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Sample records for dna model compounds

  1. Antiparasitic Compounds That Target DNA

    PubMed Central

    Wilson, W. David; Tanious, Farial A.; Mathis, Amanda; Tevis, Denise; Hall, James Edwin; Boykin, David W.

    2008-01-01

    Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites that cause diseases such as sleeping sickness and leishmania and adversely affect millions of people each year. The most active compounds bind specifically and strongly in the DNA minor groove at AT sequences. The compounds enter parasite cells rapidly and appear first in the kinetoplast that contains the mitochondrial DNA of the parasite. With time the compounds are also generally seen in the cell nucleus but are not significantly observed in the cytoplasm. The kinetoplast decays over time and disappears from the mitochondria of treated cells. At this point the compounds begin to be observed in other regions of the cell, such as the acidocalcisomes. The cells typically die in 24–48 hours after treatment. Active compounds appear to selectively target extended AT sequences and induce changes in kinetoplast DNA minicircles that cause a synergistic destruction of the catenated kinetoplast DNA network and cell death. PMID:18343228

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

    PubMed

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

    1983-09-15

    The crystal structure of the anthraquinone derivative 1,8-bis-(2-diethylaminoethylamino)-anthracene-9,10-dione has been established. This compound was prepared as a potential DNA-intercalating agent based on the proven intercalators doxorubicin and mitoxantrone. Its DNA-binding properties have been examined experimentally by spectroscopic, thermal denaturation and ccc-DNA unwinding techniques: the results are consistent with an intercalative mode of binding to DNA. Computer graphics stimulation of the intercalative docking of this compound into the self-complementary dimer of d(CpG) has provided a minimum energy geometrical arrangement for the bound drug in the intercalation site comparable to that for proflavine when intercalated into the same d(CpG) model system. Entry of the compound into the site can only occur via the major groove. PMID:6626250

  3. 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/

  4. 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)

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

    PubMed

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

    2015-10-15

    Graphite electrode was modified using multi-walled carbon nanotubes (MWCNT), chitosan (CS), glutaraldehyde (GTA) and DNA nanostructures (nsDNA). DNA nanostructures of 50 nm in size were produced from single DNA template sequence using a simple two step procedure and were confirmed using TEM and AFM analysis. The modified electrode was applied to the electrochemical detection of aromatic compounds using EIS. The modified electrode was characterized using differential pulse voltammetry (DPV), electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). For comparison, electrochemical results derived from single stranded (50 bp length) and double stranded (50 bp length) DNA based biosensors were used. The results indicate that the modified electrode prior to nsDNA immobilization provides a viable platform that effectively promotes electron transfer between nsDNA and the electrode. The mode of binding between the nsDNA and aromatic compounds was investigated using EIS, indicating that the dominant interaction is non-covalent. nsDNA based biosensor was observed to act as an efficient biosensor in selective and sensitive identification of aromatic compounds. PMID:25982727

  6. 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.

  7. 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.

  8. Structural analysis of isosteviol and related compounds as DNA polymerase and DNA topoisomerase inhibitors.

    PubMed

    Mizushina, Yoshiyuki; Akihisa, Toshihiro; Ukiya, Motohiko; Hamasaki, Yusuke; Murakami-Nakai, Chikako; Kuriyama, Isoko; Takeuchi, Toshifumi; Sugawara, Fumio; Yoshida, Hiromi

    2005-09-01

    Isosteviol (ent-16-ketobeyeran-19-oic acid) is a hydrolysis product of stevioside, which is a natural sweetener produced in the leaves of Stevia rebaudiana (Bertoni) Bertoni. In this report, we prepared isosteviol and related compounds from stevioside by microbial transformation and chemical conversion and assayed the inhibitory activities toward DNA metabolic enzymes and human cancer cell growth. Among twelve compounds obtained, only isosteviol (compound 3) potently inhibited both mammalian DNA polymerases (pols) and human DNA topoisomerase II (topo II), and IC50 value for pol alpha was 64.0 microM. This compound had no inhibitory effect on higher plant (cauliflower) pols, prokaryotic pols, human topo I, and DNA metabolic enzymes such as human telomerase, T7 RNA polymerase, and bovine deoxyribonuclease I. With pol alpha, isosteviol acted non-competitively with the DNA template-primer and nucleotide substrate. Isosteviol prevented the growth of human cancer cells, with LD50 values of 84-167 microM, and 500 microg of the compound caused a marked reduction in TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation (inhibitory effect, 53.0%). The relationship between the structure of stevioside-based compounds and these activities were discussed. PMID:15935396

  9. BTF Potts compound texture model

    NASA Astrophysics Data System (ADS)

    Haindl, Michal; Reměs, Václav; Havlíček, Vojtěch

    2015-03-01

    This paper introduces a method for modeling mosaic-like textures using a multispectral parametric Bidirectional Texture Function (BTF) compound Markov random field model (CMRF). The primary purpose of our synthetic texture approach is to reproduce, compress, and enlarge a given measured texture image so that ideally both natural and synthetic texture will be visually indiscernible, but the model can be easily applied for BFT material editing. The CMRF model consist of several sub-models each having different characteristics along with an underlying structure model which controls transitions between these sub models. The proposed model uses the Potts random field for distributing local texture models in the form of analytically solvable wide-sense BTF Markovian representation for single regions among the fields of a mosaic approximated by the Voronoi diagram. The control field of the BTF-CMRF is generated by the Potts random field model build on top of the adjacency graph of a measured mosaic. The compound random field synthesis combines the modified fast Swendsen- Wang Markov Chain Monte Carlo sampling of the hierarchical Potts MRF part with the fast and analytical synthesis of single regional BTF MRFs. The local texture regions (not necessarily continuous) are represented by an analytical BTF model which consists of single factors modeled by the adaptive 3D causal auto-regressive (3DCAR) random field model which can be analytically estimated as well as synthesized. The visual quality of the resulting complex synthetic textures generally surpasses the outputs of the previously published simpler non-compound BTF-MRF models.

  10. Mouse models of DNA polymerases.

    PubMed

    Menezes, Miriam R; Sweasy, Joann B

    2012-12-01

    In 1956, Arthur Kornberg discovered the mechanism of the biological synthesis of DNA and was awarded the Nobel Prize in Physiology or Medicine in 1959 for this contribution, which included the isolation and characterization of Escherichia coli DNA polymerase I. Now there are 15 known DNA polymerases in mammalian cells that belong to four different families. These DNA polymerases function in many different cellular processes including DNA replication, DNA repair, and damage tolerance. Several biochemical and cell biological studies have provoked a further investigation of DNA polymerase function using mouse models in which polymerase genes have been altered using gene-targeting techniques. The phenotypes of mice harboring mutant alleles reveal the prominent role of DNA polymerases in embryogenesis, prevention of premature aging, and cancer suppression. PMID:23001998

  11. Statistical Modelling of Compound Floods

    NASA Astrophysics Data System (ADS)

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

    2016-04-01

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

  12. Large, sequence-dependent effects on DNA conformation by minor groove binding compounds

    PubMed Central

    Tevis, Denise S.; Kumar, Arvind; Stephens, Chad E.; Boykin, David W.; Wilson, W. David

    2009-01-01

    To determine what topological changes antiparasitic heterocyclic dications can have on kinetoplast DNA, we have constructed ligation ladders, with phased A5 and ATATA sequences in the same flanking sequence context, as models. Bending by the A5 tract is observed, as expected, while the ATATA sequence bends DNA very little. Complexes of these DNAs with three diamidines containing either furan, thiophene or selenophene groups flanked by phenylamidines were investigated along with netropsin. With the bent A5 ladder the compounds caused either a slight increase or decrease in the bending angle. Surprisingly, however, with ATATA all of the compounds caused significant bending, to values close to or even greater than the A5 bend angle. Results with a mixed cis sequence, which has one A5 and one ATATA, show that the compounds bend ATATA in the same direction as a reference A5 tract, that is, into the minor groove. These results are interpreted in terms of a groove structure for A5 which is largely pre-organized for a fit to the heterocyclic amidines. With ATATA the groove is intrinsically wider and must close to bind the compounds tightly. The conformational change at the binding site then leads to significant bending of the alternating DNA sequence. PMID:19578063

  13. 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 650nm. 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 20μM 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. PMID:26882290

  14. Modeling Inhomogeneous DNA Replication Kinetics

    PubMed Central

    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. PMID:22412853

  15. Use of model compounds in coal chemistry

    SciTech Connect

    Collins, C J

    1980-01-01

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

  16. Computed structures of polyimides model compounds

    NASA Technical Reports Server (NTRS)

    Tai, H.; Phillips, D. H.

    1990-01-01

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

  17. 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...

  18. Towards modeling DNA sequences as automata

    NASA Astrophysics Data System (ADS)

    Burks, Christian; Farmer, Doyne

    1984-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  20. Biodegradation of coal-related model compounds

    SciTech Connect

    Campbell, J.A.; Stewart, D.L.; McCulloch, M.; Lucke, R.B.; Bean, R.M.

    1988-06-01

    We have studied the reactions of model compounds having coal-related functionalities (ester linkages, ether linkages, PAH) with the intact organism, cell-free filtrate, and cell-free enzyme of C. versicolor to better understand the process of biosolubilization. Many of the degradation products have been identified by gas chromatography/mass spectroscopy (GC/MS). Results indicate that the two compounds tested with the intact fungal organism were completely degraded. Complete degradation refers to no recovery of model compound. We can probably assume that the other two would also be totally degraded, since we have not yet found a simple compound that will survive long-term exposure to the intact fungus. The ease of degradation with the cell-free filtrate appears to be in the order: phenylbenzoate > benzylbenzoate > benzyl ether > methoxybenzophenone. Esters and ethers that are activated by aromatic rings appear to be susceptible to the fungal extract; however, aromatic ketones are not affected by the extract. From the limited results we have obtained from the isolated enzyme, it appears that the activity may parallel the cell-free filtrate. When the cell-free extract was tested with the model compounds indole, dibenzothiophene, and bibenzyl, no degradation with the enzyme was noted: however, exposure of these compounds to the intact organism resulted in complete degradation. Analysis of the controls indicated no degradation. 8 refs., 1 fig., 1 tab.

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

    PubMed

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

    2016-06-01

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

  2. Pyrolysis mechanisms of lignin model compounds

    SciTech Connect

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

    1997-06-01

    The flash vacuum pyrolysis of lignin model compounds was studied under conditions optimized for the production of liquid products to provide mechanistic insight into the reaction pathways that lead to product formation. The major reaction products can be explained by cleavage of the C-O either linkage by a free radial or concerted 1,2-elimination.

  3. 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.

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

    PubMed

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

    2016-06-20

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

  5. 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

  6. Electrochemical detection of the amino-substituted naphthalene compounds based on intercalative interaction with hairpin DNA by electrochemical impedance spectroscopy.

    PubMed

    Liang, Gang; Li, Tao; Li, Xiaohong; Liu, Xinhui

    2013-10-15

    The amino-substituted naphthalene compounds, such as 1,8-diaminonaphthalene (1,8-DANAP), 2,3-diaminonaphthalene (2,3-DANAP), 1,5-diaminonaphthalene (1,5-DANAP), 1-naphthylamine (1-NAP) and 2-naphthylamine (2-NAP), were investigated by electrochemical impedance spectroscopy (EIS), which was based on the interaction with hairpin DNA immobilized on the gold electrodes. Upon hairpin DNA interacting with the target chemicals, the charge transfer resistance (RCT) of the hairpin DNA films was significantly decreased and the charge transfer resistance change (ΔR(CT)) decreased in a sequence of ΔR(CT) (1,8-DANAP)>ΔR(CT) (2,3-DANAP)>ΔR(CT) (1,5-DANAP)>ΔR(CT) (1-NAP)>ΔR(CT) (2-NAP). The ΔR(CT) changes were due to the difference in the binding constant (K(SV)) of the target chemicals to DNA. In addition, the interaction mechanism was further explored using 1,8-DANAP as a model analyte by fluorescence spectra, Raman spectroscopy, differential pulse voltammetry (DPV) and EIS, correspondingly. The results demonstrated that the amino-substituted naphthalene compounds intercalated into "stem" appearing in the hairpin DNA. Moreover, the hairpin DNA sensor exhibited high sensitivity to the amino-substituted naphthalene compounds with the detection limit of nano-mole, and maintained high selectivity over other selected environmental pollutants. Finally, the DNA sensor was challenged in natural water sample with a recovery of 96-102%, which offered a platform for prospective future development of a simple, rapid, sensitive and low-cost assay for the detection of target aromatic amine pollutants. PMID:23693094

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

    PubMed

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

    2016-06-15

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

  8. Quantitative risk modelling for new pharmaceutical compounds.

    PubMed

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

    2005-11-15

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

  9. A Stochastic Model of DNA Fragments Rejoining

    PubMed Central

    Li, Yongfeng; Qian, Hong; Wang, Ya; Cucinotta, Francis A.

    2012-01-01

    When cells are exposed to ionizing radiation, DNA damages in the form of single strand breaks (SSBs), double strand breaks (DSBs), base damage or their combinations are frequent events. It is known that the complexity and severity of DNA damage depends on the quality of radiation, and the microscopic dose deposited in small segments of DNA, which is often related to the linear transfer energy (LET) of the radiation. Experimental studies have suggested that under the same dose, high LET radiation induces more small DNA fragments than low-LET radiation, which affects Ku efficiently binding with DNA end and might be a main reason for high-LET radiation induced RBE [1] since DNA DSB is a major cause for radiation-induced cell death. In this work, we proposed a mathematical model of DNA fragments rejoining according to non-homologous end joining (NHEJ) mechanism. By conducting Gillespie's stochastic simulation, we found several factors that impact the efficiency of DNA fragments rejoining. Our results demonstrated that aberrant DNA damage repair can result predominantly from the occurrence of a spatial distribution of DSBs leading to short DNA fragments. Because of the low efficiency that short DNA fragments recruit repair protein and release the protein residue after fragments rejoining, Ku-dependent NHEJ is significantly interfered with short fragments. Overall, our work suggests that inhibiting the Ku-dependent NHEJ may significantly contribute to the increased efficiency for cell death and mutation observed for high LET radiation. PMID:23028515

  10. Mitochondrial DNA-deficient models and aging.

    PubMed

    Olgun, Abdullah; Akman, Serif

    2007-04-01

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

  11. 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

  12. 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

  13. Coarse-grained modeling of DNA curvature

    NASA Astrophysics Data System (ADS)

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

    2014-10-01

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

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

    PubMed

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

    2016-01-15

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

  15. Itinerant electron model and conductance of DNA

    NASA Astrophysics Data System (ADS)

    Qu, Zhen; Kang, Da-Wei; Gao, Xu-Tuan; Xie, Shi-Jie

    2008-09-01

    DNA (Deoxyribonucleic acid) has recently caught the attention of chemists and physicists. A major reason for this interest is DNA’s potential use in nanoelectronic devices, both as a template for assembling nanocircuits and as an element of such circuits. However, the electronic properties of the DNA molecule remain very controversial. Charge-transfer reactions and conductivity measurements show a large variety of possible electronic behavior, ranging from Anderson and band-gap insulators to effective molecular wires and induced superconductors. In this review article, we summarize the wide-ranging experimental and theoretical results of charge transport in DNA. An itinerant electron model is suggested and the effect of the density of itinerant electrons on the conductivity of DNA is studied. Calculations show that a DNA molecule may show conductivity from insulating to metallic, which explains the controversial and profuse electric characteristics of DNA to some extent.

  16. Targeting Human Telomeric G-Quadruplex DNA with Oxazole-Containing Macrocyclic Compounds

    PubMed Central

    Pilch, Daniel S.; Barbieri, Christopher M.; Rzuczek, Suzanne G.; La Voie, Edmond J.; Rice, Joseph E.

    2008-01-01

    Oxazole-containing macrocycles, which include the natural product telomestatin, represent a promising class of anticancer agents that target G-quadruplex DNA. Two synthetic hexaoxazole-containing macrocyclic compounds (HXDV and HXLV-AC) have been characterized with regard to their cytotoxic activities versus human cancer cells, as well as the mode, thermodynamics, and specificity with which they bind to the intramolecular (3+1) G-quadruplex structural motif formed in the presence of K+ ions by human telomeric DNA. Both compounds exhibit cytotoxic activities versus human lymphoblast (RPMI 8402) and oral carcinoma (KB3-1) cells, with associated IC50 values ranging from 0.4 to 0.9 µM. The compounds bind solely to the quadruplex nucleic acid form, but not to the duplex or triplex form. Binding to the quadruplex is associated with a stoichiometry of two ligand molecules per DNA molecule, with one ligand molecule binding to each end of the host quadruplex via a nonintercalative “terminal capping” mode of interaction. For both compounds, quadruplex binding is primarily entropy driven, while also being associated with a negative change in heat capacity. These thermodynamic properties reflect contributions from favorable ligand-induced alterations in the loop configurational entropies of the quadruplex, but not from changes in net hydration. The stoichiometry and mode of binding revealed by our studies have profound implications with regard to the number of ligand molecules that can potentially bind the 3′-overhang region of human telomeric DNA. PMID:18439430

  17. Dynamical model for DNA sequences

    NASA Astrophysics Data System (ADS)

    Allegrini, P.; Barbi, M.; Grigolini, P.; West, B. J.

    1995-11-01

    We address the problem of DNA sequences, developing a ``dynamical'' method based on the assumption that the statistical properties of DNA paths are determined by the joint action of two processes, one deterministic with long-range correlations, and the other random and δ-function correlated. The generator of the deterministic evolution is a nonlinear map, belonging to a class of maps recently tailored to mimic the processes of weak chaos that are responsible for the birth of anomalous diffusion. It is assumed that the deterministic process corresponds to unknown biological rules that determine the DNA path, whereas the noise mimics the influence of an infinite-dimensional environment on the biological process under study. We prove that the resulting diffusion process, if the effect of the random process is neglected, is an α-stable Lévy process with 1<α<2. We also show that, if the diffusion process is determined by the joint action of the deterministic and the random process, the correlation effects of the ``deterministic dynamics'' are cancelled on the short-range scale, but show up in the long-range one. We denote our prescription to generate statistical sequences as the copying mistake map (CMM). We carry out our analysis of several DNA sequences and their CMM realizations with a variety of techniques, and we especially focus on a method of regression to equilibrium, which we call the Onsager analysis. With these techniques we establish the statistical equivalence of the real DNA sequences with their CMM realizations. We show that long-range correlations are present in exons as well as in introns, but are difficult to detect, since the exon ``dynamics'' is shown to be determined by the entanglement of three distinct and independent CMM's.

  18. Primary microcephaly, impaired DNA replication, and genomic instability caused by compound heterozygous ATR mutations.

    PubMed

    Mokrani-Benhelli, Houda; Gaillard, Laetitia; Biasutto, Patricia; Le Guen, Tangui; Touzot, Fabien; Vasquez, Nadia; Komatsu, Jun; Conseiller, Emmanuel; Pïcard, Capucine; Gluckman, Eliane; Francannet, Christine; Fischer, Alain; Durandy, Anne; Soulier, Jean; de Villartay, Jean-Pierre; Cavazzana-Calvo, Marina; Revy, Patrick

    2013-02-01

    Ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases are two key regulators of DNA-damage responses (DDR) that are mainly activated in response to DNA double-strand breaks and single-stranded DNA damages, respectively. Seckel syndrome, a rare genetic disorder characterized by a microcephaly and a markedly reduced body size, has been associated with defective ATR-dependent DNA damage signaling. However, the only human genetic ATR defect reported so far is a hypomorphic splicing mutation identified in five related individuals with Seckel syndrome. Here, we report the first case of primary microcephaly with compound heterozygous mutations in ATR: a 540 kb genomic deletion on one allele and a missense mutation leading to splice dysregulation on the other, which ultimately lead to a sharp decrease in ATR expression. DNA combing technology revealed a profound spontaneous alteration of several DNA replication parameters in patient's cells and FISH analyses highlighted the genomic instability caused by ATR deficiency. Collectively, our results emphasize the crucial role for ATR in the control of DNA replication, and reinforce the complementary and nonredundant contributions of ATM and ATR in human cells to face DNA damages and warrant genome integrity. PMID:23111928

  19. 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.

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

    PubMed

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

    2016-02-01

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

  1. Structural models for non-helical DNA.

    PubMed Central

    Yagil, G; Sussman, J L

    1986-01-01

    Structural modelling techniques are employed to explore the energetic requirements for the transformation of classical B DNA into unwound yet double-stranded DNA structures. Structural idealization using CORELS computer program of Sussman et al. followed by energy minimization using the EREF program of Levitt, leads to two regular non-helical models. In both models, the bases are conventionally paired and stacked, yet there is no net rotation between successive base pairs. One model, N1, has a 1-bp repeating unit; the second, N2, has a 2-bp repeating unit. The dihedral angles of the backbone all have values found either in the B or the Z form of DNA, except for the P-O5'-C5'-C4' angle, which is in the unprecedented g+ or g- domains. The energy difference found between the two N form models and B form DNA are 6.6 and 3.4 kcal/mol/nucleotide for N1 and N2 respectively. These relatively low energy differences encourage the idea that non-helical forms of DNA may contribute to the alternate DNA structures found in S1 nuclease sensitive and other regulatory regions of active genes. PMID:3017709

  2. 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

  3. Modeling and Global Optimization of DNA separation.

    PubMed

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

    2014-05-01

    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

  4. Identification of Disubstituted Sulfonamide Compounds as Specific Inhibitors of Hepatitis B Virus Covalently Closed Circular DNA Formation

    PubMed Central

    Cai, Dawei; Mills, Courtney; Yu, Wenquan; Yan, Ran; Aldrich, Carol E.; Saputelli, Jeffry R.; Mason, William S.; Xu, Xiaodong; Guo, Ju-Tao; Block, Timothy M.

    2012-01-01

    Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a central role in viral infection and persistence and is the basis for viral rebound after the cessation of therapy, as well as the elusiveness of a cure even after extended treatment. Therefore, there is an urgent need for the development of novel therapeutic agents that directly target cccDNA formation and maintenance. By employing an innovative cell-based cccDNA assay in which secreted HBV e antigen is a cccDNA-dependent surrogate, we screened an in-house small-molecule library consisting of 85,000 drug-like compounds. Two structurally related disubstituted sulfonamides (DSS), termed CCC-0975 and CCC-0346, emerged and were confirmed as inhibitors of cccDNA production, with low micromolar 50% effective concentrations (EC50s) in cell culture. Further mechanistic studies demonstrated that DSS compound treatment neither directly inhibited HBV DNA replication in cell culture nor reduced viral polymerase activity in the in vitro endogenous polymerase assay but synchronously reduced the levels of HBV cccDNA and its putative precursor, deproteinized relaxed circular DNA (DP-rcDNA). However, DSS compounds did not promote the intracellular decay of HBV DP-rcDNA and cccDNA, suggesting that the compounds interfere primarily with rcDNA conversion into cccDNA. In addition, we demonstrated that CCC-0975 was able to reduce cccDNA biosynthesis in duck HBV-infected primary duck hepatocytes. This is the first attempt, to our knowledge, to identify small molecules that target cccDNA formation, and DSS compounds thus potentially serve as proof-of-concept drug candidates for development into therapeutics to eliminate cccDNA from chronic HBV infection. PMID:22644022

  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. 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 [ 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.

  7. 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. PMID:25382683

  8. Mathematical modelling of eukaryotic DNA replication.

    PubMed

    Hyrien, Olivier; Goldar, Arach

    2010-01-01

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

  9. 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.

  10. 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

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

    PubMed

    Savelyev, Alexey; MacKerell, Alexander D

    2014-06-15

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

  12. All-Atom Polarizable Force Field for DNA Based on the Classical Drude Oscillator Model

    PubMed Central

    Savelyev, Alexey; MacKerell, Alexander D.

    2014-01-01

    Presented is a first generation atomistic force field 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 QM data and reproducing a number of experimental properties of DNA duplexes in the condensed phase. The resulting Drude force field yields stable DNA duplexes on the 100 ns time scale and satisfactorily reproduces (1) the equilibrium between A and B forms of DNA and (2) transitions between the BI and BII sub-states 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 force field, which is suggested to be due to the improved response of the model to changes in the environment associated with the explicit inclusion of polarizability. Analysis of dipole moments associated with the nucleic acid bases shows the Drude model to have significantly larger values than those present in CHARMM36, with the dipoles of individual bases undergoing significant variations during the MD simulations. Additionally, the dipole moment of water was observed to be perturbed in the grooves of DNA. PMID:24752978

  13. Modeling DNA Thermodynamics under Torsional Stress

    PubMed Central

    Wang, Qian; Pettitt, B. Montgomery

    2014-01-01

    Negatively twisted DNA is essential to many biological functions. Due to torsional stress, duplex DNA can have local, sequence-dependent structural defects. In this work, a thermodynamic model of DNA was built to qualitatively predict the local sequence-dependent mechanical instabilities under torsional stress. The results were compared to both simulation of a coarse-grained model and experiment results. By using the Kirkwood superposition approximation, we built an analytical model to represent the free energy difference ΔW of a hydrogen-bonded basepair between the B-form helical state and the basepair opened (or locally melted) state, within a given sequence under torsional stress. We showed that ΔW can be well approximated by two-body interactions with its nearest-sequence-neighbor basepairs plus a free energy correction due to long-range correlations. This model is capable of rapidly predicting the position and thermodynamics of local defects in a given sequence. The result qualitatively matches with an in vitro experiment for a long DNA sequence (>4000 basepairs). The 12 parameters used in this model can be further quantitatively refined when more experimental data are available. PMID:24606942

  14. Modeling DNA thermodynamics under torsional stress.

    PubMed

    Wang, Qian; Pettitt, B Montgomery

    2014-03-01

    Negatively twisted DNA is essential to many biological functions. Due to torsional stress, duplex DNA can have local, sequence-dependent structural defects. In this work, a thermodynamic model of DNA was built to qualitatively predict the local sequence-dependent mechanical instabilities under torsional stress. The results were compared to both simulation of a coarse-grained model and experiment results. By using the Kirkwood superposition approximation, we built an analytical model to represent the free energy difference ΔW of a hydrogen-bonded basepair between the B-form helical state and the basepair opened (or locally melted) state, within a given sequence under torsional stress. We showed that ΔW can be well approximated by two-body interactions with its nearest-sequence-neighbor basepairs plus a free energy correction due to long-range correlations. This model is capable of rapidly predicting the position and thermodynamics of local defects in a given sequence. The result qualitatively matches with an in vitro experiment for a long DNA sequence (>4000 basepairs). The 12 parameters used in this model can be further quantitatively refined when more experimental data are available. PMID:24606942

  15. 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.

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

    PubMed

    Beregovskaya, N; Maiboroda, R

    1995-01-21

    The role of mitochondrial DNA (mtDNA) damage in ageing processes and in malignant transformation of a cell is discussed. A mathematical model of the mtDNA population in a cell and in tissue is constructed. The model describes the effects of mtDNA damages accumulated during ageing and some features of malignant transformation and regeneration. PMID:7891454

  17. DNA-Binding and Topoisomerase-I-Suppressing Activities of Novel Vanadium Compound Van-7.

    PubMed

    Mo, Xiao-Mei; Chen, Zhan-Fang; Qi, Xin; Li, Yan-Tuan; Li, Jing

    2012-01-01

    Vanadium compounds were studied during recent years to be considered as a representative of a new class of nonplatinum metal anticancer agents in combination to its low toxicity. Here, we found a vanadium compound Van-7 as an inhibitor of Topo I other than Topo II using topoisomerase-mediated supercoiled DNA relaxation assay. Agarose gel electrophoresis and comet assay showed that Van-7 treatment did not produce cleavable complexes like HCPT, thereby suggesting that Topo I inhibition occurred upstream of the relegation step. Further studies revealed that Van-7 inhibited Topo I DNA binding involved in its intercalating DNA. Van-7 did not affect the catalytic activity of DNase I even up to100 μM. Van-7 significantly suppressed the growth of cancer cell lines with IC(50) at nanomolar concentrations and arrested cell cycle of A549 cells at G2/M phase. All these results indicate that Van-7 is a potential selective Topo I inhibitor with anticancer activities as a kind of Topo I suppressor, not Topo I poison. PMID:23055949

  18. DNA-Binding and Topoisomerase-I-Suppressing Activities of Novel Vanadium Compound Van-7

    PubMed Central

    Mo, Xiao-mei; Chen, Zhan-fang; Qi, Xin; Li, Yan-tuan; Li, Jing

    2012-01-01

    Vanadium compounds were studied during recent years to be considered as a representative of a new class of nonplatinum metal anticancer agents in combination to its low toxicity. Here, we found a vanadium compound Van-7 as an inhibitor of Topo I other than Topo II using topoisomerase-mediated supercoiled DNA relaxation assay. Agarose gel electrophoresis and comet assay showed that Van-7 treatment did not produce cleavable complexes like HCPT, thereby suggesting that Topo I inhibition occurred upstream of the relegation step. Further studies revealed that Van-7 inhibited Topo I DNA binding involved in its intercalating DNA. Van-7 did not affect the catalytic activity of DNase I even up to100 μM. Van-7 significantly suppressed the growth of cancer cell lines with IC50 at nanomolar concentrations and arrested cell cycle of A549 cells at G2/M phase. All these results indicate that Van-7 is a potential selective Topo I inhibitor with anticancer activities as a kind of Topo I suppressor, not Topo I poison. PMID:23055949

  19. 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

  20. 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

  1. A mathematical model for intracellular effects of toxins on DNA adduction and repair

    SciTech Connect

    Gaver, D.P.; Jacobs, P.A.; Carpenter, R.L.; Burkhart, J.G.

    1997-01-01

    The processes by which certain classes of toxic compounds or their metabolites may react with DNA to alter the genetic information contained in subsequent generations of cells or organisms are a major component of hazard associated with exposure to chemicals in the environment. Many classes of chemicals may form DNA adducts and there may or may not be a defined mechanism to remove a particular adduct from DNA independent of replication. Many compounds and metabolites that bind DNA also readily bind existing proteins; some classes of toxins and DNA adducts have the capacity to inactive a repair enzyme and divert the repair process competitively. This paper formulates an intracellular dynamic model for one aspect of the action of toxins that form DNA adducts, recognizing a capacity for removal of those adducts by a repair enzyme combined with reaction of the toxin and/or the DNA adduct to inactive the repair enzyme. This particular model illustrates the possible saturation of repair enzyme capacity by the toxin dosage and shows that bistable behavior can occur, with the potential to induce abrupt shifts away from steady-state equilibria. The model suggests that bistable behavior, dose and variation between individuals or tissues may combine under certain conditions to amplify the biological effect of dose observed as DNA adduction and its consequences as mutation. A model recognizing stochastic phenomena also indicates that variation in within-cell toxin concentration may promote jumps between stable equilibria.

  2. 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.

  3. 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 ...

  4. Induction of unscheduled DNA synthesis in HeLa cells by allylic compounds.

    PubMed

    Schiffmann, D; Eder, E; Neudecker, T; Henschler, D

    1983-10-01

    Thirteen allylic compounds, mostly with close structural relationship, were tested for their ability to induce unscheduled DNA synthesis (UDS) in HeLa cells and mutations in the Ames test; 11 induced UDS in dose dependence. Allyl isothiocyanate was negative in UDS (borderline in the Ames test) and acrolein (positive in the Ames test) proved toxic to HeLa cells, therefore UDS measurement was excluded. In general, positive qualitative and quantitative correlation between UDS, Ames test and alkylating properties (as measured in the 4-nitrobenzyl-pyridine test, NBP) were found. Among structural analogs and typical allylic compounds with various leaving groups, the amount of induced DNA repair at equimolar concentrations decreased in the same order as the mutagenic and alkylating activities in the other 2 test systems: 1,3-dichloropropene (cis) greater than 1,3-dichloropropene (trans) greater than 2,3-dichloro-1-propene; 1-chloro-2-butene greater than 3-chloro-1-butene greater than 3-chloro-2-methyl-1-propene greater than allyl chloride; allyl-methane-sulfonate greater than -iodide greater than -bromide greater than -chloride. PMID:6627227

  5. 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. PMID:25937003

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

    PubMed

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

    2016-06-17

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

  7. Resolution of mixed site DNA complexes with dimer-forming minor groove binders by using electrospray ionization mass spectrometry: Compound structure and DNA sequence effects

    PubMed Central

    Laughlin, Sarah; Wang, Siming; Kumar, Arvind; Farahat, Abdelbasset A.; Boykin, David W.; Wilson, W. David

    2015-01-01

    Small molecule targeting of the DNA minor groove is a promising approach to modulate genomic processes necessary for normal cellular function. For instance, dicationic diamindines, a well-known class of minor groove binding compounds, have been shown to inhibit interactions of transcription factors binding to genomic DNA. The applications of these compounds could be significantly expanded if we understand sequence-specific recognition of DNA better and could use the information to design more sequence-specific compounds. Aside from polyamides, minor groove binders typically recognize DNA at A-tract or alternating AT base pair sites. Targeting sites with GC base pairs, referred to here as mixed base pair sequences, is much more difficult than those rich in AT base pairs. Compound 1 is the first dicationic diamidine reported to recognize a mixed base pair site. It binds in the minor groove of ATGA sequences as a dimer with positive cooperativity. Due to the well-characterized behavior of 1 with ATGA and AT rich sequences, it provides a paradigm for understanding the elements that are key for recognition of mixed sequence sites. Electrospray ionization mass spectrometry (ESI-MS) is a powerful method to screen DNA complexes formed by analogs of 1 for specific recognition. We also report a novel approach to determine patterns of recognition by 1 for cognate ATGA and ATGA-mutant sequences. We found that functional group modifications and mutating the DNA target site significantly affect binding and stacking, respectively. Both compound conformation and DNA sequence directionality are crucial for recognition. PMID:25703690

  8. 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.

  9. Methods for modeling cytoskeletal and DNA filaments

    NASA Astrophysics Data System (ADS)

    Andrews, Steven S.

    2014-02-01

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

  10. 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.

  11. 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. PMID:25695766

  12. Theoretical modelling of epigenetically modified DNA sequences.

    PubMed

    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

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

    PubMed Central

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

    2014-01-01

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

  14. 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

  15. Synthesis of a naphthalene-hydroxynaphthalene polymer model compound

    SciTech Connect

    Kwong, C.D.

    1991-07-22

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

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

    PubMed

    Bao, J P; Yuan, R Y

    2015-01-01

    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. PMID:26782569

  17. 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. PMID:19136366

  18. Modeling anti-allergic natural compounds by molecular topology.

    PubMed

    García-Domenech, Ramón; Zanni, Riccardo; Galvez-Llompart, María; de Julián-Ortiz, J Vicente

    2013-09-01

    Molecular topology has been applied to the search of QSAR models able to identify the anti-allergic activity of a wide group of heterogeneous compounds. Through the linear discriminant analysis and artificial neural networks, correct classification percentages above 85% for both the training set and the test set have been obtained. After carrying out a virtual screening with a natural product library, about thirty compounds with theoretical anti-allergic activity have been selected. Among them, hesperidin, naringin, salinomycin, sorbitol, curcumol, myricitrin, diosmin and kinetin stand out. Some of these compounds have already been referenced as having anti-allergic activity. PMID:23597273

  19. 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. PMID:19852481

  20. DNA Vaccines: Experiences in the Swine Model.

    PubMed

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

    2016-01-01

    DNA vaccination is one of the most fascinating vaccine-strategies currently in development. Two of the main advantages of DNA immunization rely on its simplicity and flexibility, being ideal to dissect both the immune mechanisms and the antigens involved in protection against a given pathogen. Here, we describe several strategies used to enhance the immune responses induced and the protection afforded by experimental DNA vaccines tested in swine and provide with very basic protocol describing the generation and in vivo application of a prototypic DNA vaccine. Only time will tell the last word regarding the definitive implementation of DNA vaccination in the field. PMID:26458829

  1. Reactions of Lignin Model Compounds in Ionic Liquids

    SciTech Connect

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

    2009-09-15

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

  2. Modulating DNA configuration by interfacial traction: an elastic rod model to characterize DNA folding and unfolding.

    PubMed

    Huang, Zaixing

    2011-01-01

    As a continuum model of DNA, a thin elastic rod subjected to interfacial interactions is used to investigate the equilibrium configuration of DNA in intracellular solution. The interfacial traction between the rod and the solution environment is derived in detail. Kirchhoff's theory of elastic rods is used to analyze the equilibrium configuration of a DNA segment under the action of the interfacial traction. The influences of the interfacial energy factor and bending stiffness on the toroidal spool formation of the DNA segment are discussed. The results show that the equilibrium configuration of DNA is mainly determined by competition between the interfacial energy and elastic strain energy of the DNA itself, and the interfacial traction is one of the forces that drives DNA folding and unfolding. PMID:22210963

  3. Chemical degradation of fluorosulfonamide fuel cell membrane polymer model compounds

    NASA Astrophysics Data System (ADS)

    Alsheheri, Jamela M.; Ghassemi, Hossein; Schiraldi, David A.

    2014-12-01

    The durability of a polymer electrolyte fuel cell membrane, along with high proton conductivity and mechanical performance is critical to the success of these energy conversion devices. Extending our work in perfluorinated membrane stability, aromatic trifluoromethyl sulfonamide model compounds were prepared, and their oxidative degradation was examined. The chemical structures for the models were based on mono-, di- and tri-perfluorinated sulfonamide modified phenyl rings. Durability of the model compounds was evaluated by exposure to hydroxyl radicals generated using Fenton reagent and UV irradiation of hydrogen peroxide. LC-MS results for the mono-substituted model compound indicate greater stability to radical oxidation than the di-substituted species; loss of perfluorinated fonamide side chains appears to be an important pathway, along with dimerization and aromatic ring hydroxylation. The tri-substituted model compound also shows loss of side chains, with the mono-substituted compound being a major oxidation product, along with a limited amount of hydroxylation and dimerization of the starting material.

  4. 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.

  5. 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

  6. Irradiation effects on polymer-model compounds

    NASA Astrophysics Data System (ADS)

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

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

  7. 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

  8. 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. PMID:18652499

  9. 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.

  10. A stochastic model for DNA electrotransfer with finite pulses

    NASA Astrophysics Data System (ADS)

    Yu, Miao; Lin, Hao

    2011-11-01

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

  11. Synthesis of model compounds for coal liquification research

    SciTech Connect

    Sen, P.K.

    1990-10-08

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

  12. Modeling Natural Anti-Inflammatory Compounds by Molecular Topology

    PubMed Central

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

    2011-01-01

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

  13. 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)

  14. 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.

  15. A generic biokinetic model for carbon-14 labelled compounds

    NASA Astrophysics Data System (ADS)

    Manger, Ryan Paul

    Carbon-14, a radioactive nuclide, is used in many industrial applications. Due to its wide range of uses in industry, many workers are at risk of accidental internal exposure to 14C. Being a low energy beta emitter, 14C is not a significant external radiation hazard, but the internal consequences posed by 14C are important, especially because of its long half life of 5730 years [46]. The current biokinetic model recommended by the International Commission on Radiological Protection (ICRP) is a conservative estimate of how radiocarbon is treated by the human body. The ICRP generic radiocarbon model consists of a single compartment representing the entire human body. This compartment has a biological half life of 40 days yielding an effective dose coefficient of 5.8x10-10 Sv B q-1 [44, 45, 49, 53, 54]. This overestimates the dose of all radiocarbon compounds that have been studied [96]. An improved model has been developed that includes and alimentary tract, a urinary bladder, CO2 model, and an "Other" compartment used to model systemic tissues. The model can be adapted to replicate any excretion curve and excretion pattern. In addition, the effective dose coefficient produced by the updated model is near the mean effective dose coefficient of carbon compounds that have been considered in this research. The major areas of improvement are: more anatomically significant, a less conservative dose coefficient, and the ability to manipulate the model for known excretion data. Due to the wide variety of carbon compounds, it is suggested that specific biokinetic models be implemented for known radiocarbon substances. If the source of radiocarbon is dietary, then the physiologically based model proposed by Whillans [102] that splits all ingested radiocarbon compounds into carbohydrates, fats, and proteins should be used.

  16. VOC (VOLATILE ORGANIC COMPOUND) FUGITIVE EMISSION PREDICTIVE MODEL - USER'S GUIDE

    EPA Science Inventory

    The report discusses a mathematical model that can be used to evaluate the effectiveness of various leak detection and repair (LDAR) programs on controlling volatile organic compound (VOC) fugitive emissions from chemical, petroleum, and other process units. The report also descr...

  17. Enhanced removal of aqueous BPA model compounds using Metalloligs.

    PubMed

    Franz, Douglas M; Martin, Dean F

    2014-01-01

    A model compound, 4-(t-butyl)phenol, was used as a substitute for BPA (bisphenol acetone or Bisphenol A) a material used for the production of a large volume of common plastics. Unfortunately, BPA is suspected to have estrogenic properties, and there is a suspicion that even small amounts can have a deleterious effect against humans, especially female infants. The model compound has some similarities to BPA, but lacks some of the serious properties of BPA dust. Since other workers have demonstrated the capability of removing BPA from plastics by extraction with saline or alcohol, we studied whether Octolig, a polyethylenediimine supported on silica gel, or transition metal derivatives of Octolig could be used to remove concentrations for model compounds from aqueous solution. Octolig gave modest results 20%, the manganese (II) and iron (III) derivatives gave poor results, Cuprilig was an improvement over those two Metalloligs, but the cobalt(II) derivative was able to remove up to 56% of the model compound. Two methods were studied, batch and column chromatography. Under the conditions used in this study, the batch method was superior. PMID:24279622

  18. Modeling emissions of volatile organic compounds from silage

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  19. Modeling complex diffusion mechanisms in L1 2 -structured compounds

    NASA Astrophysics Data System (ADS)

    Zacate, M. O.; Lape, M.; Stufflebeam, M.; Evenson, W. E.

    2010-04-01

    We report on a procedure developed to create stochastic models of hyperfine interactions for complex diffusion mechanisms and demonstrate its application to simulate perturbed angular correlation spectra for the divacancy and 6-jump cycle diffusion mechanisms in L12-structured compounds.

  20. Laccase-mediator catalyzed conversion of model lignin compounds

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  1. Laccase-Mediator catalyzed conversion of model Lignin compounds

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  2. 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

  3. 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

  4. 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.

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

    PubMed

    Lin, Chih-Kang; Chen, Chien-Yu

    2013-07-01

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

  6. A bivariate survival model with compound Poisson frailty

    PubMed Central

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

    2015-01-01

    A correlated frailty model is suggested for analysis of bivariate time-to-event data. The model is an extension of the correlated power variance function (PVF) frailty model (correlated three-parameter frailty model). It is based on a bivariate extension of the compound Poisson frailty model in univariate survival analysis. It allows for a non-susceptible fraction (of zero frailty) in the population, overcoming the common assumption in survival analysis that all individuals are susceptible to the event under study. The model contains the correlated gamma frailty model and the correlated inverse Gaussian frailty model as special cases. A maximum likelihood estimation procedure for the parameters is presented and its properties are studied in a small simulation study. This model is applied to breast cancer incidence data of Swedish twins. The proportion of women susceptible to breast cancer is estimated to be 15 per cent. PMID:19856276

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

    PubMed

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

    2011-01-01

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

  8. 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.

  9. Analytical model study of dendrimer/DNA complexes.

    PubMed

    Qamhieh, Khawla; Nylander, Tommy; Ainalem, Marie-Louise

    2009-07-13

    The interaction between positively charged poly(amido amine) (PAMAM) dendrimers of generation 4 and DNA has been investigated for two DNA lengths; 2000 basepairs (bp; L = 680 nm) and 4331 bp (L = 1472.5 nm) using a theoretical model by Schiessel for a semiflexible polyelectrolyte and hard spheres. The model was modified to take into account that the dendrimers are to be regarded as soft spheres, that is, the radius is not constant when the DNA interact with the dendrimer. For the shorter and longer DNA, the estimated optimal wrapping length, l(opt) is ≈15.69 and ≈12.25 nm, respectively, for dendrimers that retain their original size (R(o) = 2.25 nm) upon DNA interaction. However, the values of l(opt) for the dendrimers that were considered to have a radius of (R = 0.4R(o)) 0.9 nm were 9.3 and 9.4 nm for the short and long DNA, respectively, and the effect due to the DNA length is no longer observed. For l(opt) = 10.88 nm, which is the length needed to neutralize the 64 positive charges of the G4 dendrimer, the maximum number of dendrimers per DNA (N(max)) was ≈76 for the shorter DNA, which is larger than the corresponding experimental value of 35 for 2000 bp DNA. For the longer DNA, N(max) ≈ 160, which is close to the experimental value of 140 for the 4331 bp DNA. Charge inversion of the dendrimer is only observed when they retain their size or only slightly contract upon DNA interaction. PMID:19438230

  10. Zebrafish as a model to study the role of DNA methylation in environmental toxicology.

    PubMed

    Kamstra, Jorke H; Aleström, Peter; Kooter, Jan M; Legler, Juliette

    2015-11-01

    Environmental epigenetics is a rapidly growing field which studies the effects of environmental factors such as nutrition, stress, and exposure to compounds on epigenetic gene regulation. Recent studies have shown that exposure to toxicants in vertebrates is associated with changes in DNA methylation, a major epigenetic mechanism affecting gene transcription. Zebra fish, a well-known model in toxicology and developmental biology, are emerging as a model species in environmental epigenetics despite their evolutionary distance to rodents and humans. In this review, recent insights in DNA methylation during zebra fish development are discussed and compared to mammalian models in order to evaluate zebra fish as a model to study the role of DNA methylation in environmental toxicology. Differences exist in DNA methylation reprogramming during early development, whereas in later developmental stages, tissue distribution of both 5-methylcytosine and 5-hydroxymethylcytosine seems more conserved between species, as well as basic DNA (de)methylation mechanisms. All DNA methyl transferases identified so far in mammals are present in zebra fish, as well as a number of major demethylation pathways. However, zebra fish appear to lack some methylation pathways present in mammals, such as parental imprinting. Several studies report effects on DNA methylation in zebra fish following exposure to environmental contaminants, such as arsenic, benzo[a]pyrene, and tris(1,3-dichloro-2-propyl)phosphate. Though more research is needed to examine heritable effects of contaminant exposure on DNA methylation, recent data suggests the usefulness of the zebra fish as a model in environmental epigenetics. PMID:25172464

  11. 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.

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

    PubMed

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

    2014-01-01

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

  13. 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

  14. 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.

  15. 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.

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

    PubMed Central

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

    2015-01-01

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

  17. 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

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

    PubMed Central

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

    1990-01-01

    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,N2-deoxyguanosine adducts; 7,8-cyclic guanine adducts are also found. We 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. Compounds forming saturated cyclic adducts are mutagenic in S. typhimurium strain TA100 and to a lesser extent in TA1535. Substances with a leaving group at the C-3 position form unsaturated conjugated cyclic adducts and are mutagenic only in the His D3052 frameshift strains with an intact excision repair system (no urvA mutation). 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. Our 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. PMID:2272339

  19. Modeling superhelical DNA: recent analytical and dynamic approaches.

    PubMed

    Schlick, T

    1995-04-01

    During the past year, a variety of diverse and complementary approaches have been presented for modeling superhelical DNA, offering new physical and biological insights into fundamental functional processes of DNA. Analytical approaches have probed deeper into the effects of entropy and thermal fluctuations on DNA structure and on various topological constraints induced by DNA-binding proteins. In tandem, new kinetic approaches--by molecular, Langevin and Brownian dynamics, as well as extensions of elastic-rod theory--have begun to offer dynamic information associated with supercoiling. Such dynamic approaches, along with other equilibrium studies, are refining the basic elastic-rod and polymer framework and incorporating more realistic treatments of salt and sequence-specific features. These collective advances in modeling large DNA molecules, in concert with technological innovations, are pointing to an exciting interplay between theory and experiment on the horizon. PMID:7648328

  20. Quantitative modeling of transcription factor binding specificities using DNA shape.

    PubMed

    Zhou, Tianyin; Shen, Ning; Yang, Lin; Abe, Namiko; Horton, John; Mann, Richard S; Bussemaker, Harmen J; Gordân, Raluca; Rohs, Remo

    2015-04-14

    DNA binding specificities of transcription factors (TFs) are a key component of gene regulatory processes. Underlying mechanisms that explain the highly specific binding of TFs to their genomic target sites are poorly understood. A better understanding of TF-DNA binding requires the ability to quantitatively model TF binding to accessible DNA as its basic step, before additional in vivo components can be considered. Traditionally, these models were built based on nucleotide sequence. Here, we integrated 3D DNA shape information derived with a high-throughput approach into the modeling of TF binding specificities. Using support vector regression, we trained quantitative models of TF binding specificity based on protein binding microarray (PBM) data for 68 mammalian TFs. The evaluation of our models included cross-validation on specific PBM array designs, testing across different PBM array designs, and using PBM-trained models to predict relative binding affinities derived from in vitro selection combined with deep sequencing (SELEX-seq). Our results showed that shape-augmented models compared favorably to sequence-based models. Although both k-mer and DNA shape features can encode interdependencies between nucleotide positions of the binding site, using DNA shape features reduced the dimensionality of the feature space. In addition, analyzing the feature weights of DNA shape-augmented models uncovered TF family-specific structural readout mechanisms that were not revealed by the DNA sequence. As such, this work combines knowledge from structural biology and genomics, and suggests a new path toward understanding TF binding and genome function. PMID:25775564

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

    NASA Astrophysics Data System (ADS)

    Licata, Nicholas A.

    2008-05-01

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

  2. 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.

  3. 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

  4. 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. PMID:9261542

  5. Kinetic model of DNA replication in eukaryotic organisms

    NASA Astrophysics Data System (ADS)

    Bechhoefer, John; Herrick, John; Bensimon, Aaron

    2001-03-01

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

  6. 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

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

    PubMed Central

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

    2014-01-01

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

  8. 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

  9. 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

  10. 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. PMID:27031942

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

    PubMed Central

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

    2012-01-01

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

  12. Modeling photoionization of aqueous DNA and its components.

    PubMed

    Pluhařová, Eva; Slavíček, Petr; Jungwirth, Pavel

    2015-05-19

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

  13. 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

  14. Model for compound formation during ion-beam mixing

    SciTech Connect

    Desimoni, J.; Traverse, A. )

    1993-11-01

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

  15. Computer modelling of DNA structures involved in chromosome maintenance.

    PubMed Central

    Eckdahl, T T; Anderson, J N

    1987-01-01

    Sequence-dependent DNA bending of synthetic and natural molecules was studied by computer analysis. Modelling of synthetic oligonucleotides and of 107 kb of natural sequences gave results which closely resembled published electrophoretic data, demonstrating the powerful predictive capacity of the procedure. The analysis was extended to the study of DNA structures involved in chromosome maintenance. Centromeric DNAs from yeast were found to have sequences in their functional elements which cause them to be unusually straight. Autonomous replicating sequences were found to have two structural domains, one consisting of unusually straight sequences surrounding the consensus and the other of bending elements in flanking DNA. In addition to a structural homology, centromeric and autonomous replicating sequences share common sequence elements. These observations show that computer modelling of natural sequences is a viable approach to the study of the biological implications of alternative DNA structures. PMID:3671091

  16. 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.

  17. Hydrocracking with new solid acid catalysts: Model compounds studies

    SciTech Connect

    Sharma, R.K.; Diehl, J.W.; Olson, E.S. )

    1990-01-01

    Two new solid acid catalysts have been prepared by supporting zinc chloride on silica gel and acid-exchanged montmorillonite. The acid properties of these catalysts were determined by Hammett indicator method which showed that highly Bronsted acidic sites were present. SEM/EDS studies indicated a uniform distribution of silicon, zinc, and chlorine in the silica gel-zinc chloride catalyst. The activities of these catalysts in the hydrocracking of bibenzyl, polybenzyl, alkylbenzenes, and other heteroatom substituted aromatics were investigated. Their results with model compounds account for the effectiveness of these solid acid catalysts for conversion of coals to lower molecular weight materials.

  18. Mammalian sperm chromatin as a model for chromatin function in DNA degradation and DNA replication.

    PubMed

    Ortega, Michael A; Sil, Payel; Ward, W Steven

    2011-02-01

    Reproductive biology is considered a specialty field, however, an argument can be made that it is instead generally applicable to many fields of biology. The one-cell embryo is presented here as a model system for the study of eukaryotic DNA replication, apoptotic DNA degradation, and signaling mechanisms between the cytoplasm and nucleus. Two unique aspects of this system combine to make it particularly useful for the study of chromatin function. First, the evolutionary pressure that lead to the extreme condensation of mammalian sperm DNA resulted in a cell with virtually inert chromatin, no DNA replication or transcription ongoing in the sperm cell, and all of the cells in a G(0) state. This chromatin is suddenly transformed into actively transcribing and replicating DNA upon fertilization. Therefore, the sperm chromatin is poised to become active but does not yet possess sufficient components present in somatic chromatin structure for all these processes. The second unique aspect of this system is that the one cell embryo houses two distinct nuclei, termed pronuclei, through the first round of DNA synthesis. This means the sperm cell can be experimentally manipulated to test the affects of the various treatments on the biological functions of interest. Experimental manipulations of the system have already revealed a certain level of plasticity in the coordination of both the timing of DNA synthesis in the two pronuclei and in the response to cellular signals by each pronucleus involved with the progression through the G1/S checkpoint, including the degradation of DNA in the paternal pronucleus. The fact that two nuclei in the same cytoplasm can undergo different responses infers a level of autonomy in the nuclear control of the cell cycle. Thus, the features of mammalian fertilization can provide unique insights for the normal biology of the cell cycle in somatic cells. PMID:21204750

  19. 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.

  20. 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.

  1. 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.

  2. Assimilating chemical compound with a regional chemical model

    NASA Astrophysics Data System (ADS)

    Chang, C.; Yang, S.; Liang, M.; Hsu, S.; Tseng, Y.

    2012-12-01

    To constrain the source and sink of the chemical compounds at surface during model simulation, chemical compound assimilation with Local Ensemble Transform Kalman Filter (LETKF) has been implemented for the WRF-ChemT model. In this study, a two-tier system is applied to assimilating the meteorological and chemical variables in an OSSE framework. The unobserved surface flux is estimated according to the observations in the chemical component. A long-term nature run with total constant emission of 5.3×108 g/s is assumed to be the truth state in the OSSE. The simulated observations are obtained from the truth state by adding random errors. In order to generate the initial CO2 ensembles with similar spatial distribution as truth state without other prior information, the initial perturbation fields of CO2 are randomly chosen from three long-term runs with different emissions. The results indicate that in the constant emission case, the system can successfully estimate the unobserved chemical forcing and improve the distribution of the chemical compound. Under the scenario of diurnal forcing induced by human activities, the problem in estimating surface flux becomes more complex and difficult. A set of experiments with different initial chemical states suggest that the estimation of flux is sensitive to the quality of initial CO2 and CO2 surface flux. Strategies are designed to retrieve the time-varying information. The results show that with time-varying information and reliable initial ensembles, the estimation of surface flux have been significantly improved. Couple assimilation with meteorological and chemical components Surface flux estimation

  3. Hydrometallation of model compounds of a cobalt-molybdenum catalyst

    SciTech Connect

    West, M.; Smith, M.C.; Petersen, E.E.

    1983-05-01

    One solution to corrosion and environmental problems is to remove sulfur from the fuel or feedstock before burning or processing by catalytic hydrosulfurization (HDS). Besides sulfur, heavy petroleum fractions and coal liquids contain high levels of trace metal compounds compared to traditional HDS feedstocks. In resids, these metals are mainly vanadium and nickel and in coal-liquids they are mostly titanium and iron. Under typical HDS conditions the organometallic compounds in these liquids also decompose and yield metal-free organics and metal sulfides. This hydrometallation (HDM) reaction is a double-edged sword. Since the sulfides are insoluble in the oil, the reaction effectively demetallizes the feedstock. This is desirable because, like sulfur, these metals pose environmental corrosion, and catalyst poisoning problems. The undesirable aspect of the reaction is that these insoluble metal sulfides collect in and around the HDS catalyst pellets, plugging pores and covering active surface sites thereby reducing both the HDS and the HDM catalytic activity. The deactivating effect of metal deposition on HDS and HDM is the focus of this study. Since the metal sulfides produced by HDM remain at the site of their reaction, the amount of metal at any point in the catalyst is a record of the reaction rate at that point. By carefully measuring the metal concentrations inside a series of cobalt-molybdenum-alumina catalyst pellets exposed for different lengths of time, demetallation rate profiles are measured within the pellets. There is no similar way to measure local HDS rates. Measurements of the global HDS rates, a knowledge of HDS kinetics, and measurements of the local HDM rates permit us to model the effect of metal deposits on catalyst activity. We have chosen to work with two model classes of compounds, metal naphthenates and metalloporphyrins.

  4. 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. PMID:26949974

  5. 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.

  6. Metal-based biologically active compounds: synthesis, characterization, DNA interaction, antibacterial, cytotoxic and SOD mimic activities.

    PubMed

    Patel, Mohan N; Patel, Chintan R; Joshi, Hardik N

    2013-02-01

    The square pyramidal copper(II) complexes of N, O- donor ligand and ciprofloxacin have been synthesized. Synthesized complexes were characterized by physicochemical parameters like elemental analysis, electronic, FT-IR and LC-MS spectra. The complexes were screened for their antimicrobial activity against Gram(+Ve), i.e. Staphylococcus aureus, Bacillus subtilis, and Gram(-Ve), i.e. Serratia marcescens, Pseudomonas aeruginosa and Escherichia coli, microorganisms in terms of minimum inhibitory concentration and colony-forming unit. To determine the binding mode of complexes with Herring Sperm DNA, absorption titration and viscosity measurement were employed. DNA cleavage activity was carried out by gel electrophoresis experiment using supercoiled form of pUC19 DNA. The complexes were tested for their superoxide dismutase mimic activity in terms of IC(50) value. Synthesized complexes were also screened for their cytotoxicity using brine shrimp lethality assay method. PMID:23306896

  7. Solid Phase DNA Amplification: A Simple Monte Carlo Lattice Model

    NASA Astrophysics Data System (ADS)

    Mercier, Jean-Francois; Slater, Gary W.; Mayer, Pascal

    2003-03-01

    Recently, a new type of PCR called solid phase DNA amplification, has been introduced where surface-bound instead of freely-diffusing primers are used to amplify DNA. This type of amplification is limited to two-dimensional surfaces and therefore allows the easy parallelization of the PCR process in a single system. Furthermore, solid phase DNA amplification could provide an alternate route to DNA target implantation on DNA chips for genomic studies. We propose a simple Lattice Monte Carlo model of solid phase DNA amplification. We study the growth, stability and morphology of isolated PCR colonies under various conditions. Our results indicate that, in most cases, solid phase DNA amplification is characterized by a geometric growth and a rather sharp size distribution. These results are qualitatively different those obtained for liquid PCR processes which are usually characterized (at least initially) by an exponential growth and a broad population distribution. Various non-ideal effects are studied, and we demonstrate that such effects do not generally change the nature of the process, except in extreme cases.

  8. NMR Solution Structure and DNA Binding Model of the DNA Binding Domain of Competence Protein A

    PubMed Central

    Hobbs, Carey A.; Bobay, Benjamin G.; Thompson, Richele J.; Perego, Marta; Cavanagh, John

    2010-01-01

    Competence protein A (ComA) is a response regulator protein involved in the development of genetic competence in the Gram-positive spore forming bacterium Bacillus subtilis, as well as the regulation of the production of degradative enzymes and antibiotic synthesis. ComA belongs to the NarL family of proteins which are characterized by a C-terminal transcriptional activator domain that consists of a bundle of four helices, where the second and third helices (α8 and α9) form a helix-turn-helix DNA binding domain. Using NMR spectroscopy, the high resolution three-dimensional solution structure of the C-terminal DNA-binding domain of ComA (ComAC) has been determined. In addition, surface plasmon resonance and NMR protein-DNA titration experiments allowed for the analysis of the interaction of ComAC with its target DNA sequences. Combining the solution structure and biochemical data, a model of ComAC bound to the ComA recognition sequences on the srfA promoter has been developed. The model shows that for DNA binding, ComA uses the conserved helix-turn-helix motif present in other NarL family members. However, the model also reveals that ComA may use a slightly different part of the helix-turn-helix motif and there appears to be some associated domain re-orientation. These observations suggest a basis for DNA binding specificity within the NarL family. PMID:20302877

  9. 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.

  10. Separations of Short DNA in Agarose Gels: What Model Applies?

    NASA Astrophysics Data System (ADS)

    Beheshti, Afshin

    2000-03-01

    Gel Electrophoresis is used ubiquitously for separating proteins and DNA fragments from mixtures into individual components. Molecules separate because their mobilities, μ = v / E, depend on their effective charge and effective friction imposed by the gel. Models describing the dependence of μ on molecular parameters are inadequate. For example, the reptation theory as applied in other studies suggests μ proportional to (1/L). We asked whether the relationship (1/μ) proportional to AL + B, where A and B are independent parameters, would better describe electrophoretic separations of DNA fragments over a wide range of fragment lengths. A series of DNA ladders were electrophoresed in Seakem and in Metaphor agarose and mobilities studied as a function of their DNA length. In the Metaphor agarose a range of 10 bp to 1500 bp DNA fragments were observed. While in the Seakem agarose the study was done with DNA fragments ranging from 100 bp to 10 kbp. Results of the fits for μ vs. L indicate the dependence is more complex than these simple models suggest. Supported by NSF BES 9521381 and NSF Research Training Grant Fellowship 130362022.

  11. A global model of natural volatile organic compound emissions

    NASA Astrophysics Data System (ADS)

    Guenther, Alex; Hewitt, C. Nicholas; Erickson, David; Fall, Ray; Geron, Chris; Graedel, Tom; Harley, Peter; Klinger, Lee; Lerdau, Manuel; McKay, W. A.; Pierce, Tom; Scholes, Bob; Steinbrecher, Rainer; Tallamraju, Raja; Taylor, John; Zimmerman, Pat

    1995-05-01

    Numerical assessments of global air quality and potential changes in atmospheric chemical constituents require estimates of the surface fluxes of a variety of trace gas species. We have developed a global model to estimate emissions of volatile organic compounds from natural sources (NVOC). Methane is not considered here and has been reviewed in detail elsewhere. The model has a highly resolved spatial grid (0.5°×0.5° latitude/longitude) and generates hourly average emission estimates. Chemical species are grouped into four categories: isoprene, monoterpenes, other reactive VOC (ORVOC), and other VOC (OVOC). NVOC emissions from oceans are estimated as a function of geophysical variables from a general circulation model and ocean color satellite data. Emissions from plant foliage are estimated from ecosystem specific biomass and emission factors and algorithms describing light and temperature dependence of NVOC emissions. Foliar density estimates are based on climatic variables and satellite data. Temporal variations in the model are driven by monthly estimates of biomass and temperature and hourly light estimates. The annual global VOC flux is estimated to be 1150 Tg C, composed of 44% isoprene, 11% monoterpenes, 22.5% other reactive VOC, and 22.5% other VOC. Large uncertainties exist for each of these estimates and particularly for compounds other than isoprene and monoterpenes. Tropical woodlands (rain forest, seasonal, drought-deciduous, and savanna) contribute about half of all global natural VOC emissions. Croplands, shrublands and other woodlands contribute 10-20% apiece. Isoprene emissions calculated for temperate regions are as much as a factor of 5 higher than previous estimates.

  12. Modeling of flap endonuclease interactions with DNA substrate.

    PubMed

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

    2003-05-01

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

  13. Compounded progesterone and the Behavioral Model of Health Services Use.

    PubMed

    Spark, M Joy; Willis, Jon; Iacono, Teresa

    2014-01-01

    Compounded progesterone (P₄) is a product that, from a clinical experience-based perspective, effectively relieves a range of symptoms. In contrast, from a conventional evidence-based medicine perspective, P₄ is ineffective. As P₄ is not a product prescribed by conventional medicine, it is unlikely to be prescribed by family doctors, which increases the barriers to utilization. Utilization of medicines is influenced by many contextual and individual characteristics. The Behavioral Model of Health Services Use provides a multidimensional framework to conceptualize utilization of health services including medicine use. The 4 main components of this model are: contextual characteristics, individual characteristics, health behaviors and outcomes. This paper reports on the application of The Behavioral Model of Health Services Use to medicines and shows how it can be applied to the use of P₄. The model enables some of the positive reinforcement that contributes to women continuing to use P₄ to be explained. The Behavioral Model of Health Services Use was found to offer the potential to identify and then address issues with access to prescription medicines. PMID:24055136

  14. Scoring function for DNA-drug docking of anticancer and antiparasitic compounds based on spectral moments of 2D lattice graphs for molecular dynamics trajectories.

    PubMed

    Pérez-Montoto, Lázaro G; Santana, Lourdes; González-Díaz, Humberto

    2009-11-01

    We introduce here a new class of invariants for MD trajectories based on the spectral moments pi(k)(L) of the Markov matrix associated to lattice network-like (LN) graph representations of Molecular Dynamics (MD) trajectories. The procedure embeds the MD energy profiles on a 2D Cartesian coordinates system using simple heuristic rules. At the same time, we associate the LN with a Markov matrix that describes the probabilities of passing from one state to other in the new 2D space. We construct this type of LNs for 422 MD trajectories obtained in DNA-drug docking experiments of 57 furocoumarins. The combined use of psoralens+ultraviolet light (UVA) radiation is known as PUVA therapy. PUVA is effective in the treatment of skin diseases such as psoriasis and mycosis fungoides. PUVA is also useful to treat human platelet (PTL) concentrates in order to eliminate Leishmania spp. and Trypanosoma cruzi. Both are parasites that cause Leishmaniosis (a dangerous skin and visceral disease) and Chagas disease, respectively; and may circulate in blood products collected from infected donors. We included in this study both lineal (psoralens) and angular (angelicins) furocoumarins. In the study, we grouped the LNs on two sets; set1: DNA-drug complex MD trajectories for active compounds and set2: MD trajectories of non-active compounds or no-optimal MD trajectories of active compounds. We calculated the respective pi(k)(L) values for all these LNs and used them as inputs to train a new classifier that discriminate set1 from set2 cases. In training series the model correctly classifies 79 out of 80 (specificity=98.75%) set1 and 226 out of 238 (Sensitivity=94.96%) set2 trajectories. In independent validation series the model correctly classifies 26 out of 26 (specificity=100%) set1 and 75 out of 78 (sensitivity=96.15%) set2 trajectories. We propose this new model as a scoring function to guide DNA-docking studies in the drug design of new coumarins for anticancer or antiparasitic

  15. 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

  16. 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.

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

    PubMed

    Fernandes, Ana; Neves, Jose

    2013-04-01

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

  18. 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

  19. Blackberry seed extracts and isolated polyphenolic compounds showing protective effect on human lymphocytes DNA.

    PubMed

    Gođevac, Dejan; Tešević, Vele; Vajs, Vlatka; Milosavljević, Slobodan; Stanković, Miroslava

    2011-09-01

    The tentative identification of seed extracts from 3 cultivars of blackberry (blackberry seed extracts [BSEs]) constituents was performed by LC/UV/MS technique. The identified compounds belonged to ellagitannins, galic acid derivatives, and ellagic acid derivatives. Two ellagitannins, Lambertianin C and Sanguiniin H-6, and an ellagic acid derivative, 4-α-L-arabinofuranosylellagic acid, were isolated using semipreparative High-performance liquid chromatography. The structure elucidations were based on high resolution-mass spectrometry and nuclear magnetic resonance studies. The BSEs and 3 isolated pure compounds were tested for in vitro protective effect on chromosome aberrations in peripheral human lymphocytes using cytochalasin-B blocked micronucleus (MN) assay. The frequency of MN was scored in binucleated cells, and nuclear proliferation index was calculated. Among the tested extracts, the seeds of cv. Thornfree at concentration of 1 μg/mL exhibit the most prominent effect decreasing the frequency of MN by 62.4%, when compared with the controls cell cultures. Antioxidant potential of pure ellagitannins cannot explain the strong effect of BSEs. The assumption was that better antioxidant effect of BSEs result from synergistic effects of individual compounds contained in the extracts and/or some minor components possessed strong activity. PraCTICAL APPLICATION: Our results provide evidence of protective effects of BSEs and isolated pure compounds on cytogenetic damages in human lymphocytes. Thus, BSEs could exert beneficial effects in quite a few diseases, because many of the biological actions have been attributed to their antioxidant properties. PMID:21824137

  20. 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.

  1. 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.

  2. 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.

  3. A sticker-based model for DNA computation.

    PubMed

    Roweis, S; Winfree, E; Burgoyne, R; Chelyapov, N V; Goodman, M F; Rothemund, P W; Adleman, L M

    1998-01-01

    We introduce a new model of molecular computation that we call the sticker model. Like many previous proposals it makes use of DNA strands as the physical substrate in which information is represented and of separation by hybridization as a central mechanism. However, unlike previous models, the stickers model has a random access memory that requires no strand extension and uses no enzymes; also (at least in theory), its materials are reusable. The paper describes computation under the stickers model and discusses possible means for physically implementing each operation. Finally, we go on to propose a specific machine architecture for implementing the stickers model as a microprocessor-controlled parallel robotic workstation. In the course of this development a number of previous general concerns about molecular computation (Smith, 1996; Hartmanis, 1995; Linial et al., 1995) are addressed. First, it is clear that general-purpose algorithms can be implemented by DNA-based computers, potentially solving a wide class of search problems. Second, we find that there are challenging problems, for which only modest volumes of DNA should suffice. Third, we demonstrate that the formation and breaking of covalent bonds is not intrinsic to DNA-based computation. Fourth, we show that a single essential biotechnology, sequence-specific separation, suffices for constructing a general-purpose molecular computer. Concerns about errors in this separation operation and means to reduce them are addressed elsewhere (Karp et al., 1995; Roweis and Winfree, 1999). Despite these encouraging theoretical advances, we emphasize that substantial engineering challenges remain at almost all stages and that the ultimate success or failure of DNA computing will certainly depend on whether these challenges can be met in laboratory investigations. PMID:10072080

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

    NASA Astrophysics Data System (ADS)

    Licata, Nicholas A.

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

  5. 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.

  6. 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

  7. 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. PMID:26926663

  8. 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.

  9. 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. PMID:24686397

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

    PubMed Central

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

    2013-01-01

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

  11. 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.

  12. 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). PMID:21742570

  13. 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.

  14. 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

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

    PubMed

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

    2016-01-01

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

  16. Solitary waves in twist-opening models of DNA dynamics

    NASA Astrophysics Data System (ADS)

    Gaeta, Giuseppe; Venier, Laura

    2008-07-01

    We analyze traveling solitary wave solutions in the Barbi-Cocco-Peyrard twist-opening model of nonlinear DNA dynamics. We identify conditions, involving an interplay of physical parameters and asymptotic behavior, for such solutions to exist, and provide first-order ordinary differential equations whose solutions give the required solitary waves; these are not solvable in analytical terms, but are easily integrated numerically. The conditions for existence of solitary waves are not satisfied for trivial asymptotic behavior and physical values of the parameters, i.e., the Barbi-Cocco-Peyrard model admits only solitary wave solutions that entail a global modification of the molecule; this is compared with the situation met in another recently formulated class of DNA models with two degrees of freedom per site.

  17. Discrete breathers in the Peyrard-Bishop model of DNA

    NASA Astrophysics Data System (ADS)

    Fakhretdinov, M. I.; Zakir'yanov, F. K.

    2013-07-01

    The Peyrard-Bishop model, which describes the dynamics of a DNA molecule, is considered. The solutions that represent discrete breathers are derived in the framework of the model. The dynamic stability of the stationary discrete breathers with respect to small perturbations is studied. The solutions can be interpreted as the experimentally observed opening of the base pairs in the DNA double strand at the initial stages of denaturation. It is also demonstrated that the model allows the existence of mobile breathers that move in the absence of perturbations in the environment. The interaction of the mobile breathers is numerically simulated. The Peierls-Nabarro barrier and the effective mass and velocity of the breather are estimated.

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

    PubMed

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

    2014-01-01

    Novel mixed ligand bivalent copper complexes [Cu. L. A. ClO 4 ] 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)/2,2(1)-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

  19. Modelling transcriptional interference and DNA looping in gene regulation.

    PubMed

    Dodd, Ian B; Shearwin, Keith E; Sneppen, Kim

    2007-06-22

    We describe a hybrid statistical mechanical and dynamical approach for modelling the formation of closed, open and elongating complexes of RNA polymerase, the interactions of these polymerases to produce transcriptional interference, and the regulation of these processes by a DNA-binding and DNA-looping regulatory protein. As a model system, we have used bacteriophage 186, for which genetic, biochemical and structural studies have suggested that the CI repressor binds as a 14-mer to form alternative DNA-looped complexes, and activates lysogenic transcription indirectly by relieving transcriptional interference caused by the convergent lytic promoter. The modelling showed that the original mechanisms proposed to explain this relief of transcriptional interference are not consistent with the available in vivo reporter data. However, a good fit to the reporter data was given by a revised model that incorporates a novel predicted regulatory mechanism: that RNA polymerase bound at the lysogenic promoter protects itself from transcriptional interference by recruiting CI to the lytic promoter. This mechanism and various estimates of in vivo biochemical parameters for the 186 CI system should be testable. Our results demonstrate the power of mathematical modelling for the extraction of detailed biochemical information from in vivo data. PMID:17498740

  20. 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

  1. 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.

  2. 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…

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

    PubMed

    Holley, W R; Chatterjee, A

    1996-02-01

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

  4. 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

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

    PubMed

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

    2014-05-15

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

  6. 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. PMID:24489787

  7. Solubilities of biologically active phenolic compounds: measurements and modeling.

    PubMed

    Queimada, António J; Mota, Fátima L; Pinho, Simão P; Macedo, Eugénia A

    2009-03-19

    Aqueous solubilities of natural phenolic compounds from different families (hydroxyphenyl, polyphenol, hydroxybenzoic, and phenylpropenoic) were experimentally obtained. Measurements were performed on tyrosol and ellagic, protocatechuic, syringic, and o-coumaric acids, at five different temperatures (from 288.2 to 323.2 K), using the standard shake-flask method, followed by compositional analysis using UV spectrophotometry. To verify the accuracy of the spectrophotometric method, some data points were measured by gravimetry, and in general, the values obtained with the two methods are in good agreement (deviations lower than 11%). To adequately understand the solubilization process, melting properties of the pure phenolics were obtained by differential scanning calorimetry (DSC), and apparent acid dissociation constants were measured by potentiometry titration. The aqueous solubilities followed the expected general exponential trend. The melting temperatures did not follow the same solubility tendency, and for tyrosol and ellagic acid, not only the size and extent of hydrogen bonding, but also the energy associated with their crystal structures, determine the solubility. For these binary systems, acid dissociation is not important. Approaches for modeling the measured data were evaluated. These included an excess Gibbs energy equation, the modified UNIQUAC model, and the cubic-plus-association (CPA) equation of state. Particularly for the CPA approach, a new methodology that explicitly takes into account the number and nature of the associating sites and the prediction of the pure-component parameters from molecular structure is proposed. The results indicate that these are appropriate tools for representing the water solubilities of these molecules. PMID:19243119

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

    PubMed

    Fayzullina, Saniya; Martin, Lee J

    2016-09-01

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

  9. 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

  10. 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)

  11. 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.

  12. 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

  13. 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.

  14. 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. PMID:26188387

  15. Microbial extraction of sulfur from model coal organosulfur compounds

    SciTech Connect

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

    1991-12-31

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

  16. Modeling the mechanochemistry of the ϕ29 DNA translocation motor

    NASA Astrophysics Data System (ADS)

    Perez-Carrasco, R.; Fiasconaro, A.; Falo, F.; Sancho, J. M.

    2013-03-01

    We present a study of the DNA translocation of the bacteriophage ϕ29 packaging molecular motor. From the available experimental information we present a model system based on a stochastic flashing potential, which reproduces the experimental observations such as detailed trajectories, steps and substeps, spatial correlation, and velocity. Moreover, the model allows the evaluation of the power and efficiency of this motor. We have found that the maximum power regime does not correspond with that of the maximum efficiency. This information can stimulate further experiments.

  17. Simple combined model for nonlinear excitations in DNA.

    PubMed

    Hien, D L; Nhan, N T; Ngo, V Thanh; Viet, N A

    2007-08-01

    We propose a simple model for DNA denaturation bases on the pendulum model of Englander [Proc. Natl. Acad. Sci. U.S.A. 77, 7222 (1980)] and the microscopic model of Peyrard and Bishop [Phys. Rev. Lett. 62, 2755 (1989)], so-called "combined model." The main parameters of our model are the coupling constant k along each strand, the mean stretching y* of the hydrogen bonds, the ratio of the damping constant and driven force gamma/F. We show that both the length L of unpaired bases and the velocity v of kinks depend on not only the coupling constant k but also the temperature T. Our results are in good agreement with previous works. PMID:17930079

  18. 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

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

    PubMed

    Kumar, Rajendra; Grubmüller, Helmut

    2016-01-19

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

  20. 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.

  1. Alkylation of guanine in DNA by S23906-1, a novel potent antitumor compound derived from the plant alkaloid acronycine.

    PubMed

    David-Cordonnier, Marie-Hélène; Laine, William; Lansiaux, Amélie; Kouach, Mostafa; Briand, Gilbert; Pierré, Alain; Hickman, John A; Bailly, Christian

    2002-08-01

    The discovery of a new DNA-targeted antitumor agent is a challenging enterprise, and the elucidation of its mechanism of action is an essential first step in investigating the structural and biological consequences of DNA modification and to guide the rational design of analogues. Here, we have dissected the mode of action of the newly discovered antitumor agent S23906-1. Gel retardation experiments reveal that the diacetate compound S23906-1 and its monoacetate analogue S28687 form highly stable covalent adducts with DNA. The covalent adducts formed between S23906-1 and a 7-bp hairpin oligonucleotide duplex were identified by spectrometry. In contrast, the inactive compound S23907, lacking the two acetate groups of S23906-1, fails to yield covalent DNA adducts, indicating that the C1-C2 functionality is the DNA reactive moiety. DNase I footprinting and DNA alkylation experiments indicate that S23906-1 reacts primarily with guanine residues. A 30-mer oligonucleotide containing only G.C bp forms highly stable complexes with S23906-1 and S28687, whereas the equivalent A.T oligonucleotide is not a good substrate for these two drugs. The use of an oligonucleotide duplex containing inosines instead of guanosines identifies the guanine 2-amino group exposed in the minor groove of DNA as the potential reactive site. The reactivity of S23906-1 toward the guanine-N2 group was independently confirmed by fluorescence spectroscopy. Covalent DNA adducts were also identified in the genomic DNA of B16 melanoma cells exposed to S23906-1, and the specific accumulation of the drug in the nucleus of the cells was visualized by confocal microscopy. The elucidation of the mechanism of action of this highly potent anticancer agent opens a new field for future drug design. PMID:12146956

  2. 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.

  3. General random walk model of ATP-driven helicase translocation along DNA

    NASA Astrophysics Data System (ADS)

    Chen, Y. Z.; Mi, Dong; Song, He-Shang; Wang, Xian-Ju

    1997-07-01

    A general random walk model is presented which can be used to statistically describe ATP-driven movement of a helicase (DNA unwinding enzyme) along a DNA chain with a nonuniform distribution of obstacles on the chain. These obstacles are representative of DNA-bound proteins, drugs, counterions, and DNA packing environment. We carried out a calculation on a DNA chain with an obstacle distribution that mimics DNA in chromatin (folded DNA-protein material in cells becomes chromosome in partially unfolded form). Our calculated helicase movement speed shows significant reduction with increasing obstacle strength. At the strong strength limit, the calculated speed is found to be consistent with the observed helicase unwinding rate for chromatin DNA. Therefore the model presented in this work is of potential application in the analysis of the effect of random obstacles on biomolecular translocation along DNA. The behavior of the helicase translocation under different obstacle strengths and along different lengths of DNA is discussed.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  5. 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.

  6. 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. PMID:21197618

  7. VOLATILE ORGANIC COMPOUND MODEL (VERSION 1.8) (FOR MICROCOMPUTERS)

    EPA Science Inventory

    Future emissions of volatile organic compounds (VOCs) and costs of their control can be estimated by applying growth factors, emission constraints, control cost functions, and capacity retirement rates to the base line estimates of VOC emissions and industrial VOC source capacity...

  8. SORPTION PROPERTIES OF MODEL COMPOUNDS ON C18 ADSORBENTS

    EPA Science Inventory

    The bonded silica adsorbent Bondapak-C18 was evaluated for removing organic matter from secondary sewage effluents and from solutions of pure organic compounds. The adsorbent is hydrophobic and its behavior with water samples may be erratic unless first wet with a solvent. Howeve...

  9. Modeling emissions of volatile organic compounds from silage

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  10. 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...

  11. 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

  12. 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

    2016-01-01

    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. PMID:27173346

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

    PubMed

    Ding, Yajun; Mittal, Jeetain

    2014-11-14

    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. PMID:25399156

  14. Flash vacuum pyrolysis of methoxy-substituted lignin model compounds.

    PubMed

    Britt, P F; Buchanan, A C; Cooney, M J; Martineau, D R

    2000-03-10

    The flash vacuum pyrolysis (FVP) of methoxy-substituted beta-O-4 lignin model compounds has been studied at 500 degrees C to provide mechanistic insight into the primary reaction pathways that occur under conditions of fast pyrolysis. FVP of PhCH(2)CH(2)OPh (PPE), a model of the dominant beta-O-4 linkage in lignin, proceeds by C-O and C-C cleavage, in a 37:1 ratio, to produce styrene plus phenol as the dominant products and minor amounts of toluene, bibenzyl, and benzaldehyde. From the deuterium isotope effect in the FVP of PhCD(2)CH(2)OPh, it was shown that C-O cleavage occurs by homolysis and by 1,2-elimination in a ratio of 1.4:1, respectively. Methoxy substituents enhance the homolysis of the beta-O-4 linkage, relative to PPE, in o-CH(3)O-C(6)H(4)OCH(2)CH(2)Ph (o-CH(3)O-PPE) and (o-CH(3)O)(2)-C(6)H(3)OCH(2)CH(2)Ph ((o-CH(3)O)(2)-PPE) by a factor of 7.4 and 21, respectively. The methoxy-substituted phenoxy radicals undergo a complex series of reactions, which are dominated by 1,5-, 1,6-, and 1,4-intramolecular hydrogen abstraction, rearrangement, and beta-scission reactions. In the FVP of o-CH(3)O-PPE, the dominant product, salicylaldehyde, forms from the methoxyphenoxy radical by a 1,5-hydrogen shift to form 2-hydroxyphenoxymethyl radical, 1,2-phenyl shift, and beta-scission of a hydrogen atom. The 2-hydroxyphenoxymethyl radical can also cleave to form formaldehyde and phenol in which the ratio of 1, 2-phenyl shift to beta-scission is ca. 4:1. In the FVP of o-CH(3)O-PPE and (o-CH(3)O)(2)-PPE, products (ca. 20 mol %) are also formed by C-O homolysis of the methoxy group. The resulting phenoxy radicals undergo 1,5- and 1,6-hydrogen shifts in a ratio of ca. 2:1 to the aliphatic or benzylic carbon, respectively, of the phenethyl chain. In the FVP of (o-CH(3)O)(2)-PPE, o-cresol was the dominant product. It was formed by decomposition of 2-hydroxy-3-hydroxymethylbenzaldehyde and 2-hydroxybenzyl alcohol, which are formed from a complex series of reactions from the 2

  15. 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…

  16. 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.

  17. 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.

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

    DOE PAGESBeta

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

    2015-04-22

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

  19. 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. PMID:25350567

  20. 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)

  1. Dynamic and Thermodynamic Analysis of a Simple Model of DNA

    NASA Astrophysics Data System (ADS)

    Techera, Mario Isaac Felix

    1991-02-01

    A new simple model of DNA is presented based on the results of lattice dynamics (LD) calculations in conjunction with the modified self-consistent phonon approximation (MSPA) done on a detailed model of DNA homopolymers. The model emphasizes the intrinsic nonlinearities present in the hydrogen-bonded duplex. The impetus for introducing the simplified model is to analyze the importance of the nonlinearities in the dynamics that lead to denaturation. An initial analysis is done on the possible dynamical excitations that can exist in the system due to the hydrogen bond (HB) nonlinearities. It is found that in a certain regime of base-pair motion, the nonlinearities can prevent dissipation of wave packets and thus suggesting the possibility of energy transfer along the molecule. What is also found, is the ability of the nonlinearities to "pin" excitations on the lattice thus suggesting a possible mechanism for localizing energy along the molecule for biologically significant periods of time. This analysis is done on a "cold" chain, i.e. at T = 0 K. In the latter part of this thesis, this model is shown to be thermodynamically unstable under certain circumstances. This instability is analyzed and general conclusions are drawn concerning the thermodynamics of any interaction similar to the ones used in the present case. As a result of this instability the thermodynamic analysis is done in nonequilibrium situations using stochastic methods to simulate a heat bath. Numerical calculations are performed to study the dissociation of the molecule and the possible effects of the thermal bath on the dynamical excitations mentioned in the previous paragraph. It is found that the dissociation time is very long at room temperature for long molecules.

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

    NASA Astrophysics Data System (ADS)

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

    2011-01-01

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

  3. Synthesis of model compounds for coal liquefaction research

    SciTech Connect

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

    1990-11-02

    The objectives of this project are to develop feasible synthetic routes to produce (1) 4(4{prime}- hydroxy- 5{prime},6{prime},7{prime},8{prime}- tetrahydro-1{prime}- naphthylmethyl)- 6-methyl dibenzothiophene, and (2) a 1-hydroxy naphthalene- dibenzothiophene polymer. These compounds are thought to be representative of sulfur containing molecules in coal. The program is divided into three tasks, the first of which is a project work plan that we have already submitted. Our experimental work during this quarter concentrated on Task 2: Synthesis of 4(4{prime}- hydroxy- 5{prime},6{prime},7{prime},8{prime}- tetrahydro-1{prime}- naphthylmethyl)- 6-methyldibenzothiophene. 11 refs.

  4. 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.

  5. 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

    2015-07-01

    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. PMID:26024486

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

    PubMed

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

    2014-10-11

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

  7. Cucurbit[7]uril inclusion complexation as a supramolecular strategy for color stabilization of anthocyanin model compounds.

    PubMed

    Held, Barbara; Tang, Hao; Natarajan, Palani; da Silva, Cassio Pacheco; de Oliveira Silva, Volnir; Bohne, Cornelia; Quina, Frank H

    2016-06-01

    Host-guest complexation with cucurbit[7]uril of anthocyanin model compounds in which acid-base equilibria are blocked resulted in essentially complete stabilization of their color. The color protection is a thermodynamic effect and establishes a strategy to stabilize these colored compounds at pH values of interest for practical applications. PMID:27123548

  8. 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...

  9. VOLATILE ORGANIC COMPOUND MODEL-QUALITY ASSURANCE AND SENSITIVITY TESTING (VERSION 1.8)

    EPA Science Inventory

    The report describes test runs of the Volatile Organic Compound Model (VOCM), Version 1.8. VOCM predicts future emission levels of volatile organic compounds (VOCs) by projecting uncontrolled base year emissions into the future. These projected emissions are then reduced by const...

  10. 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.

  11. 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.

  12. 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

  13. 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

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

    PubMed

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

    2016-05-01

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

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

    PubMed Central

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

    2016-01-01

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

  16. DNA strand break by 2,5-dimethyl-4-hydroxy-3(2H)-furanone, a fragrant compound in various foodstuffs.

    PubMed

    Hiramoto, K; Aso-o, R; Ni-iyama, H; Hikage, S; Kato, T; Kikugawa, K

    1996-01-16

    2,5-Dimethyl-4-hydroxy-3(2 H)-furanone (DMHF), produced by Maillard reaction of sugar/amino acid and found in various foodstuffs, showed mutagenicity to Salmonella typhimurium TA100 strain with and without S9 mix, and induced micronucleated mouse peripheral reticulocytes. DNA strand breaking activity of the compound at pH 7.4 increased with the increasing dose of the compound and with the increasing incubation time. The breaking activity was inhibited in the presence of superoxide dismutase, catalase, hydroxyl radical scavengers, spin trapping agents, thiol compounds and metal chelators, and also by removal of dissolved oxygen from the incubation mixture. Addition of Fe(III) ion to the incubation mixture enhanced the breaking activity. Incubation of DMHF with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) gave electron spin resonance signals characteristic to DMPO-OH adduct, indicating generation of hydroxyl radical. It was found that DMHF generated hydroxyl radical with an aid of a trace amount of metal ions, and induced DNA strand breaking. Mutagenicity and induction of micronucleated reticulocytes by DMHF may be caused as a result of DNA modification via hydroxyl radical. PMID:8569798

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

    PubMed

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

    1999-01-01

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

  18. Enhancement of the Microbial Dehalogenation of a Model Chlorinated Compound

    PubMed Central

    Jacobson, Stuart N.; Alexander, Martin

    1981-01-01

    A number of chlorinated aromatic and aliphatic compounds were dehalogenated when incubated with sewage. Preincubating the sewage with nonchlorinated organic substrates enhanced the subsequent dehalogenation of the chlorinated chemicals. Dehalogenation of 4-chloro-3,5-dinitrobenzoic acid (CDBA) in lake water occurred as a result of microbial growth both in the light in the absence of added nutrients and in the dark in the presence of acetate. No organism able to use CDBA as a carbon source was isolated. Axenic bacterial cultures and a nonaxenic Chlamydomonas culture released chloride from CDBA. The metabolism of CDBA by the latter culture, a process that was inhibited by 3-(3,4-dichlorophenyl)-1,1-dimethylurea, yielded a product that was identified as α-hydroxymuconic semialdehyde. This product of an apparent cometabolic transformation was mineralized by a strain of Streptomyces, thus suggesting that certain cometabolic products may not accumulate because they are carbon sources for other species. PMID:16345899

  19. Synthesis of model compounds for coal liquefaction research

    SciTech Connect

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

    1991-05-01

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

  20. 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

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

    ERIC Educational Resources Information Center

    Wagner, Joan

    1998-01-01

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

  2. 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

  3. Analogue-based approaches in anti-cancer compound modelling: the relevance of QSAR models

    PubMed Central

    2011-01-01

    Background QSAR is among the most extensively used computational methodology for analogue-based design. The application of various descriptor classes like quantum chemical, molecular mechanics, conceptual density functional theory (DFT)- and docking-based descriptors for predicting anti-cancer activity is well known. Although in vitro assay for anti-cancer activity is available against many different cell lines, most of the computational studies are carried out targeting insufficient number of cell lines. Hence, statistically robust and extensive QSAR studies against 29 different cancer cell lines and its comparative account, has been carried out. Results The predictive models were built for 266 compounds with experimental data against 29 different cancer cell lines, employing independent and least number of descriptors. Robust statistical analysis shows a high correlation, cross-validation coefficient values, and provides a range of QSAR equations. Comparative performance of each class of descriptors was carried out and the effect of number of descriptors (1-10) on statistical parameters was tested. Charge-based descriptors were found in 20 out of 39 models (approx. 50%), valency-based descriptor in 14 (approx. 36%) and bond order-based descriptor in 11 (approx. 28%) in comparison to other descriptors. The use of conceptual DFT descriptors does not improve the statistical quality of the models in most cases. Conclusion Analysis is done with various models where the number of descriptors is increased from 1 to 10; it is interesting to note that in most cases 3 descriptor-based models are adequate. The study reveals that quantum chemical descriptors are the most important class of descriptors in modelling these series of compounds followed by electrostatic, constitutional, geometrical, topological and conceptual DFT descriptors. Cell lines in nasopharyngeal (2) cancer average R2 = 0.90 followed by cell lines in melanoma cancer (4) with average R2 = 0.81 gave the

  4. 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...

  5. 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...

  6. Numerical study of a disordered model for DNA denaturation transition.

    PubMed

    Coluzzi, Barbara

    2006-01-01

    We numerically study a disordered version of the model for DNA denaturation transition consisting of two interacting self-avoiding walks in three dimensions, which undergoes a first order transition in the homogeneous case. The two possible values epsilonAT and epsilonGC of the interactions between base pairs are taken as quenched random variables distributed with equal probability along the chain. We measure quantities averaged over disorder such as the energy density, the specific heat, and the probability distribution of the loop lengths. When applying the scaling laws used in the homogeneous case we find that the transition seems to be smoother in the presence of disorder, in agreement with general theoretical arguments, although we cannot rule out the possibility of a first order transition. PMID:16486189

  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. Quantitative modeling of gene expression using DNA shape features of binding sites.

    PubMed

    Peng, Pei-Chen; Sinha, Saurabh

    2016-07-27

    Prediction of gene expression levels driven by regulatory sequences is pivotal in genomic biology. A major focus in transcriptional regulation is sequence-to-expression modeling, which interprets the enhancer sequence based on transcription factor concentrations and DNA binding specificities and predicts precise gene expression levels in varying cellular contexts. Such models largely rely on the position weight matrix (PWM) model for DNA binding, and the effect of alternative models based on DNA shape remains unexplored. Here, we propose a statistical thermodynamics model of gene expression using DNA shape features of binding sites. We used rigorous methods to evaluate the fits of expression readouts of 37 enhancers regulating spatial gene expression patterns in Drosophila embryo, and show that DNA shape-based models perform arguably better than PWM-based models. We also observed DNA shape captures information complimentary to the PWM, in a way that is useful for expression modeling. Furthermore, we tested if combining shape and PWM-based features provides better predictions than using either binding model alone. Our work demonstrates that the increasingly popular DNA-binding models based on local DNA shape can be useful in sequence-to-expression modeling. It also provides a framework for future studies to predict gene expression better than with PWM models alone. PMID:27257066

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

    PubMed

    Kweon, J H; Lawler, D F

    2005-01-01

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

  10. Oxidative DNA damage by an N-hydroxy metabolite of the mutagenic compound formed from norharman and aniline.

    PubMed

    Ohnishi, S; Murata, M; Oikawa, S; Totsuka, Y; Takamura, T; Wakabayashi, K; Kawanishi, S

    2001-07-25

    Norharman (9H-pyrido[3,4-b]indole), which is a heterocyclic amine included in cigarette smoke or cooked foodstuffs, is not mutagenic itself. However, norharman reacts with non-mutagenic aniline to form mutagenic aminophenylnorharman (APNH), of which DNA adducts formation and hepatocarcinogenic potential are pointed out. We investigated whether N-OH-APNH, an N-hydroxy metabolite of APNH, can cause oxidative DNA damage or not, using 32P-labeled DNA fragments. N-OH-APNH caused Cu(II)-mediated DNA damage. When an endogenous reductant, beta-nicotinamide adenine dinucleotide (NADH) was added, the DNA damage was greatly enhanced. Catalase and a Cu(I)-specific chelator inhibited DNA damage, suggesting the involvement of H(2)O(2) and Cu(I). Typical -*OH scavenger did not inhibit DNA damage. These results suggest that the main reactive species are probably copper-hydroperoxo complexes with DNA. We also measured 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation by N-OH-APNH in the presence of Cu(II), using an electrochemical detector coupled to a high-pressure liquid chromatograph. Addition of NADH greatly enhanced 8-oxodG formation. UV-VIS spectra and mass spectra suggested that N-OH-APNH was autoxidized to nitrosophenylnorharman (NO-PNH). We speculated that NO-PNH was reduced by NADH. Cu(II) facilitated the redox cycle. In the presence of NADH and Cu(II), very low concentrations of N-OH-APNH could induce DNA damage via redox reactions. We conclude that oxidative DNA damage, in addition to DNA adduct formation, may play an important role in the expression of genotoxicity of APNH. PMID:11423346