor binding sites (TFBSs), searching only for patterns that differentiate two sets (positive and negative sets) of sequences. On one hand, discriminative methods increase the sensitivity and specificity of motif discovery, compared to generative models. On the other hand, generative models can easily exploit unlabeled sequences to better detect functional motifs when labeled training samples are limited. In this paper, we develop a hybrid generative/discriminative model which enables us to make use of unlabeled sequences in the framework of discriminative motif discovery, leading to semisupervised discriminative motif discovery. Numerical experiments on yeast ChIP-chip data for discovering DNA motifs demonstrate that the best performance is obtained between the purely-generative and the purely-discriminative and the semisupervised learning improves the performance when labeled sequences are limited.

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

    PubMed Central

    Vorberg, Susann

    2013-01-01

    Abstract 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. PMID:27485201

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

    USDA-ARS?s Scientific Manuscript database

    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...

  5. 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...

  6. Modeling emissions of volatile organic compounds from silage

    USDA-ARS?s Scientific Manuscript database

    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. 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

  9. 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.

  10. 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

  11. 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

  12. 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…

  13. 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…

  14. Structural studies of O6-methyldeoxyguanosine and related compounds: a promutagenic DNA lesion by methylating carcinogens.

    PubMed Central

    Yamagata, Y; Kohda, K; Tomita, K

    1988-01-01

    O6-Methylation of guanine residues in DNA can induce mutations by formation of base mispairing due to the deprotonation of N(1). The electronic, geometric and conformational properties of three N(9)-Substituted O6-methylguanine derivatives, O6-methyldeoxyguanosine (O6mdGuo), O6-methylguanosine (O6mGuo) and O6, 9-dimethylguanine (O6mdGua), were investigated by X-ray and/or NMR studies. O6mdGuo crystallizes in the monoclinic space group P2(1) with cell parameters a = 5.267(1), b = 19.109(2), c = 12.330(2) A, beta = 92.45(1) degrees, V = 1239.8(3) A3, z = 4 (two nucleosides per asymmetric unit), and O6mGua in the monoclinic space group P2(1)/n with cell parameters a = 10.729(2), b = 7.640(1) c = 10.216(1) A, beta = 92.17(2) degrees, V = 836.7(2) A3, z = 4. The geometry and conformation of O6-methylguanine moieties observed in both crystals and are very similar. Furthermore, the molecular dimensions of the O6methylguanine residue resemble more closely those of adenine than those of guanine. The methoxy group is coplanar with the purine ring, the methyl group being cis to N(1). The conformation of O6-methylguanine nucleosides is variable. The glycosidic conformation of O6mdGuo is anti for molecule (a) and high-anti for molecule (b) in the crystal, while that of O6mGuo is syn [Parthasarathy, R & Fridey, S. M. (1986) Carcinogenesis 7, 221-227]. The sugar ring pucker of O6mdGuo is C(2')-endo for molecule (a) and C(1')-exo for molecule (b). The C(4')-C(5') exocyclic bond conformation in O6mdGuo is gauche- for molecule (a) but trans for molecule (b), in contrast with gauche+ for O6mGuo. The hydrogen bonds exhibited by O6-methylguanine derivatives differ from those in guanine derivatives; the amino N(2) and ring N(3) and N(7) atoms of O6-methylguanine residues are involved in hydrogen bonding. 1H-NMR data for O6mdGuo and O6mdGuo reveal the predominance of a C(2')-endo type sugar puckering. In O6mdGuo, however, a contribution of a C(1')-exo sugar puckering is significant. The

  15. Biomolecular dynamics of DNA: statistical mechanics and dynamical models

    NASA Astrophysics Data System (ADS)

    Peyrard, M.; Dauxois, T.; Hoyet, H.; Willis, C. R.

    1993-09-01

    There is a growing feeling that biomolecular structure is not sufficient to determine biological activity which is also governed by large amplitude dynamics of the molecules. The transcription of DNA or its thermal denaturation are typical examples. Traditional approaches use Ising models to describe the denaturation transition of DNA. They have to introduce phenomenological “cooperativity factors” to explain the rather sharp “melting” of this quasi one-dimensional system. We present models which describe the full dynamics of the melting. Using molecular dynamics simulations and statistical analysis, we discuss the mechanism of the denaturation, including precursor effects that can be related to large amplitude localized nonlinear excitations of the molecule in which discreteness effects play a large role. We also show the microscopic origin of the cooperativity factors.

  16. Molecular modeling of closed circular DNA thermodynamic ensembles.

    PubMed

    Sprous, D; Tan, R K; Harvey, S C

    1996-08-01

    Many modeling studies of supercoiled DNA are based on equilibrium structures from theoretical calculations or energy minimization. Since closed circular DNAs are flexible, it is possible that errors are introduced by calculating properties from a single minimum energy structure, rather than from a complete thermodynamic ensemble. We have investigated this question using molecular dynamics simulations on a low resolution molecular mechanics model in which each base pair is represented by three points (a plane). This allows the inclusion of sequence-dependent variations of tip, inclination, and twist. Three kinds of sequences were tested: (1) homogeneous DNA, in which all base pairs have the helicoidal parameters of an ideal, average B-DNA; (2) random sequence DNA; and (3) curved DNA. We examined the rate of convergence of various structural parameters. Convergence for most of these is slowest for homogeneous sequences, more rapid for random sequences, and most rapid for curved sequences. The most slowly converging parameter is the antipodes profile. In a plasmid with N base pairs (bp), the antipodes distance is the distance dij from base pair i to base pair j halfway around the plasmid, j = i + N/2. The antipodes profile at time tau is a plot of dij over the range i = 1, N/2. In a homogeneous plasmid, convergence requires that the antipodes profile averaged over time must be flat. Even in the small plasmids examined here, the average properties of the ensembles were found to differ from those of static equilibrium structures. These effects will be even more dramatic for larger plasmids. Further, average and dynamic properties are affected by both plasmid size and sequence.

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

    DOE PAGES

    Merrill, Devin R.; Moore, Daniel B.; Bauers, Sage R.; ...

    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

  18. 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.

  19. Misfit Layer Compounds and Ferecrystals: Model Systems for Thermoelectric Nanocomposites

    PubMed Central

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

    2015-01-01

    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. PMID:28788045

  20. 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

  1. A Kronig-Penney Model of Salts of DNA

    PubMed Central

    Rosen, Philip

    1968-01-01

    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 20π electrons per unit cell are calculated and exhibited in Table I. PMID:5643271

  2. 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.

  3. 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. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

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

    PubMed Central

    Fayzullina, Saniya

    2016-01-01

    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

  5. 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.

  6. Altered DNA Binding and Amplification of Human Breast Cancer Suppressor Gene BRCA1 Induced by a Novel Antitumor Compound, [Ru(η6-p-phenylethacrynate)Cl2(pta)

    PubMed Central

    Chakree, Korawan; Ovatlarnporn, Chitchamai; Dyson, Paul J.; Ratanaphan, Adisorn

    2012-01-01

    The ruthenium-based complex [Ru(η6-p-phenylethacrynate)Cl2(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane), termed ethaRAPTA, is an interesting antitumor compound. The elucidation of the molecular mechanism of drug activity is central to the drug development program. To this end, we have characterized the ethaRAPTA interaction with DNA, including probing the sequence specific modified DNA structural stability and DNA amplification using the breast cancer suppressor gene 1 (BRCA1) of human breast and colon adenocarcinoma cell lines as models. The preference of ethaRAPTA base binding is in the order A > G > T > C. Once modified, the ethaRAPTA-induced BRCA1 structure has higher thermal stability than the modified equivalents of its related compound, RAPTA-C. EthaRAPTA exhibits a higher efficiency than RAPTA-C in inhibiting BRCA1 amplification. With respect to both compounds, the inhibition of BRCA1 amplification is more effective in an isolated system than in cell lines. These data provide evidence that will help to understand the process of elucidating the pathways involved in the response induced by ethaRAPTA. PMID:23202946

  7. SCID mice containing muscle with human mitochondrial DNA mutations. An animal model for mitochondrial DNA defects.

    PubMed Central

    Clark, K M; Watt, D J; Lightowlers, R N; Johnson, M A; Relvas, J B; Taanman, J W; Turnbull, D M

    1998-01-01

    Defects of the mitochondrial genome are important causes of disease. Despite major advances in our investigation of patients, there is no effective therapy. Progress in this area is limited by the absence of any animal models in which we can evaluate treatment. To develop such a model we have injected human myoblasts into the tibialis anterior of SCID mice after inducing necrosis. After injection of normal human myoblasts, regenerating fibers expressed human beta-spectrin, confirming they were derived from fusion of human myoblasts. The stability of the muscle fibers was inferred by demonstrating the formation of motor end plates on the regenerating fibers. In addition, we show the presence of human cytochrome c oxidase subunit II, which is encoded by the mitochondrial genome, in the regenerated fibers. After injection of human myoblasts containing either the A8344G or the T8993C heteroplasmic mitochondrial DNA mutations, human beta-spectrin positive fibers were found to contain the mutation at a similar level to the injected myoblasts. These studies highlight the potential value of this model for the study of mitochondrial DNA defects. PMID:9854044

  8. Structural modeling for DNA binding to antioxidants resveratrol, genistein and curcumin.

    PubMed

    N'soukpoé-Kossi, C N; Bourassa, P; Mandeville, J S; Bekale, L; Tajmir-Riahi, H A

    2015-10-01

    Several models are presented here for the bindings of the antioxidant polyphenols resveratrol, genistein and curcumin with DNA in aqueous solution at physiological conditions. Multiple spectroscopic methods and molecular modeling were used to locate the binding sites of these polyphenols with DNA duplex. Structural models showed that intercalation is more stable for resveratrol and genistein than groove bindings, while curcumin interaction is via DNA grooves. Docking showed more stable complexes formed with resveratrol and genistein than curcumin with the free binding energies of -4.62 for resveratrol-DNA (intercalation), -4.28 for resveratrol-DNA (groove binding), -4.54 for genistein-DNA (intercalation), -4.38 for genistein-DNA (groove binding) and -3.84 kcal/mol for curcumin-DNA (groove binding). The free binding energies show polyphenol-DNA complexation is spontaneous at room temperature. At high polyphenol concentration a major DNA aggregation occurred, while biopolymer remained in B-family structure.

  9. 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

  10. 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.

  11. 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)

  12. 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)

  13. Molecular docking of the anticancer bioactive compound proceraside with macromolecules involved in the cell cycle and DNA replication.

    PubMed

    Gurung, A B; Ali, M A; Bhattacharjee, A; AbulFarah, M; Al-Hemaid, F; Abou-Tarboush, F M; Al-Anazi, K M; Al-Anazi, F S M; Lee, J

    2016-05-09

    The bioactive compounds proceraside A, frugoside and calotropin, which were extracted from the root bark of Calotropis procera (Aiton) W.T. Aiton (family Asclepiadaceae), were recently reported to inhibit the growth of inhibition against various human cancer cell lines in vitro. However, their modes of action have not been clearly defined. Therefore, we attempted an in silico approach to gain insights into their binding modes against the following selected molecular targets: CDK-2, CDK-6, topoisomerase I, BCL-2, VEGFR-2, telomere: G-quadruplex, and topoisomerase II. These targets were selected based on their key roles in cancer progression via the regulation of the cell cycle and DNA replication. Molecular-docking analyses revealed that proceraside A was the best docked ligand against all the targets, with the exception of telomere-G: quadruplex. Furthermore, it displayed the lowest binding energies and inhibition constants, and critical hydrogen bonds and hydrophobic interactions with the targets were also revealed. The present study may aid in the identification of possible targets for proceraside A, and might provide a plausible explanation for its proven anti-tumor activities. Moreover, the result of this study may further guide structure-activity relationship studies used to generate more potent target-specific inhibitors.

  14. Reference-based gene model prediction on DNA contigs

    SciTech Connect

    Xu, Y.; Uberbacher, E.C.

    1997-01-01

    This paper presents an algorithm for constructing multiple gene models on a set of contigs of a large genomic clone. The algorithm first uses pattern recognition-based methods to locate exons or partial exons in each contig, and then applies protein homology or EST information from the databases, as reference models, to parse the predicted exons into gene models. In the phase of gene model construction, the algorithm uses a unified framework for genes ranging from situation with homologous proteins/ESTs to no homologous protein/EST in the database. By exploiting protein homology or EST information, the algorithm is able to (1) parse exons into multiple gene models over a set of DNA contigs (possibly unoriented and unordered); (2) remove falsely predicted exons; and (3) identify and locate exons missed by the initial exon prediction.

  15. Insects as innovative models for functional studies of DNA methylation.

    PubMed

    Lyko, Frank; Maleszka, Ryszard

    2011-04-01

    The emerging field of epigenomics has the potential to bridge the gap between static genomic sequences and complex phenotypes that arise from multigenic, nonlinear and often context-dependent interactions. However, this goal can only be achieved if easily manageable experimental systems are available in which changes in epigenomic settings can be evaluated in the context of the phenotype under investigation. Recent progress in the characterization of insect DNA methylation patterns enables evaluation of the extent to which epigenetic mechanisms contribute to complex phenotypes in easily accessible organisms whose relatively small genomes are not only sparingly methylated, but the methylated sites are also found almost exclusively in gene bodies. The implementation of insect models in the study of DNA methylation will accelerate progress in understanding the functional significance of this important epigenetic mechanism in controlling gene splicing, in environmentally driven reprogramming of gene expression and in adult brain plasticity. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Model for the distributions of k -mers in DNA sequences

    NASA Astrophysics Data System (ADS)

    Chen, Yaw-Hwang; Nyeo, Su-Long; Yeh, Chiung-Yuh

    2005-07-01

    The evolutionary features based on the distributions of k -mers in the DNA sequences of various organisms are studied. The organisms are classified into three groups based on their evolutionary periods: (a) E. coli and T. pallidum (b) yeast, zebrafish, A. thaliana, and fruit fly, (c) mouse, chicken, and human. The distributions of 6-mers of these three groups are shown to be, respectively, (a) unimodal, (b) unimodal with peaks generally shifted to smaller frequencies of occurrence, (c) bimodal. To describe the bimodal feature of the k -mer distributions of group (c), a model based on the cytosine-guanine “ CG ” content of the DNA sequences is introduced and shown to provide reasonably good agreements.

  17. Aggregation of asphaltene model compounds using a porphyrin tethered to a carboxylic acid.

    PubMed

    Schulze, Matthias; Lechner, Marc P; Stryker, Jeffrey M; Tykwinski, Rik R

    2015-07-07

    A Ni(II) porphyrin functionalized with an alkyl carboxylic acid (3) has been synthesized to model the chemical behavior of the heaviest portion of petroleum, the asphaltenes. Specifically, porphyrin 3 is used in spectroscopic studies to probe aggregation with a second asphaltene model compound containing basic nitrogen (4), designed to mimic asphaltene behavior. NMR spectroscopy documents self-association of the porphyrin and aggregation with the second model compound in solution, and a Job's plot suggests a 1 : 2 stoichiometry for compounds 3 and 4.

  18. 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...

  19. 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.

  20. 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...

  1. Clusters of DNA damage induced by ionizing radiation: Formation of short DNA fragments. I. Theoretical modeling

    SciTech Connect

    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 composed 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 {circ}OH, {circ}H, e{sub aq}, etc.; {circ}OH attack on sugar molecules leading to strand breaks; {circ}OH attack on bases; direct ionization of the sugar molecules leading to strand breaks; direct ionization of the bases. Our calculations predict significant clustering of damage both locally, over regions up to 40 hp 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. Such fragments have subsequently been detected experimentally and are reported in an accompanying paper 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 chromatin fibers in mammalian DNA. 27 refs., 7 figs.

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

    PubMed Central

    Kumar, Rajendra; Grubmüller, Helmut

    2016-01-01

    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

  3. 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. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Solute transport model for trace organic neutral and charged compounds through nanofiltration and reverse osmosis membranes.

    PubMed

    Kim, Tae-Uk; Drewes, Jörg E; Scott Summers, R; Amy, Gary L

    2007-09-01

    Rejection of trace organic compounds, including disinfection by-products (DBPs) and pharmaceutical active compounds (PhACs), by high-pressure membranes has become a focus of public interest internationally in both drinking water treatment and wastewater reclamation/reuse. The ability to simulate, or even predict, the rejection of these compounds by high-pressure membranes, encompassing nanofiltration (NF) and reverse osmosis (RO), will improve process economics and expand membrane applications. The objective of this research is to develop a membrane transport model to account for diffusive and convective contributions to solute transport and rejection. After completion of cross-flow tests and diffusion cell tests with target compounds, modeling efforts were performed in accordance with a non-equilibrium thermodynamic transport equation. Comparing the percentages of convection and diffusion contributions to transport, convection is dominant for most compounds, but diffusion is important for more hydrophobic non-polar compounds. Convection is also more dominant for looser membranes (i.e., NF). In addition, higher initial compound concentrations and greater J(0)/k ratios contribute to solute fluxes more dominated by convection. Given the treatment objective of compound rejection, compound transport and rejection trends are inversely related.

  5. Development of Novel Repellents Using Structure - Activity Modeling of Compounds in the USDA Archival Database

    DTIC Science & Technology

    2011-01-01

    used in efforts to develop QSAR models. Measurement of Repellent Efficacy Screening for Repellency of Compounds with Unknown Toxicology In screening...CPT) were used to develop Quantitative Structure Activity Relationship ( QSAR ) models to predict repellency. Successful prediction of novel...acylpiperidine QSAR models employed 4 descriptors to describe the relationship between structure and repellent duration. The ANN model of the carboxamides did not

  6. A sequence-dependent rigid-base model of DNA

    NASA Astrophysics Data System (ADS)

    Gonzalez, O.; Petkevičiutė, D.; Maddocks, J. H.

    2013-02-01

    A novel hierarchy of coarse-grain, sequence-dependent, rigid-base models of B-form DNA in solution is introduced. The hierarchy depends on both the assumed range of energetic couplings, and the extent of sequence dependence of the model parameters. A significant feature of the models is that they exhibit the phenomenon of frustration: each base cannot simultaneously minimize the energy of all of its interactions. As a consequence, an arbitrary DNA oligomer has an intrinsic or pre-existing stress, with the level of this frustration dependent on the particular sequence of the oligomer. Attention is focussed on the particular model in the hierarchy that has nearest-neighbor interactions and dimer sequence dependence of the model parameters. For a Gaussian version of this model, a complete coarse-grain parameter set is estimated. The parameterized model allows, for an oligomer of arbitrary length and sequence, a simple and explicit construction of an approximation to the configuration-space equilibrium probability density function for the oligomer in solution. The training set leading to the coarse-grain parameter set is itself extracted from a recent and extensive database of a large number of independent, atomic-resolution molecular dynamics (MD) simulations of short DNA oligomers immersed in explicit solvent. The Kullback-Leibler divergence between probability density functions is used to make several quantitative assessments of our nearest-neighbor, dimer-dependent model, which is compared against others in the hierarchy to assess various assumptions pertaining both to the locality of the energetic couplings and to the level of sequence dependence of its parameters. It is also compared directly against all-atom MD simulation to assess its predictive capabilities. The results show that the nearest-neighbor, dimer-dependent model can successfully resolve sequence effects both within and between oligomers. For example, due to the presence of frustration, the model can

  7. 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

  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. Modelling DNA origami self-assembly at the domain level

    NASA Astrophysics Data System (ADS)

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

    2015-10-01

    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.

  10. 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

  11. Homology modeling of NAD+-dependent DNA ligase of the Wolbachia endosymbiont of Brugia malayi and its drug target potential using dispiro-cycloalkanones.

    PubMed

    Shrivastava, Nidhi; Nag, Jeetendra K; Pandey, Jyoti; Tripathi, Rama Pati; Shah, Priyanka; Siddiqi, Mohammad Imran; Misra-Bhattacharya, Shailja

    2015-07-01

    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.

  12. 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.

  13. 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.

  14. Model-based prediction of human hair color using DNA variants.

    PubMed

    Branicki, Wojciech; Liu, Fan; van Duijn, Kate; Draus-Barini, Jolanta; Pośpiech, Ewelina; Walsh, Susan; Kupiec, Tomasz; Wojas-Pelc, Anna; Kayser, Manfred

    2011-04-01

    Predicting complex human phenotypes from genotypes is the central concept of widely advocated personalized medicine, but so far has rarely led to high accuracies limiting practical applications. One notable exception, although less relevant for medical but important for forensic purposes, is human eye color, for which it has been recently demonstrated that highly accurate prediction is feasible from a small number of DNA variants. Here, we demonstrate that human hair color is predictable from DNA variants with similarly high accuracies. We analyzed in Polish Europeans with single-observer hair color grading 45 single nucleotide polymorphisms (SNPs) from 12 genes previously associated with human hair color variation. We found that a model based on a subset of 13 single or compound genetic markers from 11 genes predicted red hair color with over 0.9, black hair color with almost 0.9, as well as blond, and brown hair color with over 0.8 prevalence-adjusted accuracy expressed by the area under the receiver characteristic operating curves (AUC). The identified genetic predictors also differentiate reasonably well between similar hair colors, such as between red and blond-red, as well as between blond and dark-blond, highlighting the value of the identified DNA variants for accurate hair color prediction.

  15. 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.

  16. 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...

  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. 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...

  19. 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...

  20. A Temperature-Dependent Hysteresis Model for Relaxor Ferroelectric Compounds

    DTIC Science & Technology

    2004-01-01

    PMN-driven flextensional sonar transducer submersed in water experiences a temperature increase of approximately 40oC before equilibrium is reached [9...nonlinearities materials 1. Introduction Transducers employing relaxor ferroelectric materials are increasingly considered for applications ranging from...facilitates subsequent transducer design and model-based control implementation. A number of the initial models for the relaxor ferroelectric

  1. Near-atomic structural model for bacterial DNA replication initiation complex and its functional insights.

    PubMed

    Shimizu, Masahiro; Noguchi, Yasunori; Sakiyama, Yukari; Kawakami, Hironori; Katayama, Tsutomu; Takada, Shoji

    2016-12-13

    Upon DNA replication initiation in Escherichia coli, the initiator protein DnaA forms higher-order complexes with the chromosomal origin oriC and a DNA-bending protein IHF. Although tertiary structures of DnaA and IHF have previously been elucidated, dynamic structures of oriC-DnaA-IHF complexes remain unknown. Here, combining computer simulations with biochemical assays, we obtained models at almost-atomic resolution for the central part of the oriC-DnaA-IHF complex. This complex can be divided into three subcomplexes; the left and right subcomplexes include pentameric DnaA bound in a head-to-tail manner and the middle subcomplex contains only a single DnaA. In the left and right subcomplexes, DnaA ATPases associated with various cellular activities (AAA+) domain III formed helices with specific structural differences in interdomain orientations, provoking a bend in the bound DNA. In the left subcomplex a continuous DnaA chain exists, including insertion of IHF into the DNA looping, consistent with the DNA unwinding function of the complex. The intervening spaces in those subcomplexes are crucial for DNA unwinding and loading of DnaB helicases. Taken together, this model provides a reasonable near-atomic level structural solution of the initiation complex, including the dynamic conformations and spatial arrangements of DnaA subcomplexes.

  2. Crystal structure of the adenovirus DNA binding protein reveals a hook-on model for cooperative DNA binding.

    PubMed Central

    Tucker, P A; Tsernoglou, D; Tucker, A D; Coenjaerts, F E; Leenders, H; van der Vliet, P C

    1994-01-01

    The adenovirus single-stranded DNA binding protein (Ad DBP) is a multifunctional protein required, amongst other things, for DNA replication and transcription control. It binds to single- and double-stranded DNA, as well as to RNA, in a sequence-independent manner. Like other single-stranded DNA binding proteins, it binds ssDNA, cooperatively. We report the crystal structure, at 2.6 A resolution, of the nucleic acid binding domain. This domain is active in DNA replication. The protein contains two zinc atoms in different, novel coordinations. The zinc atoms appear to be required for the stability of the protein fold rather than being involved in direct contacts with the DNA. The crystal structure shows that the protein contains a 17 amino acid C-terminal extension which hooks onto a second molecule, thereby forming a protein chain. Deletion of this C-terminal arm reduces cooperativity in DNA binding, suggesting a hook-on model for cooperativity. Based on this structural work and mutant studies, we propose that DBP forms a protein core around which the single-stranded DNA winds. Images PMID:8039495

  3. DNA methylation in an engineered heart tissue model of cardiac hypertrophy: common signatures and effects of DNA methylation inhibitors.

    PubMed

    Stenzig, Justus; Hirt, Marc N; Löser, Alexandra; Bartholdt, Lena M; Hensel, Jan-Tobias; Werner, Tessa R; Riemenschneider, Mona; Indenbirken, Daniela; Guenther, Thomas; Müller, Christian; Hübner, Norbert; Stoll, Monika; Eschenhagen, Thomas

    2016-01-01

    DNA methylation affects transcriptional regulation and constitutes a drug target in cancer biology. In cardiac hypertrophy, DNA methylation may control the fetal gene program. We therefore investigated DNA methylation signatures and their dynamics in an in vitro model of cardiac hypertrophy based on engineered heart tissue (EHT). We exposed EHTs from neonatal rat cardiomyocytes to a 12-fold increased afterload (AE) or to phenylephrine (PE 20 µM) and compared DNA methylation signatures to control EHT by pull-down assay and DNA methylation microarray. A 7-day intervention sufficed to induce contractile dysfunction and significantly decrease promoter methylation of hypertrophy-associated upregulated genes such as Nppa (encoding ANP) and Acta1 (α-skeletal actin) in both intervention groups. To evaluate whether pathological consequences of AE are affected by inhibiting de novo DNA methylation we applied AE in the absence and presence of DNA methyltransferase (DNMT) inhibitors: 5-aza-2'-deoxycytidine (aza, 100 µM, nucleosidic inhibitor), RG108 (60 µM, non-nucleosidic) or methylene disalicylic acid (MDSA, 25 µM, non-nucleosidic). Aza had no effect on EHT function, but RG108 and MDSA partially prevented the detrimental consequences of AE on force, contraction and relaxation velocity. RG108 reduced AE-induced Atp2a2 (SERCA2a) promoter methylation. The results provide evidence for dynamic DNA methylation in cardiac hypertrophy and warrant further investigation of the potential of DNA methylation in the treatment of cardiac hypertrophy.

  4. Evidence for a transition state model compound of in-plane vinylic SN2 reaction.

    PubMed

    Yamaguchi, Torahiko; Yamamoto, Yohsuke; Fujiwara, Yoshihisa; Tanimoto, Yoshifumi

    2005-06-23

    [reaction: see text] To isolate a transition state model compound of an in-plane vinylic S(N)2 reaction, vinyl bromide 6 bearing a newly synthesized tridentate ligand derived from 1,8-dimethoxythioxanthen-9-one (5) was prepared as a precursor. Although irradiation of 6 gave demethylated benzofuran 12, a transient broad peak which indicates formation of the desired transition state model compound was observed in the laser flash photolytic study.

  5. 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.

  6. 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. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. 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

  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. Speciation of volatile organic compound emissions for regional air quality modeling of particulate matter and ozone

    NASA Astrophysics Data System (ADS)

    Makar, P. A.; Moran, M. D.; Scholtz, M. T.; Taylor, A.

    2003-01-01

    A new classification scheme for the speciation of organic compound emissions for use in air quality models is described. The scheme uses 81 organic compound classes to preserve both net gas-phase reactivity and particulate matter (PM) formation potential. Chemical structure, vapor pressure, hydroxyl radical (OH) reactivity, freezing point/boiling point, and solubility data were used to create the 81 compound classes. Volatile, semivolatile, and nonvolatile organic compounds are included. The new classification scheme has been used in conjunction with the Canadian Emissions Processing System (CEPS) to process 1990 gas-phase and particle-phase organic compound emissions data for summer and winter conditions for a domain covering much of eastern North America. A simple postprocessing model was used to analyze the speciated organic emissions in terms of both gas-phase reactivity and potential to form organic PM. Previously unresolved compound classes that may have a significant impact on ozone formation include biogenic high-reactivity esters and internal C6-8 alkene-alcohols and anthropogenic ethanol and propanol. Organic radical production associated with anthropogenic organic compound emissions may be 1 or more orders of magnitude more important than biogenic-associated production in northern United States and Canadian cities, and a factor of 3 more important in southern U.S. cities. Previously unresolved organic compound classes such as low vapour pressure PAHs, anthropogenic diacids, dialkyl phthalates, and high carbon number alkanes may have a significant impact on organic particle formation. Primary organic particles (poorly characterized in national emissions databases) dominate total organic particle concentrations, followed by secondary formation and primary gas-particle partitioning. The influence of the assumed initial aerosol water concentration on subsequent thermodynamic calculations suggests that hydrophobic and hydrophilic compounds may form external

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

    PubMed Central

    Faria, Isabel R.; Young, Thomas M.

    2011-01-01

    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 multi-solute model), widely used in the prediction of multi-solute sorption equilibrium from single solute data were used to simulate competitive sorption in our systems. The goal was to determine which multi-solute model best represented the experimentally obtained multi-solute 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 towards 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). PMID:21061392

  11. 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).

  12. In vivo validation of DNA adduct formation by estragole in rats predicted by physiologically based biodynamic modelling.

    PubMed

    Paini, Alicia; Punt, Ans; Scholz, Gabriele; Gremaud, Eric; Spenkelink, Bert; Alink, Gerrit; Schilter, Benoît; van Bladeren, Peter J; Rietjens, Ivonne M C M

    2012-11-01

    Estragole is a naturally occurring food-borne genotoxic compound found in a variety of food sources, including spices and herbs. This results in human exposure to estragole via the regular diet. The objective of this study was to quantify the dose-dependent estragole-DNA adduct formation in rat liver and the urinary excretion of 1'-hydroxyestragole glucuronide in order to validate our recently developed physiologically based biodynamic (PBBD) model. Groups of male outbred Sprague Dawley rats (n = 10, per group) were administered estragole once by oral gavage at dose levels of 0 (vehicle control), 5, 30, 75, 150, and 300mg estragole/kg bw and sacrificed after 48h. Liver, kidney and lungs were analysed for DNA adducts by LC-MS/MS. Results obtained revealed a dose-dependent increase in DNA adduct formation in the liver. In lungs and kidneys DNA adducts were detected at lower levels than in the liver confirming the occurrence of DNA adducts preferably in the target organ, the liver. The results obtained showed that the PBBD model predictions for both urinary excretion of 1'-hydroxyestragole glucuronide and the guanosine adduct formation in the liver were comparable within less than an order of magnitude to the values actually observed in vivo. The PBBD model was refined using liver zonation to investigate whether its predictive potential could be further improved. The results obtained provide the first data set available on estragole-DNA adduct formation in rats and confirm their occurrence in metabolically active tissues, i.e. liver, lung and kidney, while the significantly higher levels found in liver are in accordance with the liver as the target organ for carcinogenicity. This opens the way towards future modelling of dose-dependent estragole liver DNA adduct formation in human.

  13. 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.

  14. 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…

  15. Performance of a new 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.; Karamitros, M.

    2014-03-01

    We have recently developed an atomistic model of the B-DNA configuration, up to the 30-nm chromatin fiber. This model is intended to be used in Monte Carlo simulations of the DNA-radiation interaction, specifically in conjunction with the Geant4-DNA extension of the Geant4 Monte Carlo toolkit. In this work, 11449 parallel chromatin fibers have been arranged within a cube mimicking a cell nucleus containing about 6.5×109 base pairs. Each atom in the model is represented by a sphere with the corresponding van der Waals radius. Direct single, double and total DNA strand break yields due to the impact of protons and alpha particles with LET ranging from 4.57 to 207.1 keV/μm have been determined. Also, the corresponding site-hit probabilities have been calculated.

  16. Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti-platelet activity of morpholino-substituted-1,3-naphth-oxazines.

    PubMed

    Ihmaid, Saleh; Al-Rawi, Jasim; Bradley, Christopher; Angove, Michael J; Robertson, Murray N; Clark, Rachel L

    2011-07-01

    A number of new angular 2-morpholino-(substituted)-naphth-1,3-oxazines (compound 10b), linear 2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 13b-c), linear 6, 7 and 9-O-substituted-2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 17-22, 24, and 25) and angular compounds 14-16 and 23 were synthesised. The O-substituent was pyridin-2yl-methyl (15, 18, and 21) pyridin-3yl-methyl (16, 19, and 22) and 4-methylpipreazin-1-yl-ethoxy (23-25). Twelve compounds were tested for their inhibitory effect on collagen induced platelet aggregation and it was found that the most active compounds were compounds 19 and 22 with IC(50)=55±4 and 85±4 μM, respectively. Furthermore, the compounds were also assayed for their ability to inhibit DNA-dependent protein kinase (DNA-PK) activity. The most active compounds were 18 IC(50)=0.091 μM, 24 IC(50)=0.191 μM, and 22 IC(50)=0.331 μM. Homology modelling was used to build a 3D model of DNA-PK based on the X-ray structure of phosphatidylinositol 3-kinases (PI3Ks). Docking of synthesised compounds within the binding pocket and structure-activity relationships (SAR) analyses of the poses were performed and results agreed well with observed activity. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

  17. 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.

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

    USDA-ARS?s Scientific Manuscript database

    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 ...

  19. HIGH TEMPERATURE HIGH PRESSURE THERMODYNAMIC MEASUREMENTS FOR COAL MODEL COMPOUNDS

    SciTech Connect

    Vinayak N. Kabadi

    1999-02-20

    It is well known that the fluid phase equilibria can be represented by a number of {gamma}-models , but unfortunately most of them do not function well under high temperature. In this calculation, we mainly investigate the performance of UNIQUAC and NRTL models under high temperature, using temperature dependent parameters rather than using the original formulas. the other feature of this calculation is that we try to relate the excess Gibbs energy G{sup E}and enthalpy of mixing H{sup E}simultaneously. In other words, we will use the high temperature and pressure G{sup E} and H{sup E}data to regress the temperature dependant parameters to find out which model and what kind of temperature dependant parameters should be used.

  20. 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).

  1. 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.

  2. A computational study of pyrolysis reactions of lignin model compounds

    Treesearch

    Thomas Elder

    2010-01-01

    Enthalpies of reaction for the initial steps in the pyrolysis of lignin have been evaluated at the CBS-4m level of theory using fully substituted b-O-4 dilignols. Values for competing unimolecular decomposition reactions are consistent with results previously published for phenethyl phenyl ether models, but with lowered selectivity. Chain propagating reactions of free...

  3. From organic superconductors to DNA: Fragment orbital-based model

    NASA Astrophysics Data System (ADS)

    Castet, Frédéric; Ducasse, Laurent; Fritsch, Alain

    A semi-empirical valence bond/Hartree-Fock (VB/HF) method is developed to calculate one- and two-electron interactions between molecular fragments in conducting supramolecular stacks. This fragment orbital-based formalism allows for consistent extraction of an effective Hamiltonian defined as a "frontier orbital" model. This Hamiltonian quantitatively describes transfer and electrostatic interactions between conducting electrons, while reducing the active space so dramatically that the electronic eigenstates of very large systems may be investigated. The capabilities of the VB/HF method are illustrated on two different supramolecular stacks involving a π-π interacting fragment. In the first part of this study, the framework of the VB/HF method is used to evaluate the relative magnitude of the electronic interactions between conduction electrons in organic conductors and superconductors derived from Bechgaard salts. In the second part of this study, the VB/HF formalism is extended to derive an effective model for conduction holes along doped DNA double strands. Transferable intra- and intersite parameters were first evaluated from VB/HF calculations carried out on nucleoside pairs. From this interaction databank, the effective Hamiltonian of any type of nucleoside sequence can be defined. The thermalized charge distribution for a single hole delocalized along a DNA sequence containing 240 Watson-Crick pairs is then calculated and compared with the experimental yields of damage revealed by photocleavage experiments.

  4. Carbonyl side-chain of catechol compounds is a key structure for the suppression of copper-associated oxidative DNA damage in vitro.

    PubMed

    Ando, Motozumi; Nishida, Hiroyuki; Nishino, Yoshihiko; Ohbayashi, Manabu; Ueda, Koji; Okamoto, Yoshinori; Kojima, Nakao

    2010-12-15

    Catechol is possibly carcinogenic to humans (International Agency for Research on Cancer, IARC). The key mechanism could include its oxidative DNA-damaging effect in combination with reductive-oxidative metals like Cu. We found that DNA damage was suppressed by introducing an α-carbonyl group to catechol at C4-position to produce carbonyl catechols. During the oxidative DNA-damaging process, catechols but not carbonyl catechols were oxidized to o-quinone; however, coexisting Cu(II) was reduced to Cu(I). Carbonyl catechols were possibly arrested at the oxidation step of semiquinones in the presence of Cu(II). Cu(I)-binding to DNA was stronger than Cu(II)-binding, on the basis of the circular dichroism spectral change. None of the carbonyl catechols induced such change, suggesting sequestration of Cu(I) from DNA. Solid-phase extraction experiments and spectrophotometric analyses showed the formation of semiquinone chelates with Cu(I). Thus, chelate formation could explain the suppression mechanism of the Cu-catechol-dependent DNA damage by terminating the reduction-oxidation cycle. Structural modifications such as introducing an α-carbonyl group to catechol at C4-position would contribute to reducing the risk and improving industrial and medical potentials of aromatic/phenolic compounds sustaining our daily lives.

  5. Interaction between bioactive compound 11a-N-tosyl-5-deoxi-pterocarpan (LQB-223) and Calf thymus DNA: Spectroscopic approach, electrophoresis and theoretical studies.

    PubMed

    Silva, Marina M; Nascimento, Eduarda O O; Silva, Edeíldo F; Araújo, João Xavier de; Santana, Camilla C; Grillo, Luciano Aparecido M; de Oliveira, Rafaela S; R R Costa, Paulo; Buarque, Camilla D; Santos, Josué Carinhanha C; Figueiredo, Isis M

    2017-03-01

    The interaction of small molecules with DNA has been quite important, since this biomolecule is currently the major target for a wide range of drugs in clinical use or advanced clinical research phase. Thus, the present work aimed to assess the interaction process between the bioactive compound 11a-N-tosyl-5-carba-pterocarpan, (LQB-223), that presents antitumor activity, with DNA, employing spectroscopic techniques, electrophoresis, viscosity and theoretical studies. Through UV-vis and molecular fluorescence spectroscopy, it was possible to infer that the preferential quenching mechanism was static, characterized by non-fluorescent supramolecular complex formation between the LQB-223 and DNA. The binding constant was 1.94∙10(3)Lmol(-1) (30°C) and, according to the thermodynamic parameters, the main forces involved in the interaction process are hydrophobic. Potassium iodide assay, competition with ethidium bromide, fluorescence contact energy transfer and melting temperature profile of DNA were employed to evaluate the binding mode. Except for KI assay, all results obtained indicated minor groove as the preferential binding mode of LQB-223 to DNA. These observations were supported by ionic strength assay, viscosity and molecular dynamics and docking studies. Finally, electrophoresis analysis demonstrated that the interaction does not promote DNA fragmentation, but it leads to variation in the migration profile after increasing the ligand concentration. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Molecular modeling and spectroscopic studies of semustine binding with DNA and its comparison with lomustine-DNA adduct formation.

    PubMed

    Agarwal, Shweta; Chadha, Deepti; Mehrotra, Ranjana

    2015-01-01

    Chloroethyl nitrosoureas constitute an important family of cancer chemotherapeutic agents, used in the treatment of various types of cancer. They exert antitumor activity by inducing DNA interstrand cross-links. Semustine, a chloroethyl nitrosourea, is a 4-methyl derivative of lomustine. There exist some interesting reports dealing with DNA-binding properties of chloroethyl nitrosoureas; however, underlying mechanism of cytotoxicity caused by semustine has not been precisely and completely delineated. The present work focuses on understanding semustine-DNA interaction to comprehend its anti-proliferative action at molecular level using various spectroscopic techniques. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy is used to determine the binding site of semustine on DNA. Conformational transition in DNA after semustine complexation is investigated using circular dichroism (CD) spectroscopy. Stability of semustine-DNA complexes is determined using absorption spectroscopy. Results of the present study demonstrate that semustine performs major-groove-directed DNA alkylation at guanine residues in an incubation-time-drug-concentration-dependent manner. CD spectral outcomes suggest partial transition of DNA from native B-conformation to C-form. Calculated binding constants (Ka) for semustine and lomustine interactions with DNA are 1.53 × 10(3) M(-1) and 8.12 × 10(3) M(-1), respectively. Moreover, molecular modeling simulation is performed to predict preferential binding orientation of semustine with DNA that corroborates well with spectral outcomes. Results based on comparative study of DNA-binding properties of semustine and lomustine, presented here, may establish a correlation between molecular structure and cytotoxicity of chloroethyl nitrosoureas that may be instrumental in the designing and synthesis of new nitrosourea therapeutics possessing better efficacy and fewer side effects.

  7. 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. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. A semiempirical model for estimating the hydration free energy of neutral nonpolar compounds

    NASA Astrophysics Data System (ADS)

    Ratkova, E. L.

    2012-10-01

    An improved semiempirical model for determining the hydration free energy of neutral nonpolar compounds is presented. The model is based on a combination of the RISM approach of the integral equation theory and empirical correlations. It is demonstrated that the developed model has high predictive ability for alkanes, alkenes, and dienes (present only in the test set of compounds). It is concluded that this semiempirical model can be applied in estimating the hydration free energy of more complicated structures based on saturated and nonsaturated aliphatic hydrocarbons.

  9. Synthesis, spectroscopic characterization and DFT calculations of β-O-4 type lignin model compounds

    NASA Astrophysics Data System (ADS)

    Mostaghni, Fatemeh; Teimouri, Abbas; Mirshokraei, Seyed Ahmad

    2013-06-01

    β-O-4 type lignin model compounds with the title of Erythro-2-(2-methoxyphenoxy)-1-(3,4,5-trimethoxyphenyl)-1,3-propanediol and Erythro-2-(2-methoxyphenoxy)-1-(4-Hydroxy-3,5-dimethoxyphenyl)-1,3-propanediol were synthesised and some modifications and improvements on them were introduced. These compounds were characterized by IR, Mass and NMR spectroscopy. Density functional theory (DFT) calculations were performed for the title compounds using the standard 6-31G* basis set. IR, 13C and 1H NMR of the title compounds were calculated at the DFT-B3LYP level of theory using the 6-31G* basis set. In this work comparison between the experimental and the theoretical results indicates that the DFT-B3LYP method is able to provide satisfactory results for predicting the properties of the considered compounds.

  10. In situ catalytic hydrogenation of model compounds and biomass-derived phenolic compounds for bio-oil upgrading

    Treesearch

    Junfeng Feng; Zhongzhi Yang; Chung-yun Hse; Qiuli Su; Kui Wang; Jianchun Jiang; Junming Xu

    2017-01-01

    The renewable phenolic compounds produced by directional liquefaction of biomass are a mixture of complete fragments decomposed from native lignin. These compounds are unstable and difficult to use directly as biofuel. Here, we report an efficient in situ catalytic hydrogenation method that can convert phenolic compounds into saturated cyclohexanes. The process has...

  11. Marcus model of spontaneous point mutation in DNA

    NASA Astrophysics Data System (ADS)

    Turaeva, N.; Brown-Kennerly, V.

    2015-11-01

    The theoretical model of Löwdin's mechanism of spontaneous mutation based on 2D Marcus theory of DPT has been proposed in this work. The equation for the kinetics of DPT during DNA replication has been established, and the expression for the probability of spontaneous mutation has been received. The probability of spontaneous mutation formation has been estimated for tautomeric G∗-C∗ complexes, which is in the range of experimental results. The probability of spontaneous mutation as a function of temperature, replication rate, and solvent effect has been discussed. It increases with temperature and decreases with replication rate. The solvent and pH effects on the probability of spontaneous mutation can also be discussed within the framework of the model.

  12. 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

  13. 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.

  14. 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.

  15. Computational Models of the Representation of Bangla Compound Words in the Mental Lexicon.

    PubMed

    Dasgupta, Tirthankar; Sinha, Manjira; Basu, Anupam

    2016-08-01

    In this paper we aim to model the organization and processing of Bangla compound words in the mental lexicon. Our objective is to determine whether the mental lexicon access a Bangla compound word as a whole or decomposes the whole word into its constituent morphemes and then recognize them accordingly. To address this issue, we adopted two different strategies. First, we conduct a cross-modal priming experiment over a number of native speakers. Analysis of reaction time (RT) and error rates indicates that in general, Bangla compound words are accessed via partial decomposition process. That is some word follows full-listing mode of representation and some words follow the decomposition route of representation. Next, based on the collected RT data we have developed a computational model that can explain the processing phenomena of the access and representation of Bangla compound words. In order to achieve this, we first explored the individual roles of head word position, morphological complexity, orthographic transparency and semantic compositionality between the constituents and the whole compound word. Accordingly, we have developed a complexity based model by combining these features together. To a large extent we have successfully explained the possible processing phenomena of most of the Bangla compound words. Our proposed model shows an accuracy of around 83 %.

  16. Progress in the discovery of compounds inhibiting orthopoxviruses in animal models.

    PubMed

    Smee, Donald F

    2008-01-01

    Surrogate animal models must be used for testing antiviral agents against variola (smallpox) virus infections. Once developed, these, compounds can be stockpiled for use in the event of a bioterrorist incident involving either variola or monkeypox virus, or used to treat an occasional serious orthopoxvirus infection, such as disseminated vaccinia complication following exposure to the live virus vaccine. Recently, considerable progress has been made in the discovery of novel antiviral agents found active against orthopoxviruses in vivo. This includes the development of new animal models or refinement of existing ones for compound efficacy testing. Current mouse models employ ectromelia, cowpox and vaccinia (WR and IHD strains) viruses with respiratory (lung) or tail lesion infections commonly studied. Rabbitpox and vaccinia (WR strain) viruses are available for rabbit infections. Monkeypox and variola viruses are used for infecting monkeys. This review describes these and other animal models, and covers compounds found active in vivo from 2003 to date. Cidofovir, known to be active against orthopox virus infections prior to 2003, has been studied extensively over recent years. New compounds showing promise are orally active inhibitors of orthopoxvirus infections that include ether lipid prodrugs of cidofovir and (S)-HPMPA, ST-246, N-methanocarbathymidine (N-MCT) and SRI 21950 (a 4'-thio derivative of iododeoxyuridine). Another compound with high activity but requiring parenteral administration is HPMPO-DAPy. Further development of these compounds is warranted.

  17. 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)

  18. 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)

  19. Lessons for neurotoxicology from selected model compounds: SGOMSEC joint report.

    PubMed Central

    Rice, D C; Evangelista de Duffard, A M; Duffard, R; Iregren, A; Satoh, H; Watanabe, C

    1996-01-01

    The ability to identify potential neurotoxicants depends upon the characteristics of our test instruments. The neurotoxic properties of lead, methylmercury, polychlorinated biphenyls, and organic solvents would all have been detected at some dose level by tests in current use, provided that the doses were high enough and administered at an appropriate time such as during gestation. The adequacy of animal studies, particularly rodent studies, to predict intake levels at which human health can be protected is disappointing, however. It is unlikely that the use of advanced behavioral methodology would alleviate the apparent lack of sensitivity of the rodent model for many agents. PMID:8860323

  20. An elastic compound tube model for a single osteon.

    PubMed

    Braidotti, P; Branca, F P; Sciubba, E; Stagni, L

    1995-04-01

    A model is developed whereby the secondary osteon--the dominant microstructural component of the cortical bone tissue--is considered as an n-layered cylinder with internal stresses in linear isotropic elasticity. An exact solution is obtained for a loading condition represented by a tensile-compressive force. The lengthening, the side deformation, and the strain energy of the system are explicitly calculated. The behavior of the main elastic quantities is illustrated by graphs. In particular, the important role played by the parity of the number of lamellae is revealed.

  1. HIGH TEMPERATURE HIGH PRESSURE THERMODYNAMIC MEASUREMENTS FOR COAL MODEL COMPOUNDS

    SciTech Connect

    Vinayak N. Kabadi

    1999-02-24

    The enthalpy of a fluid measured with respect to some reference temperature and pressure (enthalpy increment or Cp) is required for many engineering designs. Different techniques for determining enthalpy increments include direct measurement, integration of heat capacity as a function of temperature at constant pressure, and calculation from accurate density measurements as a function of temperature and pressure with ideal-gas enthalpies. Techniques have been developed for measurement of heat capacities using differential scanning calorimeters, but routine measurements with a precision better than 3% are rare. For thermodynamic model development, excess enthalpies or enthalpies of mixing of binary and ternary systems are generally required. Although these data can be calculated from measured values of incremental enthalpies of mixtures and corresponding pure components, the method of calculation involves subtraction of large numbers, and it is impossible to obtain accurate results from relatively accurate incremental enthalpy data. Directly measured heats of mixing provide better data for model development. In what follows, we give a brief literature survey of experimental methods available for measurement of incremental enthalpies as well as heats of mixing.

  2. 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/.

  3. Determination of significant variables in compound wear using a statistical model

    SciTech Connect

    Pumwa, J.; Griffin, R.B.; Smith, C.M.

    1997-07-01

    This paper will report on a study of dry compound wear of normalized 1018 steel on A2 tool steel. Compound wear is a combination of sliding and impact wear. The compound wear machine consisted of an A2 tool steel wear plate that could be rotated, and an indentor head that held the 1018 carbon steel wear pins. The variables in the system were the rpm of the wear plate, the force with which the indentor strikes the wear plate, and the frequency with which the indentor strikes the wear plate. A statistically designed experiment was used to analyze the effects of the different variables on the compound wear process. The model developed showed that wear could be reasonably well predicted using a defined variable that was called the workrate. The paper will discuss the results of the modeling and the metallurgical changes that occurred at the indentor interface, with the wear plate, during the wear process.

  4. 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

  5. Characterization of commercial inactive dry yeast preparations for enological use based on their ability to release soluble compounds and their behavior toward aroma compounds in model wines.

    PubMed

    Pozo-Bayón, Maria Angeles; Andujar-Ortiz, Inmaculada; Alcaide-Hidalgo, Juan María; Martín-Alvarez, Pedro J; Moreno-Arribas, M Victoria

    2009-11-25

    The characterization of commercial enological inactive dry yeast (IDY) with different applications in wine production has been carried out. This study was based on the yeast's ability to release soluble compounds (high molecular weight nitrogen, free amino nitrogen, peptidic nitrogen, free amino acids, and polysaccharides) into model wines and on its behavior toward the volatility of seven wine aroma compounds. Important differences in soluble compounds released into the model wines supplemented with commercial IDY were found, with the free amino acids being among the most released. The volatility of most of the aroma compounds was affected by the addition of IDY preparations at a concentration usually employed during winemaking. The extent of this effect was dependent on the physicochemical characteristics of the aroma compound and on the length of time the IDY preparations remained in contact with the model wines. Whereas shorter contact times (2, 4, and 6 days) mainly promoted a "salting-out" effect, longer exposure (9 and 13 days) provoked a retention effect, with the consequent reduction of aroma compounds in the headspace. The use of different commercial preparations also promoted different effects toward the aroma compounds that may be at least in part due to differences in their ability to release soluble compounds of yeast origin into the wines.

  6. Modeling associated protein-DNA pattern discovery with unified scores.

    PubMed

    Chan, Tak-Ming; Lo, Leung-Yau; Sze-To, Ho-Yin; Leung, Kwong-Sak; Xiao, Xinshu; Wong, Man-Hon

    2013-01-01

    Understanding protein-DNA interactions, specifically transcription factor (TF) and transcription factor binding site (TFBS) bindings, is crucial in deciphering gene regulation. The recent associated TF-TFBS pattern discovery combines one-sided motif discovery on both the TF and the TFBS sides. Using sequences only, it identifies the short protein-DNA binding cores available only in high-resolution 3D structures. The discovered patterns lead to promising subtype and disease analysis applications. While the related studies use either association rule mining or existing TFBS annotations, none has proposed any formal unified (both-sided) model to prioritize the top verifiable associated patterns. We propose the unified scores and develop an effective pipeline for associated TF-TFBS pattern discovery. Our stringent instance-level evaluations show that the patterns with the top unified scores match with the binding cores in 3D structures considerably better than the previous works, where up to 90 percent of the top 20 scored patterns are verified. We also introduce extended verification from literature surveys, where the high unified scores correspond to even higher verification percentage. The top scored patterns are confirmed to match the known WRKY binding cores with no available 3D structures and agree well with the top binding affinities of in vivo experiments.

  7. 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.

  8. LAMMPS framework for dynamic bonding and an application modeling DNA

    NASA Astrophysics Data System (ADS)

    Svaneborg, Carsten

    2012-08-01

    We have extended the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) to support directional bonds and dynamic bonding. The framework supports stochastic formation of new bonds, breakage of existing bonds, and conversion between bond types. Bond formation can be controlled to limit the maximal functionality of a bead with respect to various bond types. Concomitant with the bond dynamics, angular and dihedral interactions are dynamically introduced between newly connected triplets and quartets of beads, where the interaction type is determined from the local pattern of bead and bond types. When breaking bonds, all angular and dihedral interactions involving broken bonds are removed. The framework allows chemical reactions to be modeled, and use it to simulate a simplistic, coarse-grained DNA model. The resulting DNA dynamics illustrates the power of the present framework. Catalogue identifier: AEME_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEME_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GNU General Public Licence No. of lines in distributed program, including test data, etc.: 2 243 491 No. of bytes in distributed program, including test data, etc.: 771 Distribution format: tar.gz Programming language: C++ Computer: Single and multiple core servers Operating system: Linux/Unix/Windows Has the code been vectorized or parallelized?: Yes. The code has been parallelized by the use of MPI directives. RAM: 1 Gb Classification: 16.11, 16.12 Nature of problem: Simulating coarse-grain models capable of chemistry e.g. DNA hybridization dynamics. Solution method: Extending LAMMPS to handle dynamic bonding and directional bonds. Unusual features: Allows bonds to be created and broken while angular and dihedral interactions are kept consistent. Additional comments: The distribution file for this program is approximately 36 Mbytes and therefore is not delivered directly

  9. 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)

  10. 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)

  11. Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models

    PubMed Central

    TANAKA, NOZOMU; SAKAMOTO, KAZUKI; OKABE, HIROYUKI; FUJIOKA, AKIO; YAMAMURA, KEISUKE; NAKAGAWA, FUMIO; NAGASE, HIDEKI; YOKOGAWA, TATSUSHI; OGUCHI, KEI; ISHIDA, KEIJI; OSADA, AKIKO; KAZUNO, HIROMI; YAMADA, YUKARI; MATSUO, KENICHI

    2014-01-01

    TAS-102 is a novel oral nucleoside antitumor agent containing trifluridine (FTD) and tipiracil hydrochloride (TPI). The compound improves overall survival of colorectal cancer (CRC) patients who are insensitive to standard chemotherapies. FTD possesses direct antitumor activity since it inhibits thymidylate synthase (TS) and is itself incorporated into DNA. However, the precise mechanisms underlying the incorporation into DNA and the inhibition of TS remain unclear. We found that FTD-dependent inhibition of TS was similar to that elicited by fluorodeoxyuridine (FdUrd), another clinically used nucleoside analog. However, washout experiments revealed that FTD-dependent inhibition of TS declined rapidly, whereas FdUrd activity persisted. The incorporation of FTD into DNA was significantly higher than that of other antitumor nucleosides. Additionally, orally administered FTD had increased antitumor activity and was incorporated into DNA more effectively than continuously infused FTD. When TAS-102 was administered, FTD gradually accumulated in tumor cell DNA, in a TPI-independent manner, and significantly delayed tumor growth and prolonged survival, compared to treatment with 5-FU derivatives. TAS-102 reduced the Ki-67-positive cell fraction, and swollen nuclei were observed in treated tumor tissue. The amount of FTD incorporation in DNA and the antitumor activity of TAS-102 in xenograft models were positively and significantly correlated. These results suggest that TAS-102 exerts its antitumor activity predominantly due to its DNA incorporation, rather than as a result of TS inhibition. The persistence of FTD in the DNA of tumor cells treated with TAS-102 may underlie its ability to prolong survival in cancer patients. PMID:25230742

  12. Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models.

    PubMed

    Tanaka, Nozomu; Sakamoto, Kazuki; Okabe, Hiroyuki; Fujioka, Akio; Yamamura, Keisuke; Nakagawa, Fumio; Nagase, Hideki; Yokogawa, Tatsushi; Oguchi, Kei; Ishida, Keiji; Osada, Akiko; Kazuno, Hiromi; Yamada, Yukari; Matsuo, Kenichi

    2014-12-01

    TAS-102 is a novel oral nucleoside antitumor agent containing trifluridine (FTD) and tipiracil hydrochloride (TPI). The compound improves overall survival of colorectal cancer (CRC) patients who are insensitive to standard chemotherapies. FTD possesses direct antitumor activity since it inhibits thymidylate synthase (TS) and is itself incorporated into DNA. However, the precise mechanisms underlying the incorporation into DNA and the inhibition of TS remain unclear. We found that FTD-dependent inhibition of TS was similar to that elicited by fluorodeoxyuridine (FdUrd), another clinically used nucleoside analog. However, washout experiments revealed that FTD-dependent inhibition of TS declined rapidly, whereas FdUrd activity persisted. The incorporation of FTD into DNA was significantly higher than that of other antitumor nucleosides. Additionally, orally administered FTD had increased antitumor activity and was incorporated into DNA more effectively than continuously infused FTD. When TAS-102 was administered, FTD gradually accumulated in tumor cell DNA, in a TPI-independent manner, and significantly delayed tumor growth and prolonged survival, compared to treatment with 5-FU derivatives. TAS-102 reduced the Ki-67-positive cell fraction, and swollen nuclei were observed in treated tumor tissue. The amount of FTD incorporation in DNA and the antitumor activity of TAS-102 in xenograft models were positively and significantly correlated. These results suggest that TAS-102 exerts its antitumor activity predominantly due to its DNA incorporation, rather than as a result of TS inhibition. The persistence of FTD in the DNA of tumor cells treated with TAS-102 may underlie its ability to prolong survival in cancer patients.

  13. Prediction of biological targets for compounds using multiple-category Bayesian models trained on chemogenomics databases.

    PubMed

    Nidhi; Glick, Meir; Davies, John W; Jenkins, Jeremy L

    2006-01-01

    Target identification is a critical step following the discovery of small molecules that elicit a biological phenotype. The present work seeks to provide an in silico correlate of experimental target fishing technologies in order to rapidly fish out potential targets for compounds on the basis of chemical structure alone. A multiple-category Laplacian-modified naïve Bayesian model was trained on extended-connectivity fingerprints of compounds from 964 target classes in the WOMBAT (World Of Molecular BioAcTivity) chemogenomics database. The model was employed to predict the top three most likely protein targets for all MDDR (MDL Drug Database Report) database compounds. On average, the correct target was found 77% of the time for compounds from 10 MDDR activity classes with known targets. For MDDR compounds annotated with only therapeutic or generic activities such as "antineoplastic", "kinase inhibitor", or "anti-inflammatory", the model was able to systematically deconvolute the generic activities to specific targets associated with the therapeutic effect. Examples of successful deconvolution are given, demonstrating the usefulness of the tool for improving knowledge in chemogenomics databases and for predicting new targets for orphan compounds.

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

    PubMed

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

    2016-05-06

    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.

  15. Thinner inhalation effects on oxidative stress and DNA repair in a rat model of abuse.

    PubMed

    Martínez-Alfaro, Minerva; Cárabez-Trejo, Alfonso; Gallegos-Corona, Marco-Antonio; Pedraza-Aboytes, Gustavo; Hernández-Chan, Nancy Georgina; Leo-Amador, Guillermo Enrique

    2010-04-01

    Humans can come into contact with thinner by occupational exposure or by intentional inhalation abuse. Numerous studies of workers for genotoxic effects of thinner exposure have yielded conflicting results, perhaps because co-exposure to variable other compounds cannot be avoided in workplace exposure studies. In contrast, there is no data concerning the genotoxic effects of intentional inhalation abuse. The aim of this project was to examine the genotoxic effects of thinner inhalation in an animal model of thinner abuse (rats exposed to 3000 ppm toluene, a high solvent concentration over a very short, 15 min time period, twice a day for 6 weeks). The data presented here provides evidence that thinner inhalation in our experimental conditions is able to induce weight loss, lung abnormalities and oxidative stress. This oxidative stress induces oxidative DNA damage that is not a characteristic feature of genotoxic damage. No significant difference in DNA damage and DNA repair (biomarkers of genotoxicity) in lymphocytes from thinner-treated and control rats was found. Lead treatment was used as a positive control in these assays. Finally, bone marrow was evaluated as a biomarker of cellular alteration associated with thinner inhalation. The observed absence of hemopoietic and genetic toxicity could be explained in part by the absence of benzene, the only carcinogenic component of thinner; however, benzene is no longer a common component of thinner. In conclusion, thinner did not cause genotoxic effects in an experimental model of intentional abuse despite the fact that thinner inhalation induces oxidative stress. (c) 2009 John Wiley & Sons, Ltd.

  16. Computational classification models for predicting the interaction of compounds with hepatic organic ion importers.

    PubMed

    You, Hwan; Lee, Kyungro; Lee, Sangwon; Hwang, Sung Bo; Kim, Kwang-Yon; Cho, Kwang-Hwi; No, Kyoung Tai

    2015-10-01

    Hepatic transporters, a major determinant of pharmacokinetics, have been used to profile drug properties like efficacy. Among hepatic transporters, importers alter the concentration of the drug by facilitating the transport of a drug into a cell. Despite vast pharmacokinetic studies, the interacting mechanisms of the importers with its substrates or inhibitors are not well understood. Hence, we developed compound binary classification models of whether a compound is binder or nonbinder to a hepatic transporter with experimental data of 284 compounds for four representative hepatic importers, OATP1B1, OATP1B3, OAT2, and OCT1. Support Vector Machine (SVM) along with Genetic Algorithm (GA) was used to construct the classification models of binder versus nonbinder for each target importer. To construct the models, we prepared two data sets, a training data set from Fujitsu database (284 compounds) and an external validation data set from ChEMBL database (1738 compounds). Since an experimental classification criterion between binder and nonbinder has some ambiguity, there is an intrinsic limitation to expect high predictability of the binary classification models developed with the experimental data. The predictability of the classification models calculated with external validation sets were obtained as 77.72%, 84.31%, 84.21%, and 76.38 for OATP1B1, OATP1B3, OAT2, and OCT1, respectively.

  17. Towards intelligent bioreactor systems: triggering the release and mixing of compounds based on DNA-functionalized hybrid hydrogel.

    PubMed

    Zhou, Li; Chen, Cuie; Ren, Jinsong; Qu, Xiaogang

    2014-09-14

    We have designed and synthesized an intelligent mesoporous silica nanoparticle-DNA hydrogel bioreactor system that can be controlled by external stimuli. The system allowed the simultaneous incorporation of multiple components, and the separation between the components can be destroyed by a structural change of the DNA to initiate a reaction.

  18. Catalytic conversion of lignin pyrolysis model compound- guaiacol and its kinetic model including coke formation

    NASA Astrophysics Data System (ADS)

    Zhang, Huiyan; Wang, Yun; Shao, Shanshan; Xiao, Rui

    2016-11-01

    Lignin is the most difficult to be converted and most easy coking component in biomass catalytic pyrolysis to high-value liquid fuels and chemicals. Catalytic conversion of guaiacol as a lignin model compound was conducted in a fixed-bed reactor over ZSM-5 to investigate its conversion and coking behaviors. The effects of temperature, weight hourly space velocity (WHSV) and partial pressure on product distribution were studied. The results show the maximum aromatic carbon yield of 28.55% was obtained at temperature of 650 °C, WHSV of 8 h-1 and partial pressure of 2.38 kPa, while the coke carbon yield was 19.55%. The reaction pathway was speculated to be removing methoxy group to form phenols with further aromatization to form aromatics. The amount of coke increased with increasing reaction time. The surface area and acidity of catalysts declined as coke formed on the acid sites and blocked the pore channels, which led to the decrease of aromatic yields. Finally, a kinetic model of guaiacol catalytic conversion considering coke deposition was built based on the above reaction pathway to properly predict product distribution. The experimental and model predicting data agreed well. The correlation coefficient of all equations were all higher than 0.90.

  19. Catalytic conversion of lignin pyrolysis model compound- guaiacol and its kinetic model including coke formation

    PubMed Central

    Zhang, Huiyan; Wang, Yun; Shao, Shanshan; Xiao, Rui

    2016-01-01

    Lignin is the most difficult to be converted and most easy coking component in biomass catalytic pyrolysis to high-value liquid fuels and chemicals. Catalytic conversion of guaiacol as a lignin model compound was conducted in a fixed-bed reactor over ZSM-5 to investigate its conversion and coking behaviors. The effects of temperature, weight hourly space velocity (WHSV) and partial pressure on product distribution were studied. The results show the maximum aromatic carbon yield of 28.55% was obtained at temperature of 650 °C, WHSV of 8 h−1 and partial pressure of 2.38 kPa, while the coke carbon yield was 19.55%. The reaction pathway was speculated to be removing methoxy group to form phenols with further aromatization to form aromatics. The amount of coke increased with increasing reaction time. The surface area and acidity of catalysts declined as coke formed on the acid sites and blocked the pore channels, which led to the decrease of aromatic yields. Finally, a kinetic model of guaiacol catalytic conversion considering coke deposition was built based on the above reaction pathway to properly predict product distribution. The experimental and model predicting data agreed well. The correlation coefficient of all equations were all higher than 0.90. PMID:27869228

  20. A new hybrid model to simulate interaction between DNA and carbon nanostructure

    NASA Astrophysics Data System (ADS)

    Glukhova, O. E.; Savostyanov, G. V.; Slepchenkov, M. M.; Zyktin, A. A.

    2017-02-01

    A new hybrid mathematical model allowing us to investigate the interaction between the components of the DNA + carbon nanostructure molecular complex on the atomic and molecular levels are developed. Within the developed model we proposed to describe the carbon nanostructures by means of the methods and approaches of atomistic modeling, and to describe the DNA molecule using the methods and approaches of coarse-grained modeling. A coarse-grained structure of DNA is built based on 3-Site-Per-Nucleotide model. The proposed hybrid model has been implemented in the original software complex for molecular modeling KVAZAR using modern IT-solutions. The novelty of the model is concluded to a finding the weight coefficients for the interaction of large particles, simulating DNA, and conventional particle, simulating carbon nanostructure, and also for the intermolecular interactions. On the basis of established regularities for interaction between DNA and carbon nanostructures we will develop the model of the sensor device.

  1. Multivariate Statistical Modelling of Compound Events via Pair-Copula Constructions: Analysis of Floods in Ravenna

    NASA Astrophysics Data System (ADS)

    Bevacqua, Emanuele; Maraun, Douglas; Hobæk Haff, Ingrid; Widmann, Martin; Vrac, Mathieu

    2017-04-01

    Compound events are multivariate extreme events in which the individual contributing variables may not be extreme themselves, but their joint - dependent - occurrence causes an extreme impact. The conventional univariate statistical analysis cannot give accurate information regarding the multivariate nature of these events. We develop a conceptual model, implemented via pair-copula constructions, which allows for the quantification of the risk associated with compound events in present day and future climate, as well as the uncertainty estimates around such risk. The model includes meteorological predictors which provide insight into both the involved physical processes, and the temporal variability of CEs. Moreover, this model provides multivariate statistical downscaling of compound events. Downscaling of compound events is required to extend their risk assessment to the past or future climate, where climate models either do not simulate realistic values of the local variables driving the events, or do not simulate them at all. Based on the developed model, we study compound floods, i.e. joint storm surge and high river runoff, in Ravenna (Italy). To explicitly quantify the risk, we define the impact of compound floods as a function of sea and river levels. We use meteorological predictors to extend the analysis to the past, and get a more robust risk analysis. We quantify the uncertainties of the risk analysis observing that they are very large due to the shortness of the available data, though this may also be the case in other studies where they have not been estimated. Ignoring the dependence between sea and river levels would result in an underestimation of risk, in particular the expected return period of the highest compound flood observed increases from about 20 to 32 years when switching from the dependent to the independent case.

  2. Mathematical modeling of atmospheric fine particle-associated primary organic compound concentrations

    NASA Astrophysics Data System (ADS)

    Rogge, Wolfgang F.; Hildemann, Lynn M.; Mazurek, Monica A.; Cass, Glen R.; Simoneit, Bernd R. T.

    1996-08-01

    An atmospheric transport model has been used to explore the relationship between source emissions and ambient air quality for individual particle phase organic compounds present in primary aerosol source emissions. An inventory of fine particulate organic compound emissions was assembled for the Los Angeles area in the year 1982. Sources characterized included noncatalyst- and catalyst-equipped autos, diesel trucks, paved road dust, tire wear, brake lining dust, meat cooking operations, industrial oil-fired boilers, roofing tar pots, natural gas combustion in residential homes, cigarette smoke, fireplaces burning oak and pine wood, and plant leaf abrasion products. These primary fine particle source emissions were supplied to a computer-based model that simulates atmospheric transport, dispersion, and dry deposition based on the time series of hourly wind observations and mixing depths. Monthly average fine particle organic compound concentrations that would prevail if the primary organic aerosol were transported without chemical reaction were computed for more than 100 organic compounds within an 80 km × 80 km modeling area centered over Los Angeles. The monthly average compound concentrations predicted by the transport model were compared to atmospheric measurements made at monitoring sites within the study area during 1982. The predicted seasonal variation and absolute values of the concentrations of the more stable compounds are found to be in reasonable agreement with the ambient observations. While model predictions for the higher molecular weight polycyclic aromatic hydrocarbons (PAH) are in agreement with ambient observations, lower molecular weight PAH show much higher predicted than measured atmospheric concentrations in the particle phase, indicating atmospheric decay by chemical reactions or evaporation from the particle phase. The atmospheric concentrations of dicarboxylic acids and aromatic polycarboxylic acids greatly exceed the contributions that

  3. DNA strand scission by the nephrotoxin [2,2'-bipyridine]-3,3',4,4'-tetrol-1,1'-dioxide and related compounds in the presence of iron.

    PubMed

    Cantin-Esnault, D; Oubrahim, H; Richard, J M

    2000-08-01

    The capacity of non-illuminated nephrotoxin orellanine ([2,2'-bipyridine]-3,3',4,4'-tetrol-1,1'-dioxide) to induce DNA damage in the presence of ferrous iron and dioxygen has been evaluated. Maximal single-strand breaks in plasmid DNA were obtained with a metal to ligand ratio 1:3. Instantaneous oxidation of Fe2+ in presence of orellanine under air was responsible for oxy-radical production concomitant to a stable ferric complex Fe(III)Or3 formation, leading to oxidative DNA breakage at physiological pH. DNA damage was lowered in the presence of SOD and catalase or DMSO, indicating a set of reactions that leads to oxy-radical generation. Iron chelators such as DTPA and EDTA had no protecting effect, Desferal slightly protected. GSH acted as an oxy-radical scavenger, whereas cysteine induced stronger damage. Closely related bipyridine compounds were also studied in presence of Fe2+ and O2 using a combination of spin-trapping and DNA-nicking experiments, none of which were able to chelate iron and induce damage at pH 7. Both catecholic moieties and aminoxide groups are required for observing breakage at physiological pH.

  4. Titanocene-Phosphine Derivatives as Precursors to Cytotoxic Heterometallic TiAu2 and TiM (M = Pd, Pt) Compounds. Studies of their Interactions with DNA

    PubMed Central

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

    2011-01-01

    A series of tri- and bimetallic titanium-gold, titanium-palladium and titanium-platinum derivatives of general formulas [Ti{η5-C5H4(CH2)nPPh2(AuCl)}2].2THF n = 0 (1); n = 2 (2); n = 3 (3) and [TiCl2{η5-C5H4κ-(CH2)nPPh2}2(PtCl2)].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 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 (CDCl3, d6-dmso, mixtures 50:50 d6-dmso/D2O, 1:99 d6-dmso/D2O at acidic pH and at neutral pH) has been evaluated by 31P and 1H NMR spectroscopy showing a higher stability for these compounds than for Cp2TiCl2 or precursors [Ti{η5-C5H4(CH2)nPPh2}2]. The new compounds display a lower acidity (1 to 2 units) than Cp2TiCl2. 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. TiAu2 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, 7) spectroscopic methods. All these complexes show a stronger interaction with DNA than that displayed by Cp2TiCl2 at neutral pH. The data is consistent with electrostatic interactions with DNA for TiAu2 compounds and for a covalent binding mode for TiM (M = Pd, Pt) complexes. PMID:21958150

  5. Modeling forward stutter: toward increased objectivity in forensic DNA interpretation.

    PubMed

    Bright, Jo-Anne; Buckleton, John S; Taylor, Duncan; Fernando, M A C S S; Curran, James M

    2014-11-01

    Forward stutter, or over stutter, one repeat unit length larger than the parent allele (N + 1 stutter), is a relatively rare product of the PCR amplification of STRs used in forensic DNA analysis. We have investigated possible explanatory variables for the occurrence and size of forward stutter for four different autosomal multiplexes. In addition, we have investigated models used to predict the expected heights of forward stutter. For all tetra and penta-nucleotide repeats we can find no correlation between allelic peak height, marker, or longest uninterrupted sequence in the allele. The data fit a gamma distribution with no explanatory variables. For the single trinucleotide repeat present in two of the four multiplexes (D22S1045) forward stutter is much more common and the best explanatory variable appears to be back stutter height. This suggests some fundamental cocausation of high backward and forward stutter for this locus.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  7. 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

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

    PubMed

    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.

  9. 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

  10. QSPR modeling of thermal stability of nitroaromatic compounds: DFT vs. AM1 calculated descriptors.

    PubMed

    Fayet, Guillaume; Rotureau, Patricia; Joubert, Laurent; Adamo, Carlo

    2010-04-01

    The quantitative structure-property relationship (QSPR) methodology was applied to predict the decomposition enthalpies of 22 nitroaromatic compounds, used as indicators of thermal stability. An extended series of descriptors (constitutional, topological, geometrical charge related and quantum chemical) was calculated at two different levels of theory: density functional theory (DFT) and semi-empirical AM1 approaches. Reliable models have been developed for each level, leading to similar correlations between calculated and experimental data (R(2) > 0.98). Hence, both of them can be employed as screening tools for the prediction of thermal stability of nitroaromatic compounds. If using the AM1 model presents the advantage to be less time consuming, DFT allows the calculation of more accurate molecular quantum properties, e.g., conceptual DFT descriptors. In this study, our best QSPR model is based on such descriptors, providing more chemical comprehensive relationships with decomposition reactivity, a particularly complex property for the specific class of nitroaromatic compounds.

  11. Modeling of half-Heusler compound NiMnSb within tight-binding approximation

    NASA Astrophysics Data System (ADS)

    Sugiyanto, Majidi, M. A.; Nanto, D.

    2017-07-01

    Heusler compounds are families of magnetic materials with general stoichiometry of either X2YZ (full-Heusler compound) or XYZ (half-Heusler compound), with X and Y being transition metal elements, and Z a main-group element. Their various potentials for technology development make them be still relevant as a subject of both experimental and theoretical studies. Half-Heusler compounds are generally crystallized in the C1b-type structure. The magnetic moments of such materials may be predicted using Slater-Pauling rule, giving m = (Nvalence electrons - 18)µB per formula unit. However, this simple counting rule does not always work for all compounds in this group. This motivates us to perform a theoretical study to investigate the mechanism of magnetic moment formation microscopically. As a case study, we focus on NiMnSb, a particular half-Heusler compound, for which comparison between existing experimental results and theoretical predictions of its magnetic moment has not yet been quite convincing. We model the system by constructing a tight-binding-based Hamiltonian, incorporating Hubbard repulsive as well as spin-spin interactions for the electrons occupying the d-orbitals. We solve the model using Green's function approach, and treat the interaction terms within the mean-field approximation. At this stage, we aim to formulate the computational algorithm for the overall calculation process. Our final goal is to compute the total magnetic moment per unit cell of this system and compare it with available experimental data.

  12. Chicken Fetal Liver DNA Damage and Adduct Formation by Activation-Dependent DNA-Reactive Carcinogens and Related Compounds of Several Structural Classes

    PubMed Central

    Williams, Gary M.; Duan, Jian-Dong; Brunnemann, Klaus D.; Iatropoulos, Michael J.; Vock, Esther; Deschl, Ulrich

    2014-01-01

    The chicken egg genotoxicity assay (CEGA), which utilizes the liver of an intact and aseptic embryo-fetal test organism, was evaluated using four activation-dependent DNA-reactive carcinogens and four structurally related less potent carcinogens or non-carcinogens. In the assay, three daily doses of test substances were administered to eggs containing 9–11-day-old fetuses and the fetal livers were assessed for two endpoints, DNA breaks using the alkaline single cell gel electrophoresis (comet) assay and DNA adducts using the 32P-nucleotide postlabeling (NPL) assay. The effects of four carcinogens of different structures requiring distinct pathways of bioactivation, i.e., 2-acetylaminofluorene (AAF), aflatoxin B1 (AFB1), benzo[a]pyrene (B[a]P), and diethylnitrosamine (DEN), were compared with structurally related non-carcinogens fluorene (FLU) and benzo[e]pyrene (B[e]P) or weak carcinogens, aflatoxin B2 (AFB2) and N-nitrosodiethanolamine (NDELA). The four carcinogens all produced DNA breaks at microgram or low milligram total doses, whereas less potent carcinogens and non-carcinogens yielded borderline or negative results, respectively, at higher doses. AAF and B[a]P produced DNA adducts, whereas none was found with the related comparators FLU or B[e]P, consistent with comet results. DEN and NDELA were also negative for adducts, as expected in the case of DEN for an alkylating agent in the standard NPL assay. Also, AFB1 and AFB2 were negative in NPL, as expected, due to the nature of ring opened aflatoxin adducts, which are resistant to enzymatic digestion. Thus, the CEGA, using comet and NPL, is capable of detection of the genotoxicity of diverse DNA-reactive carcinogens, while not yielding false positives for non-carcinogens. PMID:24973097

  13. Chicken fetal liver DNA damage and adduct formation by activation-dependent DNA-reactive carcinogens and related compounds of several structural classes.

    PubMed

    Williams, Gary M; Duan, Jian-Dong; Brunnemann, Klaus D; Iatropoulos, Michael J; Vock, Esther; Deschl, Ulrich

    2014-09-01

    The chicken egg genotoxicity assay (CEGA), which utilizes the liver of an intact and aseptic embryo-fetal test organism, was evaluated using four activation-dependent DNA-reactive carcinogens and four structurally related less potent carcinogens or non-carcinogens. In the assay, three daily doses of test substances were administered to eggs containing 9-11-day-old fetuses and the fetal livers were assessed for two endpoints, DNA breaks using the alkaline single cell gel electrophoresis (comet) assay and DNA adducts using the (32)P-nucleotide postlabeling (NPL) assay. The effects of four carcinogens of different structures requiring distinct pathways of bioactivation, i.e., 2-acetylaminofluorene (AAF), aflatoxin B1 (AFB1), benzo[a]pyrene (B[a]P), and diethylnitrosamine (DEN), were compared with structurally related non-carcinogens fluorene (FLU) and benzo[e]pyrene (B[e]P) or weak carcinogens, aflatoxin B2 (AFB2) and N-nitrosodiethanolamine (NDELA). The four carcinogens all produced DNA breaks at microgram or low milligram total doses, whereas less potent carcinogens and non-carcinogens yielded borderline or negative results, respectively, at higher doses. AAF and B[a]P produced DNA adducts, whereas none was found with the related comparators FLU or B[e]P, consistent with comet results. DEN and NDELA were also negative for adducts, as expected in the case of DEN for an alkylating agent in the standard NPL assay. Also, AFB1 and AFB2 were negative in NPL, as expected, due to the nature of ring opened aflatoxin adducts, which are resistant to enzymatic digestion. Thus, the CEGA, using comet and NPL, is capable of detection of the genotoxicity of diverse DNA-reactive carcinogens, while not yielding false positives for non-carcinogens.

  14. Effect of thickeners on aroma compound behavior in a model dairy gel.

    PubMed

    Lubbers, Samuel; Decourcelle, Nicolas; Martinez, Daniel; Guichard, Elisabeth; Tromelin, Anne

    2007-06-13

    The effects of thickeners on the headspace release of aroma compounds from a model dairy gel were investigated. Starch, pectin, and locust bean gum (LBG) were introduced separately to the fat-free dairy gel via sugar syrups. The release of nine aroma compounds was analyzed by solid-phase microextraction (SPME), and the partition coefficients of retention were calculated. For an increase in starch concentration, there was an overall decrease in aroma release. Pectin concentrations in gel higher than 0.04% caused an increase in aroma release. For LBG no major effect was observed. A quantitative structure-property relationship (QSPR) approach was used to propose which types of interactions were involved between aroma molecules and thickener macromolecules in the complex foodstuff. Twenty molecular descriptors of volatile compounds appeared to be significant in correlation with the partition coefficients of retention. The surface-weighted negatively charged partial surface area seemed to play a critical role in the behavior of aroma compound.

  15. Mouse models of DNA mismatch repair in cancer research

    PubMed Central

    Lee, Kyeryoung; Tosti, Elena; Edelmann, Winfried

    2016-01-01

    Germline mutations in DNA mismatch repair (MMR) genes are the cause of hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS) one of the most common cancer predisposition syndromes, and defects in MMR are also prevalent in sporadic colorectal cancers. In the past, the generation and analysis of mouse lines with knockout mutations in all of the known MMR genes has provided insight into how loss of individual MMR genes affects genome stability and contributes to cancer susceptibility. These studies also revealed essential functions for some of the MMR genes in B cell maturation and fertility. In this review, we will provide a brief overview of the cancer predisposition phenotypes of recently developed mouse models with targeted mutations in MutS and MutL homologs (Msh and Mlh, respectively) and their utility as preclinical models. The focus will be on mouse lines with conditional MMR mutations that have allowed more accurate modeling of human cancer syndromes in mice and that together with new technologies in gene targeting, hold great promise for the analysis of MMR-deficient intestinal tumors and other cancers which will drive the development of preventive and therapeutic treatment strategies. PMID:26708047

  16. Mouse models of DNA mismatch repair in cancer research.

    PubMed

    Lee, Kyeryoung; Tosti, Elena; Edelmann, Winfried

    2016-02-01

    Germline mutations in DNA mismatch repair (MMR) genes are the cause of hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS) one of the most common cancer predisposition syndromes, and defects in MMR are also prevalent in sporadic colorectal cancers. In the past, the generation and analysis of mouse lines with knockout mutations in all of the known MMR genes has provided insight into how loss of individual MMR genes affects genome stability and contributes to cancer susceptibility. These studies also revealed essential functions for some of the MMR genes in B cell maturation and fertility. In this review, we will provide a brief overview of the cancer predisposition phenotypes of recently developed mouse models with targeted mutations in MutS and MutL homologs (Msh and Mlh, respectively) and their utility as preclinical models. The focus will be on mouse lines with conditional MMR mutations that have allowed more accurate modeling of human cancer syndromes in mice and that together with new technologies in gene targeting, hold great promise for the analysis of MMR-deficient intestinal tumors and other cancers which will drive the development of preventive and therapeutic treatment strategies.

  17. Toward multiscale modeling of the chromatin fiber: a coarse grain model for DNA

    NASA Astrophysics Data System (ADS)

    Savelyev, Alexey; Papoian, Garegin

    2008-03-01

    In eukaryotic cells DNA is compacted a million-fold into a chromatin. Understanding the mechanism of chromatin folding is of great biological importance. All-atom Molecular Dynamics (MD) simulations could provide crucial insights into the electrostatic and structural mechanisms of chromatin folding. However, because of the enormous size of even short chromatin fiber segment and long folding time-scales, atomistic simulations are computationally impractical. Our long-term aim is to build an accurate coarse-grain (CG) model of the chromatin, derived systematically from all-atom simulations of its smaller parts. Here we report the development of the CG model for a linear DNA chain, playing the role of a linker DNA segment in the chromatin. We derived CG inter-DNA electrostatic potential from atomistic simulations with explicit solvent and mobile ions, instead of relying on the standard models of continuum electrostatics, which are inadequate at small intermolecular distances. In addition, we used the ideas of renormalization group theory to construct an optimization scheme for parameterizing the CG force field. This novel approach is designed to accurately reproduce correlations among various CG degrees of freedom. The implementation of these correlations was left as an open question in the prior studies of CG polymer models.

  18. 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.

  19. 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.

  20. 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

  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. 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

  3. 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.

  4. Which Compound to Select in Lead Optimization? Prospectively Validated Proteochemometric Models Guide Preclinical Development

    PubMed Central

    van Westen, Gerard J. P.; Wegner, Jörg K.; Geluykens, Peggy; Kwanten, Leen; Vereycken, Inge; Peeters, Anik; IJzerman, Adriaan P.; van Vlijmen, Herman W. T.; Bender, Andreas

    2011-01-01

    In quite a few diseases, drug resistance due to target variability poses a serious problem in pharmacotherapy. This is certainly true for HIV, and hence, it is often unknown which drug is best to use or to develop against an individual HIV strain. In this work we applied ‘proteochemometric’ modeling of HIV Non-Nucleoside Reverse Transcriptase (NNRTI) inhibitors to support preclinical development by predicting compound performance on multiple mutants in the lead selection stage. Proteochemometric models are based on both small molecule and target properties and can thus capture multi-target activity relationships simultaneously, the targets in this case being a set of 14 HIV Reverse Transcriptase (RT) mutants. We validated our model by experimentally confirming model predictions for 317 untested compound – mutant pairs, with a prediction error comparable with assay variability (RMSE 0.62). Furthermore, dependent on the similarity of a new mutant to the training set, we could predict with high accuracy which compound will be most effective on a sequence with a previously unknown genotype. Hence, our models allow the evaluation of compound performance on untested sequences and the selection of the most promising leads for further preclinical research. The modeling concept is likely to be applicable also to other target families with genetic variability like other viruses or bacteria, or with similar orthologs like GPCRs. PMID:22132107

  5. Protective effects of garlic sulfur compounds against DNA damage induced by direct- and indirect-acting genotoxic agents in HepG2 cells.

    PubMed

    Belloir, C; Singh, V; Daurat, C; Siess, M H; Le Bon, A M

    2006-06-01

    The aim of this study was to assess the antigenotoxic activity of several garlic organosulfur compounds (OSC) in the human hepatoma cell line HepG2, using comet assay. The OSC selected were allicin (DADSO), diallyl sulfide (DAS), diallyl disulfide (DADS), S-allyl cysteine (SAC) and allyl mercaptan (AM). To explore their potential mechanisms of action, two approaches were performed: (i) a pre-treatment protocol which allowed study of the possible modulation of drug metabolism enzymes by OSC before treatment of the cells with the genotoxic agent; (ii) a co-treatment protocol by which the ability of OSC to scavenge direct-acting compounds was assessed. Preliminary studies showed that, over the concentration range tested (5-100 microM), the studied OSC neither affected cell viability nor induced DNA damage by themselves. In the pre-treatment protocol, aflatoxin B1 genotoxicity was significantly reduced by all the OSC tested except AM. DADS was the most efficient OSC in reducing benzo(a)pyrene genotoxicity. SAC and AM significantly decreased DNA breaks in HepG2 cells treated with dimethylnitrosamine. Additionally, all the OSC studied were shown to decrease the genotoxicity of the direct-acting compounds, hydrogen peroxide and methyl methanesulfonate. This study demonstrated that garlic OSC displayed antigenotoxic activity in human metabolically competent cells.

  6. 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.

  7. Interaction of a biguanide compound with membrane model interface systems: probing the properties of antimalaria and antidiabetic compounds.

    PubMed

    Samart, Nuttaporn; Beuning, Cheryle N; Haller, Kenneth J; Rithner, Chris D; Crans, Debbie C

    2014-07-29

    Since membrane penetration is important for drug efficacy, how antimalarial precursor material 1-phenylbiguanide (PBG) interacts with an interface was characterized using a reverse micelle (RM) model system. (1)H NMR studies show that PBG partitions across the membrane interface. Specifically, the (1)H NMR studies showed that the 1-phenylbiguanide compound in an aqueous environment changed when placed near an interface. PBG is known to affect hydrogen bonding in water, and as the size of the RMs changes, the water organization in the water pool is changed. The NOESY spectrum of PBG in AOT RM contains cross-peak signals between the PBG protons and AOT protons, which is consistent with the penetration of the PBG into the interface. At the same time, there is a cross peak between the biguanide moiety and the HOD signal. This shows that these NH protons are near the HOD protons, placing the biguanide functional group in the water pool. Preliminary differential FTIR spectroscopic studies confirmed this location. In summary, we found that PBG interacts with different regions of the interface, with the phenyl group penetrating the hydrophobic interface while the biguanide remains in the water pool.

  8. 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.

  9. Detoxification of model phenolic compounds in lignocellulosic hydrolysates with peroxidase for butanol production from Clostridium beijerinckii.

    PubMed

    Cho, Dae Haeng; Lee, Yun Jie; Um, Youngsoon; Sang, Byoung-In; Kim, Yong Hwan

    2009-07-01

    In the present study, we investigated the peroxidase-catalyzed detoxification of model phenolic compounds and evaluated the inhibitory effects of the detoxified solution on butanol production by Clostridium beijerinckii National Collection of Industrial and Marine Bacteria Ltd. 8052. The six phenolic compounds, p-coumaric acid, ferulic acid, 4-hydroxybenzoic acid, vanillic acid, syringaldehyde, and vanillin, were selected as model fermentation inhibitors generated during pretreatment and hydrolysis of lignocellulose. The enzyme reaction was optimized as a function of the reaction conditions of pH, peroxidase concentration, and hydrogen peroxide to substrate ratio. Most of the tested phenolics have a broad optimum pH range of 6.0 to 9. Removal efficiency increased with the molar ratio of H(2)O(2) to each compound up to 0.5-1.25. In the case of p-coumaric acid, ferulic acid, vanillic acid, and vanillin, the removal efficiency was almost 100% with only 0.01 microM of enzyme. The tested phenolic compounds (1 g/L) inhibited cell growth by 64-74%, while completely inhibiting the production of butanol. Although syringaldehyde and vanillin were less toxic on cell growth, the level of inhibition on the butanol production was quite different. The detoxified solution remarkably improved cell growth and surprisingly increased butanol production to the level of the control. Hence, our present study, using peroxidase for the removal of model phenolic compounds, could be applied towards the detoxification of lignocellulosic hydrolysates for butanol fermentation.

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

    PubMed

    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.

  12. Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds.

    PubMed

    Makhaeva, Galina F; Rudakova, Elena V; Hein, Nichole D; Serebryakova, Olga G; Kovaleva, Nadezhda V; Boltneva, Natalia P; Fink, John K; Richardson, Rudy J

    2014-12-01

    Inhibition and aging of neuropathy target esterase (NTE) by neuropathic organophosphorus (OP) compounds triggers OP compound-induced delayed neuropathy (OPIDN), whereas inhibition of acetylcholinesterase (AChE) produces cholinergic toxicity. The neuropathic potential of an OP compound is defined by its relative inhibitory potency toward NTE vs. AChE assessed by enzyme assays following dosing in vivo or after incubations of direct-acting compounds or active metabolites with enzymes in vitro. The standard animal model of OPIDN is the adult hen, but its large size and high husbandry costs make this species a burdensome model for assessing neuropathic potential. Although the mouse does not readily exhibit clinical signs of OPIDN, it displays axonal lesions and expresses brain AChE and NTE. Therefore, the present research was performed as a further test of the hypothesis that inhibition of mouse brain AChE and NTE could be used to assess neuropathic potential using mouse brain preparations in vitro or employing mouse brain assays following dosing of OP compounds in vivo. Excellent correlations were obtained for inhibition kinetics in vitro of mouse brain enzymes vs. hen brain and human recombinant enzymes. Furthermore, inhibition of mouse brain AChE and NTE after dosing with OP compounds afforded ED(50) ratios that agreed with relative inhibitory potencies assessed in vitro. Taken together, results with mouse brain enzymes demonstrated consistent correspondence between in vitro and in vivo predictors of neuropathic potential, thus adding to previous studies supporting the validity of a mouse model for biochemical assessment of the ability of OP compounds to produce OPIDN.

  13. Using the Theory of Elasticity to Model the Structure of DNA Loops

    NASA Astrophysics Data System (ADS)

    Balaeff, Alexander; Mahadevan, L.; Schulten, Klaus

    2000-03-01

    A fast computational method to study the conformation and energetics of short DNA loops is presented. The DNA is modeled as an electrically charged elastic rod. The ensemble of equilibrium conformations of the DNA loop, attainable for given boundary conditions, is generated as a set of numerical solutions to the equations of the Kirchhoff-Love theory of elasticity. The equations are augmented by electrostatic and van der Waals force terms. These modifications allow one to account for the DNA self-repulsion and to model the DNA loop interactions with other macromolecules, involved in a biomolecular system. We demonstrate the application of the method to the test system: the looped lac operon promoter of E. coli clamped by the repressor protein and stabilized by the catabolite gene activator protein. The developed coarse-grained modeling method provides the basis for multi-resolution modeling of protein-DNA complexes, e.g., in combination with all-atom molecular dynamics simulations.

  14. pH- and salt-dependent molecular combing of DNA: experiments and phenomenological model.

    PubMed

    Benke, Annegret; Mertig, Michael; Pompe, Wolfgang

    2011-01-21

    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.

  15. 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

  16. Identification and functional modelling of DNA sequence elements of transcription.

    PubMed

    Werner, T

    2000-11-01

    Identification of transcriptional elements in large sequences is a very difficult task, as individual transcription elements (eg transcription factor binding sites,TF-sites) are not clearly correlated with regions exerting transcription control. However, elucidation of the molecular organisation of genomic regions responsible for the control of gene expression is an essential part of the efforts to annotate the genomic sequences, especially within the Human Genome Project. The task for bioinformatics in this context is twofold. The first step required is the approximate localisation of regulatory sequences in large anonymous DNA sequences. Once those regions are located, the second task is the identification of individual transcriptional control elements and correlation of a subset of such elements with transcriptional functions. Part of this second task can be achieved by constructing organisational models of regulatory regions like promoters which can reveal elements important for a gene class or the coexpression of a set of genes. Comparative genomics in non-coding regions (eg phylogenetic footprinting) is a very promising approach that allows identification of potential new regulatory elements which may be used in modelling approaches.

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

    PubMed Central

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

    2005-01-01

    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

  18. 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

    2014-03-03

    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. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  19. Prooxidant action of furanone compounds: implication of reactive oxygen species in the metal-dependent strand breaks and the formation of 8-hydroxy-2'-deoxyguanosine in DNA.

    PubMed

    Murakami, K; Haneda, M; Makino, T; Yoshino, M

    2007-07-01

    Prooxidant properties of furanone compounds including 2,5-furanone (furaneol, 4-hydroxy-2,5-dimethyl-furan-3-one), 4,5-furanone (4,5-dimethyl-3-hydroxy-2(5H)-furanone) (sotolone) and cyclotene (2-hydroxy-3-methyl-2-cyclopenten-1-one) were analyzed in relation to the metal-reducing activity. Only 2.5-furanone known as a "strawberry or pineapple furanone" inactivated aconitase the most sensitive enzyme to active oxygen in the presence of ferrous sulfate, suggesting the furaneol/iron-mediated generation of reactive oxygen species. 2,5-Furanone caused strand scission of pBR322 DNA in the presence of copper. Treatment of calf thymus DNA with 2,5-furanone plus copper produced 8-hydroxy-2'-deoxyguanosine in DNA. 2,5-Furanone showed a potent copper-reducing activity, and thus, DNA strand breaks and the formation of 8-hydroxy-2'-deoxyguanosine by 2,5-furanone can be initiated by the production of superoxide radical through the reduction of cupric ion to cuprous ion, resulting in the conversion to hydrogen peroxide and hydroxyl radical. However, an isomer and analog of 2,5-furanone, 4,5-furanone and cyclotene, respectively, did not show an inactivation of aconitase, DNA injuries including strand breakage and the formation of 8-hydroxy-2'-deoxyguanosine, and copper-reducing activity. Cytotoxic effect of 2,5-furanone with hydroxyketone structure can be explained by its prooxidant properties: furaneol/transition metal complex generates reactive oxygen species causing the inactivation of aconitase and the formation of DNA base damage by hydroxyl radical.

  20. Exploring sources of biogenic secondary organic aerosol compounds using chemical analysis and the FLEXPART model

    NASA Astrophysics Data System (ADS)

    Martinsson, Johan; Monteil, Guillaume; Sporre, Moa K.; Kaldal Hansen, Anne Maria; Kristensson, Adam; Eriksson Stenström, Kristina; Swietlicki, Erik; Glasius, Marianne

    2017-09-01

    Molecular tracers in secondary organic aerosols (SOAs) can provide information on origin of SOA, as well as regional scale processes involved in their formation. In this study 9 carboxylic acids, 11 organosulfates (OSs) and 2 nitrooxy organosulfates (NOSs) were determined in daily aerosol particle filter samples from Vavihill measurement station in southern Sweden during June and July 2012. Several of the observed compounds are photo-oxidation products from biogenic volatile organic compounds (BVOCs). Highest average mass concentrations were observed for carboxylic acids derived from fatty acids and monoterpenes (12. 3 ± 15. 6 and 13. 8 ± 11. 6 ng m-3, respectively). The FLEXPART model was used to link nine specific surface types to single measured compounds. It was found that the surface category sea and ocean was dominating the air mass exposure (56 %) but contributed to low mass concentration of observed chemical compounds. A principal component (PC) analysis identified four components, where the one with highest explanatory power (49 %) displayed clear impact of coniferous forest on measured mass concentration of a majority of the compounds. The three remaining PCs were more difficult to interpret, although azelaic, suberic, and pimelic acid were closely related to each other but not to any clear surface category. Hence, future studies should aim to deduce the biogenic sources and surface category of these compounds. This study bridges micro-level chemical speciation to air mass surface exposure at the macro level.

  1. 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.

  2. Effect of plasma and carboxylesterase on the stability, mutagenicity, and DNA cross-linking activity of some direct-acting N-nitroso compounds.

    PubMed

    Aukerman, S L; Brundrett, R B; Hilton, J; Hartman, P E

    1983-01-01

    The effects of mouse plasma, human plasma, and purified porcine liver carboxylesterase on nitrosourea, nitrosamide, and nitrosocarbamate chemical stability, mutagenicity, and DNA cross-linking activity were compared. These three classes of N-nitroso compounds are chemically similar but displayed different biological activities and were affected differently by plasma and carboxylesterase. Nitrosourea stability as well as mutagenicity and DNA cross-linking activity were affected negligibly by esterase or plasma. In contrast, nitrosamide and nitrosocarbamate stability, mutagenicity, and DNA cross-linking activity were rapidly decreased in the presence of plasma or carboxylesterase. For example, chemical half-lives were from 10- to 20-fold shorter for the nitrosamides and nitrosocarbamates in the presence of 5% mouse plasma. Similar decreases were seen for mutagenicity and DNA cross-linking activity. Preliminary studies indicated one active plasma component to be an enzyme, possibly an esterase. Additional factors such as sulfhydryls may also participate. Whereas some nitrosoureas are active antitumor agents, the lack of antitumor activity for analogous nitrosamides and nitrosocarbamates may reside predominantly in their rapid in vivo inactivation. These results may help to account for the high in vitro mutagenicity as compared with the low in vivo activities of nitrosamides and nitrosocarbamates.

  3. 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.

  4. Extending transfer-matrix studies of charge transport in dsDNA: diagonal ladder model

    NASA Astrophysics Data System (ADS)

    Wells, Stephen; Roemer, Rudoph

    2008-03-01

    The π-stacking of aromatic bases along the axis of the DNA double helix suggests that DNA should be capable of supporting electron transport. This possibility has been investigated by a variety of experimental methods, including charge-transfer between intercalated dye molecules and direct measurement of conductivity in DNA molecules bridging two electrodes. In order to explore either the biological or nanotechnological significance of charge transport in DNA, we need theoretical models capable of predicting the influence of DNA sequence and structure on its charge transport properties. Transfer matrix methods have been used in conjunction with a ladder model of dsDNA (incorporating charge transfer between adjacent bases along a strand, and between hydrogen-bonded base pairs) to predict different transport properties for random, repetitive, or coding DNA sequences. It has been suggested that DNA charge transport may be involved in cellular mechanisms to detect and repair damage to DNA strands. We present extensions to the ladder model to allow for, firstly, charge transfer ``diagonally'' (from a base on a 5' strand to an adjacent base on a 3' strand, for example), and secondly, variations in hopping amplitudes due to bending of the helix (for example, in wrapping round a histone complex). Hence we take into account the extent of the electronic states and the geometry of the DNA strand in our modeling.

  5. 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…

  6. 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…

  7. 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.

  8. Accelerated cure of phenol-formaldehyde resins : studies with model compounds

    Treesearch

    Anthony H. Conner; Linda F. Lorenz; Kolby C. Hirth

    2002-01-01

    2-Hydroxymethylphenol (2-HMP) and 4-hydroxymethylphenol (4-HMP) were used as model compounds to study the reactions that occur during cure of phenol-formaldehyde (PF) resin to which cure accelerators (ethyl formate, propylene carbonate, g-butyrolactone, and triacetin) have been added. The addition of cure accelerators significantly increased the rate of condensation...

  9. A process-based emission model for volatile organic compounds from silage sources on farms

    USDA-ARS?s Scientific Manuscript database

    Silage on dairy farms can emit large amounts of volatile organic compounds (VOCs), a precursor in the formation of tropospheric ozone. Because of the challenges associated with direct measurements, process-based modeling is another approach for estimating emissions of air pollutants from sources suc...

  10. 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…

  11. 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...

  12. 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...

  13. 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.

  14. 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…

  15. Evidential evaluation of DNA profiles using a discrete statistical model implemented in the DNA LiRa software.

    PubMed

    Puch-Solis, Roberto; Clayton, Tim

    2014-07-01

    The high sensitivity of the technology for producing profiles means that it has become routine to produce profiles from relatively small quantities of DNA. The profiles obtained from low template DNA (LTDNA) are affected by several phenomena which must be taken into consideration when interpreting and evaluating this evidence. Furthermore, many of the same phenomena affect profiles from higher amounts of DNA (e.g. where complex mixtures has been revealed). In this article we present a statistical model, which forms the basis of software DNA LiRa, and that is able to calculate likelihood ratios where one to four donors are postulated and for any number of replicates. The model can take into account dropin and allelic dropout for different contributors, template degradation and uncertain allele designations. In this statistical model unknown parameters are treated following the Empirical Bayesian paradigm. The performance of LiRa is tested using examples and the outputs are compared with those generated using two other statistical software packages likeLTD and LRmix. The concept of ban efficiency is introduced as a measure for assessing model sensitivity.

  16. 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.

  17. Evaluation of DNA bending models in their capacity to predict electrophoretic migration anomalies of satellite DNA sequences.

    PubMed

    Matyášek, Roman; Fulneček, Jaroslav; Kovařík, Aleš

    2013-09-01

    DNA containing a sequence that generates a local curvature exhibits a pronounced retardation in electrophoretic mobility. Various theoretical models have been proposed to explain relationship between DNA structural features and migration anomaly. Here, we studied the capacity of 15 static wedge-bending models to predict electrophoretic behavior of 69 satellite monomers derived from four divergent families. All monomers exhibited retarded mobility in PAGE corresponding to retardation factors ranging 1.02-1.54. The curvature varied both within and across the groups and correlated with the number, position, and lengths of A-tracts. Two dinucleotide models provided strong correlation between gel mobility and curvature prediction; two trinucleotide models were satisfactory while remaining dinucleotide models provided intermediate results with reliable prediction for subsets of sequences only. In some cases, similarly shaped molecules exhibited relatively large differences in mobility and vice versa. Generally less accurate predictions were obtained in groups containing less homogeneous sequences possessing distinct structural features. In conclusion, relatively universal theoretical models were identified suitable for the analysis of natural sequences known to harbor relatively moderate curvature. These models could be potentially applied to genome wide studies. However, in silico predictions should be viewed in context of experimental measurement of intrinsic DNA curvature. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Fruit Tree model for uptake of organic compounds from soil and air.

    PubMed

    Trapp, S

    2007-01-01

    The current European risk assessment for chemicals considers only tap water, while in reality other beverages play an important role. A good part of beverages are made from fruits, for example apple juice and vine. A mathematical model was developed to predict uptake of neutral organic chemicals from soil and air into fruits. The new fruit tree model considers eight compartments, i.e. two soil compartments, fine roots, thick roots, stem, leaves, fruits, and air. Chemical equilibrium, advective transport in xylem and phloem, diffusive exchange to soil and air and growth dilution are the main processes. The parameterization is for a square-meter of an apple orchard. The model predicts that polar, non-volatile compounds will effectively be transported from soil to fruits, while lipophilic compounds will preferably accumulate from air into fruits. Results from various experiments show no disagreement with the model predictions.

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

    PubMed Central

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

    2010-01-01

    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. PMID:20507912

  20. 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.

  1. 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.

  2. Kinetic analysis of polyoxometalate (POM) oxidation of non-phenolic lignin model compound

    Treesearch

    Tomoya Yokoyama; Hou-min Chang; Ira A. Weinstock; Richard S. Reiner; John F. Kadla

    2003-01-01

    Kinetic and reaction mechanism of non-phenolic lignin model compounds under anaerobic polyoxometalate (POM), Na5(+1.9)[SiV1(-0.1)MoW10(+0.1) 40], bleaching conditions were examined. Analyses using a syringyl type model, 1-(3,4,5-trimethoxyphenyl)ethanol (1), a guaiacyl type, 1-(3,4- imethoxyphenyl)ethanol (2), and 1- (4-ethoxy-3,5-dimethoxyphenyl)ethanol (3) suggest...

  3. Evaluation of Models for Solubility and Volatility of Copper Compounds Under Steam Generation Conditions

    SciTech Connect

    Palmer, D.; Petrov, A.

    1999-09-12

    The loss in efficiency of power plants with mixed metallurgy, due to transport and deposition of copper and its oxides in HP turbines, has been recognized as one of the key problems to be solved in the utility industry worldwide. Within this context, the most important problem to be addressed is the solubility and volatility of copper compounds under steam generation condition. This paper presents an evaluation of different solubility end volatility models for copper compounds, and presents a comparison between the calculated and test data.

  4. Repeat instability during DNA repair: Insights from model systems

    PubMed Central

    Usdin, Karen; House, Nealia C. M.; Freudenreich, Catherine H.

    2015-01-01

    The expansion of repeated sequences is the cause of over 30 inherited genetic diseases, including Huntington disease, myotonic dystrophy (types 1 and 2), fragile X syndrome, many spinocerebellar ataxias, and some cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansions are dynamic, and disease inheritance and progression are influenced by the size and the rate of expansion. Thus, an understanding of the various cellular mechanisms that cooperate to control or promote repeat expansions is of interest to human health. In addition, the study of repeat expansion and contraction mechanisms has provided insight into how repair pathways operate in the context of structure-forming DNA, as well as insights into non-canonical roles for repair proteins. Here we review the mechanisms of repeat instability, with a special emphasis on the knowledge gained from the various model systems that have been developed to study this topic. We cover the repair pathways and proteins that operate to maintain genome stability, or in some cases cause instability, and the cross-talk and interactions between them. PMID:25608779

  5. Gene 5 protein-DNA complex: modeling binding interactions.

    PubMed

    Hutchinson, D L; Barnett, B L; Bobst, A M

    1990-08-01

    A helical (not toroidal) complex consisting of eight gene 5 protein dimers per turn is proposed for the extension of DNA from dimer to dimer using known bond length constraints, postulated protein-nucleic acid interactions (determined from NMR and chemical modification studies), other physical properties of the complex, and data from electron micrographs. The binding channel has been dictated by these known parameters and the relative ease of geometrically fitting these constituents. This channel is different from that previously reported by other modelers. The channel lies underneath the long arm "claw-like" extension of the monomer, so that it rests inside the outer surface of the protein complex. An explanation is proposed for the two binding modes, n = 4 (the predominate mode) and n = 3, based on the weak binding interaction of Tyrosine 34. Also, the site of the less mobile nucleic acid base as reported from ESR studies (S.-C. Kao, E.V. Bobst, G.T. Pauly and A.M. Bobst, J. Biom. Struc. Dyn. 3,261 (1985)) is postulated as involving the fourth nucleotide, and this particular base is stacked between Tyrosine 34 and Phenylalanine 73'.

  6. The MCRA model for probabilistic single-compound and cumulative risk assessment of pesticides.

    PubMed

    van der Voet, Hilko; de Boer, Waldo J; Kruisselbrink, Johannes W; Goedhart, Paul W; van der Heijden, Gerie W A M; Kennedy, Marc C; Boon, Polly E; van Klaveren, Jacob D

    2015-05-01

    Pesticide risk assessment is hampered by worst-case assumptions leading to overly pessimistic assessments. On the other hand, cumulative health effects of similar pesticides are often not taken into account. This paper describes models and a web-based software system developed in the European research project ACROPOLIS. The models are appropriate for both acute and chronic exposure assessments of single compounds and of multiple compounds in cumulative assessment groups. The software system MCRA (Monte Carlo Risk Assessment) is available for stakeholders in pesticide risk assessment at mcra.rivm.nl. We describe the MCRA implementation of the methods as advised in the 2012 EFSA Guidance on probabilistic modelling, as well as more refined methods developed in the ACROPOLIS project. The emphasis is on cumulative assessments. Two approaches, sample-based and compound-based, are contrasted. It is shown that additional data on agricultural use of pesticides may give more realistic risk assessments. Examples are given of model and software validation of acute and chronic assessments, using both simulated data and comparisons against the previous release of MCRA and against the standard software DEEM-FCID used by the Environmental Protection Agency in the USA. It is shown that the EFSA Guidance pessimistic model may not always give an appropriate modelling of exposure.

  7. Development and validation of quantitative structure-activity relationship models for compounds acting on serotoninergic receptors.

    PubMed

    Zydek, Grażyna; Brzezińska, Elżbieta

    2012-01-01

    A quantitative structure-activity relationship (QSAR) study has been made on 20 compounds with serotonin (5-HT) receptor affinity. Thin-layer chromatographic (TLC) data and physicochemical parameters were applied in this study. RP2 TLC 60F(254) plates (silanized) impregnated with solutions of propionic acid, ethylbenzene, 4-ethylphenol, and propionamide (used as analogues of the key receptor amino acids) and their mixtures (denoted as S1-S7 biochromatographic models) were used in two developing phases as a model of drug-5-HT receptor interaction. The semiempirical method AM1 (HyperChem v. 7.0 program) and ACD/Labs v. 8.0 program were employed to calculate a set of physicochemical parameters for the investigated compounds. Correlation and multiple linear regression analysis were used to search for the best QSAR equations. The correlations obtained for the compounds studied represent their interactions with the proposed biochromatographic models. The good multivariate relationships (R(2) = 0.78-0.84) obtained by means of regression analysis can be used for predicting the quantitative effect of biological activity of different compounds with 5-HT receptor affinity. "Leave-one-out" (LOO) and "leave-N-out" (LNO) cross-validation methods were used to judge the predictive power of final regression equations.

  8. Temperature-dependent kinetics of grape seed phenolic compounds extraction: experiment and model.

    PubMed

    Bucić-Kojić, Ana; Sovová, Helena; Planinić, Mirela; Tomas, Srećko

    2013-02-15

    The kinetics of a batch solid-liquid extraction of total phenolic compounds (PC) from milled grape seed (Vitis vinifera L. cv. "Frankovka") using 50% ethanol at different extraction temperatures (25-80°C) was studied. The maximum yield of PC was 0.13 kg(GAE)/kg(db) after 200 min of extraction in agitated vessel at 80°C. A new model based on the assumptions of a first order kinetics mechanism for the solid-liquid extraction and a linear equilibrium at the solid-liquid interface was developed. The model involves the concept of broken and intact cells in order to describe two successive extraction periods: a very fast surface washing process followed by slow diffusion of phenolic compounds from grape seeds to the solvent. The proposed model is suited to fit experimental data and to simulate the extraction of phenolic compounds, which was confirmed by the correlation coefficient (r≥0.965), the root mean square error (RMSE≤0.003 kg(GAE)/kg(db)) and the mean relative deviation modulus (E≤2.149%). The temperature influenced both equilibrium partition coefficients of phenolic compounds and transport properties, which is manifested by a relatively high value of activation energy (23-24) kJ/mol and by values of effective diffusivity in seed particles.

  9. Modeling of protein and phenolic compound removal from aqueous solutions by electrocoagulation.

    PubMed

    Robić, Goran; Miranda, Everson Alves

    2010-01-01

    Electrocoagulation is a technique basically applied in water and wastewater treatment, but which has a number of potential applications in polymer, protein, drug, and vaccine delivery. In this work, we correlate the current applied between the electrodes to the removal of phenolic compounds or protein from aqueous solutions, but the principle can also be applied to other biological compounds such as plant pigments and sugars. Simple and time-dependent models were developed based on the complex formation between these biological substances and the aluminium hydroxide gel phase. The models developed represent a good agreement with experimental data (R(2) as high as 0.992). Besides construction of the models, the effect of pH on the efficiency of removal of proteins and phenolic compounds was evaluated. It was found that this parameter has significant effect on the efficiency of the electrocoagulation and the maximal removal efficiency for bovine serum albumin and phenolic compound catechin was observed at pH 8.0.

  10. Modelling Charge Transport in DNA Using Transfer Matrices with Diagonal Terms

    NASA Astrophysics Data System (ADS)

    Wells, Stephen A.; Shih, Chi-Tin; Römer, Rudolf A.

    There is increasing evidence that DNA can support a considerable degree of charge transport along the strand by hopping of holes from one base to another, and that this charge transport may be relevant to DNA regulation, damage detection and repair. A surprisingly useful amount of insight can be gained from the construction of simple tight-binding models of charge transport, which can be investigated using the transfer-matrix method. The data thus obtained indicate a correlation between DNA charge-transport properties and the locations of cancerous mutation. We review models for DNA charge transport and their extension to include more physically realistic diagonal-hopping terms.

  11. Modelling Charge Transport in DNA Using Transfer Matrices with Diagonal Terms

    NASA Astrophysics Data System (ADS)

    Wells, Stephen A.; Shih, Chi-Tin; Römer, Rudolf A.

    2010-12-01

    There is increasing evidence that DNA can support a considerable degree of charge transport along the strand by hopping of holes from one base to another, and that this charge transport may be relevant to DNA regulation, damage detection and repair. A surprisingly useful amount of insight can be gained from the construction of simple tight-binding models of charge transport, which can be investigated using the transfer-matrix method. The data thus obtained indicate a correlation between DNA charge-transport properties and the locations of cancerous mutation. We review models for DNA charge transport and their extension to include more physically realistic diagonal-hopping terms.

  12. Integrative modelling of tumour DNA methylation quantifies the contribution of metabolism

    PubMed Central

    Mehrmohamadi, Mahya; Mentch, Lucas K.; Clark, Andrew G.; Locasale, Jason W.

    2016-01-01

    Altered DNA methylation is common in cancer and often considered an early event in tumorigenesis. However, the sources of heterogeneity of DNA methylation among tumours remain poorly defined. Here we capitalize on the availability of multi-platform data on thousands of human tumours to build integrative models of DNA methylation. We quantify the contribution of clinical and molecular factors in explaining intertumoral variability in DNA methylation. We show that the levels of a set of metabolic genes involved in the methionine cycle is predictive of several features of DNA methylation in tumours, including the methylation of cancer genes. Finally, we demonstrate that patients whose DNA methylation can be predicted from the methionine cycle exhibited improved survival over cases where this regulation is disrupted. This study represents a comprehensive analysis of the determinants of methylation and demonstrates the surprisingly large interaction between metabolism and DNA methylation variation. Together, our results quantify links between tumour metabolism and epigenetics and outline clinical implications. PMID:27966532

  13. Bond cleavage of lignin model compounds into aromatic monomers using supported metal catalysts in supercritical water

    PubMed Central

    Yamaguchi, Aritomo; Mimura, Naoki; Shirai, Masayuki; Sato, Osamu

    2017-01-01

    More efficient use of lignin carbon is necessary for carbon-efficient utilization of lignocellulosic biomass. Conversion of lignin into valuable aromatic compounds requires the cleavage of C–O ether bonds and C–C bonds between lignin monomer units. The catalytic cleavage of C–O bonds is still challenging, and cleavage of C–C bonds is even more difficult. Here, we report cleavage of the aromatic C–O bonds in lignin model compounds using supported metal catalysts in supercritical water without adding hydrogen gas and without causing hydrogenation of the aromatic rings. The cleavage of the C–C bond in bibenzyl was also achieved with Rh/C as a catalyst. Use of this technique may greatly facilitate the conversion of lignin into valuable aromatic compounds. PMID:28387304

  14. Modeling interactions between C₆₀ antiviral compounds and HIV protease.

    PubMed

    Al Garalleh, Hakim; Thamwattana, Ngamta; Cox, Barry J; Hill, James M

    2015-01-01

    Fullerenes have generated a great deal of interest in recent years, due to their properties and potential applications in many fields, including medicine. In this paper, we study an antiviral fullerene compound which may be used to treat the human immunodeficiency virus (HIV). We formulate a mathematical model which can describe the interaction energy between the C[Formula: see text] antiviral compounds and the HIV. In particular, this paper predicts the energy and force arising from the interaction between HIV active region and the antiviral molecule which is attached to the external surface of a fullerene C[Formula: see text]. These interactions are calculated based on the structure of the antiviral molecules. Our results show that the binding of fullerene C[Formula: see text] to the antiviral molecules increases the efficiency of the compound to prohibit the activity of HIV.

  15. Development of Models for Predicting the Predominant Taste and Odor Compounds in Taihu Lake, China

    PubMed Central

    Sun, Xiaoxue; Deng, Xuwei; Niu, Yuan; Xie, Ping

    2012-01-01

    Taste and odor (T&O) problems, which have adversely affected the quality of water supplied to millions of residents, have repeatedly occurred in Taihu Lake (e.g., a serious odor accident occurred in 2007). Because these accidents are difficult for water resource managers to forecast in a timely manner, there is an urgent need to develop optimum models to predict these T&O problems. For this purpose, various biotic and abiotic environmental parameters were monitored monthly for one year at 30 sites across Taihu Lake. This is the first investigation of this huge lake to sample T&O compounds at the whole-lake level. Certain phytoplankton taxa were important variables in the models; for instance, the concentrations of the particle-bound 2-methylisoborneol (p-MIB) were correlated with the presence of Oscillatoria, whereas those of the p-β-cyclocitral and p-β-ionone were correlated with Microcystis levels. Abiotic factors such as nitrogen (TN, TDN, NO3-N, and NO2-N), pH, DO, COND, COD and Chl-a also contributed significantly to the T&O predictive models. The dissolved (d) T&O compounds were related to both the algal biomass and to certain abiotic environmental factors, whereas the particle-bound (p) T&O compounds were more strongly related to the algal presence. We also tested the validity of these models using an independent data set that was previously collected from Taihu Lake in 2008. In comparing the concentrations of the T&O compounds observed in 2008 with those concentrations predicted from our models, we found that most of the predicted data points fell within the 90% confidence intervals of the observed values. This result supported the validity of these models in the studied system. These models, basing on easily collected environmental data, will be of practical value to the water resource managers of Taihu Lake for evaluating the probability of T&O accidents. PMID:23284835

  16. Predicting reactivity of model DOM compounds towards chlorine with mediated electrochemical oxidation.

    PubMed

    de Vera, Glen Andrew; Gernjak, Wolfgang; Radjenovic, Jelena

    2017-05-01

    Chlorine demand of a water sample depends on the characteristics of dissolved organic matter (DOM). It is an important parameter for water utilities used to assess oxidant and/or disinfectant consumption of source waters during treatment and distribution. In this study, model compounds namely resorcinol, tannic acid, vanillin, cysteine, tyrosine, and tryptophan were used to represent the reactive moieties of complex DOM mixtures. The reactivity of these compounds was evaluated in terms of Cl2 demand and electron donating capacity (EDC). The EDC was determined by mediated electrochemical oxidation (MEO) which involves the use of 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) as an electron shuttle. The Cl2 demand of readily oxidizable compounds (resorcinol, tannic acid, vanillin, and cysteine) was found to correlate well with EDC (R(2) = 0.98). The EDC values (mol e(-)/mol C) of the model compounds are as follows: 1.18 (cysteine) > 0.77 (resorcinol) > 0.59 (vanillin) > 0.52 (tannic acid) > 0.36 (tryptophan) > 0.19 (tyrosine). To determine the effect of pre-oxidation on EDC, ozone was added (0.1 mol O3/mol C) into each model compound solution. Ozonation caused a general decrease in EDC (10-40%), chlorine demand (10-30%), and UV absorbance (10-40%), except for tyrosine which showed both increased UV275 and EDC. Before and after ozonation, 24 h disinfection byproduct (DBP) formation potential tests (Cl2 residual = 1.5 mg/L) were conducted to evaluate the use of EDC for DBP formation prediction. The results indicate that there was no significant correlation between the EDC of the model compounds and the formation potentials of adsorbable organic chlorine, trichloromethane, and trichloroacetic acid. This suggests that while EDC correlates with Cl2 demand, chlorine consumption may not directly translate to DBP formation because oxidation reactions may dominate over substitution reactions. Overall, this study provides useful insights on the

  17. Behavior of platinum(iv) complexes in models of tumor hypoxia: cytotoxicity, compound distribution and accumulation.

    PubMed

    Schreiber-Brynzak, Ekaterina; Pichler, Verena; Heffeter, Petra; Hanson, Buck; Theiner, Sarah; Lichtscheidl-Schultz, Irene; Kornauth, Christoph; Bamonti, Luca; Dhery, Vineet; Groza, Diana; Berry, David; Berger, Walter; Galanski, Markus; Jakupec, Michael A; Keppler, Bernhard K

    2016-04-01

    Hypoxia in solid tumors remains a challenge for conventional cancer therapeutics. As a source for resistance, metastasis development and drug bioprocessing, it influences treatment results and disease outcome. Bioreductive platinum(iv) prodrugs might be advantageous over conventional metal-based therapeutics, as biotransformation in a reductive milieu, such as under hypoxia, is required for drug activation. This study deals with a two-step screening of experimental platinum(iv) prodrugs with different rates of reduction and lipophilicity with the aim of identifying the most appropriate compounds for further investigations. In the first step, the cytotoxicity of all compounds was compared in hypoxic multicellular spheroids and monolayer culture using a set of cancer cell lines with different sensitivities to platinum(ii) compounds. Secondly, two selected compounds were tested in hypoxic xenografts in SCID mouse models in comparison to satraplatin, and, additionally, (LA)-ICP-MS-based accumulation and distribution studies were performed for these compounds in hypoxic spheroids and xenografts. Our findings suggest that, while cellular uptake and cytotoxicity strongly correlate with lipophilicity, cytotoxicity under hypoxia compared to non-hypoxic conditions and antitumor activity of platinum(iv) prodrugs are dependent on their rate of reduction.

  18. 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.

  19. 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.

  20. 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.

  1. Bilirubin conjugates of human bile. Nuclear-magnetic-resonance, infrared and optical spectra of model compounds

    PubMed Central

    Kuenzle, Clive C.

    1970-01-01

    N.m.r., i.r. and optical spectra of model compounds were recorded. These were to help in elucidating the structures of the phenylazo derivatives of bilirubin conjugates isolated from human bile. Model compounds included commercial and human bile bilirubin, mesobilirubin, bilirubin dimethyl ester, dimethoxybilirubin dimethyl ester and the corresponding phenylazo derivatives. The phenylazo derivative of vinylneoxanthobilirubinic acid was also investigated. All compounds were of the type IXα, and no other isomer could be detected with the spectroscopic methods employed. The compounds crystallize as the lactams, except for dimethoxybilirubin dimethyl ester and its phenylazo derivative, which are held in the lactim ether configuration. With all other compounds no tautomeric forms other than the lactams could be detected, although small proportions of bilirubin must exist as the lactim. Bilirubin does not form a betaine, a structure that has been proposed by von Dobeneck & Brunner (1965) to explain the bathochromic shift of its optical spectrum as compared with the expected position of the absorption maximum at 420nm. However, this shift to 453nm can be explained on the basis of internal hydrogen bonds occurring between the carboxylic protons and the pyrrole rings of bilirubin, as proposed by Fog & Jellum (1963), and new evidence for such a bonding has been accumulated. The bilirubin sulphate described by Watson (1958), which is formed by treatment of bilirubin with concentrated sulphuric acid and acetic anhydride, was also investigated. The main product of this reaction was isolated as its phenylazo derivative, and was shown to be 3,18-di(ethylidene sulphate)-2,7,13,17-tetramethylbiladiene-ac-8,12-dipropionic acid. The reaction leading to this compound is an addition of sulphuric acid to the vinyl side chains of bilirubin according to Markownikoff's rule. PMID:5500301

  2. Synthesis and antitumor activity of duocarmycin derivatives: modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups.

    PubMed

    Amishiro, N; Nagamura, S; Murakata, C; Okamoto, A; Kobayashi, E; Asada, M; Gomi, K; Tamaoki, T; Okabe, M; Yamaguchi, N; Yamaguchi, K; Saito, H

    2000-02-01

    A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin bearing the simplified DNA-binding moieties such as cinnamoyl or heteroarylacryloyl groups were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted analogues in aqueous solution and the conversion to their active form (cyclopropane compound) from the 8-O-substituted analogues in mice or human serum were examined. The 8-O-substituted A-ring pyrrole derivatives bearing the simplified DNA-binding moieties showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment-B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreover, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result indicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW-2189.

  3. Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks.

    PubMed

    Ocio, Enrique M; Maiso, Patricia; Chen, Xi; Garayoa, Mercedes; Alvarez-Fernández, Stela; San-Segundo, Laura; Vilanova, David; López-Corral, Lucía; Montero, Juan C; Hernández-Iglesias, Teresa; de Alava, Enrique; Galmarini, Carlos; Avilés, Pablo; Cuevas, Carmen; San-Miguel, Jesús F; Pandiella, Atanasio

    2009-04-16

    Multiple myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC(50) values from picomolar to low nanomolar ranges. It also showed remarkable ex vivo potency in plasma cells from patients and in MM cells in vivo xenografted in mice. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand breaks (DSBs), evidenced by an increase in phospho-histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53 wild-type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSBs and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumors also demonstrated histone-H2AX phosphorylation and p53 overexpression. Gene expression profile studies were concordant with these results, revealing an important deregulation of genes involved in DNA damage response. The potent in vitro and in vivo antimyeloma activity of Zalypsis uncovers the high sensitivity of tumor plasma cells to DSBs and strongly supports the use of this compound in MM patients.

  4. Measurement of unscheduled DNA synthesis and S-phase synthesis in rodent hepatocytes following in vivo treatment: Testing of 24 compounds

    SciTech Connect

    Mirsalis, J.C.; Tyson, C.K.; Steinmetz, K.L.; Loh, E.K.; Hamilton, C.M.; Bakke, J.P. ); Spalding, J.W. )

    1989-01-01

    The in vivo-in vitro hepatocyte DNA repair assay has been shown to be useful for studying genotoxic hepatocarcinogens. In addition, measurement of S-phase synthesis (SPS) provides an indirect indicator of hepatocellular proliferation, which may be an important mechanism in rodent carcinogenesis. This assay was used to examine 24 chemicals for their ability to induce unscheduled DNA synthesis (UDS) or SPS in Fischer-344 rats or B6C3F1 mice following in vivo treatment. Hepatocytes were isolated by liver perfusion and incubated with {sup 3}H-thymidine following in vivo treatment by gavage. Chemicals chosen for testing were from the National Toxicology Program (NTP) genetic toxicology testing program and most were also evaluated in long-term animal studies conducted by the NTP. Dinitrotoluene and Michler's Ketone induced positive UDS response in rat, while N-nitrosodiethanolamine and selenium sulfide induced equivocal UDS results in mouse and rat, respectively. BCMEE, bromoform, chloroform, PBB, 1,1,2-trichloroethane, and trichloroethylene were all potent inducers of SPS in mouse liver, while C.I. Solvent Yellow 14, and 1,1,2,2-tetrachloroethane yielded equivocal SPS results in rat and mouse, respectively. These results indicate that most of the test compounds do not induced UDS in the liver; however, the significant S-phase response induced by many of these compounds, especially the halogenated solvents, may be an important mechanism in their hepatocarinogenicity.

  5. Estimating emissions of carbonaceous compounds from southern african fires : a re-analysis of modeling techniques

    NASA Astrophysics Data System (ADS)

    Hély, C.; Caylor, K. K.; Alleaume, S.; Swap, R. J.; Shugart, H. H.

    2003-04-01

    When simulating emissions from biomass burning in southern Africa for the SAFARI 2000, we detected what appears to be a systematic bias in the model used to predict the emissions of various carbon compounds from fires. The summation of carbon in the compounds released to the atmosphere during burning does not have a mass balance with the amount of carbon lost from the fuel sources in the ecosystem. One might expect minor inconsistencies in mass balance because empirical measurements of carbon compounds emitted by a fire are measured with some degree of sampling error. On the contrary, we find that the field measurements on which the model is derived do not exhibit persistent errors with respect to mass balance. A reanalysis of the data used to develop the emissions model indicates that the use of emission factors instead of emission ratios in model formulation is the most fundamental cause for the persistent bias observed in the overestimation of emissions. We also find that the use of a modeling methodology that independently relates the emission factors of multiple carbon-bearing compounds to fuel load in fires has led to an over-simplification of the ways in which the quantity of compound-specific emissions are co-limited through mass balance. Finally, our reanalysis reveals the presence of auto-correlation in the regressions used to estimate model parameters, and the removal of these auto-correlated parameters greatly reduces the model's explanatory power. This leads to the conclusion that current data on fires in southern Africa are sufficient to support a dynamic model of emission ratios based on fuel composition for CO2 and CO only, and that constant emission ratios based on remaining mass balance are more appropriate for CH4, NMHC and PM2.5. We compare emission estimates of southern African fires using both the previous emission ratio models and the new model derived from our reanalysis. We conclude that the new approach does a better job of constraining

  6. Moving beyond Watson-Crick models of coarse grained DNA dynamics

    NASA Astrophysics Data System (ADS)

    Linak, Margaret C.; Tourdot, Richard; Dorfman, Kevin D.

    2011-11-01

    DNA produces a wide range of structures in addition to the canonical B-form of double-stranded DNA. Some of these structures are stabilized by Hoogsteen bonds. We developed an experimentally parameterized, coarse-grained model that incorporates such bonds. The model reproduces many of the microscopic features of double-stranded DNA and captures the experimental melting curves for a number of short DNA hairpins, even when the open state forms complicated secondary structures. We demonstrate the utility of the model by simulating the folding of a thrombin aptamer, which contains G-quartets, and strand invasion during triplex formation. Our results highlight the importance of including Hoogsteen bonding in coarse-grained models of DNA.

  7. Chromatin dynamics after DNA damage: the legacy of the Access-Repair-Restore model

    PubMed Central

    Polo, Sophie E.; Almouzni, Geneviève

    2016-01-01

    Eukaryotic genomes are packaged into chromatin, which is the physiological substrate for all DNA transactions, including DNA damage and repair. Chromatin organization imposes major constraints on DNA damage repair and thus undergoes critical rearrangements during the repair process. These rearrangements have been integrated into the “Access-Repair-Restore” (ARR) model, which provides a molecular framework for chromatin dynamics in response to DNA damage. Here, we take a historical perspective on the elaboration of this model and describe the molecular players involved in damaged chromatin reorganization in human cells. In particular, we present our current knowledge of chromatin assembly coupled to DNA damage repair, focusing on the role of histone variants and their dedicated chaperones. Finally, we discuss the impact of chromatin rearrangements after DNA damage on chromatin function and epigenome maintenance. PMID:26429064

  8. Chromatin dynamics after DNA damage: The legacy of the access-repair-restore model.

    PubMed

    Polo, Sophie E; Almouzni, Geneviève

    2015-12-01

    Eukaryotic genomes are packaged into chromatin, which is the physiological substrate for all DNA transactions, including DNA damage and repair. Chromatin organization imposes major constraints on DNA damage repair and thus undergoes critical rearrangements during the repair process. These rearrangements have been integrated into the "access-repair-restore" (ARR) model, which provides a molecular framework for chromatin dynamics in response to DNA damage. Here, we take a historical perspective on the elaboration of this model and describe the molecular players involved in damaged chromatin reorganization in human cells. In particular, we present our current knowledge of chromatin assembly coupled to DNA damage repair, focusing on the role of histone variants and their dedicated chaperones. Finally, we discuss the impact of chromatin rearrangements after DNA damage on chromatin function and epigenome maintenance. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Acquisition of a comprhensive air quality model evaluation data set for organic compounds

    SciTech Connect

    Fraser, M.P.; CAss, G.R.; Grosjean, E.; Grosjean, D.

    1995-12-01

    In previous work, photochemical airshed models have been formulated and tested that are capable of predicting the concentrations of more than 50 individual vapor-phase organic compounds that are found in the urban atmosphere. In a separate development, air quality models that account for the concentration of nearly 100 particle-phase organic compounds have been tested. The opportunity thus exists to create a combined air quality model that simultaneously tracks both gas-phase, semi-volatile, and particle-phase organic compounds that range in carbon number from C1 to about C34. Such a tool can be used both to explore the relationship between source emissions and ambient air quality, and to study gas-to-particle conversion processes for organic compounds. A major barrier to the development of such a comprehensive model for atmospheric organic air pollution is the absence of an equally comprehensive atmospheric data base against which such a model can be tested. During September, 1993, an experiment designed to acquire such an air quality model validation data set for organics was conducted in Southern California. At four urban locations and at one upwind offshore island, consecutive measurements over four hour averaging limes were made of speciated vapor phase hydrocarbons, chlorinated organics, and certain gas phase oxygenates via stainless steel canister collection followed by GC/FID and GC/MS analysis. Semi-volatile organics were collected on PUF cartridges, and particle phase organics were collected by filtration, followed by GC/MS analysis. Aldehydes were collected on DNPH impregnated cartridges, and PAN`s were measured by electron capture GC. The design and selected results of that experiment will be discussed.

  10. Identifying Intracellular pDNA Losses From a Model of Nonviral Gene Delivery.

    PubMed

    Martin, Timothy; Wysocki, Beata; Wysocki, Tadeusz; Pannier, Angela

    2015-01-23

    Nonviral gene delivery systems are a type of nano-communication system that transmit plasmid packets (i.e. pDNA packets) that are programmed at the nanoscale to biological systems at the microscopic cellular level. This engineered nano-communication system suffers large pDNA losses during transmission of the genetically encoded information, preventing its use in biotechnological and medical applications. The pDNA losses largely remain uncharacterized, and the ramifications of reducing pDNA loss from newly designed gene delivery systems remain difficult to predict. Here, the pDNA losses during primary and secondary transmission chains were identified utilizing a MATLAB model employing queuing theory simulating delivery of pEGFPLuc transgene to HeLa cells carried by Lipofectamine 2000 nonviral DNA carrier. Minimizing pDNA loss during endosomal escape of the primary transmission process results in increased number of pDNA in the nucleus with increased transfection, but with increased probability of cell death. The number of pDNA copies in the nucleus and the amount of time the pDNAs are in the nucleus directly correlates to improved transfection efficiency. During secondary transmission, pDNAs are degraded during distribution to daughter cells. Reducing pDNA losses improves transfection, but a balance in quantity of nuclear pDNA, mitosis, and toxicity must be considered in order to achieve therapeutically relevant transfection levels.

  11. Toxic effects of perfluorinated compounds at human cellular level and on a model vertebrate.

    PubMed

    Rainieri, Sandra; Conlledo, Nadia; Langerholc, Tomaž; Madorran, Eneko; Sala, Martin; Barranco, Alejandro

    2017-06-01

    This work aims at deepening the understanding of the mode of action of some of the most prominent perfluorinated compounds (PFCs) by detecting in a realistic way their effects. To this end, after adjusting the exposure media taking into account the biological model employed and the physico-chemical properties of PFCs, we evaluated the toxic effects of PFOA, PFOS and PFNA in a human macrophage cell line (TLT cells) and in zebrafish embryos. We performed such evaluation on individual compounds and mixtures. Acute toxicity was greater for PFOS in zebrafish; however, it was greater for PFNA in TLT cells. PFNA was also the compound producing the greatest levels of oxidative stress, both in zebrafish and TLT cells. Additionally, in both biological systems, it showed a much stronger effect on mixtures in comparison to the others PFCs tested in this work. Mixture studies in zebrafish showed that acute toxicity depended on the concentration and that the mixture was far more toxic than the individual compounds. This study highlights the importance of studying PFCs in realistic conditions on various biological models. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. 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. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

    PubMed

    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.

  14. 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

  15. Novel Class of Thiourea Compounds That Inhibit Herpes Simplex Virus Type 1 DNA Cleavage and Encapsidation: Resistance Maps to the UL6 Gene

    PubMed Central

    van Zeijl, Marja; Fairhurst, Jeanette; Jones, Thomas R.; Vernon, Steven K.; Morin, John; LaRocque, James; Feld, Boris; O'Hara, Bryan; Bloom, Jonathan D.; Johann, Stephen V.

    2000-01-01

    In our search for novel inhibitors of herpes simplex virus type 1 (HSV-1), a new class of thiourea inhibitors was discovered. N-{4-[3-(5-Chloro-2,4-dimethoxyphenyl)-thioureido]-phenyl}-acetamide and its 2-fluoro-benzamide derivative inhibited HSV-1 replication. HSV-2, human cytomegalovirus, and varicella-zoster virus were inhibited to a lesser extent. The compounds acted late in the replication cycle by impairing both the cleavage of concatameric viral DNA into progeny genome length and the packaging of the DNA into capsids, indicative of a defect in the encapsidation process. To uncover the molecular target of the inhibition, resistant HSV-1 isolates were generated, and the mutation responsible for the resistance was mapped using marker transfer techniques. Each of three independent isolates had point mutations in the UL6 gene which resulted in independent single-amino-acid changes. One mutation was located in the N terminus of the protein (E121D), while two were located close together in the C terminus (A618V and Q621R). Each of these point mutations was sufficient to confer drug resistance when introduced into wild-type virus. The UL6 gene is one of the seven HSV-1 genes known to play a role in DNA packaging. This novel class of inhibitors has provided a new tool for dissection of HSV-1 encapsidation mechanisms and has uncovered a new viable target for the treatment of herpesviral diseases. PMID:10982350

  16. Comparison of receptor models for source apportionment of volatile organic compounds in Beijing, China.

    PubMed

    Song, Yu; Dai, Wei; Shao, Min; Liu, Ying; Lu, Sihua; Kuster, William; Goldan, Paul

    2008-11-01

    Identifying the sources of volatile organic compounds (VOCs) is key to reducing ground-level ozone and secondary organic aerosols (SOAs). Several receptor models have been developed to apportion sources, but an intercomparison of these models had not been performed for VOCs in China. In the present study, we compared VOC sources based on chemical mass balance (CMB), UNMIX, and positive matrix factorization (PMF) models. Gasoline-related sources, petrochemical production, and liquefied petroleum gas (LPG) were identified by all three models as the major contributors, with UNMIX and PMF producing quite similar results. The contributions of gasoline-related sources and LPG estimated by the CMB model were higher, and petrochemical emissions were lower than in the UNMIX and PMF results, possibly because the VOC profiles used in the CMB model were for fresh emissions and the profiles extracted from ambient measurements by the two-factor analysis models were "aged".

  17. 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 deo